New Jersey insurance fraud officials are investigating a Fort Lee pain treatment center linked to two patient deaths, said a spokesman for state Attorney General Peter C. Harvey.

The spokesman, John Hagerty, declined to elaborate, but a source close to the investigation said the state will try “to determine the nature and cause” of the deaths. Investigators are also examining the Fort Lee Surgery Center’s records, patient charts and billing practices “to see whether the treatments provided to a large number of patients were medically necessary.”

The New Jersey Board of Medical Examiners, the state Department of Health and some insurance companies have joined the Office of the Insurance Fraud Prosecutor in what the source called a “multi- pronged, multi-focused” investigation.

At the same time, the family of one of the center’s patients – a 47-year-old New Brunswick man who was paralyzed in March after doctors gave him an injection for neck and back pain – sued the center Tuesday, claiming negligence.

“He went to Englewood Hospital as a quadriplegic, after having walked into the Fort Lee Surgery Center,” the family’s lawyer, Roy J. Konray of Rahway, said of Stephen A. Cromedy. “He left [Fort Lee] on a stretcher, unable to move his arms or legs, and able to just blink his eyes.”

Cromedy died two weeks later.

State Health Department officials closed the center, at 1608 Lemoine Ave., in April following Cromedy’s death. The center was cited for not notifying the state of the incident and for code violations, including sanitation and supervision. At the time, Deputy Health Commissioner Marilyn Dahl said the center presented “a life-threatening emergency, and an ongoing and immediate risk of harm to the public.”

In 2002, health officials cited the center for waiting five hours to call an ambulance after a North Bergen man turned blue and unresponsive.

Like Cromedy, that patient also had received a cervical epidural – a needle injection of steroids in the neck.

In such a treatment, “death is essentially unheard of,” said Dr. James Rathmell, an anesthesiologist and authority on cervical epidural procedures. At worst, patients face a remote risk of minor injury from the procedure, said Rathmell, director of the Center for Pain Medicine at the Fletcher Allen Health Care main hospital at the University of Vermont in Burlington.

Two owners studied

The state’s investigation is focusing on two of the five owners listed on the center’s licensing application: Dr. Ulises Sabato, an Englewood neurologist, and Dr. Sri Kantha, a Madison anesthesiologist, the source said.

State fraud investigators are examining the number of diagnostic tests such as MRIs and EMGs – electromyograms, which measure muscle nerve function – to see if the center “generated other tests and billings for procedures never performed,” the source said.

“We’re looking at potential false billings to the Medicaid program and to insurance companies,” the source said.

Auto insurer Allstate New Jersey is cooperating with the state’s investigation, said a spokesman, Manuel Goncalves.

“We are very, very familiar with the Fort Lee Surgery Center, Dr. Kantha and Dr. Sabato,” Goncalves said.

“Over the past several years, Allstate New Jersey has identified significant diagnostic testing abuses in New Jersey,” he said. Those cases involved abuses of the auto insurer’s personal injury protection coverage.

“This case is no different,” Goncalves said.

The Fort Lee Center reflects a pattern in North Jersey in which attorneys, chiropractors or physicians refer patients, particularly auto accident victims, usually to a handful of non-board-certified neurologists who order unnecessary numbers of expensive tests and procedures, according to a doctor who reviews nearly 1,000 such cases in the state each year at the request of insurance companies.

“This then leads to a cycle of treatment, referrals and testing … and concludes with tremendous expenses and certifications of permanent injury with which the attorney can press his lawsuit,” he said.

Each cycle of testing, treatment and referrals can end up costing $10,000 to $50,000 per patient, he said.

Thousands treated

The center is also known as the Fort Lee Surgery and Medical Center and the Fort Lee Institute for Minimally Invasive Spine Surgery and Interventional Pain Management. In an interview this spring, Sabato said the center has treated “tens of thousands of people.”

Sabato and Kantha could not be reached for comment Tuesday. Steven R. Antico of Hackensack, a lawyer who represents the center, said he had not heard about the state’s investigation. He had no comment on the Cromedy family’s lawsuit.

That lawsuit, filed in state Superior Court in Hackensack, charges that “combined negligence” caused Cromedy “extreme disability, pain, fear and anguish before dying,” as well as his death.

Cromedy, a machinist and grandfather, sought treatment in March for lingering neck and back pain from an auto accident in 2004, Konray said.

But the injection, allegedly administered by Kantha, left Cromedy totally paralyzed. He was taken to Englewood Hospital and Medical Center, where he spent about two weeks on a respirator at Englewood and died there of a pulmonary embolism, or blood clot, Konray said.

According to the lawsuit, the center also broke “many promises” to correct “dirty and unsanitary conditions” cited by several state health inspections between 1998 and 2005.

The center’s medical director, who is not named, is not certified by the American Board of Medical Specialists, as required by state law, the suit charges. Kantha is described by the center’s Web site as “world renowned,” but he “is not board-certified in pain medicine, anesthesiology or any other specialty,” the suit says. The center also failed to have a board-certified physician to review credentials of the doctors who worked there, it says.

“The closer I look, the more I see a trail littered with broken promises and dead bodies,” Konray said. “This is shocking because they have been so consistently cited by the state for violations. … So this is not an isolated incident.”

Doctors at the center are also being sued by the family of Ericberto Ortiz, a 28-year-old North Bergen man injured in an auto accident, who also died at Englewood Hospital following pain treatment at the center.

In another pending suit against the center and Kantha, Angela Levi claims that she was fired as a surgical technician there for refusing to take patient X-rays, a job she was not licensed to perform.

Attorneys for the doctors deny claims in both lawsuits.

Although the surgery rooms are closed, doctors’ offices in the same building remain open. The surgery center is working on a plan of correction before the state will allow it to reopen, Jennifer Sciortino, a spokeswoman for the state Department of Health, said Tuesday.

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Staff Writer Ben Lesser and Librarian Leonard Iannaccone contributed to this article.

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In recent years communities across the United States have instituted specialized criminal courts for defendants with substance abuse disorders and mental illness. These specialized courts seek to prevent incarceration and facilitate community-based treatment for offenders, while at the same time protecting public safety. The authors describe two types of specialized courts: drug courts and mental health courts. They critically examine the strengths and weaknesses of these courts and conclude with implications for social work education, practice, research, and advocacy.

KEYWORDS: drug courts; mental health courts; mental illness; specialized courts; substance abuse

In 2004,roughly 2.1 million people were incarcerated in U.S. jails and prisons (Harrison & Beck, 2004), many of whom can be expected to have substance abuse problems. Surveys of inmates conducted in 1997 and 1998 found, for example, that 70 percent of jail inmates committed a drug-related offense or used drugs regularly (Wilson, 2000) and that more than 80 percent of state prisoners and more than 70 percent of federal prisoners reported prior drug use (Mumola, 1999) .The 1997 survey also found that more than half of state prisoners and one-third of federal prisoners used drugs or alcohol at the time of their offense.

The large number of inmates with substance abuse problems is attributable in part to the increased number of people convicted for drug offenses. In 1980, for example, 19,000 state inmates were convicted for drug offenses; the number increased to 251,000 by 1999 (U.S. Department of Justice, Bureau of Justice Statistics, n.d.). Much of the increase in drug-related convictions is a function of changes in criminal behavior, drug laws, expanded drug law enforcement efforts, sentencing policies, and release practices (Blumstein & Beck, 1999; Field, 2002).

Another survey conducted in 1997 estimated that 16 percent of jail and state prison inmates and 7 percent of federal inmates-a total of 283,000 inmates-had a mental illness (Ditton, 1999) .The high number of inmates with mental illness has led some people to refer to jails as America’s new mental hospitals, because on any given day, there are twice as many people with mental illness in jails than there are in public psychiatric hospitals (Torrey, 1995; Torrey et al., 1992). It is widely accepted that the high number of inmates with mental illness is attributable to the deinstitutionalization of psychiatric services that began in the 1960s (Lamb & Weinberger, 1998; Smiley, 2001). Deinstitutionalization resulted in the discharge of a large number of patients from public psychiatric hospitals without adequate mental health and support services to maintain them in the community (Bachrach, 1983).

Drug courts and mental health courts have been developed to reduce the number of incarcerated people with substance abuse disorders and mental illness.These specialized courts seek to prevent incarceration and facilitate community-based treatment for offenders, while at the same time protecting public safety. The number of different types of specialized courts is increasing. In addition to drug courts and mental health courts, some jurisdictions, for example, operate specialized courts for people who are homeless and for people who engage in domestic violence (Binder, 2001; Rottman, 2000). Rottman described the therapeutic value of specialized courts: “Specialized courts provide a forum in which the adversarial process can be relaxed and problem solving and treatment processes emphasized. Specialized courts can be structured to retain jurisdiction over defendants, promoting the continuity of supervision and accountability of defendants for their behavior in treatment programs” (pp. 23-24).

DESCRIPTION OF COURTS

Drug Courts

The first drug court was opened in 1989 in Miami’s Dade County to divert nonviolent offenders to mandatory and intensive treatment programs (Belenko, 2002; Cooper, 2000).This court worked with defendants at the presentence stage of the judicial process and included periodic drug testing, ongoing judicial supervision, sanctions and incentives, and close monitoring. The majority of drug courts follow the presentence or diversion model, wherein if defendants complete the program requirements, criminal charges against them are dismissed (Belenko). Drug courts also can be held postsentence, wherein drug court program graduates receive reduced probation sentences or avoid incarceration (Belenko).As of 2002,a total of 1,238 drug courts were operated or planned, and existed in all 50 states, the District of Columbia, Puerto Rico, and Guam (Cooper, 2000; Office of Justice Programs, 2002). They are also a part of Native American Tribal Courts in 14 states (Cooper, 2000). Based largely on the U.S. model, drug courts have also been developed in Australia, Canada, and Great Britain and are in the planning stages in Brazil and several other countries (Turner et al., 2002).

In response to the recognition that traditional enforcement and punishment of drug offenders has had little impact on substance abuse and the cycle of criminal recidivism, the federal government provided funds for the development of drug courts (Belenko, 2002). Specifically, the development of drug courts nationwide was facilitated by federal funds distributed by the U.S. attorney general to local jurisdictions through the Violent Crime Control and Law Enforcement Act of 1994. Between 1995 and 1999, this act provided more than 100 million dollars for the development and implementation of drug courts (Belenko).

Some drug courts have been modified to address the unique problems faced by families, women, juveniles, and Native Americans residing on reservations (Cooper, 2002; McNeece, Springer, & Arnold, 2001). Family drug courts, for example, are designed to mandate substance abuse treatment for parents who are in danger of losing custody or visitation rights of their minor children as a consequence of their drug use or drug-related criminal offenses (Cooper, 2000).Tribal drug courts in the Native American justice system adapt the drug court model to meet the specific needs of the Native American reservation community devastated by generational drug and alcohol abuse (Cooper, 2000; Tribal Court Clearinghouse, 2002).

As the number of drug courts expanded and diversified, the need arose for a defining set of components of drug courts to ensure their integrity. The federal Drug Courts Program Office provided funding to the National Association of Drug Court Professionals for such an endeavor. That organization issued a set of 10 components of drug courts

in 1997 (Hora,2002) (Table 1).These components have helped define what constitutes drug courts and to guide development and implementation thereof.

Mental Health Courts

The first criminal court to focus solely on mental health issues was opened in Broward County, Florida, in 1997, although the application of the term “mental health court” first appeared in the early 1980s (Sipes, Schmetzer, Stewart, & Bojrab, 1986). AJuIy 2004 survey identified 98 mental health courts in local jurisdictions in 33 states (Survey of Mental Health Courts, 2004).To promote development of mental health courts, the federal Bureau of Justice Assistance provided grants of approximately $150,000 each to 24 local mental health courts in 2002 and 14 courts in 2003 (Bureau of Justice Assistance, 2004; Criminal Justice/Mental Health Consensus Project, 2004).

Mental health courts arose from the popularity of drug courts. Like drug courts, mental health courts can be used at the presentence stage to divert defendants with mental illness from the criminal justice system or at the postsentence phase to prevent incarceration and reduce time on probation (Goldkamp & Irons-Guynn, 2000). Unlike drug courts, mental health courts do not have an accepted set of guidelines, which has led some to conclude that the term “mental health courts” has little meaning (Steadman, Davidson, & Brown, 2001). Steadman and colleagues (2001) offered four criteria that help define what constitutes a mental health court: (1) a court docket specifically set aside for people with mental illness; (2) a team of criminal justice and mental health professionals to recommend a treatment and supervision plan and identify a responsible party; (3) assurance that the recommended treatment is available to the defendant or client; and (4) court monitoring with possible sanctions for noncompliance, such as reinstituting charges or sentences. The National Mental Health Association (2001), a leading mental health advocacy organization, recently developed a position paper on mental health courts and offered its own guidelines. In the absence of other guidelines, these can be useful for local communities considering development and implementation of mental health courts.Table 2 provides most of these guidelines.

Table 1: Key Components of Drug Courts, Office of Justice Programs, 1997

CRITICAL REVIEW OF DRUG COURTS AND MENTAL HEALTH COURTS

Positive Aspects

One of the most positive aspects of drug courts and mental health courts is that they largely serve a vulnerable population. One review of drug courts found, for example, that 25 percent of participants were f\emale, 48 percent were racial minorities, 74 percent had prior felony convictions, 49 percent were unemployed at the time of arrest, 76 percent had undergone prior failed drug treatment, 20 percent had attempted suicide, and between 15 percent and 56 percent reported past sexual or physical abuse (Belenko, 2002). A review of two of the largest mental health courts found that approximately 25 percent were women, about 25 percent were from racial minority groups, between 25 percent and 45 percent had a major mental illness and a substance abuse disorder, more than half were not receiving mental health treatment at the time of arrest, most were receiving disability income, and 25 percent were homeless at the time of arrest (Goldkamp & Irons-Guynn, 2000). The two specialized courts also provide an alternative to incarceration. This is particularly important for people with severe mental illness who tend to do poorly in correctional settings (Smiley, 2001;Torrey et al., 1992). Incarceration can exacerbate psychiatric symptoms, and inmates with mental illness are at increased risk of suicide and being assaulted and raped by other inmates.

As an alternative to incarceration, drug courts and mental health courts provide access to an array of community treatment and support services. A survey of drug court treatment found that the vast majority of drug courts offered participants outpatient treatment, access to Alcoholics Anonymous and Narcotics Anonymous support groups, mental health treatment, relapse prevention, educational and vocational training, and residential services (Peyton & Grossweiler, 2000). Mental health courts also seek to offer a variety of services. An examination of the four pioneering mental health programs in the United States found that these programs usually seek to duplicate drug court program principles and use of existing communitybased mental health treatment services (Goldkamp & Irons- Guynn, 2000). One mental health court, for example, had intensive support teams that linked clients to psychiatric treatment and skill training, provided housing vouchers to participants who were homeless, and paired participants with volunteer peer mentors to provide additional longterm support (Linden, 2000).

Table 2: Mental Health Court Guidelines, National Mental Health Association, 2001

These specialized courts can adapt to meet the needs of the participants and the communities in which the courts are enacted. In Anchorage, Alaska, for example, although a local culture of criminal responsibility would not permit a pretrial diversion component to its mental health court, the community created a postsentence mental health court (Watson, Luchins, Hanrahan, Heyrman, & Lurigio, 2000).These specialized courts can also be tailored to the special needs of rural areas, suburban areas, and large cities (Watson, Hanrahan, Luchins, & Lurigio, 2001). Drug courts, especially, have demonstrated the ability to adapt to participants’ needs, as evidenced by the creation of subdivisions of drug courts that focus on juveniles, families, women, and people with mental illness (Belenko, 2002; Cooper, 2000, 2002; McNeece et al., 2001).

Drug courts and mental health courts, overall, have demonstrated positive outcomes. In a review of research on drug courts, Belenko (2002) concluded that participation in drug courts reduced substance abuse and reoflences both during and after court supervision. He also found that drug courts were cost-effective because of reduced costs in comparison with incarceration. However, as we note in the next section on negative aspects of drug courts, this research is based on relatively weak methodologies. In an evaluation of Seattle’s two mental health courts,Trupin and Richards (2003), using a relatively small sample, found that participants were less likely to be reincarcerated, to spend fewer days in jail, and to be more engaged in treatment than those who chose not to take part in the mental health court program.

Finally, the establishment of drug courts and mental health courts has resulted in a positive unintended outcome in many communities.The coalition of diverse parties that often formed to create these courts has remained together in many instances to work on other related projects and lobby for increased substance abuse and mental health resources.This was particularly noted in the formation of mental health courts (Petrila, Poythress, McGaha, & Boothroyd, 2001; Watson et al., 2000). Petrila and colleagues went so far as to say that the coalitions that formed as a result of mental health courts represent an important development in the mental health field, particularly when judges are involved in mental health services planning and advocating for increased funding for mental health services.

Negative Aspects

Drug courts and mental health courts can serve only a limited number of people with substance abuse disorders and mental illness. Although the number of courts has rapidly increased in recent years, many jurisdictions still do not offer them. Hunter (2000) found, for example, that only 2 percent of drug users are able to participate in drug court programs because of availability issues. This limitation stems in part from a lack of funding and resistance to specialized courts on the part of some judges and prosecutors (Tashiro, Cashman, & Mahoney, 2000).

Another significant limitation is the lack of ongoing resources to operate drug courts and mental health courts and a shortage of substance abuse and mental health treatment services to support them (Goldkamp & Irons-Guynn, 2000; Peyton & Gossweiler, 2000;Tashiro et al., 2000). Existing services typically do not include an adequate range of services, and access can be difficult. Drug court services include residential treatment, mental health treatment for participants with dual disorders, and specialized services for women and racial and ethnic minority groups (Peyton & Gossweiler). Mental health court services include housing, treatment for the dual diagnosis with substance abuse, monitoring of compliance with agreed- on treatment, and specialized services for women who have been traumatized, participants with head injuries, and those with a history of aggressive behavior (Petrila et al., 2001; Steadman et al., 2001; Trupin, Richards, Wertheimer, & Bruschi, 2001). Steadman and colleagues (2001) concluded that without access to a range of mental health and supportive services, mental health courts have limited impact on the people most in need of help.

In addition, a “creaming” process may occur in the selection of participants, particularly in drug courts. For example, Peyton and Gossweiler (2000) found that the majority of drug courts eliminate candidates whom they judge to lack motivation for treatment, and that more than one-third of drug courts exclude people with co- occurring disorders of substance abuse and mental illness. Mental health courts, however, are typically designed to address the needs of people with mental illness or co-occurring disorders (substance abuse and mental illness) who become involved with the criminal justice system (Goldkamp & Irons-Guynn, 2000).

Another concern held by some is the use of these courts to force offenders into substance abuse and mental health treatment (Goldkamp & IronsGuynn, 2000; Goldsmith & Latessa, 2001; Watson et al., 2000). Given that prosecutors, judges, and defense attorneys must work in concert to divert the offender to treatment resources, the adversarial system is set aside and may result in the offender being coerced into treatment (Goldkamp & IronsGuynn; Watson et al., 2000). Although participation in these programs is typically voluntary, an element of coercion exists when defendants are presented with an option of going to jail or participating in the treatment program. This is a particular concern for defendants with mental illness who may lack the capacity to make informed disposition decisions (Goldkamp & Irons-Guynn; Watson et al.,2000). Others,however, are less concerned about perceptions of coercion. They view these courts as offering defendants an additional option (Lamb, Weinberger, & Reston-Parham, 1996; Mikhail, Akinkumi, & Poythress, 2001). In addition, coerced treatment for substance abuse and mental illness produces outcomes as good as or better than those of noncoerced treatment (Farabee, Prendergast, & Anglin, 1998; Farabee, Shen, & Sanchez, 2002; Lamb et al.; Miller & Flaherty, 2000).

Another concern about drug courts is the variability of outcomes. Although substantial evidence exists that drug courts are effective, overall, in reducing substance use and new criminal behavior, considerable variation exists. For example, Belenko (2002) found that rates of completion of drug court programs ranged from 36 percent to 60 percent, and rates of one positive drug screen ranged from 18 percent to 71 percent. In addition, he found that two of six major programs that conducted followup studies after program completion reported similar outcomes from drug court participants and comparison groups. One can speculate that these variations can be attributable to many factors, including differential admission criteria, variation in the intensity of monitoring compliance with treatment, the degree to which noncompliance results in sanctions, and the availability of treatment services in the community. It remains to be seen whether outcome studies of mental health courts will produce similar variable outcomes.

Some believe that mental health courts further stigmatize and criminalize mental illness (Watson et al., 2000).Holders of this view believe that stigma is increased when criminal courts are involved in the mental health system. They also fear that if services associated with mental health courts are adequately funded, more charges may be filed against people with mental illness to get them services, further criminalizing them. Other\s, however, contend that mandated treatment of mental illness should be a function of the court, because judges attempt to balance public safety with the rights and needs of defendants (Lamb et al., 1996).

A final concern is the quality of drug court outcome studies.The U.S. General Accounting Office (2002) concluded that data on drug courts collected by the Justice Department were inadequate for evaluating drug court effectiveness.This study suggested that a federally funded national longitudinal evaluation is needed to gauge the overall impact and efficacy of drug courts in reducing criminal behavior and drug relapse. In a similar vein, when RAND conducted evaluations of 14 drug treatment programs, it found that treatment providers failed to gather in-depth or comparable data to permit rigorous evaluations (Harrison & Scarpitti, 2002).Moreover, Harrison and Martin (2001) suggested that longitudinal outcome studies covering at least five years are needed to effectively evaluate client outcomes.

IMPLICATIONS FOR SOCIAL WORK

Social workers may interact with drug courts and mental health courts in a variety of ways.They may be members of a task force that develops a specialized court, or they may fill administrative or direct services positions in substance abuse, mental health, or criminal justice agencies that are parts of the court system and network of service providers. Social workers also may have sporadic contact with drug courts and mental health courts, such as when a client or a client’s family member encounters the criminal justice system and has a substance abuse disorder or mental illness. Regardless of the type of involvement with drug courts or mental health courts, social workers should have basic knowledge of the criminal justice system, substance abuse, and mental illness, as well as the availability of substance abuse and mental health treatment services at the local levels.

To promote effective social work practice, the curriculums of schools of social work should reflect the changing incarceration demographics that include increased numbers of inmates with substance abuse disorders and mental illness by including content on drug use, mental illness, and the intersection of these with the criminal justice system. In addition, social work students should receive training in working with coerced clients and their family members to ensure they are competent to use their authority comfortably and appropriately. A number of excellent resources are available that facilitate work with coerced or involuntary clients (for example, Dennis & Monahan, 1996; Ivanoff, Blythe, & Tripoli, 1994; Trotter, 1999). Schools of social work should also offer practicum opportunities in criminal justice settings to further develop students’ knowledge and skills in working effectively with criminal justice populations, particularly those with substance abuse disorders and mental illness.

The need continues for research on drug courts, mental health courts, and other jail diversion projects (McNeece et al.,2001;Steadman et al., 1999). Given the variability of program outcomes, social work researchers should evaluate court program processes and outcomes. Particular attention should be paid to comparing outcomes across race and ethnicity, age, gender, and other socioeconomic variables. Further study is also needed on the long- term consequences to diverted offenders, with research focusing especially on their outcomes several years after completion of the court program.

Clearly, drug courts cannot solve the drug-related crime problem, nor can mental health courts solve the problems faced by people with mental illness when they come into contact with the criminal justice system. However, these courts may benefit some members of these highly vulnerable populations. With their long history of working with and advocating on behalf of disadvantaged populations, social workers can advocate at the local level for the creation of drug courts, mental health courts, and other projects that divert people with substance abuse disorders and mental illness from the criminal justice system. At the state and federal levels, social workers should work to influence change in social policies regarding the substance abuse, mental health, and criminal justice systems.

Drug courts can be held postsentence, wherein drug court program graduates receive reduced probation sentences or avoid incarceration.

Drug courts and mental health courts can serve only a limited number of people with substance abuse disorders and mental illness.

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Survey of Mental Health Courts. (2004, July). Published jointly by NAMI, National GAINS Center for People with Co-Occurring Disorders in the Criminal Justice System, TAPA Center for Jail Diversion, and Criminal Justice/Mental Health Consensus Project. Retrieved August 27, 2004 from http:// www.mentalhealthcourtsurvey.com/

Tashiro, S., Cashman.V, & Mahoney, B. (2000). Institutionalizing drug courts: A focus group meeting report. U.S. Department of Justice, Drug Courts Program Office, Office of Justice Programs. Retrieved July 2002, from http://www.ojp.usdoj.gov/dcpo/ publications/ idc/index.html

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Sabrina W. Tyuse, PhD, MSW, MA, is assistant professor, School of Social Service, Saint Louis University, 3550 Lindell Boulevard, St. Louis, MO 63103; e-mail: tyuses@ slu.edu. Donald M. Linhorst, PhD, MSW, is associate professor, School of Social Service, Saint Louis University.

Original manuscript received October 7, 2002

Final revision received September 12, 2003

Accepted November 7, 2003

Copyright National Association of Social Workers, Incorporated Aug 2005

Thousand Oaks, CA, USA (August 9, 2005) ““ There has been much controversy regarding implementation of legislation to regulate hospital nurse-patient staffing ratios and its impact on patient safety and quality outcomes. According to a new study published in the August 2005 issue of the journal Policy, Politics & Nursing Practice, nurse staffing levels have increased significantly in California hospitals following implementation of that state’s landmark legislation requiring nurse-patient staffing ratios.

This groundbreaking study–the first evaluation of California’s much-watched ratios law”“was written by a team of researchers headed by Nancy E. Donaldson, DNSc, RN, FAAN, of the University of California, San Francisco. The researchers are affiliated with the California Nursing Outcomes Coalition (CalNOC), which collects and analyzes data on nurse staffing and outcomes from participating hospitals.

In 1999, California became the first state in the nation to enact legislation requiring hospitals to meet minimum staffing standards, limiting the numbers of patients that registered nurses (RNs) and licensed vocational nurses (LVNs–known in most other states as licensed practical nurses) may care for at any one time. That legislation , AB 394, charged the California Department of Health Services (CDHS) with determining those staffing standards. CDHS regulations implementing the new ratios requirements went into effect in January 2004. The bill’s proponents cited a growing body of research linking nurse staffing levels and positive patient care outcomes.

In the study, Donaldson’s team examined staffing and outcomes data from 268 medical-surgical and step-down units in 68 hospitals. They found that mean total RN hours of care per patient day increased by 20.8% in medical-surgical units and that the number of patients per RN decreased by 17.5%. Despite concerns that hospitals might seek to meet the ratios requirements by increasing their use of LVNs (since the regulations permit the complement of licensed nurses to include up to 50% LVNs), this did not occur. Similarly, there was no significant increase in use of contracted nursing staff (i.e., nurses supplied by outside staffing agencies or registries). Staffing in step-down units did not increase significantly.

The authors found no significant changes in the incidence of patient falls or the prevalence of pressure ulcers (bedsores), but they emphasized the preliminary nature of these findings and the limitations of the study, concluding that more research would be needed to determine the effect of mandatory staffing ratios on patient outcomes.

In an accompanying editorial, the journal’s editor, David M. Keepnews, PhD, JD, RN, FAAN, noting that “California’s decision to mandate staffing ratios was hotly debated [and] continues to be closely watched throughout the United States and beyond,” pointed to the value of the Donaldson team’s research in providing an “initial assessment” of the impact of staffing ratios. He explained that “Regardless of how anyone feels about government-mandated staffing ratios, it should be clear that California’s experience with ratios will produce valuable and important policy lessons. The work of evaluating that experience has begun, which is a welcome development for anyone concerned with nurse staffing and patient care quality.”

The authors of this study included Nancy E. Donaldson, DNSc, RN, FAAN, Linda Burnes Bolton RN, DrPH, FAAN, Diane Brown RN, PhD, FNAHQ., Janet Elashoff PhD, and Meenu Sandhu, MS.

On the World Wide Web:

SAGE Publications

Breast cancer patients could find out whether they will respond positively to chemotherapy treatment by testing for the activity of certain genes. In a study published today in the Open Access journal, Journal of Translational Medicine, researchers analysed the genes expressed in the tumours of eighty-three patients with primary breast cancer. The researchers were able to predict which breast tumours would improve from chemotherapy in all cases of partial remission and nearly three quarters of the cases of complete remission based on the analysis of less than sixty genes present in the tumours. The authors of this study state that the ability to predict which patients will respond to chemotherapy, and which would not, would be a “powerful tool” in the treatment of breast cancer.

Olga Modlich and colleagues, from the University of Dsseldorf and Bayer HealthCare AG in Germany, analysed samples of breast tissue from five healthy individuals and tumour tissue from fifty-six breast cancer patients treated with preoperative systemic chemotherapy (PST) with a combination of the anti-cancer drugs epirubicin and cyclophosphamide. The genes present in the samples were analysed using a DNA microarray – a collection of microscopic DNA spots attached to a solid surface used to measure the expression levels of large numbers of genes simultaneously.

From the DNA microarray analysis the authors were able to identify a total of fifty-seven ‘predictor’ genes active in tumours: thirty-one genes associated with a favourable response and twenty-six genes associated with a poor response. The authors then tested the ability of these genes to predict the response of twenty-seven breast cancer patients, who were then treated with PST.

The predictor genes could be used to correctly predict the outcome of PST in all cases of partial remission and nearly 75% of cases of complete remission of primary tumours. According to the authors the use of microarray technology to identify genes that can predict response to chemotherapy could represent a powerful tool to identify patients for whom PST is the most appropriate, and would be the most successful form of treatment.

Currently, decisions about whether to use chemotherapy as a breast cancer treatment are based on factors such as patients’ age and type and size of tumour. These factors do not provide sufficient information to tailor treatment to the individual patient. Nearly all breast cancer patients receive standard chemotherapy treatment, despite the potential for a poor response to therapy, adverse side effects and excess healthcare costs. According to the authors “the identification of molecular markers predictive of patients’ responsiveness to treatment is becoming a central focus of research”. The ability to predict a patient’s response to chemotherapy for breast cancer would be of benefit to doctors and patients, shifting the focus away from a standard treatment for all patients and towards treatment based on predictions made from patients’ genetic background.

On the World Wide Web:

BioMed Central

Aug. 7–Mentor Corp. hopes the reintroduction of gel-filled artificial testicles will help restore emotional health to men who’ve experienced cancer or other trauma.

On the verge of being the first to offer silicone gel breast implants for cosmetic surgery since they were pulled from the market 13 years ago, Mentor Corp. also wants to bring back the equivalent implant for men: the gel-filled artificial testicle.

Some urologists argue that the prosthetic testicle, which the formerly Minneapolis-based medical device company has been selling in a saline-filled version for the past few years, has received short shrift from the medical community. Few doctors and patients even know they are available.

Dr. Paul Turek wants to change that. He set out to see if the benefits of testicular implants were deeper than just cosmetic by heading a clinical trial involving 149 implant recipients. The study, published in the October 2004 issue of the Journal of Urology, concluded that recipients enjoyed a significant boost in their quality of life.

“It’s not simply cosmetic,” said Turek, a urologist at the University of California-San Francisco. “We found that it can be vastly important in self-esteem and body image — it restores men’s self-image.”

Mentor makes its prosthetic testicle, which is the only one approved by the U.S. Food and Drug Administration, at its complex in Minneapolis. The company was based there until 1985, when Mentor moved the headquarters to Santa Barbara, Calif., where the breast implant company it had just bought was based.

The testicle implant is one of dozens of products made at the Minnesota site, where 350 workers are spread among two manufacturing facilities, a research and development lab and an administrative office building.

Of the 10,000 to 15,000 boys and men in the potential market in any given year, fewer than one of four gets the testicular implant. Mentor hopes that by spreading the word among doctors and patients, it can reach about half of those candidates.

Turek’s study has already helped, said Charlie Pitman, the product manager for Mentor’s implant as well as other surgical urology and oncology products.

“Many urologists were unaware the prosthetic testicle was back on the market when they saw the Turek study,” he said.

Even though Mentor has a virtual monopoly in the market, sales of the prosthetic testicle barely register a blip in sales for the company — and will never be a big seller. The saline-filled version accounted for only a fraction of 1 percent of the company’s $483 million in total sales for the most recent fiscal year, Pitman said. Even if it doubles unit sales and sells the more costly gel-filled version, sales would barely crack the 1 percent mark.

Compare that with breast implants, which accounted for $217 million — nearly half of last year’s sales. And next year, breast implant sales are expected to rise significantly with the reintroduction of the silicone gel version for breast augmentation.

The gel version has remained available for women needing reconstructive surgery after having a breast removed. The prospect of expanding the use is why most investment analysts who follow Mentor focus on the breast implant business to the exclusion of its other products.

The prosthetic testicle is one of dozens of niche products that Mentor offers as part of its portfolio, which includes penile implants to treat erectile dysfunction, urological catheters, and a variety of cosmetic implants. Mentor does not make the breast implants here.

By offering a wide array of niche products as well as standard ones, Mentor may be able to win more urologists as customers, said Thomas Gunderson, an analyst for Piper Jaffray Cos.

Still, it faces competition from dozens of urological companies competing for urologists’ attention, including Twin Cities-based firms such as Medtronic, American Medical Systems and Urologix and such national firms as Johnson & Johnson and Boston Scientific.

“In competition with all the other urological companies, Mentor may gain an edge with surgeons by providing more of these types of products,” Gunderson said.

The prime market for the prosthetic testicle comprises men who have had a testicle removed because of testicular cancer or other trauma, or those who were born with an undescended testicle that had to be removed, said Dr. Jon Pryor, chairman of urological surgery at the University of Minnesota.

The surgical procedure is easy, low-risk and takes from 15 minutes to 20 minutes, Pryor said. The worst thing that can happen is that the site can become infected, but then the prosthetic testicle can be removed.

“It doesn’t have as much to do with health as it does with treating a disfigurement or improving the patient’s psychological health,” Pryor said.

Although the absence of a testicle is not quite as apparent to the casual observer as is the absence of a female breast, it can still be an issue.

“When you’re in the showers at the gym, it’s quite obvious you are missing a testicle,” Pryor said.

The need is particularly acute among adolescent males, he said. One young man was nearly suicidal about the loss of his testicle, but largely recovered his psychological health once he received the implant, Pryor said.

“They don’t feel complete — this is a way of dealing with that,” Pryor said.

Before Mentor’s prosthetic testicle was back on the market, Turek said one of his patients had asked if he would implant a “neuticle,” a prosthetic testicle used in dogs. He wouldn’t, but it helped him recognize how desperate some men are to feel “whole” again.

“It depends on where you are in life as to how important it is to you,” Pitman said.

Older men, especially those who are in happy, stable relationships, are less likely to feel the need to have the implant, Pryor said.

Charles Johnson, a 50-year-old who lives north of Minneapolis, sees himself in that category, but he decided to have the implant done anyway.

He was born with an undescended testicle, and had the testicle surgically lowered when he was 5 years old. But the testicle never felt normal, either in size or texture, and it caused him intermittent pain. About five years ago, the pain and the increased risk of cancer convinced him to have it surgically removed.

“At that time, they didn’t have an implant available,” Johnson said.

A couple of years later, he discovered that they were doing implants again, and he thought about getting one done.

“My wife asked me why,” he said. “It didn’t matter to her.”

But it felt odd having just one testicle — especially after having two for most of his life.

As it turns out, Johnson was not satisfied with either the size or the texture of the implant.

“It wasn’t even close to being the same size as my other one, and it doesn’t feel the same either — it has a superball feel to it,” Johnson said. “I expected the size and texture to be better.”

Pryor, who performed Johnson’s procedure, agrees that if there is one area of improvement Mentor should consider, it would be to offer a larger size.

Mentor plans to add a larger size when it reintroduces the silicone gel testicle, Pitman said.

Mentor sells the prosthetic testicle for $1,150. The procedure, typically done on an outpatient basis, can cost anywhere from $2,500 to $3,500. Johnson says health insurance covered all but a “few hundred dollars” of his procedure.

Shortly after the breast implant scare of the early 1990s, in which leaky implants were suspected of creating a hazard for patients, Mentor also decided to pull its silicone gel-filled prosthetic testicle off the market. Only the saline-filled version has been available in recent years.

But for testicles as for breasts, silicone gel has a more natural feel to it than saline.

“Saline has less give to it and it only compresses a certain way,” Pitman said. “Gel has a more natural density to it.”

Pitman says the gel-filled testicle is a good year and a half away from passing muster with the Food and Drug Administration, which regulates medical devices.

In contrast, Mentor will likely reintroduce the gel version of the breast implant for cosmetic purposes later this year.

That prospect has excited Mentor investors– and it’s the main reason the company’s stock price has skyrocketed more than 60 percent in the last year, Gunderson said.

Late last month, Mentor said the FDA has outlined certain conditions the company must meet to receive final approval for its MemoryGel silicone gel-filled implants. Gunderson estimates that it will take the FDA another two to six months to monitor Mentor’s data and finalize approval. Inamed Corp., its only competitor, might hit the market about three to six months after Mentor, said Gunderson, who does not own shares of either company.

Silicone-gel implants were banned in the United States 13 years ago after thousands of women claimed that leaking implants had damaged their health. The product liability was enough to force Dow Corning, a joint venture of Dow Chemical and Corning Inc., into bankruptcy in 1995. Many other firms abandoned the product in the face of product liability lawsuits.

After a decade of study and some improvements that make the implants less prone to leak, the implants are ready to go back on the market.

Consumers are anxious for the gel version because they think the look and feel is more natural than their saline-filled counterparts. About three of 10 women would switch to gel, according to a survey Gunderson did last year.

The reintroduction of silicone gel implants should accelerate both sales and profits at Mentor, Gunderson said. Although the gel version costs only about 10 percent more to make than the saline version, the company plans to charge about twice the price for it. That’s a recipe for higher sales and higher profits, especially because there is likely to be a spike in sales once the gel version is on the market.

Even with FDA approval, breast implants carry with them the high-profile controversies from 13 years ago that prompted the FDA to pull them off the market for further study.

“There will always be lingering concern,” Pitman said.

Still, that’s preferable to the key issue faced by prosthetic testicles — obscurity. That’s a battle Turek hopes his study on the quality of life benefits of the prosthetic testicle will help win.

Women who lose a breast to cancer are required to be informed that a prosthetic implant is available.

Turek argues that the boys or men who lose a testicle to cancer or injury should be “given the same opportunity” by being informed of the prosthetic testicle.

“Doctors are required by law to inform women of their options so their quality of life can be restored,” Turek said. “For a man, there was nothing. Men have deserved the same option, and now there is something for them.”

—–

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MNT,

Aug. 7–He’s not a doctor. He’s a former high school football coach and pharmaceuticals salesman. But that didn’t stop Ed Cota, with his wife, Tracey, from building a chain of for-profit OB-GYN clinics.

Cota is targeting the patients that hospitals complain are sinking emergency rooms with financial losses: poor, often illiterate, mostly uninsured immigrants — many of them in the United States illegally.

Cota, though, is convinced it’s a lucrative and underserved niche.

The Cotas began with one clinic in 1998 and now own five, each called Clinica de la Mama, served by a total of nine doctors.

All the clinics are in metro Atlanta, but the Cotas plan to open three elsewhere in Georgia in the next year and are considering other states.

Their clinic on Jimmy Carter Boulevard occupies a former Po’ Folks restaurant, with the clinic’s lab in what had been the part of the kitchen. In the parking lot, a Volkswagen is wrapped in an advertisement for the couple’s latest venture — an eye care service at the clinics.

Mothers-to-be who come in for prenatal care are charged a straight fee, Cota says. It’s $1,700 — payable on a monthly basis — for doctors’ fees, ultrasounds and lab work until, but not including, delivery. The fee also covers picking up patients for appointments at the clinic. There’s a 24-hour call-in service — in Spanish — for patients who have questions. And patients are given a sort of ID card with their photographs and basic information about their prenatal care and lab results.

Ed Cota estimates that 96 percent of the clinic’s patients have no medical insurance to cover prenatal care and that the majority are in the United States illegally. Still, Tracey Cota, who serves as a sort of chief operating officer for the business, estimates that 95 percent of patients pay their bills in full.

QUESTION: Tell me about the clinics.

ANSWER: Ed: We are providing a real conduit between a population that no one knows how to deal with. Before, everyone went to the ER. … The misconception was that Hispanics didn’t like prenatal care. That wasn’t it. They didn’t have access to it. …

Prior to us, they didn’t have prenatal care as a whole. They showed up at the last minute at the hospital. They walk in. They don’t speak (English). You assume they’ve had no prenatal care, so the hospital has to treat them as a brand new (patient), which causes the costs to go up.

Q: Tracey, what is your background?

A: Tracey: My interest has always been international markets. There are three very large international markets here — Hispanic, Asian and Russian. … Hispanic was the demographic that was young, child-bearing women.

They were exploding in growth much faster than other markets. …

This is where you look for OB. You want the child-bearing years.

A: Ed: The fastest-growing minority in the U.S. — that’s the Hispanic population. I speak Spanish. Obviously, I’m a Hispanic. We said, let’s set up an OB practice with the guys we know, friends of ours, the OBs, and provide a prenatal package for this population that no one wants to do, no one cares to do and they don’t understand. … But it has to be seen, regardless of the anti-immigration sentiments that are going on.

Q: What do you do, Ed, vs. Tracey?

A: Tracey: He markets. He is the king of marketing.

A: Ed: I bring in the patients, bring in the contracts, deal with the docs, set up the new companies. She’s the person who runs it all.

Tracey: I’m much more of a micro person. … I enjoy dealing with the patients, the operational issues.

Q: What was the biggest mistake you made as far as the business?

A: Ed: Probably not being ready for the volume of people that showed up. We underestimated the market.

A: Tracey: We had to play catch-up.

A: Ed: The computer system wasn’t set up to follow and track every patient. We should have been computerized from day one. … The ability to provide transportation: We thought we were going to transport 40 people in a week. We were transporting 40 people in a day.

Q: What happened? Did you end up losing a lot of customers?

A: Ed: No. What happened is we had to work every day, 12 hours a day.

Every day. … We thought we were going to open a practice that would go five days a week, 40 hours.

A: Tracey: We didn’t lose a lot of people. Yeah, people got upset. But we had a very hands-on relationship. We still do with our patients.

… I think little mistakes are forgiven.

Q: Why did you think it would be a good business to aim at low-income people who don’t have health insurance?

A: Ed: Volume. Volume drives everything.

A: Tracey: It’s an extremely large group of people.

Q: What percentage of your customer base is in the country illegally, and does that pose any special challenges for your business?

A: Ed: Sixty percent undocumented. It doesn’t place any issues to us because no one is going to stop this undocumented immigration.

They are going to keep coming whether you like it, whether I like it. We have to deal with it. We know that the more undocumented people come in, they need care.

Q: Do you have to treat them differently? Are they more or less likely to pay?

A: Ed: They are more compliant. The Hispanic community as a whole is very compliant. Besides their religion and their family, I think the next most important is probably medical. They hold it in very high regard. … You give them care with respect and dignity and, let me tell you what, our volume will always increase at 30-40 percent a year. …

Once you have good business with one of them, you’ve made a friend.

They will always come to you, and they will tell everybody.

Q: Are there any disadvantages to serving this community?

A: Tracey: This is a transient community. They move a lot. … Your attrition rate is higher than a normal practice. It’s above 15 percent.

—–

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The large body of literature on resilience and coping gives promise to finding specific ways in which teachers, counselors, and schools can enhance success among gifted and talented children and youth placed at risk. While high intelligence is not a requirement for resilient outcomes, cognitive ability appears to be a supporting factor, especially as it relates to problem solving and coping. To the extent that low-income and culturally diverse children and youth have more experience overcoming adversity, they may possess a greater range of and flexibility in coping strategies that can be shared with others. This article summarizes findings from resilience literature relevant to the development of children and adolescents and derives specific strategies for enhancing outcomes for gifted children and youth most at risk for encountering adversity.

As a graduate student in the 1970s, the first author of this paper was inspired by an idea presented in a course on childhood psychopathology: Garmezy’s (1976) notion of the “invulnerable” child. This concept of children and youth thriving despite adversity seemed to hold the key to social change. If we could identify and recreate the factors that made children invulnerable to hardship stemming from severe family dysfunction, trauma, or intense poverty, we could raise the emotional and academic functioning of children who might otherwise succumb to failure. “Resilience” has since replaced the overly optimistic language of invulnerability, and research in psychology on this topic has continued to flourish. In the aftermath of September 11, resilience has become a public focus with the intent of providing information on supporting recovery from trauma wrought by terrorism (e.g., American Psychological Association Task Force on Promoting Resilience in Response to Terrorism; Alpert et al., 2004; Dudley-Grant, Comas-Diaz, Todd- Bazemore, & Hueston, 2004). Research has expanded to focus on “educationally” or “academically” resilient children-those who succeed in school despite the stresses of poverty and inadequate childrearing conditions. Wang, Haertel, and Walberg (1998) and Waxman, Gray, and Padrn (2003), among others, investigated educational resilience and derived recommendations for schools.

Over the years, professionals in gifted education have explored the relationship between resilience and giftedness. Bland, Sowa, and Callahan ( 1994) suggested that resilient individuals share many characteristics with gifted children and that further study may identify coping skills that counselors can teach. Ford (1994) described barriers to resilience among gifted African American youth and made recommendations for enhancing resilience among this population. Hbert (1996) examined coping strategies of young gifted Latino men, and Frydenberg (1997) those of gifted adolescents in general. More recently, psychologist Neihart (2002) suggested that resilience might serve as a theoretical framework for systematically addressing the social and emotional issues of gifted individuals (e.g., lack of challenging curricula, asynchronies in development). Attention to affective development of gifted students is particularly important given that IQ accounts for only about 25% of the variance in schooling outcomes and 4% to 30% of the variance in job performance (Sternberg, Grigorenko, & Bundy, 2001). Sternberg et al. point to self-efficacy, a factor supporting resilience, as an important contributor beyond intelligence.

A resilience approach would serve especially well the needs of underrepresented populations of gifted students-those most at risk for serious hardships. “At risk” would include gifted children and youth living in poverty or in circumstances of abuse and neglect; children and youth who experience discrimination based on race, language, gender, or sexual orientation; and students from all backgrounds who have experienced trauma. The focus on successful individuals from at-risk environments and the strategies they can share makes a resilience framework particularly compelling.

This article summarizes findings from resilience literature relevant to the development of children and youth and derives specific strategies for enhancing outcomes for gifted children and youth most at risk for encountering adversity.

Research on Resilience and Coping

“Resilience” describes the phenomenon of surviving and thriving in the face of adversity typically predictive of negative outcomes: poverty, family psychopathology, trauma. Resilience improves conditions affecting an individual’s ability to cope (Osofsky & Thompson, 2000). Psychologists have studied resilience and coping since the 1970s, producing an abundance of literature. Following a description of types of factors critical to understanding resilience literature, we focus on studies relating intelligence, development, and diversity to resilience-topics that can inform practice with gifted children and youth, particularly those at risk.

Central to understanding the literature is the concept that four types of factors function in predictable ways to influence resilience: compensatory, risk, protective, and vulnerability factors. According to Tiet et al. (1998), the first two factors yield consistent effects across levels of risk. Compensatory factors (e.g., healthy family functioning, high educational aspirations) always have a beneficial consequence irrespective of risk level. In contrast, risk factors (e.g., poverty, substance abuse, incarceration) always have a potentially harmful effect, whether there is low or high risk. In contrast, the consequences of protective and vulnerability factors vary depending on risk level. Protective factors (e.g., self-esteem, positive coping strategies, internal locus of control, social skills) exert a buffering effect at high risk but little or no effect at low risk. Vulnerability factors are the opposite of protective factors and have little or no effect at low risk and detrimental effects at high risk. A life absent of stress, for example, might constitute a vulnerability factor-inconsequential when there is no risk, but disadvantageous at high risk if the individual as a result has no successful experience coping with hardship.

Intelligence and Resilience

Level of intelligence appears to play a role in resilience, though the operating rules for its influence have yet to be defined. At least one study suggests that higher intelligence may function as a risk factor (Luthar, 1991). However, most experts view it as a protective factor (e.g., Condly, in press; Doll & Lyon, 1998; Tiet et al., 1998; Werner, 2000). Findings may differ depending on outcomes investigated (e.g., psychological adjustment or school achievement; drop out status or delinquency), measures used (e.g., psychiatric diagnoses, teacher ratings), and subjects studied (e.g., age, economic status, ethnicity).

Luthar (1991), in a study of primarily African American and Hispanic high risk, inner city adolescents, found intelligence and positive events to operate as vulnerability factors in determining peer- and teacher-rated social competence under stress. Luthar interpreted the findings as suggesting that for older adolescents, in contrast to younger children, sensitivity associated with higher intelligence may increase susceptibility to stressors. Additionally, the author suggests that chronology of positive and negative events may affect whether positive events serve as buffers against stress. In contrast, findings from a cross-sectional study including White, Latino, and African American youth ages 9 to 17 (Tiet et al., 1998) indicated that IQ operated as a protective factor and that it was significant in predicting psychological adjustment among youth at high risk but not low risk. The authors suggested that adolescents with high risk who possess higher intelligence may be better able to cope with adverse life events than their peers with lower intelligence.

Werner (2000) observed that not all resilient children are unusually gifted or talented but that “at least average intelligence” (p. 123) acts as a protective factor.

Even though there is little evidence that high intelligence alone promotes more effective coping, most longitudinal studies of resilient children and youth report that intelligence (especially communication and problem-. solving skills) and scholastic competence (especially reading skills) are associated positively with the ability to overcome adversity (Werner, p. 122).

Reviewers of resilience literature agree that average or above average intellectual development supports resilience (CondIy, in press; Doll & Lyon, 1998) and perhaps constitutes the most important personal quality serving as a protective factor (Osofsky & Thompson, 2000).

Intelligence may be related to qualitative differences in preferred coping strategies. Using the Adolescent Coping Scale, Frydenberg (1997) found gifted adolescents more inclined to use problem solving, working hard, and achieving than their peers in the general population and less likely to use wishful thinking, investing in close friends, reducing tension, or not coping. Rutter (2000, p. 671) concluded that cognitive functioning is important in resilience beyond its role in educational attainment, but the precise mechanism remains uncle\ar.

The preponderance of literature suggests that average to above average intelligence contributes to positive outcomes among high risk children and youth, though alone it is insufficient.

Personal, Coping, and Environmental Factors in Developing Resilience

Building resilience can be viewed as a developmental process in which, over time, experience in successfully overcoming adverse situations increases self-efficacy and confidence in one’s ability to influence the environment (Werner, 2000). Development of resilience involves internal personality characteristics, coping strategies, and environmental factors.

Characteristics supportive of resilience appear in early childhood. Osofsky and Thompson (2000) describe resilient infants and young children as possessing an adaptable, easy temperament that elicits positive responses from adults. They have good interpersonal skills and show signs of early coping strategies-planning how to manage what happens to them. For example, by preschool age, resilient children have developed a strong sense of autonomy and ability to ask for support when needed (Werner, 2000). Even young children may protect themselves by withdrawing from a dysfunctional family situation and finding outside support (Osofsky & Thompson).

With age, children develop greater ability to use cognitive approaches, such as reappraising and refraining the challenge (Fields & Prinz, 1997). Older resilient children actively plan how to cope with events, continuing to develop a sense of greater control over their lives. By middle childhood (age 10), they demonstrate selfesteem, self-efficacy, internal locus of control, impulse control, and independence. They concentrate on schoolwork and pursue interests and hobbies that are not sex-typed-activities that provide solace and a sense of mastery and pride under stressful situations (Werner, 2000). Resilient children tend to be sociable and assertive, are liked by peers and adults, and exhibit good communication and problem-solving skills. Faced with adversity, they flexibly use a range of coping strategies and reach out for support from teachers and peers (Werner). With the emergence during middle childhood of the capacity to make social comparisons and take other people’s perspectives, seeking social support from peers becomes another coping strategy used increasingly in adolescence (Fields & Prinz).

The increasing cognitive development and metacognitive awareness of older children and adolescents permit improved ability to appraise stressors, to estimate duration and controllability, and to consider various alternatives and consequences (Fields & Prinz, 1997). Resilient adolescents and adults possess an internal locus of control, a more positive self-concept, and greater social maturity, nurturance, empathy, sense of responsibility, and independence (Werner, 2000). As they mature, adolescents and young adults display increasing flexibility and planfulness in applying coping strategies. A study of primarily White, middle class adolescents by Williams and McGillicuddy-De Lisi (2000) indicated that older adolescents use a greater variety of coping strategies to reduce stress than younger adolescents. They also tend to use cognitively oriented coping strategies, such as planful problem solving and reappraisal. The authors infer that increasing cognitive maturation and life experiences that come with age support awareness of a greater range of coping strategies and the ability to analyze specific factors in a stressful situation and make effective choices.

Features of the environment that promote children’s development of resilience include effective parenting or a strong, trusting relationship with a competent, caring adult (Osofsky & Thompson, 2000) and opportunities to exercise responsibility, make decisions, and learn from their mistakes and successes (Rutter, 2000). Schools and teachers who communicate high expectations, provide caring and support, encourage student engagement and involvement (Waxman et al., 2003) as well as offer a rich, rigorous, learner-centered curriculum and experience solving complex, real-life problems (Wang, Haertel, & Walberg, 1998) contribute to educational resilience.

The literature demonstrates some consensus regarding favorable personality, coping, and environmental factors linked to resilience. However, it is not clear that all factors must be present for successful outcomes to occur. Further, resilience may not be continuously evident in an individual’s life over time, and positive changes indicative of resilience can occur well beyond the developmental years. Risk conditions, such as poverty, may be subjectively determined, and a child’s perceptions of risk events (e.g., parental divorce) may be different from the adult’s perception.

Gordon and Song ( 1994) suggest that achievement among individuals at risk probably results from a collection of factors and their interaction, and they caution against focusing on the presence or absence of single, specific factors. They also conclude that while resources and supports are required at all developmental stages, influential factors and the appearance of success may occur at any age. Among their African American sample, some participants entered the path for career success at early ages; others found their way later in life by accident or with guidance. Although a meaningful relationship appears to be a consistently positive factor in resilience, negative factors may be subjectively determined by the individual and may operate to induce a constructive response; for example, striving to prove a detractor wrong. In fact, completely removing stress or hardship may not promote resilience in young children, who may benefit from gradually encountering and successfully overcoming challenges, which can enhance a sense of confidence and ability to influence what happens to them (Rutter, 2000). Aldwin, Sutton, and Lachman ( 1996) found that past stressors had helped younger and older adults develop effective coping skills to handle new problems.

Diversity

Poverty, culture, and ethnicity play a key role in development of resilience in several ways. Poverty and its sequelae are clear risk factors and may interact with aspects of culture (e.g., primary language other than English) to negatively affect school achievement. Racism continues to be a stressor affecting outcomes across economic groups (College Board, 1999). Most important for educators, culture influences how children and youth understand and cope with adversity (Dudley-Grant, Comas-Diaz, Todd-Bazemore, & Hueston, 2004).

Based on their review of the literature, Dudley-Grant et al. (2004) concluded that for people of color, connectivity (social ties, belief systems, community supports, connection to a community) constitutes a primary contributor to resilience. They cite research indicating positive relationships between resilience and valuing of family needs among Mexican American youth; Afrocentric values and cultural identity among African Americans; and emphasis on traditional culture, positive traditional Native identity, and intergenerational relationships among Native Americans. The authors identify lessons on coping with racism as a protective factor. They note that spirituality and the desire to promote the next generation’s well being support resilience across several groups.

Types of coping strategies used may be related to cultural experiences and values. Plummer and Slane (1996), comparing White and African American college students on the Ways of Coping Questionnaire, found that African American students reported using a greater variety of coping strategies. They engaged in more problemfocused and more emotion-focused coping strategies than did White students. Problem-focused strategies concentrate on modifying the stressor or changing the situation and include accepting responsibility, confrontive coping (aggressive tactics), planful problem solving, and seeking social support. Emotion-focused coping strategies attempt to regulate one’s emotional state or to reduce tension. Strategies include distancing, escape avoidance, self- controlling, and positive reappraisal (creating positive meaning by reframing). African American students also reported more incidents of racial stress. The authors suggest that African American students may have greater experience with stress and may consequently be more practiced and flexible in their use of strategies. When faced with racially as opposed to generally stressful situations, both African Americans and Whites reported being less likely to accept responsibility, engage in planful problem solving, and seek social support, and more likely to use confrontive coping.

A comparison of stress-affected and stress-resilient urban African American and White children (Magnus, Cowen, Wyman, Fagen, & Work, 1999) found that a sense of competence, positive selfview, empathy, and realistic control attributions predicted resilient outcomes across racial groups. Internal locus of control differentiated resilient from stress-affected children among White but not African American participants. The authors suggest that the difference may be attributable to a focus on individualism in White families under stress. The authors used the What I Usually Do scale to assess positive (self-reliance and seeking support) and negative (immobilization, wishful thinking, and distancing) coping styles. African American resilient children exceeded their stressaffected counterparts on positive coping styles but were similar to them on negative coping strategies. White resilient children used fewer negative coping styles than did White stress-affected children. These findings are consistent with Plummer and Slane’s (1996) data for college-age students, with African Americans exhibiting a wider range of coping strategies. Magnus et al. propose that the positive or negative status of sp\ecific coping strategies may depend on their adaptiveness within the cultural context and may differ by cultural group.

Research on gifted individuals from diverse backgrounds points to additional, specific factors among cultural groups that may affect resilience. Plucker (1998) found little evidence of gender or grade differences but significant racial differences in gifted adolescents’ coping strategies. African American and Latino adolescents were more likely to report seeking spiritual support than their White peers. Latino students scored higher in worrying and Whites lower. White student reported more self-blame. Similar to Frydenberg’s (1997) findings, these gifted students (across ethnic groups) were more likely to use working hard and achieving as coping strategies than social action, seeking professional help, reducing tension, or ignoring the problem.

In a study of Latino students attending a prestigious university, Arellano and Padilla (1996) found that identification as gifted may be a protective factor, supporting a self-concept that included ability to achieve. Rumbaut (2000), examining factors influencing immigrant children’s achievement, reported a positive link between fluent bilingualism and cognitive achievement. Identification as gifted also was related to superior academic outcomes. Ford (1994) observed that biculturalism contributes to resilience among gifted African American students, and biculturalism has been associated with greater self esteem, motivation, and achievement (Magnus et al., 1999).

A series of studies on high achieving women from diverse backgrounds (Kitano, 1997, 1998a, 1998b; Kitano & Perkins, 2000) identified an array of positive coping strategies, some of which were common across groups (e.g., persistence in the face of hardship) and some that appear culturally related. The African American sample described specific strategies for coping with discrimination including monitoring the environment and using their observations, finding alternative paths, actively ignoring or managing racism, affirming oneself, and having a clear sense of cultural identity (Kitano, 1998a). Consistent with Ford’s (1994) finding, achieving African American women cited being bicultural as a survival strategy, as in purposively modifying language and style as the situation demands. The Asian American sample (primarily of Japanese or Chinese descent) commonly described school achievement for positive recognition, working harder and persisting, being flexible (e.g, changing oneself or one’s job), and assimilating as ways of coping (Kitano, 1997). The highly achieving Latinas engaged in self-assessing and planning, taking action, using individual achievement as a vehicle for contributing to family and community, and challenging and confronting dishonesty or injustice (Kitano, 1998b). White women’s examples focused on thinking through, taking responsibility and action, consciously making good choices, persisting, and networking (Kitano & Perkins, 2000).

While resilient children and youth share some common characteristics across ethnic groups, there appear to be differences between groups in types of coping strategies related to cultural values and experiences. Biculturalism, having a positive ethnic identity, and connecting to community may be protective factors for gifted students from African American, Native American, and Latino backgrounds. Having specific coping strategies for addressing discriminatory incidents may also support resilience.

Value of Resilience Concept for Gifted

As noted earlier, Neihart (2002) suggested that a resilience framework has potential for addressing the social and emotional needs of gifted and talented individuals, addressed comprehensively elsewhere (see Cross, 2001 ; Neihart, 1999; Neihart, Reis, Robinson, & Moon, 2002). This review supports that suggestion, and not necessarily because of any hypothesized similarities between resilient and gifted individuals. The literature offers scant evidence that a preponderance of resilient individuals are gifted or that most gifted individuals are resilient. Resilience does not require high intelligence, though cognitive capacity may contribute to positive outcomes to the extent that it supports effective coping strategies.

The value of a resilience framework lies in its potential for improving outcomes of the most underserved gifted: those placed at risk by adversity. Families and individuals of all racial, cultural, and socioeconomic backgrounds can and do encounter hardship in their lives. Peterson (1997) presented emotionally jarring case studies of “bright, tough, and resilient” abused and neglected 1 White high ability students not identified as gifted. In so doing, she challenged the field to consider and provide the extensive interventions needed for these students to succeed. No group is immune from adversity. The success stories of j individuals (and groups) overcoming odds are often stories of cultural diversity, linguistic difference, and/or economic disadvantage, as well as resilience and coping. These are stories that can benefit students from all backgrounds, including gifted students who have faced few stressors in their lives and possess less experience with coping. Sharing of culturally derived coping strategies may help students of any background increase their range of positive strategies and flexibility in applying them.

Limitations

Despite several decades of research on stress and coping, there continue to be conceptual and methodological issues, including the need for coherent theoretical frameworks, consistent operational definitions, and measures beyond questionnaires (Luthar, Cicchetti, & Becker, 2000). No single style of coping appears to be effective in all situations, and effective coping is characterized by flexibility and change (Compas, 1987). Researchers have proposed both macro and micro typologies of specific coping strategies. Problem/emotion focused (described earlier) and approach/avoidance (actively planning vs. trying to ignore or escape) models are examples of macro-level categories. Micro typologies list an array of specific coping strategies. While macro-level approaches mask distinctions, micro-level approaches do not show tremendous consistency from study to study or derive from compelling conceptual frameworks (Fields & Prinz, 1997).

Whether some are more adaptive than others may depend on context (e.g., family conflict, medical event, academic issue) and culturally related perceptions. However, there is some evidence that problem solving and engaging in rewarding activities are related to better overall adjustment across early and middle childhood and adolescence. For older children and adolescents, approach coping appears to be more associated with achievement than defensive and self-blame strategies (Fields & Prinz, 1997). Somerfield and McCrae (2000) suggest changing the focus of research from a search for universal ways of dealing with stress to individual differences that affect choice of coping strategies as well as strategies effective for specific stressful contexts.

Implications and Recommendations

Within these limitations, the literature consistently indicates that families, communities, and schools can enhance both psychological and educational resilience by focusing on alterable factors, such as social support, interpersonal skills, educational aspirations, self-efficacy, empathy, problem solving, and coping strategies. Cowen, Wyman, Work, and Iker (1995) reported that inner- city elementary-age children participating in a 12-session program demonstrated significant improvement on teacher ratings of learning problems and task orientation, and on child ratings of self- efficacy, control attributions, and anxiety. The curriculum centered on perspective taking, social problem solving, solvable and unsolvable problems, and self-efficacy. Activities included applying a structured problem-solving process and having children serve as consultants to help other children apply the process to their own issues. Gillham, Reivich, Jaycox, and Seligman (1995) found cognitive- and social-problem-solving techniques effective in teaching fifth- and sixth-grade students to be more optimistic and less likely to experience depression two years after a 12-week intervention.

Hess and Copeland (2001) cited additional studies indicating that instruction in coping skills and problem solving can help adolescents decrease stress and improve problem solving. They claim that a strong relationship with a caring teacher who has high expectations can decrease susceptibility to negative peer influences and that schools can play a key role in enabling children and youth to acquire effective coping skills through training from early elementary through high school. The complex relationships among personal traits, coping skills, and environmental supports in determining resilience argue for collaborative efforts between teaching and counseling personnel. Given their daily contact with immense numbers of students at risk, schools potentially can play a major role in enhancing resilience (Doll & Lyon, 1998). Wang et al. (1998) further caution that increasing children’s educational resilience requires a comprehensive effort (teachers with high expectations; learner-centered instruction; challenging, non- remedial curriculum; rigor and depth) and cannot be effected by a simple set of activities.

Within this context, the literature reviewed here indicates components of such a comprehensive intervention appropriate for gifted students placed at risk:

1. Enhance connectivity. Teachers can help ensure a strong, meaningful relationship with a significant, positive other: a parent, relative, teacher, counselor, religious leader, peer. A caring teacher can serve in this capacity by working to identify a mentor; help students make good choices about friendships (to include ach\ieving peers); encourage them to engage with nuclear and extended families, community, and school (Hess & Copeland, 2001); and develop classroom projects that increase opportunities for teamwork, sense of community, and respect (Alpert et al., 2004). Parent programs can help families understand their children’s needs for consistent, nurturing, authoritative parenting and high expectations for performance and educational attainment.

2. Encourage a sense of self-efficacy and agency. Teachers and families can provide opportunities for children and youth to take responsibility and make decisions as developmentally appropriate and learn from their successes and failures. They can provide opportunities to develop a sense of ability to influence the environment, for example, by helping others in the community or solving a real-life problem. They can encourage students to develop and pursue interests and hobbies as a source of personal satisfaction. They can ensure normal protection without removal of all stress.

3. Encourage optimism. Counselors, teachers, and families can help youth process their bad experiences and incorporate them into their concept of self, think optimistically, accept the reality of a bad experience without self-blame for events outside their control, and build on positive aspects of a bad situation (Rutter, 2000).

4. Teach directly and indirectly a range of culturally consonant coping strategies and coach implementation. Teachers can support student awareness and flexible implementation of effective coping strategies. They can help students develop attitudes and metacognitive skills supportive of flexibly applying a range of positive coping strategies (Rutter, 2000). Teachers and students can share a variety of positive coping strategies that have worked for them and for others who have succeeded despite hardships. Teachers can offer culturally consonant coping strategies, such as using humor and creativity in coping and achieving as a way of helping their communities and next generations to succeed (Dudley-Grant et al, 2004). They may need to enlist families and communities to support culturally specific coping strategies found effective in the literature (Dudley-Grant et al.), such as promoting spirituality, encouraging use of traditional knowledge (e.g., healing ceremonies) and ways of knowing, encouraging story telling, and drawing on past experiences of overcoming trauma. Awareness of varied alternatives may be insufficient to improve younger adolescents’ coping in the absence of practice, role playing, and scaffolding (Williams & McGillicuddy-De Lisi, 2000). Teachers can encourage students to practice coping skills by problem solving and role playing (Cowen et al., 1995) or by using positive-self statements in the face of typical stresses (Alpert et al., 2004). They can model planning, problem solving, persisting, and coping positively in stressful situations.

5. Validate (rather than ignore or minimize) children’s experiences with bias. Teachers can recognize and acknowledge social injustices experienced by children and youth (DudleyGrant et al., 2004) and help them identify effective strategies for overcoming them. They can enlist family and community members to provide stories and examples of positive strategies for coping with racism, sexism, homophobia, ableism and other forms of discrimination.

6. Support pride in heritage. Teachers can work with families and communities to strengthen students’ ethnic identity through their engagement in intercultural activities. Teachers and families can encourage and provide opportunities for students to become bilingual and bicultural. Assimilation may serve as an effective coping strategy for some individuals, depending on cultural values.

The large body of literature on resilience and coping gives promise to finding specific ways in which teachers and counselors can enhance success among at-risk children and youth, including those who are gifted and talented. While high intelligence is not a requirement for resilient outcomes, cognitive ability appears to be a supporting factor, especially as it relates to problem solving and coping. For example, intellectually gifted adolescents across ethnic groups appear more likely to use the coping strategies of working hard and achieving than ignoring the stresser. Programs and curriculum for enhancing resilience should be consistent with developmental expectations, for example, with respect to perspective taking. Successful experience overcoming hardships supports children’s self-efficacy, and protecting children from all stresses may not encourage their resilience. Resilient children and youth across ethnic groups display some common characteristics. However, culture may influence how individuals perceive and cope with stress, and resilience programs should include culturally consonant coping strategies. What constitutes an effective coping strategy depends on the situation and context. Successful coping among adolescents appears to require a metacognitive set conducive to considering a range of strategies and flexibility in their application. To the extent that low-income and culturally diverse children and youth have more experience overcoming adversity, they may possess a greater range and flexibility in coping strategies that can be shared with others. These findings offer a foundation from which curriculum can be developed for supporting resilience.

Manuscript submitted June 28, 2004.

Revision accepted August 27, 2004.

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Margie Kitano serves as Associate Dean of the College of Education and Professor of Special Education at San Diego State University (SDSU). She co-developed and works with the San Diego Unified School District collaborative certificate in gifted education and SDSU’s graduate certificate and master’s degree program in Developing Gifted Potential. Her current research and publications focus on improving services to culturally and linguistically diverse gifted learners from lowincome backgrounds. E- mail: [email protected]

Rena Lewis, Professor of Special Education at San Diego State University, is currently Associate Dean of Faculty Development and Research in the College of Education. She is co-author of two well known texts in special education and has directed research projects investigating use of assistive technology to enhance literacy skills of students with learning disabilities. Among her current interests are school-based intervention programs for highly gifted students from diverse backgrounds. E-mail: [email protected]

Copyright The Roeper School Summer 2005

The Health Insurance Portability and Accountability Act (HIPAA) of 1996 was developed to combat fraud, abuse, and waste in health care and to improve the system’s efficiency. By creating national standards, the federal government strived to create one format for each type of health care transaction in an attempt to alleviate the administrative weight of various formats.

In addition, Section 264 of HIPAA suggested that the Department of Health and Human Services (HHS) propose standards that would safeguard the privacy of patients’ health information. HHS developed privacy regulations designed to improve patients’ faith in health care via a regulatory structure that would preserve their health information. Furthermore, HHS produced policies that would regulate agreements between health care groups and third-party organizations that completed their management and administrative functions. Basically, these policies required that contracts with third parties include guarantees that all health information revealed to third parties would not be divulged in a manner that violated the privacy policies.

Even though HIPAA was supposed to decrease the cost and ease the delivery of health care, the early stages of compliance are estimated to be expensive. Small health plans (plans with annual receipts of $5 million or less) had until April 14, 2004, to comply. Although the objective of the act is to reduce the cost of delivering health care through the standardization of business practices, the short-term financial cost to organizations could be substantial.

One study has established that just 32 percent of health-care groups were able to approximate their estimated costs related to implementing HIPAA. Within the groups surveyed, projected costs varied from $10,000 for a small physician group practice to approximately $14 million for one of the larger integrated-delivery organizations. The average of the projected costs ($3.1 million) was significantly higher than the $450,000 average of healthcare providers’ original (2001) HIPAA budgets.

In addition, a study by the American Hospital Association determined that hospitals (in total) could incur as much as $22.5 billion in additional costs complying with merely three of the privacy provisions of HIPAA during its initial five-year period. These costs are also significantly higher than the federal government’s initial estimate of $3.8 billion estimated costs for compliance with all of the privacy regulations. With such dire projections, it is crucial that financial managers be able to forecast accurately the impact of HIPAA on their businesses.

While HIPAA does not establish a personal right to sue health care workers who leak information, state laws in many circumstances do establish such a right. For example, emergency rooms are sometimes known as places to work for those who want to know what is going on in the community, according to a statement in the Emergency Medical Treatment and Labor Act (EMTALA). Personal information can sometimes be distributed throughout a hospital within a short period of time and can often spread into the community almost as quickly. Such occurrences are one of the factors that resulted in the privacy regulations included in HIPAA.

In a civil case filed in Wisconsin (even before the implementation of HIPAA), an emergency medical technician (EMT) responded to a 911 call for a woman with a “possible overdose.” After she was taken to the hospital, the EMT told an acquaintance who worked for the woman that the woman had experienced a drug overdose. The story circulated throughout the community. Simply telling one person would have been a violation of the patient’s privacy rights.

The patient filed suit in Wisconsin for “invasion of privacy involving intentional actions,” and the EMT, the volunteer fire department, and others were named in the suit. Usually the plaintiff will sue for all potential causes of action and seek the greatest recovery. The court ruled in favor of the plaintiff, ordering a $3,000 judgment plus more than $30,000 in legal fees and interest against the EMT.

Although HIPAA was enacted in 1996, its delayed timeframes for compliance caused many health plans to be unprepared for the numerous regulations that affect all self-insured health plans. For example, one of the major mistakes that self-insured employers have made is underestimating the law’s impact on their workers’ compensation claims and other medical claims. Since HIPAA relates at the present time only to health (group benefits) programs and not specifically to workers’ compensation claims, many employers are preparing their group benefit programs to be HIPAA-compliant only for employee information, privacy transmittals, and coded medical information. However, most medical providers are making all of their transmittals and medical information HIPAA-compliant in order to be cost-efficient in the processing of medical information. The result is that many self-insured worker’s compensation programs will be required to send and receive all employee information and medical information to medical providers in a HIPAA-compliant format (even though workers’ compensation is not technically covered by HIPAA).

A number of the other HIPAA provisions that could affect employers include: (1) creating policies related to privacy issues for medical information and employee information; (2) developing medical-employee transactions and coding; (3) ending the use of employees’ Social Security numbers as identifying codes; (4) addressing the topics of electronic signatures and security issues; and (5) encrypting all electronic transmittal of medical or personal information.

* Editor’s note: Dr. Les Nunn and Dr. Brian McGuire are faculty members in the College of Business at the University of Southern Indiana. Nunn is associate professor of businesses law, and McGuire is associate professor of accounting and chair of the Department of Accounting and Business Law.

Summary: Mondor’s disease of the penis, otherwise known as superficial thrombophlebitis (STP) or thrombosis of the dorsal vein, is an under-reported benign condition, the aetiology of which is poorly understood. It is characterized by a sudden, indurated swelling of the vein, often occurring after vigorous sexual activity. We report a case of Mondor’s disease occurring 24 h following a 15-h flight. This gentleman also reported a history of STP of his left lower limb varicose veins following a similar- length flight three years previously. In the absence of any other clear predisposing factor, we propose long-haul flight as an important factor contributing to the development of dorsal vein thrombosis.

Keywords: Mondor’s disease, dorsal vein thrombosis, flight, thrombophlebitis

Case report

A 33-year-old British Caucasian heterosexual man presented to our genitourinary clinic concerned with a five-day history of prominent enlargement of the penile dorsal vein. It had enlarged, suddenly, 24 h following a 15-h flight home from a short business trip to the Philippines and was causing mild discomfort. He reported no meatal discharge, frequency or urethral dysuria.

The patient reported an isolated episode of unprotected fellatio with a Philippino (non-commercial sex worker) woman, nine days prior to presentation. He said that this activity had not been vigorous, traumatic or prolonged. At 14 days prior to presentation and before his trip to the Philippines, he reported unprotected vaginal intercourse with his British-born wife of five years. The patient had not used constriction rings, sex aids, or penile injections, excessively masturbated or otherwise suffered trauma to the genitals.

Previous medical history included mitral valve prolapse and lower limb greater saphenous vein varicosities. He reported a history of acute superficial thrombophlebitis (STP) of the left leg veins following a similar flight from the Philippines three years previously, but denied any family or personal history of deep venous thrombo-embolism, coagulation disorders, and periods of immobility or surgery. The patient was generally physically well, not overweight, and did not smoke.

On examination, the patient had a 2-cm long, indurated, cord- like lesion, palpable within the dorsal vein of the penis, extending to the base of the penile shaft (Figure 1). The vein was poorly compressible, minimally tender with no oedema or cellulitis evident. The presence of two long-standing epipidymal cysts was documented. Examination was otherwise unremarkable. He received a full genitourinary screen and was diagnosed with non-specific urethritis and treated with azithromycin. His genitourinary screen proved negative for Chlamydia trachomatis, Neisseria gonorrhoeae, and syphilis. We diagnosed Mondor’s disease clinically.

Discussion

Mondor’s disease, otherwise known as superficial dorsal penile vein thrombosis (DoVT) or thrombophlebitis, is an under-reported condition. It was first described as STP of the thoraco-epigastric veins and/or their confluent vessels in 1939, but the definition since 1958 includes the dorsal penile vein.1 It presents as a sudden, indurated cord-like swelling of the vein, measuring up to 5 cm in length.2 It may be associated with inflammation, pain, and fever.

Important differential diagnoses of penile swelling and deformity should include ruptured corpus cavernosum, Peyronie’s disease, and lymphoedema.

The exact aetiology of the thrombus remains unclear, but sexual activity, specifically of a traumatic, vigorous, prolonged or excessive nature, has been a consistent predisposing factor, usually reported to have occurred 24-48 h prior to its development.3-6 This activity may induce stretching or torsion of the vein, causing endothelial necrosis and subsequent thrombus formation.7 Other precipitants include trauma to the genitals such as penile strangulation or injection, presence of a pelvic tumour or distended bladder, sepsis, inguinal hernia repair, deep vein thrombosis, prolonged abstinence, and contact with menstrual blood, possibly acting as an irritant.3,4,8,9 The diagnosis is usually based on clinical findings, but Doppler ultrasound can be useful in cases of diagnostic uncertainty, where it may reveal a non-compressible distended vein.2 The patient need not require further investigation unless clinically indicated.2

Figure 1 Dorsal vein thrombosis of the penis

Spontaneous resolution following venous recanalization occurs within a mean of three weeks, but can take up to eight weeks.3 Non- steroidal anti-inflammatory agents may be used for symptomatic relief, although they do not affect the resolution rate.4 For refractory cases, venous resection can be effective in reducing pain, induration, and improving cosmesis.3,7 Anticoagulants are not necessary and may cause excess blood leakage if a ruptured corpus cavernosum is incorrectly diagnosed as DoVT.2

Mondor’s disease is generally a benign pathology with few complications. Phimosis has been reported rarely secondary to oedema.10 Erectile difficulties do not result although Mondor’s dis ease can mimic Peyronie’s disease.2 Recurrence can occur in relation to predisposing sexual activity.4 Above-knee STP of greater saphenous vein varieosities can be associated with deep vein thrombosis and, very rarely, pulmonary embolus. These conditions have fortunately not been reported with Mondor’s disease.

This is the first case of DoVT reported in relation to a recent long-haul flight. The aetiology of STP is associated with one or more components of the Virchow triad: intimai damage secondary to trauma, inflammation, and infection; venous stasis; change in blood constituents such as coagulation abnormalities. Evans et al. did not identify any coagulation abnormalities during the extensive work-up of their DoVT case series. In the absence of trauma, inflammation, and sepsis, or a clear predisposing factor for the development of Mondor’s disease and in view of the previous history of varicose vein STP, venous stasis due to prolonged immobility and dehydration as a result of longhaul travel may precipitate the development of Mondor’s disease.

Acknowledgements: We would like to acknowledge the staff in medical photography at St Thomas’ Hospital for their help in producing the photographic prints. We would like to thank the patient for allowing us to report this case and present his photographic imaging.

References

1 Katz R, Blachar A. Superficial dorsal penile vein thrombosis (Mondor’s disease). Harefuah 1997;132:544-5, 607

2 Evans DT, Ward OE. Dorsal vein thrombosis of the penis presenting to an STD clinic. Gcnitonrin Med 1994;70:406-9

3 Sasso F, Gulino G, Basar M, Carbone AD, Torricelli P, Alcini E. Penile Mondor’s disease: an underestimated pathology. Br J Ural 1996;77:729-32

4 Swierzewski III SJ, Denil J, OhI DA. The management of penile Mondor’s phlebitis: superficial dorsal penile vein thrombosis. J Urol 1993;150:77-8

5 Dicuio M, Pomara G, Cuttano MG, et ni. Penile Mondor’s disease after intensive masturbation in a 31- and a 33-yearold man. Thromb Haemost 2003;90:155-6

6 Ozkara H, Akkus E, Alici B, Akpinar H, Hattat H. Superficial dorsal penile vein thrombosis (penile Mondor’s disease). Int Urol Nephrol 1996;28:387-91

7 Kraus S, Ludecke G, Weidner W. Mondor’s disease of the penis. Urol Int 2000;64:99-100

8 Bird V, Krasnokutsky S, Zhou HS, Jarrahy R, Khan SA. Traumatic thrombophlebitis of the superficial dorsal vein of the penis: an occupational hazard. Am J Emerg Med 1997; 15:67-9

9 Nickel WR, Plumb RT. Nonvenereal sclerosing lymphangitis of the penis. Arch Derm 1962;86:761-3

10 Lilas LA, Mumtaz FH, Madders DJ, McNicholas TA. Phimosis after penile Mondor’s phlebitis. BJU Int 1999; 83:520

(Accepted 26 July 2004)

S Day MRCP and J S Bingham FRCP FRCOG

Lydia Department, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK

Correspondence to: Dr S Day, 52 Hayes Grove, East Dulwich, London SE22 8DF, UK

Email: [email protected]

Copyright Royal Society of Medicine Press Ltd. Jul 2005

PITTSBURGH, Aug. 4 /PRNewswire/ — The Centers for Medicare & Medicaid Services (CMS) announced Tuesday that Highmark Medicare Services will serve as the Medicare Part A fiscal intermediary for the state of Maryland and the District of Columbia. Operations will be transitioned to Highmark by Sept. 30, with no interruption of service to providers and beneficiaries. As part of this transition, Highmark plans to locate operations in Timonium, MD, and offer employment to many current CareFirst employees.

“Serving as Medicare’s fiscal intermediary for hospitals and skilled nursing facilities in these two important regions will complement our existing role with this critical government program and allow us to grow our longtime relationship with CMS,” said Patrick Kiley, Senior Vice President of Highmark Medicare Services, the government business unit within Highmark established to manage Medicare Part A and Part B contracts.

Highmark has been engaged with the Medicare program since 1966, acting as both a Part A fiscal intermediary for health care facilities and a Part B carrier for health care professionals. The company’s existing Part A region includes Pennsylvania, along with skilled nursing facility chains in 19 states and rural health clinics in 12 states and the Virgin Islands. Highmark also serves as the Part B carrier for Pennsylvania.

Highmark was awarded the Part A Medicare work for Maryland and the District of Columbia based on the results of a bidding process conducted by the Blue Cross Blue Shield Association (BCBSA) among its member plans. BCBSA, the prime Blues Medicare Part A contractor, conducted the competition to identify a replacement for CareFirst of Maryland Inc., after it announced it was withdrawing from the Medicare fee-for-service business.

Highmark is the nation’s ninth largest Medicare Part A intermediary with more than 1,500 facility providers. Last year, the company processed more than 7.6 million Part A claims and paid more than $6 billion in Medicare benefits. As a Part B carrier, the company processed more than 40 million claims for Pennsylvanians with Medicare and paid more than $3 billion in benefits.

Highmark

CONTACT: Aaron Billger, +1-412-544-7826, [email protected], orLeilyn Perri, +1-717-302-4243, [email protected], both of Highmark

Of Indiana’s 36 doctors who have their medical licenses on probation, more than half ran into trouble over drug or alcohol abuse, a Courier & Press analysis of Indiana Medical Licensing Board records shows.

But that may be only the tip of the iceberg in terms of how many doctors are treating patients while struggling to conquer addictions. Many doctors get assistance through the Physicians Assistance Program run by the Indiana State Medical Association.

Randy Stevens, a Terre Haute family physician who heads the committee that oversees the program, said he could not reveal the number of doctors participating because of confidentiality rules.

But he said that generally doctors suffer from addictions at about the same rate as the general population, meaning about 13 percent of doctors probably are tackling issues of substance abuse.

That would mean that for Indiana’s 21,380 licensed doctors, about 2,780 have addictions.

For the doctors now on probation, an arrest often triggered their review by the Medical Licensing Board. Jeffrey Seizys, a Michigan City, Ind., doctor, said he was caught ordering prescriptions through the mail and using them himself.

His license was suspended, he went through a rehab program and then signed up for the medical association monitoring program. He went back to work at his previous employer. After a couple of years, he relapsed but lied on his probationary visits and fooled the drug screens.

As he approached the expiration of his probation, he confessed his relapse to regulators.

“I had a breakthrough in honesty,” Seizys said.

Stevens said his group always tries to get troubled doctors help before things deteriorate because, under state administrative rules, doctors in the program are not reported to state regulators unless they fall off the wagon.

“We really save a lot of careers by having the program,” Stevens said, adding the medical association regularly fields phone calls from concerned colleagues and sets up interventions.

Stevens said doctors usually sign a five-year contract to stay in the program, meaning they have to check in daily to see if they’re up that day for random drug and alcohol screenings. The doctors also must participate in individual and group counseling. In his own practice, Stevens also specializes in addictions.

“I wish I could offer this type of program to anyone who has any type of chemical dependency,” he said, adding that the regimented monitoring and intense support really help keep people on the right track.

Going back to work

Stevens said the success rate for the medical association assistance program is high. Among doctors who successfully complete the entire five-year contract, fewer than 20 percent relapse.

But success does not automatically mean acceptance back into the work force. Seizys said he still is trying to win back his job.

“My place of employment and the hospital associated with it are very nervous about me coming back,” he said. He said he’s thought about moving, but prefers to stay put in part because everyone in his hometown knows about his struggle.

“I have a sense of duty to my patients I left behind and I need to make amends to my partners,” he said. He said doctors sometimes debate the pros and cons of moving, calling it a “geographic cure” to the problem.

“There is an appeal to running away,” he said, but he added that it felt sneaky and that it might lead to temptation to hide his recovery efforts and fall into old patterns.

Are doctors special?

Many of those in the assistance system seem torn — on the one hand they said doctors are just like anyone trying to overcome an addition. But they also said doctors face some special circumstances.

Access to addictive prescription drugs is one hurdle. Of the 20 doctors on probation for substance abuse issues, about half were caught writing false prescription to get the drugs for personal use.

Seizys also said that the personality traits that lead someone into a career in medicine — perfectionism, a need to be needed and in control — also are some common traits for addicts.

Despite those issues, Seizys said he didn’t think doctors tackling addictions were any different than anyone else.

“I really think that’s a copout,” he said. “It’s a life issue, not just a work issue.”

Not just substance abuse

While the majority of doctors run into problems with substance abuse, other stories lie behind the stacks of probationary files. Two doctors are on probation for child molestation convictions and cannot practice around children. A psychiatrist had sexual contact with female patients and now works in the prison system counseling only male patients.

Three doctors ran into trouble after they were found to have defrauded state and private insurance programs. And three doctors are being monitored for mental health issues.

One, Glenn Ballengee, an Indianapolis-based anesthesiologist, said he doesn’t think he was unfit to practice.

After working at an Indianapolis hospital for more than 20 years, Ballengee lapsed into a severe depression about two years ago. He called in two prescriptions for sleep medications and took several in what he called a “suicidal gesture.”

He said he got treatment for the depression and returned to work. But he failed to report the incident on his next license renewal form, according to medical board records. After being back at work for six weeks, Ballengee received a letter from the attorney general’s office that said he was being investigated.

He said he surrendered his license, signed a treatment agreement and got the OK from his doctors to return to work.

His position at the hospital was filled in the interim and he now is looking for a job. He said he is happy with the oversight by the Medical Licensing Board but resents the attorney general’s office because he said its investigation and subsequent demands obligated him to sign a settlement agreement if he wanted to get his license back.

“I talked to (the attorney general’s office) at length,” he said. “They were pretty unyielding.”

According to Indiana Medical Licensing Board records, no doctors with licenses on probation currently are working in Southwestern Indiana.

* * *

At a glance

For the 36 doctors, residents and physician assistants on probation now, here are the issues that got them in trouble:

* 20 for personal substance abuse issues

* Three for mental illness

* Three for fraudulent billings to Medicaid or private insurance

* Three for medical mistakes

* Two for sexually molesting minors

* One for sexual contact and exposing himself to patients

* One for prescribing drugs to patients over the Internet without consultation

* One for prescribing drugs to wife with substance abuse problems

* One for practicing without a license in California and not passing the appropriate exams in Indiana

* One unknown because file is missing

Indiana has :

* 21,380 licensed medical doctors

* 1,398 licensed doctors of osteopathy

* 1,136 licensed residents

* 102 doctors with licenses revoked, cannot practice

* 69 doctors with suspended licenses, cannot practice

* 36 doctors and others with licenses on probation, can practice under the conditions of their probation.

To check the status of a doctor’s license, log onto: https:// extranet.in.gov/ WebLookup/Search.aspx

Jul. 31–President Bush’s former health secretary Tommy Thompson is putting the final touches to a plan that could result in US citizens having a radio frequency identification (RFID) chip inserted under their skin, The Business has learned.

The RFID capsules would be linked to a computerised database being created by the US Department of Health to store and manage the nation’s health records. It could be the precursor to a similar scheme in the UK.

The president’s budget for 2006 continues to support the use of health information technology by increasing funding to $125m (£70m, E103m) for pilot schemes.

Thompson, now a director of Applied Digital Solutions, the company that makes the chips, intends to publish the proposal in the next 50 days, by which time he plans to have had a VeriChip inserted in his arm. Thompson believes the capsules could help save thousands of lives every year.

VeriChip spokesman John Procter says around 98,000 people die needlessly in the US every year after being given inappropriate treatment because their medical history was not available.

“There is a vast range of people who could benefit from having an RFID chip inserted under their skin as insurance against an accident. People with adverse reactions to certain medicines such as penicillin, people with pacemakers, people with allergies, people with weak hearts, would be made safer by a process that costs around $200 per person. In fact, virtually everyone could benefit from having a chip inserted.”

The company intends to lobby the UK health authorities to inject the chips into British patients.

According to Procter, the chips can also be used for financial transactions. In Europe, the Baja Beach Club chain has introduced chipping in the Netherlands and Spain.

The VeriChip is inserted at the club and means club-goers will no longer have to wait in line to pay to get in and will be able to use the chip to pay their bar bill.

Civil liberties groups such as Caspian in the US fear that the need for increased security in the wake of terrorist attacks could act as a catalyst for a more widespread use of VeriChips.

—–

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Copyright (c) 2005, The Business, London

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

ADSX,

In a 24-7 world, tens of thousands of Americans fall victim to shift-work sleep disorder _ they’re terribly sleepy during their night of work, but suffer from insomnia when they try to sleep in the daytime.

A study published Thursday shows that a drug first prescribed for narcolepsy sufferers also offers some relief to night workers trying to stay awake on the job.

The drug, called modafinil and sold under the brand name Provigil, extended the length of time it took shift workers between the ages of 18 and 60 to nod off at night from an average of about two minutes to nearly four minutes.

And it improved the workers’ self-reported wakefulness and their vigilance in tests.

Researchers say nearly 6 million Americans work at night on a permanent or rotating basis, and some 5 percent to 10 percent suffer from the shift-work disorder.

“Shift-work sleep disorder adversely affects many working Americans,” said Dr. Charles Czeisler, chief of the sleep-medicine division at Brigham and Women’s Hospital in Boston and leader of the study presented in The New England Journal of Medicine.

“It can compromise personal safety and significantly impact quality of life. This study demonstrates that while modafinil can significantly improve symptoms and reduce sleep tendency during night-work hours, patients remain excessively sleepy even after treatment for this sleep-wake disturbance.”

Originally intended to treat narcoleptics _ people with a rare brain disorder that causes them to uncontrollably fall asleep _ the drug is now approved for people with the shift-work disorder as well as those suffering from sleep apnea. The drug’s manufacturer, Cephalon, sponsored the new research, and Czeisler is a paid consultant to the firm.

The pills generally keep people awake with less of the jitteriness and other side effects seen from using caffeine or amphetamines. In previous trials by the U.S. military and others, the drug has allowed healthy people to stay up safely while remaining almost as focused, alert and capable of dealing with problems as people who are well-rested.

People with shift-work sleep disorder tend to miss family and social activities more frequently and have higher rates of ulcers, sleep-related accidents, depression and absenteeism than other night-shift workers who don’t suffer from the disorder.

In the three-month trial, the researchers randomly assigned 209 patients to take either 200 milligrams of modafinil or a placebo at the start of each shift. Neither the researchers nor the patients knew who got the actual drug.

Night-shift workers were defined as those who worked at least five night shifts for 12 hours or less, with six hours or more between 10 p.m. and 8 a.m., and at least three shifts that they worked on consecutive nights.

Nodding-off time, or sleep latency, was measured through various physical changes detected during sleep, while alertness was measured with a performance test. The patients also kept electronic diaries of how sleepy they felt during the tests.

The researchers found that clinical symptoms of the disorder, which include excessive sleepiness during night work and insomnia when trying to sleep during the day, improved among 74 percent of the patients taking Provigil, vs. 36 percent among those in the placebo group.

Accidents or near-accidents were reduced by 25 percent, and lapses of attention were also significantly reduced in the group getting active treatment. But those taking the drug reported increased problems with insomnia compared with those who took the dummy pills.

Sleep experts say that no matter what drug a person uses to stay alert, skipping sleep creates a deficit in rest that eventually takes a toll on the body, both with the accumulated need for rest and with problems of digestion, the immune system and other functions.

“It is simplistic to consider that a pill alone could sufficiently modify the effects of this disorder,” Dr. Robert Basner, a sleep specialist at Columbia University who did not take part in the study, observed in a Journal editorial.

While modafinil so far seems to be relatively safe and may prove to be part of comprehensive treatment strategies for shift-work disorders, the study “does not justify writing more prescriptions for modafinil,” Basner added.

On the Net: www.nejm.org

BREAKOUT BOX

Shift-work sleep disorder

While it’s tough, most of the country’s nearly 6 million shift workers manage to reset their natural clocks to sleep at least part of the day and remain awake overnight. But about 10 percent get terribly sleepy and nod off on the job, yet suffer from insomnia when they try to sleep during the day. Researchers find that a wakefulness pill helps such patients stay alert on the job, but doesn’t make them sleep better or feel less tired overall.

(Contact Lee Bowman at BowmanL(at)SHNS.com. Distributed by Scripps Howard News Service, http://www.shns.com)

© 2005 Scripps Howard News Service.

All Rights Reserved.

Santa Barbara, Calif.) ““ Materials scientists working with biologists at the University of California, Santa Barbara have developed “smart” bio-nanotubes “” with open or closed ends “” that could be developed for drug or gene delivery applications.

The nanotubes are “smart” because in the future they could be designed to encapsulate and then open up to deliver a drug or gene in a particular location in the body. The scientists found that by manipulating the electrical charges of lipid bilayer membranes and microtubules from cells, they could create open or closed bio-nanotubes, or nanoscale capsules. The news is reported in an article to be published in the August 9 issue of the Proceedings of the National Academy of Sciences. It is currently available on-line in the PNAS Early Edition. See: http://www.pnas.org/cgi/content/abstract/0502183102v1

The findings resulted from a collaboration between the laboratories of Cyrus R. Safinya, professor of materials and physics and faculty member of the Molecular, Cellular, and Developmental Biology Department, and Leslie Wilson, professor of biochemistry in the Department of Molecular, Cellular and Developmental Biology and the Biomolecular Science and Engineering Program. The first author of the article is Uri Raviv, a post-doctoral researcher in Safinya\’s lab and a fellow of the International Human Frontier Science Program Organization. The other co-authors are Daniel J. Needleman, formerly Safinya\’s graduate student who is now a postdoctoral fellow at Harvard Medical School; Youli Li, researcher in the Materials Research Laboratory; and Herbert P. Miller, staff research associate in the Department of Molecular, Cellular and Developmental Biology.

The scientists used microtubules purified from the brain tissue of a cow for their experiments. Microtubules are nanometer-scale hollow cylinders derived from the cell cytoskeleton. In an organism, microtubules and their assembled structures are critical components in a broad range of cell functions ““”“ from providing tracks for the transport of cargo to forming the spindle structure in cell division. Their functions include the transport of neurotransmitter precursors in neurons.

“In our paper, we report on a new paradigm for lipid self-assembly leading to nanotubule formation in mixed charged systems,” said Safinya.

Raviv explained, “We looked at the interaction between microtubules ““”“ negatively charged nanometer-scale hollow cylinders derived from cell cytoskeleton ““”“ and cationic (positively charged) lipid membranes. We discovered that, under the right conditions, spontaneous lipid protein nanotubules will form.”

They used the example of water beading up or coating a car, depending on whether or not the car has been waxed. Likewise the lipid will either bead up on the surface of the microtubule, or flatten out and coat the whole cylindrical surface of the microtubule, depending on the charge.

The new type of self-assembly arises because of an extreme mismatch between the charge densities of microtubules and cationic lipid, explained Raviv. “This is a novel finding in equilibrium self-assembly,” he said.

The nanotubule consisting of a three-layer wall appears to be the way the system compensates for this charge density mismatch, according to the authors.

“Very interestingly, we have found that controlling the degree of overcharging of the lipid-protein nanotube enables us to switch between two states of nanotubes,” said Safinya. “With either open ends (negative overcharged), or closed ends (positive overcharged with lipid caps), these nanotubes could form the basis for controlled chemical and drug encapsulation and release.”

The inner space of the nanotube in these experiments measures about 16 nanometers in diameter. (A nanometer is a billionth of a meter.) The whole capsule is about 40 nanometers in diameter.

Raviv explained that the chemotherapy drug Taxol is one type of drug that could be delivered with these nanotubes. The scientists are already using Taxol in their experiments to stabilize and lengthen the lipid-protein nanotubes.

The work was performed using state-of-the-art synchrotron x-ray scattering techniques at the Stanford Synchrotron Radiation Laboratory (SSRL), combined with sophisticated electron microscopy at UCSB. The work was funded by the National Institutes of Health and the National Science Foundation. SSRL is supported by the U.S. Department of Energy. Raviv was also supported by the International Human Frontier Science Program and the European Molecular Biology Organization.

On the World Wide Web:

University of California – Santa Barbara

RALEIGH, N.C., Aug. 3 /PRNewswire/ — LipoScience, Inc. today announced that it has entered into an agreement with Laboratory Corporation of America Holdings (LabCorp(R)) , a leading national clinical laboratory, to offer its proprietary NMR LipoProfile(R) test.

(Photo: http://www.newscom.com/cgi-bin/prnh/20050803/CLW005 )

LabCorp serves more than 220,000 physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies, providing a greatly expanded market for the patented LipoScience test.

This multi-year agreement will make the NMR LipoProfile test readily available through LabCorp’s sales and distribution network and will add an important cardiovascular test to LabCorp’s comprehensive menu of testing services.

The NMR LipoProfile test is a blood test which has been shown in numerous clinical studies to be superior to LDL-cholesterol in predicting coronary heart disease (CHD) events.

Unlike traditional cholesterol tests or lipid panels, the NMR LipoProfile test uses NMR spectroscopy to measure the actual number of atherogenic LDL particles that build up in the arteries and cause heart disease. Physicians have traditionally estimated the number of particles by measuring the cholesterol they contain – known as LDL cholesterol (or LDL-C).

Patients with a high number of LDL particles (LDL-P) are at increased risk for heart disease, even if they have “normal” cholesterol levels. By knowing how many of these particles are circulating in the blood, a physician can get a more accurate picture of a patient’s heart health and, therefore make better patient care decisions.

“Entering into this agreement with LabCorp accelerates our strategy of making our technology available for broad use in clinical laboratories worldwide,” said Richard O. Brajer, President and CEO, LipoScience, Inc.

Brajer added, “Clinicians increasingly understand the need to go beyond cholesterol measurement in assessing risk for heart disease and monitoring response to therapy. This relationship with LabCorp will help address that need.”

About LipoScience

Headquartered in Raleigh, N.C., LipoScience develops and markets new clinical applications of NMR spectroscopy in the areas of cardiovascular disease and metabolic disorders. Its flagship product, the NMR LipoProfile blood test, was introduced for clinical research in 1997 and for use in patient care in 1999.

Results previously reported from the Cardiovascular Health Study, Women’s Health Study, PLAC-1 and VA-HIT, among others, have all shown that numbers of atherogenic LDL particles to be more predictive of coronary heart disease events than LDL cholesterol. Further information is available on the company’s Web site: http://www.liposcience.com/.

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20050803/CLW005AP Archive: http://photoarchive.ap.org/PRN Photo Desk, [email protected]

LipoScience, Inc.

CONTACT: Michelle Turenne of LipoScience, Inc., +1-919-256-1306, [email protected]

Web site: http://www.liposcience.com/

Aug. 1–Steve Farber’s days were numbered.

The powerful and politically connected Denver attorney had known for nearly a year that he had severe kidney disease. Without a transplant or dialysis, he would die.

His typically well-tanned skin was pale. His appetite was down. His energy was flagging. His passion for work was eclipsed by fear for his health.

These troubles weighed on his mind as he dined with two friends at the Blue Bonnet Cafe & Lounge Mexican restaurant on a Sunday evening in April 2004.

Farber, then 60, had all but rejected kidney dialysis as too burdensome. And he wasn’t well enough to wait three years to become eligible on a wait list for a donor kidney.

That left two stark choices. He could fly to Turkey for a risky kidney transplant of questionable legality.

Or he could accept a kidney from the eldest of his three sons, Gregg, then 31. Farber considered that a last resort. His wife, Cindy, was a protective mother who didn’t want to endanger Gregg. Cindy preferred the Turkey option.

At the Blue Bonnet that night, Farber discussed his dilemma with his dining companions. Farber had delayed making a decision for months. But his health crisis was an open secret in the social circles in which he moves: the realms of law, politics, charity and Denver’s Jewish community.

“It’s impossible to keep a secret in Denver,” Farber said later.

At the restaurant, the secret spilled out during a terse encounter with a kidney doctor who happened to be sitting near Farber’s table.

The two knew each other socially. A conversation ensued between them about Farber’s situation.

The doctor, who wasn’t involved in Farber’s care, was shocked to learn from him that night just how far his illness had advanced. He also couldn’t believe Farber was considering turning to the black market.

The conversation grew strained. The doctor told Farber that he should accept his son’s offer and get the transplant immediately.

“The best thing you can do for him is to take his kidney so you can live,” the doctor told Farber.

Farber was stunned by the doctor’s bluntness — and upset that his health problems had been aired in public. But what the doctor said hit home.

Farber confronted a grim reality: All his contacts, influence and power could not help him. His health was failing. His family was in conflict. The law firm he had helped build over 35 years was running without him.

The power broker was powerless.

Farber rose from humble roots in a tight-knit Jewish neighborhood on Denver’s west side. His father worked as a general manager of a Denver produce wholesaler, and his mother worked at a May department store.

His childhood friendship with Norman Brownstein, the son of Russian immigrants, grew to become a lifelong partnership that became a power in state and national Democratic politics.

After graduating from the University of Colorado’s law school in 1968, Farber and Brownstein started Brownstein Hyatt & Farber with Jack Hyatt, another friend from the neighborhood.

In 1971, Farber married Denver native Cindy Cook, whose family had earned a fortune in sporting goods and real estate.

The law firm scrambled to win business in the early years, but the founding partners’ penchant for working their contacts in the community quickly put it on the fast track. A key early client was Larry Mizel, now head of Denver-based MDC Holdings, which has become one of the nation’s largest homebuilders and a Fortune 500 company.

“They built the practice on extraordinary service. They literally worked day and night to do it,” said former U.S. Sen. Hank Brown. “They delivered. They really hustled to build that practice.”

Brown knew them in college when he recruited them to the Delta Tau Delta fraternity at CU even though Jews apparently had never pledged there before.

Brownstein forged a reputation as a top lobbyist on the national stage. He was an early booster of Tim Wirth, the former U.S. senator from Colorado. Brownstein also worked to elect and re-elect President Bill Clinton, with whom he remains friends, as he is with former Vice President Al Gore.

Farber’s political juice is closer to home, though he, too, has broad national connections. He was campaign chairman for former Colorado Gov. Roy Romer, for whom he raised millions of dollars, and he worked closely with former Denver Mayor Federico Peña. Farber has known Clinton since the late 1980s, when he met the then-governor of Arkansas on a trip to Aspen.

At the law firm, Farber is known as a rainmaker and a deal broker in complex negotiations between business and government.

He helped United Airlines negotiate its lease at the new Denver International Airport in the early 1990s. Later, he led Ascent Entertainment Group’s tortured negotiations with the city to finance and build the Pepsi Center. He also represents the Denver Broncos.

Farber also is active in the city’s charitable organizations. He has a long association with Rose Medical Center and the Rose Community Foundation. He and Cindy have hosted fundraisers for a variety of organizations, including Children’s Hospital and the University of Colorado Hospital.

His death-defying battle with kidney disease prompted Farber to launch the Denver-based Transplant Foundation, which Farber says will raise millions to increase awareness about organ donorship, fund science and research and influence public policy.

With former colleague Harlan Abrahams, Farber is also co-authoring a book on the subject, titled, “The Peasant and the Power Broker: Journeys Through Organ Transplant Realities.” There are more than 60,000 people waiting for kidneys in the U.S., and each year fewer than 15,000 of the organs are available for transplant. An estimated 3,300 Americans died waiting for kidney transplants in 2003.

The two fist-sized, bean-shaped organs are located on either side of the spine under the lower ribs of the back. They stimulate production of red blood cells and regulate blood pressure. The kidneys also filter waste from the blood to be excreted as urine. If left in the blood at high levels, that waste can poison the body.

Farber had a history of kidney problems. When he was 18 months old, his kidneys stopped functioning and he almost died. He was treated at Children’s Hospital in Denver and the Mayo Clinic in Minnesota.

Later, health insurers wouldn’t cover him because of his medical history, saying he wouldn’t live to 30. In the early years, Farber’s law firm funded his health insurance — at a hefty premium.

In the spring of 2003, Farber noticed that he was “slowing down” a bit. His morning workouts and regular tennis matches and golf outings left him short of breath. Increasingly, he would go to bed right after dinner. Farber figured his age was starting to catch up with him.

But during a routine checkup that June he learned from Dr. Rick Abrams at Rose that his kidneys weren’t working well. Tests and exams over the next few weeks confirmed that Farber’s kidneys were functioning at about 25 percent of their normal level, and that their effectiveness would continue to decline.

Farber had between six months and two years to get a new kidney — or go on dialysis. But it would take him at least 3K years to become eligible for a kidney through an organ-recipient list. He briefly considered moving to another state where the list was shorter.

He visited Johns Hopkins Hospital in Maryland and spoke to kidney specialists at the Mayo Clinic and Massachusetts General Hospital. They confirmed what he had learned in Denver.

Yet the magnitude of the diagnosis hadn’t sunk in.

“I continued to play tennis and work out,” Farber said. “I felt pretty good, but mentally it was a huge burden. I was managing partner of the firm. I was chairman of the board of the Rose Foundation. I had a lot of clients who relied on me.””Superman” faces mortality Farber, who was used to being in control, began to learn about the disease in order to regain his health.

“He wasn’t frantic,” Brownstein said. “He said, ‘I’ve got a problem and I have to figure out what to do with it.’ And I said, ‘We’ll all have to figure out what to do with it.’ — I knew we’d figure a way out.”

During the fall of 2003, months into his health crisis, Farber was still working 10-hour days and frequently attending charity functions at night. He and Cindy co-hosted a fundraising gala for Children’s Hospital that September.

But gradually he was spending more time on his health problem. To get on CU Hospital’s kidney-recipient list he had to undergo more tests and biopsies. In October, his name was placed at the bottom of the list of about 600 people.

One day that fall, two senior partners at Brownstein Hyatt & Farber knocked on the door of his spacious 22nd-floor corner office, which boasts a mountain view. They asked him if he was sick.

“Not really,” Farber replied.

They said there was a rumor going around that he was dying.

“Not that I’m aware of, but I am going to need a kidney transplant,” he said.

The next day, Farber gathered the company’s 110 attorneys and told them what was happening. With dark humor, he made it absolutely clear he would be staying at the firm.

“I said my points are not available,” referring to his ownership in the firm, “and neither is my office.” Word had spread. Longtime friends offered Farber their kidneys for transplant and said they would get tested.

“When a friend of yours says, ‘Look, I want to give you my kidney’ — it was quite touching to find out who your friends really are,” Farber said.

In the end, none of those offers came through. And Farber didn’t pursue it.

Some people needing an organ transplant reach out to everyone they know — even by e-mail — soliciting help. Farber, who is intensely private, wanted to solve his health problem on his own.

“I internalized it and hoped it would work out. I didn’t reach out to the community. I couldn’t do that,” he said.

Proud and self-reliant, Farber became more isolated.

“He likes to limit his vulnerabilities because he is, after all, Superman,” said developer Jim Sullivan, a longtime friend of Farber’s. “He doesn’t want people to know about the kryptonite.” That puzzled some who wanted to help.

“He really didn’t talk about it,” said Jimmy Lustig, a close friend whose wife, Debbie, is Cindy Farber’s sister. “I don’t know what he was really thinking. Outwardly, it appeared it was being handled, but it wasn’t being handled.” Six months after he had first been diagnosed, Farber was no closer to making a decision. He didn’t want kidney dialysis, which can take four or five hours a day three days a week.

The other option was a transplant. But who? And how long would he have to wait? His kidney function was now below 20 percent. His family and friends began sounding the alarm.

The rules of organ transplants in the U.S. are clear. Social status, wealth, race and other subjective factors don’t play a role in determining eligibility for an organ.

Once someone has qualified for a transplant, an organ recipient is placed on regional and national lists. The wait for an organ can last between one and six years, depending on the organ needed and blood and tissue type. The wait varies from region to region.

“There’s no way to move up the list. You can be rich or poor. When the time comes you will get your organ transplant,” said Dr. Igal Kam, chief transplant surgeon at the University of Colorado Hospital in Denver.

In January 2004, Brownstein, Sullivan and Cindy Farber met with Dr. James Shore, chancellor of the CU Health Sciences Center, over lunch at the Pinnacle Club atop a downtown Denver skyscraper. The trio asked Shore if Farber might get priority on the transplant list because of his strong record of community service.

A few years earlier, Steve and Cindy Farber headed a fundraising campaign that raised $4 million to equip CU’s new cancer center with a cutting-edge PET scanner.

At lunch, Sullivan said he promised Shore more fundraising.

“Did I stop to think who might be in front of him in line and might lose their spot? No,” Sullivan said later. “I just wanted to help a friend.” Shore’s answer was a polite but emphatic no, according to Brownstein and Sullivan. Shore declined to comment for this story.

“The purpose of the lunch was to get a clear understanding of the criteria to get a kidney,” and whether community service could play a role, Brownstein recalled. “During the conversation it became clear to me he was the wrong guy to ask, and in fact there was no right guy.” Brownstein doesn’t apologize for trying everything possible to save the life of his friend.

“We didn’t leave any stone unturned,” he said.

But he said organ donation lists should take into account those who have contributed to society in a measurable way — not based on wealth, but community service, which could include teachers or veterans.

“Steve would have ranked at the top of the list of people who have given to their community,” Brownstein said. “It should matter, but it didn’t work out that way.” Farber said he played no part in the meeting with Shore. “I never felt an entitlement,” he said.

Steve and Cindy’s bedroom in their Cherry Hills Village home was the scene of family powwows during Farber’s ordeal. One such meeting occurred in March or April.

All three sons — as well as Cindy — had been tested and could have been a kidney donor for Farber. The eldest son, Gregg, was the best match and was willing. But Cindy, concerned about the risks to Gregg, who was married and planning to have children, wouldn’t hear of it. Farber said his wife declined to comment for this article.

“Mom was creating such a stir it didn’t matter what I said,” Gregg Farber recalled. “For my dad, it was a lose-lose situation.” They resolved that Farber should pursue his last remaining option: fly to Turkey for a kidney transplant, which would cost at least $100,000. He knew a Denver man who had done it.

Farber spoke with an Israeli doctor who performed kidney transplants at a clinic in Istanbul. He was told the donor most likely also would be an Israeli man, whom Farber could meet before the surgery.

Under U.S. law, anyone convicted of buying or selling human organs for transplant may have to pay up to $50,000 and spend five years in prison.

The sale of human organs is illegal in almost every country except Iran. Yet, thousands of kidneys from live donors are sold each year on the international black market for $5,000 to $10,000 apiece. Turkey is a center of this activity.

Farber said he was uncertain about the legality of what he was planning. A doctor from Denver would accompany Farber to Turkey, as would Sullivan.

Farber stayed up at night worrying whether he would survive the surgery, or if he would have trouble getting care in the U.S. should complications arise. He thought of the 1978 movie “Midnight Express” and its harrowing portrayal of an American drug smuggler jailed in Turkey.

“It was very sketchy. It started hitting me that something is wrong,” Farber said. “I was worried I’d get charged with a crime and get thrown into a Turkish prison.” A difficult decision Farber was running out of options when the doctor confronted him in public at the Blue Bonnet in April 2004. The doctor told him he should get a kidney transplant from his son.

Shaken, Farber talked to Gregg the next day when his son dropped by the Farbers’ home. Cindy wasn’t there.

“I’ve never seen my dad that scared in my life,” Gregg Farber recalled. “He had no control over the situation for the first time in his life. It was humbling for him — knowing what life can throw at you, that you’re not invincible.” Gregg Farber told his father to come to his senses.

“I said enough of this Turkey thing. I’ll do it. He said, ‘Are you sure?’ I knew then he really wanted that. That was his hope,” he said.

Farber called the family together again and explained. Cindy was on board this time, realizing there was no other choice, he said.

“We could see it in his face that he didn’t want to go to Turkey,” Gregg Farber said. “He was waiting for mom to come around.” Farber and his son underwent the 2K-hour transplant operation on May 11, 2004, at the University of Colorado Hospital. CU’s kidney- and liver-transplant program is highly regarded.

The world’s first liver transplant was performed there in 1963, and the world’s longest-surviving kidney-transplant recipient — who is still alive — received his new organ there the same year.

A kidney was removed from Gregg Farber’s upper abdomen. Three small incisions were made. Doctors inserted a laparoscope into one hole and the scalpel into another to sever the kidney. Gas was pumped into the abdomen to create a cavity for room to operate and remove the kidney.

At the same time, Dr. Kam cut open Steve Farber. His son’s kidney was placed in his lower abdomen in the front near the bladder. There were no major complications.

Nearly a year after Farber was diagnosed, his life-or-death drama had concluded.

Farber left the hospital in a few days and ramped back up to his old activity level in about 2 months. Friends who saw him after the surgery said the return of color to his face happened almost overnight.

Two months after the surgery, Farber hosted Clinton at his home during a trip by the former president to publicize his autobiography and raise money for his library.

Gregg Farber stayed a bit longer at the hospital than his father and recovered at home for several more days, which is customary. The surgery is more painful for the donor, mainly because of the gas pumped into the body.

“I didn’t realize how bad the pain would be in the first few days,” he said. “If I knew how bad it would be I might have had second thoughts.”

Within 10 days he returned to his job working with Sullivan’s development company. An avid athlete, Gregg Farber played a semi-pro baseball game seven weeks after the surgery. He said he doesn’t worry about the fact that he has just one kidney now, though a serious injury to his remaining kidney could put his life in danger.

Steve and Gregg Farber say that the experience has strengthened their relationship.

“I think we communicate better. He probably respects me more than before,” Gregg Farber said. “He grew up from humble beginnings and he made it. I’ve had everything. Maybe I haven’t lived up to everything he expected. This takes off some of the pressure.” Farber said his son acted heroically.

“It’s still difficult for me to believe what he did,” Farber said. “How can you help but look at someone like that as a hero in your life?”

TRANSPLANT FACTS:

–More than 88,000 Americans currently await lifesaving transplants. In Colorado, 1,500 people are on the waiting list for organs.

–Last year, 27,000 organ transplants were performed in the United States. In Colorado, there were 382.

–An average of 17 Americans die each day from the lack of available organs for transplant.

–The wait for a kidney from a deceased donor in Colorado is about four years, comparable to the national average. Wait times vary depending on issues such as blood and tissue type and medical urgency.

–Living donors provided 26 percent of organs for U.S. transplants in 2004, up from 17 percent a decade earlier.

–Living donors are usually relatives or close friends of recipients, but not always. A living donor can give a kidney, a portion of their liver or lung, intestine, blood or bone marrow.

–One deceased donor can supply vital organs to eight recipients and bones and tissues to as many as 50.

–Organs that can be donated after death include the heart, kidneys, liver, lungs, pancreas and small intestines. Tissues include bones, corneas, skin, veins, heart valves, tendons and ligaments.

–To register to donate organs or tissues after death, go to www.Colorado DonorRegistry.org or say “yes” to donation at the Department of Motor Vehicles when obtaining or renewing a driver’s license or ID card.

–About 60 percent of Coloradans are registered to donate their organs after death.

–Each year about 15,000 kidneys become available for transplant. There are 62,000 Americans awaiting kidneys for transplant.

–One in nine adult Americans has chronic kidney disease. More than 400,000 of those require dialysis.

–Diabetes is the most common cause of kidney failure in the U.S. In part because diabetes is on the rise, the number of patients with kidney failure who will need dialysis is predicted to nearly double by 2010.

Sources: United Network for Organ Sharing; Donor Alliance; American Kidney Fund; American Association of Kidney Patients; University of Colorado Hospital.

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Copyright (c) 2005, The Denver Post

Distributed by Knight Ridder/Tribune Business News.

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MDC, UALAQ, PEP, MAY,

Aug. 2–A devastating morning collision between a bus and a bicycle Monday killed a prominent Erie heart surgeon and left investigators combing for clues about its cause.

David Sanders — a prolific Saint Vincent Health Center surgeon known for his skill with a scalpel and a razor-sharp wit — died shortly after 6 a.m. Monday after his bicycle was hit by an Erie Metropolitan Transit Authority bus.

The accident, which happened on Sterrettania Road just north of West 38th Street, happened as the southbound bus was making a left turn into the parking lot of a Kwik Fill/Red Apple convenience store.

Sanders was riding northbound on Sterrettania Road in front of the entrance to the convenience store’s parking lot.

Millcreek police said the impact of the crash killed the 36-year-old surgeon almost instantly.

Sanders had left Saint Vincent in early July to accept a job at an Indiana hospital, said Joseph Cacchione, M.D., a Saint Vincent cardiologist and executive vice president. He had taken some time off before the move to enjoy the summer with his wife, Danielle, and their three daughters — Victoria, Olivia and Emma.

His sudden death stunned employees at both Saint Vincent and Consultants in Cardiovascular Diseases, the Erie medical practice Sanders had joined.

“Some people went home for the day, and we have a grief counselor available if anyone needs one,” said Cacchione, who is also a member of the medical practice.

The driver of the bus, David M. Justka, of East Fifth Street, is on paid leave pending the results of drug and alcohol screenings, EMTA operations manager Mike Will said.

Federal law requires the screenings for any accident involving injuries.

The results of the tests will likely be available by the end of the week.

Justka — who was described by Will as a veteran driver — was also behind the wheel of an EMTA bus that hit and injured a woman who was walking in a crosswalk in August 2000.

The 2000 accident, which took place at State Street and North Park Row, put the Erie woman in intensive care as a result of her injuries.

Will said Justka was “pretty shook up” about the accident, which was the first fatality involving an EMTA bus in six years.

Charlene Loomis, a 51-year-old Erie woman, died in February 1999 after she was hit by an EMTA bus at the intersection of State and 21st streets. The bus struck the woman during Monday morning rush hour after she had gotten off of another EMTA bus and was crossing State Street.

An EMTA bus was also involved in a two-vehicle accident that killed two people in 1988.

The cause of Monday’s crash, meanwhile, remains under investigation.

Erie County Deputy Coroner Dennis Suschek said Monday that Sanders died of blunt-force trauma, but said his office must first wait for the results of its autopsy to release a formal cause of death.

Though Sanders had only been in Erie for about three years, he was well known locally.

The Millcreek Township resident had performed stand-up comedy at Jr.’s Last Laugh Comedy Club and liked to joke with patients, families, staff — almost anyone within hearing distance, Cacchione said.

“We had a pep rally for the Heart Center in February, and David came out and performed a rap song he wrote,” Cacchione said.

“He even dressed up as a rapper, with a wig and the whole outfit.”

Sanders was also one of the state’s busiest heart surgeons, performing 243 open-heart and coronary-bypass heart surgeries in 2003, 10th most among Pennsylvania surgeons.

“Heart surgery isn’t an 8-to-5 job, and David would spend many weekends and holidays in the hospital,” Cacchione said. “He had a really good rapport with patients and their families.”

—–

To see more of the Erie Times-News, or to subscribe to the newspaper, go to http://www.GoErie.com.

Copyright (c) 2005, Erie Times-News, Pa.

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LAST week, it emerged that skipping meals may actually be good for us – and could even help us live longer. Here, solicitor Joel Kordan, 43, who lives with his wife Dawn and their five children in Worcestershire, explains how he discovered the benefits of eating once a day completely by chance.

FLICKING through my newspaper last week, an eminent American scientist was telling the world what I have been telling my disbelieving friends and family for over a year: that far from being bad for you, skipping meals not only helps you lose weight, but may actually benefit your health.

I’ve never been one for diets.

In fact, I have always regarded them with a healthy disdain. I’ve seen friends try the Atkins and various other weight-loss programmes, only to end in failure.

Frankly, I loved my food too much to contemplate trying to give up bread or pasta or eat endless sticks of celery. As far as I was concerned, life was too short. Until, that was, last year.

I had been plagued by gout since 1993, and the pain the condition was causing in the big toe of my right foot was agony. I went to see a specialist and his message was blunt.

He told me that my weight – 16st 6lb – was far too much for my 6ft frame, and that unless I lost weight I would soon lose my big toe.

It was a real wakeup call.

For the first time in years, I was forced to take a long, hard look at myself. I realised that my sedentary life as a solicitor, the long hours and obligatory client lunches, had taken their toll.

Far from being the slim and sporty man I had been in my 20s, I was now quite seriously overweight, and facing the prospect of having a toe amputated at the age of 42.

I’m a man of extremes and I never do things by half. I resolved there and then to do something about my predicament. I reasoned that, as I am so busy during my working day, the easiest way to cut back on food would be to skip breakfast and lunch – and eat only in the evenings.

MY FRIENDS, family and colleagues were all aghast.

They quoted studies at me that breakfast was the healthiest meal of the day. They even told me research showed that people who skipped breakfast were fatter than those who ate a proper meal.

I was undeterred. It seemed to make sense to me, and I decided to do my own thing.

Until my radical diet, I would always have a good breakfast before I left the house – a big bowl of cereal or a couple of eggs and toast.

At lunch, I’d have soup and a sandwich, crisps and some fruit. In the afternoon, I’d think nothing of eating a few chocolate bars to keep me going until my evening meal.

Overnight, I gave all this up.

I simply ate as much as I wanted once a day – usually around 9pm. But I have never counted a single calorie.

I admit I found the diet hard to begin with. For the first few weeks, by lunchtime I found my concentration lagging and I’d have to have a biscuit to ease my gnawing hunger. But I soldiered on – and soon I felt my body was used to my new way of eating.

Each night, I would look forward to eating as much as I wanted. I’d devour a good homecooked meal – often fish or a steak with a huge salad or a big bowl of pasta, several sandwiches, a couple of fried eggs for good measure, a couple of bowls of cereal, and some fruit.

I’d often go to bed so full that my stomach was distended. But the amazing thing was I would sleep better than I used to and wake up feeling great. And soon, incredibly, the weight began to drop off me.

In August last year – four months after my diet began – my weight was down to 13 stone. I’d lost three-and-a-half stone and I felt like a new man.

My gout felt much better and I had much more energy.

Rather than huffing and puffing my way around the garden with my young children, I now had plenty of energy to play football with them. I even bought a bicycle and now cycle 30 miles a week during summer.

I’ve continued to eat this way ever since and still feel fantastic. I haven’t put any weight back on and my gout has completely cleared.

However, my friends and family remained scathing until the latest diet research hit the headlines last week.

Dr Mark Mattson, from the National Institute on Ageing in Baltimore, has just completed a study into the benefits of skipping breakfast and lunch and eating just the one evening meal.

Earlier studies had already shown that rats who ate just every other day lost weight and lived longer than those allowed to eat as and when they liked.

Over time, it was found that they had eaten 30 to 40 per cent less food.

They also had lower blood pressure, clearer arteries and a lower risk of developing diabetes and cancer.

THE initial results from Dr Mattson’s study into what happens when humans fast by day and feast in the evening – just as I do – suggest it may be the key to losing weight, and bring similar health benefits to those experienced by the rats.

Dr Mattson claims the secret lies in our distant past: that our metabolism was set up when we were huntergatherers to expect a mixture of feast and famine.

It’s thought the diet works by coaxing the body into producing proteins and other chemicals normally released during short periods of stress such as exercise. These include compounds that protect brain cells from degeneration, and other cells from cancer.

I have to say I’m thrilled at the news – and not surprised in the slightest.

This diet has made me feel fantastic, and I finally feel as though everything I’ve been telling my friends and family has been vindicated.

I don’t pretend that my diet was ever based on any medical science, and I know that many nutritionists believe people who fast and then blow out overcompensate and end up eating more.

But I feel that, accidentally, I may have hit on the best way yet to not only lose weight – but improve your health to boot.

JOEL KORDAN hopes to bring out a book , called The Logical Diet, later this year.

WHEN pop singer Darius Danesh discovered his father had terminal cancer, he prepared for the worst. But incredibly, 17 months later Booth Danesh, 63, a surgeon who lives in Glasgow with his GP wife Avril, 48, and their younger sons Aria, 20, and Cyrus, ten, is in full remission. Here Darius, 24, who rose to fame in the TV series Pop Idol, tells TESSA CUNNINGHAM the story of his father’s recovery

SITTING beside my father at home in Glasgow on Father’s Day in June I got out my guitar and to the tune of Happy Birthday I sang a song especially for him.

It may sound hopelessly soppy but, although I’ve always adored my father, I never knew just how much he mattered to me until I was faced with losing him.

The past 17 months have been the most devastating time not just for Dad, but for the entire family. When my father was diagnosed with Non-Hodgkin’s lymphoma in February last year we were told he had three months to live.

Just 12 months ago he was so frail, his heart actually stopped beating – yet he is now in remission and getting fitter every day.

The tumour which was once the size of a large orange, has completely disappeared.

His eyes sparkle and his skin, which was once paper-thin, is now fresh.

Just recently he’s had the strength to go swimming again – an amazing milestone.

Not surprisingly Dad – a leading surgeon specialising in the digestive system – is utterly convinced that the powerful combination of chemotherapy and radiotherapy gave him a fighting chance against the cancer.

BUT given that Dad’s a leading surgeon, it may surprise people to learn that he believes it was complementary therapies such as meditation, acupuncture and reiki that helped him win the final battle. Without them, he doubts he would still be alive.

He believes these treatments gave him the psychological strength he needed to carry on fighting the cancer when complications left him so weak he almost lost the will to go on.

Dad first started feeling ill in late 2002. As a gastroenterologist at Glasgow’s Stobhill Hospital, he was under huge pressure and working incredibly long hours. Ironically, like many doctors, he put his own health way down his list of priorities. It almost cost him his life.

He felt permanently exhausted. Then he began having flu-like symptoms – cold sweats and shivers. At first he thought he had a virus. After a few months he began getting pain in his hip. He put it down to arthritis.

My mother, who’s a GP, urged him to get a second opinion. But doctors always think they can cure themselves.

Although my father was dealing with sick people virtually every day, he believed it would never happen to him.

Finally, after suffering for about nine months, he went for a check-up. By that stage the cancer in his lymph glands was well advanced. But even so it was missed. He didn’t even have a scan. Instead, Dad was told he had arthritis and was offered physiotherapy.

But things still weren’t right and he was feeling so exhausted as a result of the undiagnosed cancer that he decided to take early retirement.

Then in February 2004, Dad was at home alone when he collapsed. When he came to, he rang Mum at work. As soon as she got home she realised something was terribly wrong and drove him straight to hospital. A body scan revealed the devastating news.

Dad had lymphatic cancer.

It was 18 months since he’d first started feeling unwell, and the cancer had gone undetected for so long it had spread from the lymph glands – the drainage system for the body – to his spine and bone marrow. He had a tumour in his pelvis the size of a large orange.

At the time this was happening, I had just celebrated seeing my album, Dive In, go platinum and was back in Scotland at the end of a world tour. I walked into the kitchen that evening and when I saw Mum and Dad huddled at the table, I knew instantly something was terribly wrong.

Dad told me and my brother Aria outright. He had cancer and it was terminal.

Although he broke the news more gently to my younger brother Cyrus – who was just nine – Dad realised there was no point in pretending. We’re not that sort of family.

But, however gloomy the prognosis, right from the start Dad was determined to stay positive. He said: ‘I’d rather die fighting than give up now.’ He’s been through so much in his life. The son of a Persian diplomat, he was brought up in a palace in Iran.

But, in the Iranian revolution, his family lost everything. He came to Britain in the Sixties to study medicine and after he qualified, he met Mum in Glasgow. They’ve been married for 26 years.

We’re a close-knit family and we were all determined to help him. Our way of rescuing Dad was to show him every ounce of love and support. He needed all his energy to deal with the cancer.

Ironically, in the months that followed, he was more of a support to us than we ever were to him. Aria, who was at medical school, decided to put his studies on hold. There was no way he could concentrate properly. I was due to record an album, but I pulled out. Luckily my management company understood completely.

Within a week of his diagnosis, Dad started his treatment at London’s Royal Marsden Hospital, one of the world’s leading cancer hospitals. He was pleased to discover that one of the top oncologists was a former student of his from 15 years ago.

But even they couldn’t offer more than a glimmer of hope.

Dad never slept a night alone. Mum, Aria or I were always with him. Cyrus – who was still at school – lived with friends in Glasgow, flying down at weekends.

The cancer was too advanced to operate on. Instead, Dad was started immediately on a powerful course of chemotherapy.

The drugs – meant to kill off cancer cells – ravaged his body. He had been 15st, but within three months he was down to 11st and too weak to leave his bed. My dad has always been a powerhouse. Now he was frail and his skin was paper-thin. He lost all his hair.

DAD had been told he had three months to live.

Doctors didn’t dare hope the chemo would destroy the cancer, but they hoped it might buy him extra time. When he passed that milestone in May last year, we were all stunned – and ecstatic.

The tumour had shrunk to the size of a walnut.

Dad had huge doses of chemotherapy and radiotherapy, staggered over six months – from February to August 2004. At one stage he was so weak, he clinically died.

It was July 2004 and his body was so ravaged by the drugs his heart stopped beating for a minute. I was holding his hand when it happened. Then, there was the faintest flicker. He was back.

For my birthday last August, Mum, Aria, Cyrus and I all gathered around Dad’s bed with a little cake. He looked so proud. ‘Every morning I wake up and the first thoughts are of my children, not of my life,’ he said. ‘I’ve lived my life. I’m not living for me any more.

I’m living for you.’ As a surgeon himself, Dad put his complete faith in the doctors. He has always believed that conventional medicine provides scientific answers.

But that didn’t stop him being openminded. He was convinced the more he knew about cancer and its treatment, the better chance he had – mentally and physically.

In the first few months, he was far too weak to read books on alternative therapies or research the internet himself so we did it for him. Mum, Aria and I read every scrap of literature on medical science and complementary therapies. My mother practises homeopathy and my aunt is a reiki master so we knew a little already.

I was hugely impressed by the story of one woman who was diagnosed months there. At Christmas the doctors said officially that his cancer was in remission. Last month, a scan confirmed he was free of cancer. Now Dad is writing a book about his experience. He has spent the past five months travelling around America – talking to experts in both conventional and complementary medicines.

with inoperable stomach cancer.

She believes she survived through the power of meditation.

It’s very simple. She believed that the cells in our body become flooded with toxins when we’re under stress or have a bad argument and replicate abnormally and this can trigger the start of illnesses, including cancer.

Although many experts would dispute this because there is not enough proof, it made sense to me.

Meditation – and many other complementary medicines – may work by reducing this stress and encourage the growth of healthy, non- cancerous cells. An American study funded by the U.S.

government, and published in the American Journal of Cardiology, found that of 202 elderly people, those who had practised transcendental meditation had 49 per cent fewer deaths from cancer.

In July, with the full support of his doctors, Dad started a series of complementary therapies. My aunt came in regularly to give him reiki sessions. It’s a hands-on healing technique developed in Japan in the 1900s.

Reiki practitioners believe they can channel the patient’s natural energy to destroy energy blockages and get the whole body working in harmony.

He also had acupuncture, where needles are used to stimulate and heal different parts of the body.

Studies of patients given acupuncture for cancer pain have shown that half of the patients reported a relief in symptoms within a week. More research showed it helps alleviate the nausea caused by chemotherapy.

Dad also tried aromatherapy – a holistic treatment to relieve pain and stress – meditated and practised techniques which help you think positively.

By October, he was well enough to leave hospital after nine He always believed passionately in the power of science. But while the drugs definitely killed the cancer, he feels that without complementary medicine he wouldn’t be here.

He has seen cancer patients lose the will to live and says there were times he also felt so weak that he almost gave up the mental battle to carry on a physical fight. But the complementary therapies gave him an inner strength.

He also found acupuncture helped relieve terrible pains in his legs and bones.

Lymphatic cancer is one of the fastest growing in the UK. It’s increasing by 7 per cent every year and is the most common cancer among the under-30s.

Around 1,400 new cases are diagnosed every year. Yet while women know about examining their breasts and men are now encouraged to check for signs of testicular cancer, few people have even heard of lymphatic cancer – let alone know what to look for.

Telltale signs are swelling in the armpit, neck or groin, night sweats and exhaustion.

Since Dad was diagnosed, I’ve become involved with the Lymphoma Association.

I believe in raising awareness not just of the cancer – but of the help that’s available. It’s not just about dealing with the cancer physically, you’ve got to deal with it mentally, too.

That’s why charities such as the Lymphoma Association, which provide buddy schemes for sufferers are so vital.

I almost lost my Dad. If I can stop just one other son going through the same pain, it will be worth it.

NON-HODGKIN’S LYMPHOMA – THE FACTS

LYMPHOMA affects the cells of the lymphatic system, known as white blood cells or lymphocytes.

These infection-fighting cells aremade and stored in the lymph nodes and carried through the body by narrow tubes similar to blood vessels, known as lymph vessels.

There are two types of cancer – Hodgkin’s and Non-Hodgkin’s – both named after Dr Thomas Hodgkin who first identified the disease in 1832.

Hodgkin’s lymphoma more often occurs between the ages of 15 and 35 and affects more men than women. It can be successfully treated and most patients will be completely cured.

Non-Hodgkin’s is now the seventh most common cancer in the UK, with more than 8,000 cases being diagnosed each year. It is more common in people over 50 and affects more men than women.

In Non-Hodgkin’s, the lymphocytes start to behave like cancerous cells and grow and multiply uncontrollably. They can collect in the lymph nodes – for example, in the neck or groin – which then become swollen.

But, because lymphocytes circulate throughout the body, collections of abnormal lymphocytes often form outside the nodes too, spreading to the liver and other organs and tissue.

There are more than 20 different types of Non-Hodgkin’s lymphoma, varying in degrees of severity. Treatment includes chemotherapy, radiotherapy, bone marrow and stem cell transplants.

Symptoms include painless swelling of a node in the armpit, neck or groin; extreme fatigue; night sweats; loss of appetite and unexpected weight loss.

THE Lymphoma Association offers emotional support and information to patients and their families and friends. Contact 0808808 5555 or www.lymphoma.org.uk

NEW YORK (Reuters Health) – Conventional walking is good
for older adults, and walking on a synthetic mat embedded with
smooth stones is even better, researchers have shown.

Walking on the so-called cobblestone mat improves physical
function and reduces blood pressure to a greater extent than
regular walking, according to findings published in the Journal
of the American Geriatrics Society.

The idea is that the stone surfaces stimulate acupoints on
the soles of the feet, which “elicit therapeutic responses that
may contribute to health aging.”

To look into this, Dr. Fuzhong Li, of the Oregon Research
Institute, Eugene, and colleagues compared the effects of
cobblestone mat walking with regular walking in 108 adults who
averaged 77.5 years in age. They were physically inactive but
free of neurological and mobility-limiting orthopedic
conditions.

The subjects participated in 60-minute group exercise
sessions of cobblestone mat walking or regular walking three
times per week for 16 weeks.

“Compared to the control condition of regular walking,
walking on the uneven, bumpy river-rock like surface of these
mats brought about health-related outcomes of reduced blood
pressure … as well as improvements in selected measures of
balance and physical function (reach, standing and rising from
a chair, and walking speed) in our sample of older adults,” Li
told Reuters Health.

“Since hypertension is a major risk factor for
cardiovascular disease and stroke, the outcomes have potential
for improving the overall heart health of many people who may
be at risk for cardiovascular disease,” Li noted.

While cobblestone mat walking was effective, he said, “it
must also be said that regular walking was also beneficial to
the walkers, and must continue to be a wonderful and popular
form of exercise for people of all ages.”

Future research “might explore the potential for this
exercise modality on patients with higher blood pressure levels
than our participants,” he added.

In addition, “it would be interesting to explore the
mechanisms … that might help to explain the reasons why foot
stimulation influences blood pressure, balance, and functional
performance of older adults.”

SOURCE: Journal of the American Geriatrics Society, August
2005.

And Why It Affects So Many Blacks

ITS victims are usually young and full of vigor. Their cases run the gamut from mildly irritating to life-threatening. The inflammatory disease is sarcoidosis, a systemic condition that can affect every organ in the body, although it most often begins in the lungs.

Sarcoidosis has puzzled doctors for years , specifically its prevalence among African-Americans. The mysterious disease, which often affects the lungs, has victimized actor/comedian Bernie Mac (top, right) and doctors say it contributed to the death of NFL All- Pro Reggie White (bottom, right).

African-Americans, along with Swedes and Danes, have the highest rates of sarcoidosis in the world, according to the American Lung Association. Black women are victimized twice as often as Black men, and Blacks are also more likely to have more severe, chronic symptoms than Whites. And although deaths from the disease are rare, the mortality rate among Blacks is more than 16 times that of Whites.

In December 2004 sarcoidosis sufferer and NFL great Reggie White died at age 43. Medical experts believe sarcoidosis contributed to his death. Earlier this year comedian and actor Bernie Mac revealed that he’s had the disease since 1983, and basketball legend Bill Russell and his daughter Karen Russell are both battling the mysterious disease.

Sarcoidosis (pronounced SARKOI-DOE-SIS) can appear in almost any organ in the body, although the inflammation of the body’s tissues can begin in any organ and usually affects more than one organ.

The disease, which most commonly strikes young adults between the ages of 20 and 40, is a puzzling one, with no known cause and no cure.

“Most of the patients are young and this works to their disadvantage,” says Dr. Talmadge E. King Jr., chief of medical services at San Francisco General Hospital and a fellow of the American College of Chest Physicians. “Patients often develop intense fatigue, and because they are so young, doctors tend not to believe them.”

In fact, many patients complain that the disease is often routinely misdiagnosed. “The disease is often diagnosed serendipitously,” Dr. King adds, “through a chest x-ray or routine physical exam.”

For instance, it took more than a year to properly diagnose Dr. Marsha Thornhill’s sarcoidosis-and she is a physician. A former marathon runner, she says she knew about fatigue-both from finishing a long race and from staying up all night as a resident on-call. “This kind of fatigue [associated with sarcoidosis] is indescribable and immobilizing,” she says. “It’s like trying to come up out of quicksand. You never feel refreshed, even after rest.”

Sarcoidosis has puzzled doctors for years, specifically its prevalence among African-Americans. The mysterious disease, which often affects the lungs, has victimized actor/comedian Bernie Mac (top, right) and doctors say it contributed to the death of NFL All- Pro Reggie White (bottom, right).

And because she was in such good physical shape, her physicians initially attributed her fatigue to a stressful workload. Although she was diagnosed in 2001 with multisystem sarcoidosis manifesting in very severe symptoms, her physicians now believe she may have had the disease anywhere from a year to 16 years prior to the 2001 diagnosis.

The 43-year-old New Jersey anesthesiologist says the frustration associated with getting a proper diagnosis motivated her to become more involved with helping sarcoidosis patients. “If this could happen to a physician in a major metropolitan area where we have access to the best care, [it could happen anywhere],” she says. She credits thoracic expert Dr. King with saving her life. “If it wasn’t for him, I wouldn’t be here right now,” she says.

Open and honest communication between doctor and patient is a vital key to managing this disease, patients say. Andrea Wilson, founder of the Foundation for Sarcoidosis Research (FSR) in Chicago, has a virulent and potentially life-threatening form of the disease. She was first diagnosed in 1994, after eight years of battling perplexing symptoms. “They said I had multiple sclerosis, a brain tumor, inner-ear issues-just about everything under the sun,” she says. “Finally I was lucky enough to get a doctor who was savvy enough to go the extra mile and order a chest x-ray that showed dramatic inflammation in both lungs.”

After a brief respite from the disease, during pregnancy with her now 10-year-old daughter, “all hell broke loose” as the disease returned with a vengeance, and she was told bluntly by one physician to “go home and get your affairs in order.” At that time she had a 2- month-old daughter at home, and she says she literally got up and walked out of his office. “I was mad as hell,” she says now. Frustrated with the lack of knowledge about the disease, both in the medical and patient communities, she and her investment banker husband, Reading Wilson-who took a year’s leave of absence from his job-formed the FSR in 2000. Their mission is twofold-to find the causes of and the cure for sarcoidosis, and to take care of the patients.

NBA Hall of Famer Bill Russell and his daughter Karen are among the African-Americans who are affected by sarcoidosis. Dr. Talmadge E. King Jr. (below) says the disease is puzzling.

“Unfortunately, we get too many memorials-Reggie White and sportscaster Darrian Chapman, here in Chicago, died of sarcoidosis.” FSR, she says, is the only privately funded organization funding groundbreaking research in sarcoidosis. To date, the organization has raised almost $1 million and funded six research projects, while partnering with the American Thoracic Society.

Wilson says former Boston Celtics star and Hall of Famer Bill Russell and his daughter have filmed a series of public service announcements for the group. Russell, who has sarcoidosis in his lungs, is championing this cause and working to raise awareness of the devastating disease.

Another advocate, Paula Yette Polite of Memphis, Tenn., says things have improved since her initial diagnosis in 1981 when she was in her early 20s. “It was five years from my diagnosis before I met anyone who had this disease,” she says. “There were no patient organizations at that time.” Polite has no internal organ involvement; her problems are limited mostly to her skin and joints. However, she says the numbing fatigue and side effects from prednisone, a corticosteroid drug treatment generally used to treat sarcoidosis, have dramatically affected her quality of life.

Once active and outgoing, the divorce now she has to conserve her strength, working part-time to care for her 9-year-old daughter Adira. In 1991, she formed a patient education association to focus on “patient education and public awareness.”

Some signs and symptoms of sarcoidosis include fever, fatigue, weight loss, night sweats, small red bumps on the face, arms or buttocks (more common in Blacks than in Whites), red, watery eyes, arthritis in ankles, elbows, wrists and hands.

Physicians say the lungs are affected in more than 90 percent of sarcoidosis patients. A persistent cough and shortness of breath, particularly with exertion and chest pain, are prominent symptoms.

With this disease, Dr. King says, fatigue and chest pain are additional common symptoms that first send patients to a physician. Because these symptoms can mimic other diseases, doctors often use blood tests, chest x-rays, breathing tests and biopsy to diagnosis sarcoidosis.

Self-care is important when battling a chronic disease. Physicians and patients offer the following recommendations to facilitate living with sarcoidosis: Find a doctor you can communicate with. Polite and others recommend one central doctor- usually an internist-to coordinate the many specialists involved in sarcoidosis treatment; have your eyes examined every year, Dr. King says, because severe visual impairment or blindness can be side effects of the disease; keep a journal to record treatments, medications and how your body responds to the disease; exercise and therapeutic massage have been helpful to some patients; developing and/or maintaining a strong spiritual relationship helps buoy patients to fight the disease, experts say; maintain a strong support system. Along with family, friends and loved ones, a number of organizations and support groups exist to help people cope with sarcoidosis.

Despite the mysteries surrounding sarcoidosis, researchers are making significant progress in finding a cure, experts say. Wilson says her scientific advisory board is currently reviewing the results of some “very exciting and groundbreaking” research that will be revealed later this year. “We do have a way to go,” she says, “however, it’s a very exciting time.”

-Joy Bennett Kinnon

Copyright Johnson Publishing Company Aug 2005

Jul. 31–After years on the fringe of the healthcare industry, sought after only by the desperate, discount medical plans may be gaining a toehold on respectability.

Twenty-four have made it through the arduous licensing process the state of Florida started requiring this year. Even Aetna and UnitedHealth Group have entered the field, which has been beset in the past by accusations of fraud and misrepresentation.

Though far from ideal, these plans may seem attractive to the estimated 60 million Americans who either have no health coverage or are underinsured. In Miami-Dade and Broward, about 750,000 have no insurance. More than 20 million persons nationwide may now be carrying these cards.

“With health insurance costs so very high and getting higher, the need for these plans is huge and growing,” says James Quiggle of the Coalition Against Health Fraud.

The theory behind the plans is simple: For a monthly fee that’s usually $30 to $70, a person gets discounts for doctor visits and drugs that might range from 15 to 50 percent. In most cases, consumers must pay in cash when services are rendered to get the deal.

A Herald survey of plans offered in the state found some significant discounts, though there are still glitches with some cards. Deals with hospitals remain at best problematic, at worst nonexistent.

Under the new law, discount plans sold in Florida must now say clearly in all their literature that they are not insurance. They are also required to post on a website a full list of providers that accept their discount cards so that shoppers can select a doctor who will accept a plan before they sign up for it.

The law is intended to correct past problems because many plans hinted they were insurance when they weren’t, and consumers often had to sign up for a discount plan before they were given a network list — which many found was filled with doctors who said they had never heard of the card company.

“We’re very pleased the state has stepped in,” says Richard Keelor, president of MedMore, a Miami-based discount plan. The state application ends up being a three-inch document that can cost $50,000 or more in legal and advisory fees to complete. “The ones that remain are serious players,” Keelor says. “It got rid of all the rift-raft.”

Still, experts are concerned. “Consumers need to be extremely cautious,” says Quiggle of the Coalition Against Health Fraud. “The states are having a hard time staying on top of scams.”

Concerned about such an image, some of the larger discount plans have formed a trade group with a code of conduct that includes many provisions of the Florida law.

“Florida has been a leader in the cause,” says Barry Friedman of AmeriPlan USA, a Texas-based discount plan, which supports regulation to weed out bad plans.

Two big insurers are entering the market on its fringes. Aetna has registered in Florida because it offers a discount dental plan for employers who have Aetna health coverage but don’t include dental, says spokesman Walt Cherniak.

UnitedHealth Group, meanwhile, became involved by purchasing Health Allies, a California company that has 8.7 million members nationwide. The company lists some physicians and hospitals in its network, but its primary focus is on areas not generally covered by insurance, including LASIK eye surgery, vision exams, dental work, weight loss programs, gym memberships and infertility treatments.

One Health Allies card is available through Sam’s Club outlets for $8.75 a month. “The intent here is make your healthcare dollar go farther,” says spokesman Daryl Richard.

Many of the large, Texas-based companies started out as dental discount plans, and for some it remains their primary strength. Careington International, for example, offers a dental plan for $7.95 a month for an individual, $13.95 for a family. Through AmeriPlan, basic cleaning can cost $20 and braces are available at 25 percent off.

South Florida companies are attempting to compete with the big players. MedMore, which reports it has 3,000 members, offers multiple options. One plan costs $30 a month for the basic medical service for families; $29.95 for pharmacy discounts and $63.31 for hospital indemnity insurance. The company provides subscribers with a book listing specific discounts and prices. Some doctors, for example, are shown to charge MedMore members $45 for a basic office visit.

Still, consumers need to call up to verify. The Herald tried four doctors’ offices in the book. Two said they accepted MedMore for discounts, one said they had never heard of it and another said it didn’t know but if its name was in the book, “come on in.”

One happy MedMore customer is Nora Marrero, a hostess at Larios restaurant on South Beach. She pays $7.52 a month for the card, with her employer picking up the rest. When she needed a colon scan, the MedMore card knocked the price down from $500 to $225. “This is a good plan,” she says.

Another South Florida plan, Cinergy Health, charges families $59.95, including pharmacy discounts. “We separate ourselves from most plans,” says founder Daniel Touizer, “because we will do a lot of the legwork.” Cinergy volunteers to make the first appointment with a doctor, to make sure that they will accept the discounts.

Pro Medical Plan, based in Plantation, charges $48 a month for an individual to access a network of 100 South Florida providers. Doctors have agreed to fixed fees, and owner Jose Volosin says he has contracts with 15 urgent care centers to treat a patient for a lump sum of $80 to $120.

Florida Health Solution, based in western Miami-Dade, has already been serving a mostly Hispanic clientele of 10,000 for three years. It charges $29.95 a month per person and contracts directly with physicians for office visits as low as $20 and blood tests for $5.

FHS President Marcos Socorro says he has also worked out arrangements to get discounts from local hospitals, including Kendall Regional. Peter Jude, spokesman for the hospital, says it has no contract with FHS, but works out discounts for its members.

Hospitals, the most expensive part of healthcare, are generally a problem for discount plans. Though major insurers have contracts with hospitals in which they pay a third or less of gross charges, hospitals have been generally reluctant to offer discounts to the uninsured.

—–

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Copyright (c) 2005, The Miami Herald

Distributed by Knight Ridder/Tribune Business News.

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UNH,

Oak Brook, IL, Aug. 1, 2005 ““Women may be avoiding colon cancer screening because of the gender of their doctors, even though colon cancer causes a higher percentage of deaths among women each year in the United States than those women diagnosed with breast cancer.

In a study conducted by researchers at the Division of Gastroenterology, University of Michigan, Ann Arbor, and published in the current (August) issue of Gastrointestinal Endoscopy (GIE) by the American Society for Gastrointestinal Endoscopy (ASGE), 43% of the women who were asked their preference of a male or female endoscopist said female, while only 1.4% said male and the rest had no preference.

When asked questions to further gauge how strongly those who preferred a woman physician felt, 87% of this group said they would be willing to wait 30 days for a female endoscopist and 14% would be willing to pay more (up to $200) to have the procedure done by a female endoscopist. Five percent stated that they would not undergo a colonoscopy unless they were guaranteed it was performed by a female endoscopist.

The research results were collected through a self-administered questionnaire given to 202 women who were awaiting primary care appointments at four outpatient facilities at the University of Michigan Health System in Ann Arbor. The female respondents were 40-70 years old, 85% Caucasian, 70% married, 99% high school graduates, 49% held college or advanced degrees, 57% were employed, 21% retired, and over half had a gross annual household income of greater than $60,000.

Having a female primary care physician (PCP) was a positive independent predictor for preferring a female endoscopist. Of the women who preferred a female endoscopist, 69% had a female PCP, 27% had a male PCP and 4% did not respond to the question.

According to Stacy Menees, MD, lead author of the study, the research shows that the primary reason listed for a female gender preference was that it would make the procedure less embarrassing (75%). Fifty percent also felt that the same gender was more empathetic, while 36% listed women as “better listeners” as a reason and 20% marked “technically better” as a reason to prefer a female physician to administer the colon cancer screening test.

While this study corroborates earlier studies in other specialties that women prefer female physicians, this is the first study to demonstrate female endoscopist preference among women in the primary care setting, as opposed to female patients awaiting endoscopy procedures, said Dr. Grace Elta of the study team.

“This study has important implications for future prevention and educational programs for colorectal cancer,” the research team stated in the report. “Programs targeting the female population should consider concordant gender preference for an endoscopist as a barrier to screening. A choice in gender of the endoscopist may help to increase adherence to colonoscopy among women.”

“The number of women enrolled in medical schools and residency programs in the U.S. has risen dramatically over the past several decades, with women making up more than 50% of enrolled medical students and 25% of practicing physicians,” the report says.

However, the current number of female physicians practicing gastroenterology only represents approximately 8% of the total, based on membership in the ASGE. In addition, females only occupy 16% of the GI fellowship positions today, so it will present a dilemma for some time to those women who prefer having a female physician to conduct their cancer screening tests.

“Colon cancer has an equal incidence between men and women,” stated Blair Lewis, MD, Clinical Professor of Medicine, The Mount Sinai Medical Center, New York, and an ASGE spokesperson. He explained that the total number of new colon cancer cases, according to the American Cancer Society’s Annual Report, is 145,290, of which 73,470 (50%) are women. The total colon cancer deaths are 56,290, of which 27,750 (49%) are women. For breast cancer, new cases in women are 211,240 and annual deaths are 40,410 (19%).

“So while breast cancer is more than twice as prevalent, a higher percentage of women die of colon cancer each year,” Dr. Lewis stated. “That is why colon cancer screening is so important for both men and women over 50 years old.” Currently, only 43.4% of the population has had a lower gastrointestinal endoscopy within the last 10 years, according to The Behavioral Risk Factor Surveillance System (BRFSS).

Colorectal cancer is the third most commonly diagnosed cancer in men and women and the second leading cause of cancer-related deaths in the United States and Western Europe.

“Early detection of colon cancer and, more importantly, the identification and removal of polyps that ultimately could become cancers can decrease the mortality for this disease,” stated Dr. Elta.

On the World Wide Web:

American Society for Gastrointestinal Endoscopy

Parabens are a group of the alkyl esters ofp-hydroxybenzoic acid and typically include methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, isopropylparaben, and benzylparaben. Parabens (or their salts) are widely used as preservatives in cosmetics, toiletries, and pharmaceuticals due to their relatively low toxicity profile and a long history of safe use. Testing of parabens has revealed to varying degrees that individual paraben compounds have weakly estrogenic activity in some in vitro screening tests, such as ligand binding to the estrogen receptor, regulation of CAT gene expression, and proliferation of MCF-7 cells. Reported in vivo effects include increased uterine weight (i.e., butyl-, isobutyl-, and benzylparaben) and male reproductive-tract effects (i.e., butyl- and propylparaben). However, in relation to estrogen as a control during in vivo studies, the parabens with activity are many orders of magnitude less active than estrogen. While exposure to sufficient doses of exogenous estrogen can increase the risk of certain adverse effects, the presumption that similar risks might also result from exposure to endocrine-active chemicals (EACs) with far weaker activity is still speculative. In assessing the likelihood that exposure to weakly active EACs might be etiologically associated with adverse effects due to an endocrine- mediated mode of action, it is paramount to consider both the doses and the potency of such compounds in comparison with estrogen. In this review, a comparative approach involving both dose and potency is used to assess whether in utero or adult exposure to parabens might be associated with adverse effects mediated via an estrogen- modulating mode of action. In utilizing this approach, the paraben doses required to produce estrogenic effects in vivo are compared with the doses of either 17 β-estradiol or diethylstilbestrol (DES) that are well established in their ability to affect endocrine activity. Where possible and appropriate, emphasis is placed on direct comparisons with human data with either 17 β-estradiol or DES, since this does not require extrapolation from animal data with the uncertainties inherent in such comparisons. Based on these comparisons using worst-case assumptions pertaining to total daily exposures to parabens and dose/potency comparisons with both human and animal no-observed-effect levels (NOELs) and lowest-observed- effect levels (LOELs) for estrogen or DES, it is biologically implausible that parabens could increase the risk of any estrogen- mediated endpoint, including effects on the male reproductive tract or breast cancer. Additional analysis based on the concept of a hygiene-based margin of safety (HBMOS), a comparative approach for assessing the estrogen activities of weakly active EACs, demonstrates that worst-case daily exposure to parabens would present substantially less risk relative to exposure to naturally occurring EACs in the diet such as the phytoestrogen daidzein.

Keywords Breast Cancer, Endocrine Active Chemicals (EACs), Estrogen, Male Reproductive-Tract Effects, Parabens, Risk Assessment

INTRODUCTION

The objective of this review is to assess the potential endocrine activity of paraben compounds that are commonly used as preserving agents and whether they pose any risk to human health. The issue of environmental endocrine-active chemicals (EACs) and whether exposure to such chemicals might adversely affect human health is a subject of intense debate. The basis for the discussion hinges on the issue that while chemicals may mimic some types of activity demonstrated by the naturally occurring hormone estrogen, the magnitude of activity (i.e., potency) is substantially lower and the potential to result in an adverse effect mediated via an estrogen mode of action has not been established in humans. There is no question that exposure to sufficient doses of high-potency exogenous estrogen, either in utero (e.g., diethylstilbestrol, DES) or from adolescence into adulthood (e.g., oral contraceptives, hormone replacement therapy), can increase the risk of deleterious effects. However, the presumption that similar risks might also result from exposure to other chemicals such as EACs with far weaker estrogenic activity is still speculative. In particular, it has been hypothesized that in utero exposure to weakly EACs might be associated with a range of adverse effects on the developing fetus, including reproductive- tract abnormalities in males and increased risk of breast, testicular, or prostate cancer later in life. In reviewing this issue, the U.S. Environmental Protection Agency (U.S. EPA, 1997) noted that “With few exceptions (e.g., DES), a causal relationship between exposure to a specific environmental agent and an adverse effect on human health operating via an endocrine disruption mechanism has not been established” (p. 6).

Due to the fact that both endogenous estrogen (e.g., 17β- estradiol) and exogenous estrogen (e.g., DES) are established risk factors for a range of adverse outcomes, it is prudent to consider whether exposure to exogenous chemicals with substantially weaker estrogenic activity might also have similar effects. In attempting to address this complex issue, it is not sufficient to simply demonstrate that a particular chemical has either in vitro or in vivo estrogenic activity, but rather to consider how this activity compares to the estrogenic activity (i.e., potency) in humans of 17β-estradiol, DES, or phytoestrogens. In addition, the absorption and metabolism of these compounds are also important. Because the effects resulting from in utero and postnatal exposure to estrogen have been well studied in both animals and humans, there is a broad database from which to judge the likelihood that weak EACs might have similar effects in humans.

In this review, a comparative approach involving both dose and potency is used to assess whether in utero or adult exposure to parabens might be associated with adverse effects mediated via an estrogenic mode of action. In utilizing this approach, the paraben doses required to produce effects in vivo are compared with the doses of a known estrogenic compound (e.g., 17β-estradiol or DES) that are required to produce similar in vivo effects. In addition, exposure to parabens is also contrasted with exposure to weakly estrogenic phytoestrogens commonly found in foods. By comparing the potency of parabens with the established estrogenic potency of DES, 17β-estradiol, and several ubiquitous phytoestrogens, it is possible to assess the likelihood that exposure to parabens at typically used concentrations might be capable of causing adverse effects mediated via an estrogen mode of action.

FIG. 1. Structures of paraben compounds.

As illustrated in Figure 1, parabens are a group of alkyl esters of p-hydroxybenzoic acid and typically include methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, isopropylparaben, and benzylparaben, which are considered in this review. Parabens (or their salts) are widely used as preservatives in cosmetics, toiletries, and pharmaceuticals due to their relatively low toxicity (CIR, 1994, 1995; Soni et al., 2001, 2002).

Parabens are lipophilic compounds with increasing octanol/water partition coefficients (K^sub ow^, usually expressed as log K^sub ow^) and antimicrobial activity with increasing molecular weight and length of the alkyl side chain. The molecular weights and log octanol/water partition coefficients of the parabens are summarized in Table 1.

This review summarizes the in vitro data on the interaction of parabens with estrogen receptors in various screening assay cell culture systems, followed by a summary of in vivo data. This is followed by a critical assessment of whether parabens might be associated with increased risk of estrogen-mediated endpoints as a consequence of either in utero or adult exposure. The endpoints considered include adverse effects on the male reproductive tract from in utero exposure and breast cancer in women as a consequence of adult exposure.

TABLE 1

Molecular weights and log k^sub ow^ of parabens

Despite almost 10 years of concern about the potential effects to humans from exposure to EACs, there has been no official guidance on how to systematically assess potential risks. Several expert authoritative bodies have, however, concluded that the use of existing screening level assays is inappropriate for use in the hazard assessment characterization of endocrine modulating chemicals (CSTEE, 1999; SCCNFP, 2001; IPCS, 2002). Therefore, a methodology to assess potential risks from exposure to exogenous EACs must rely substantially on a comparative approach where effects are scaled in proportion to either estrogen or DES. While in vitro studies are rapid, relatively easy to conduct, and offer clear advantages in terms of their ability to screen large numbers of compounds, they suffer from an inability to account for critical in vivo metabolic processes. An obvious analogy would be with mutagenicity testing and carcinogenicity testing, with the former providing important insights into possible outcomes or modes of action and the later critical in confirming the correctness of preliminary observations.

The dilemma concerning how to assess the likelihood that exposure to EAC\s might be etiologically associated with adverse effects has been questioned. In 1993, Sharpe and Skakkebaek put forth the “estrogen hypothesis” as a biologically plausible explanation for an apparent increase in male reproductive tract disorders. They speculated that in utero exposure to a number of weakly estrogenic compounds could explain this phenomenon. In revisiting this hypothesis, Sharpe (2003) noted that “all of the identified ‘environmental estrogens’ possess weak or very weak intrinsic estrogenic activity when measured by conventional in vitro and in vivo assays for estrogenicity…. Based on estrogenic potency, human exposure to the most potent environmental estrogens would need to be at least 1000-fold higher than this level for adverse effects relevant to the human male to be induced, and such levels of exposure are remote” (p. 9). As demonstrated in the following review, because of their extraordinarily weak activity as measured by either in vitro or in vivo estrogen assays, it appears that parabens fall precisely into the category of compounds where extremely weak estrogenic activity and the lack of substantial exposure would lead to negligible potential for adverse effects.

POTENTIAL FOR ENDOCRINE ACTIVITY OF PARABENS

Parabens have been studied in a number of in vitro and in vivo systems that examine the estrogenic activity of these compounds. Both in vitro and in vivo data are valuable in assessing the likelihood that exogenous weakly estrogenic compounds might pose a risk to humans. In vitro screening data provide useful order-of- magnitude approximations between tested compounds and estrogen and also can determine the nature and extent to which substances interact with a hormone receptor, as well as solve mechanistic issues. On the other hand, only in vivo data can provide evidence of how hormonally active substances are influenced by absorption, distribution, metabolism and excretion in an intact animal. Consequently, a combined in vitro/in vivo approach is warranted to gain a complete understanding of the activities of the compound in question. Throughout this evaluation, whether derived from in vitro or in vivo data, potency comparisons between a tested paraben and the estrogen reference compound are noted. For in vitro data, magnitude comparisons are typically based on a comparison of the molar ratio of a tested paraben required to produce an equivalent effect (e.g., competitive binding to ERa in human MCF-7 cells) as the reference compound (e.g., estradiol). In the in vivo studies (e.g., Routledge et al., 1998) potency comparisons are based on the lowest dose of a tested paraben that produced a statistically significant effect (e.g., increased uterine weight) compared to the reference compound used in that study (e.g., 600 mg/kg/day butylparaben produced a significant uterotrophic effect compared to 0.04 mg/kg/day estradiol to yield a potency difference of 15,000). It should be noted that in making potency comparisons, particularly for in vivo effects, the evaluation must also consider the magnitude of the effect. For example, in the preceding illustration, 600 mg/ kg/day significantly increased uterine weight to 38.8 mg compared to 27.1 mg in controls. However, in the same experiment, uterine weight from an estradiol dose of 0.04 mg/kg/day increased uterine weight to 108.7 mg compared to 27.1 mg in controls. While not explicitly considered in the various comparisons presented in this review, it is important to keep in mind that this phenomenon actually provides an additional margin of safety over and above the wide margins derived later.

In Vitro Estrogenicity Data

Byford et al. (2002) studied the estrogenic activity of four parabens (methyl, ethyl, propyl, and butyl) and Darbre et al. (2003) the estrogenic-activity of benzylparaben in estrogensensitive MCF-7 human breast cancer cells. In addition to determining ligand ability to bind estrogen receptor (ER) a in a competitive binding assay, both studies also examined other aspects of estrogenicity including ligand ability to regulate an estrogen-responsive gene (ERE-CAT) transfected into MCF-7 cells, and ligand ability to regulate estrogen-dependent proliferation of MCF-7 cells. In the competitive binding assay, all parabens studied were at least 10,000 to 100,000 times less potent than 17β-estradiol. In MCF-7 cells with a stably transfected estrogen-regulated ERE-CAT reporter gene, the tested parabens showed effects similar to 17β-estradiol, although at 1000-10,000 times greater concentrations. These data are summarized in Table 2, which shows that, depending on the end-point measured and the specific paraben under study, these compounds are from 1000 to 1,000,000 times less potent than 17β-estradiol.

TABLE 2

Summary of in vitro potency data of parabens in MCF-7 cells

Routledge et al. (1998) studied the in vitro estrogen receptor (ER) binding activity of methyl-, ethyl-, propyl-, and butylparaben. In a competitive binding assay using rat ER, butylparaben was able to compete with [3H]estradiol with an affinity approximately five orders of magnitude less than diethylstilbestrol (DES). All of the parabens were positive (i.e., estrogenic) in a yeast estrogen screen (E-screen) with potency in the order butyl > propyl > ethyl > methyl; the main paraben metabolite/>hydroxybenzoic acid (PHBA) was inactive in this assay. Methylparaben was the weakest, with a potency approximately 2,500,000 less than 17/S-estradiol, while the other parabens were several orders of magnitude more potent than methylparaben.

In an extensive assessment of the estrogenic properties of parabens, Okubo et al. (2001) studied the ER-dependent activity of methyl-, ethyl-, propyl-, butyl-, isopropyl-, and isobutylparaben in human breast cancer MCF-7 cells and binding affinity for human ERa and ERβ. In MCF-7 cells, the relative proliferative potency (RPP) of isopropyl- and isobutylparaben (the most potent of the compounds tested) was approximately 170,000 times lower than 17β-estradiol; the RPP of the other parabens were one to two orders of magnitude less than isopropyl- or isobutylparaben. The relative binding affinity (RBA) of parabens for human ERa and ERβ was determined with DES as a positive control. RBA values were greater for parabens with longer or branched side chains, although all were at least 1000 times less potent than DES. The RBAs for methylparaben were not calculated because the binding was so weak. The relative binding affinities to the two estrogen receptors are apparently similar (Okubo et al., 2001; Satoh et al., 2000). All of these reported effects were demonstrated to be related to the ability of parabens to interact with the ER, since the anti- estrogen ICI 182,780 inhibited their proliferative effects in a dose- dependent manner.

In a recombinant yeast assay, cells transfected with the human estrogen receptor (ERα) gene together with expression plasmids (containing estrogen-responsive elements) were incubated in medium containing benzyl-, butyl-, propyl-, ethyl-, or methylparaben to determine their estrogenic activity in comparison with estrogen (17β-estradiol) (Miller et al., 2001). There was a progressive increase in the estrogenic activity with increasing molecular weight with methyl-, ethyl-, propyl-butyl-, and benzylparaben, demonstrating relative responses of 1/3,000,000, 1/200,000, 1/ 30,000, 1/8000, and 1/4000 the potency of estrogen, respectively.

In a similar study, Blair et al. (2000) determined the in vitro rat uterine estrogen receptor RBA for methyl-, ethyl-, propyl-, butyl-, and benzylparaben in comparison with 17β-estradiol (RBA =1). The results of this study demonstrated increasing RBA values with increasing alkyl side-chain length with values of 0.0004, 0.0006, 0.0006, 0.0009, and 0.003, for methyl-, ethyl-, propyl-, butyl-, and benzylparaben, respectively. All of the preceding in vitro data demonstrate that whether compared to DES or 17β- estradiol, parabens are many orders of magnitude less potent based on several measures of estrogenic activity (i.e., ligand binding to or proliferation of MCF-7 cells, regulation of CAT gene expression or ligand binding to ERa or ERβ).

In Vivo Data in Female Animals

Many of the parabens that are the subject of this review have been tested for their in vivo effects in the immature or ovariectomized mouse or rat uterotrophic assay. The results of these assays more closely reflect the full spectrum of in vivo absorption, distribution, metabolism, and excretion. However, as described later, even with in vivo systems, there is some question concerning the biological relevance of subcutaneous dosing studies, since this exposure route may bypass important dermal metabolic processes. Ideally, the results of uterotrophic assays are presented as uterine weight and uterine weight normalized to body weight, and doses are provided as milligrams per kilogram per day. Because doses in the studies presented later were sometimes provided only as dose per animal (rather than per body weight), without providing body weights for each dose group, potency estimates are calculated by dividing the paraben dose/animal (or mg/kg/day dose) that caused an effect by the dose/animal (or mg/kg/day dose) of the study’s reference compound that caused an effect.

The topical application of benzylparaben to immature CD1 mice at a dose of 33 mg (equivalent to approximately 2500 mg/kg/day) produced a significant increase in normalized uterine weight compared to control, although this increase was only one third of that produced by 17β-estradiol at a dose of 100 ng (a potency difference of approximately 330,000) (Darbre et al., 2003). Similarly, subcutaneous injection of isobutylparaben in CDl mice at a dose of 12.0 mg (equivalent to approximately 720 mg/kg/day)* increased normalized uterine weight comparable to a dose of approximately 5 n\g of 17β-estradiol (a potency difference of approximately 2,400,000) (Darbre et al., 2002).

Lemini et al. (1997) reported that subcutaneously administered p- hydroxybenzoic acid (PHBA; the major metabolite of parabens) was estrogenic in both immature and ovariectomized mice as measured by increased cornification of vaginal epithelial cells and increased uterine weight. Compared with 17β-estradiol (1 g/100 g), PHBA demonstrated dose-dependent effects, with a dose of 500/g/100 g producing cornification that was almost comparable in both intact and ovariectomized animals. With respect to effects on uterine weight, in intact animals doses of PHBA of 5 and 50 g/100 g were essentially without effect while a dose of 500/ug/100 g produced an effect comparable to estrogen. The relative uterotrophic potency of PHBA with respect to 17β-estradiol was 1000 times less, as calculated by the authors using molar doses.

In contrast to the positive uterotrophic findings reported by Lemini et al. (1997) for PHBA, similar results were not confirmed by Hossaini et al. (2000) in either immature B6D2F1 mice or Wistar rats exposed to test compounds for 3 days. In this study, PHBA, methyl-, ethyl-, propyl-, and butylparaben were subcutaneously administered to mice at doses of 1, 10, and 100 mg/kg/day for 3 days.[dagger] No dose of PHBA or any of the parabens produced an estrogeniclike response in the mouse uterotrophic assay. Methyl-, ethyl-, and propylparaben also did not result in significant uterotrophic effects following oral exposure at doses up to 100 mg/kg/day for methyl- and propylparaben and 1000 mg/kg/day for ethylparaben. In the rat uterotrophic assay a subcutaneous dose of 5 mg/kg/day of PHBA (the only dose tested) produced no response, while 100-, 400-, and 600mg/kg/day doses of butylparaben produced increased uterine wet weights, with only the highest dose (i.e., 600 mg/kg) showing a significant effect after normalizing for body weight. A subcutaneous dose of 0.1 mg/kg/day estradiol benzoate consistently caused significantly increased normalized uterine weights (Hossaini et al., 2000). The inability of Hossaini et al. (2000) to reproduce the positive uterotrophic findings in mice at a subcutaneous PHBA dose 200 times greater calls into question the validity of positive findings reported by Lemini et al. (1997).

Routledge et al. (1998) examined methyl- and butylparaben (representing the extremes of estrogen receptor binding in the E- screen assay) in the immature rat uterotrophic assay (intact and ovariectomized) following oral and subcutaneous administration over 3 successive days. Uterine weights were not normalized to body weights; the authors provided the results as wet and dry uterine weights. Methylparaben administered orally up to 800 mg/kg/day or subcutaneously at up to 80 mg/kg/day did not increase uterine weights in immature rats. There were no significant effects on uterine weight following oral administration of butylparaben at up to 1200 mg/kg/day. Following subcutaneous administration of butylparaben, the lowest dose that produced a positive effect on wet and dry uterine weight was 600 mg/kg/day. Butylparaben doses of 200 and 400 mg/kg/day significantly increased dry but not wet uterine weights. Subcutaneous doses of 0.04-0.4 mg/kg/day estradiol increased uterine wet and dry weight. A possible explanation for the disparity in results for butylparaben following oral or subcutaneous administration is discussed later in the section on pharmacokinetics.

Depending on the assay (i.e., MCF-7 cells, yeast E-screen, rat or mouse uterotrophic assay, etc.), all of the testing conducted on the parabens, whether in vitro or in vivo, indicates that these compounds are orders of magnitude less potent than estrogens. Parabens with shorter side chains are less potent (i.e., less estrogenic) than those with longer or branched side chains, with the following potency pattern prevailing: isobutylparaben > isopropylparaben > benzylparaben > butylparaben > propylparaben > ethylparaben > methylparaben. As illustrated in Table 3, methyl-, ethyl-, and propylparaben have no in vivo uterotrophic activity; therefore, estimates of potency differences compared to estradiol were not calculated. While high subcutaneous doses of butylparaben and isobutylparaben showed a positive uterotrophic response, both compounds were at least three orders of magnitude less potent than 17β-estradiol.

In Vivo Data in Male Animals

Butylparaben, DES, and a number of other compounds (i.e., bisphenol A, octylphenol, and genistein) were studied in neonatal Wistar rats to determine effects on the male reproductive tract (Fisher et al., 1999). Butylparaben was administered subcutaneously at a dose* of 2 mg/kg on postnatal day (PND) 2-18; DES was administered subcutaneously at doses of 10, 1, or 0.1 g/animal, equivalent to 0.37, 0.037, or 0.0037 mg/kg/day, respectively, while ethinyl estradiol was administered at a dose of 10 g/animal (equivalent to 0.37 mg/kg). Testes weight was determined in treated animals at 18, 25, 35, and 75 days of age; other endpoints considered were effects on the rete testis and efferent ducts and epithelial cell height in the efferent ducts. Both estradiol and DES (at all dose levels, although with decreasing severity) produced significant reductions in testes weight at all days at which this endpoint was assessed, while butylparaben had no effects on testes weight on any day or on any other endpoints studied. Table 4 summarizes the data on the effects of parabens on the male reproductive tract.

TABLE 3

Summary of paraben uterotrophic assay results and potency comparison with estradiol

In a study of the potential reproductive effects in male Wistar rats, 3-week-old animals were exposed to butylparaben at dietary levels of 0.00%, 0.01%, 0.10%, and 1.00% for 8 weeks (Oishi, 2001).[dagger] While there were no significant effects on body weight, there were significant reductions in absolute epididymides and seminal vesicle weights at the highest dose and a significant effect on relative epididymides weight at the two highest doses (i.e., 0.10 and 1.0%); there were no treatment-related effects on weight of the testes, ventral prostate, and preputial gland (either absolute or relative to body weight). All doses showed significant decreased sperm reserves in the cauda epididymides, daily sperm count (DSP) in the testes, and efficiency of sperm production (DSP/ g testes); reduction in sperm concentration in the cauda epididymides was only significant at the highest dose. Serum testosterone levels decreased with dose with significance at the two highest doses (0.10 and 1.0%), although it should be noted that the biological significance of changes in a variable parameter like serum testosterone is perhaps questionable. The author noted that the decrease in sperm number could have been a direct toxic effect of butylparaben consistent with the spermicidal properties reported by Song et al. (1989, 1991). Consequently, it remains to be determined if butylparaben exerts the reported effects on sperm- related parameters as a result of direct toxicity or through an estrogen-mediated mode of action.

TABLE 4

Summary of data on effects of parabens on rodent male reproductive tract

Oishi (2002b) also conducted a study on the effect of butylparaben on reproductive function in male ICR (Crj:CD-1) mice. The mice, aged 27-29 days, were exposed to butylparaben at dietary levels of 0.00%, 0.01%, 0.10%, and 1.00% for 10 weeks.* There was no effect on body weight at any dose; the only significant effect on potential target organs was an increase in absolute and relative epididymides weight at the highest dose. There were no significant reductions in sperm counts, but significant decreases in elongated spermatids at the lowest dose (0.01%) and round spermatids at the highest dose were observed. Serum testosterone levels were significantly decreased at the highest dose (1.0%). No lesions were noted in Sertoli or Leydig cells at any dose. The reason for the paradoxical increase in epididymides weight and decreased testosterone at the highest dose could not be explained.

Oishi (2002a) also conducted a study on the effect of propylparaben on reproductive function in male Wistar rats. In this study, 3-week-old animals were exposed to propylparaben at dietary levels of 0.00%, 0.01%, 0.10%, and 1.00% for 4 weeks.[dagger] While final body weights were significantly lower at the highest dose, there were no significant reductions in absolute or relative weights of testes, epididymides, ventral prostate, seminal vesicles, or preputial gland at any dose. The two highest doses produced significant reductions in sperm reserves and concentration in the cauda epididymides; all doses produced decreases in daily sperm count (DSP) in the testes and efficiency of sperm production (DSP/g testes). Serum testosterone levels appeared to decline with dose (no trend test was done); however, a significant decrease was only observed at the highest dose (1.0%).*

In another study to investigate the effects of in utero exposure to offspring, butylparaben was injected subcutaneously into pregnant Sprague-Dawley rats at doses of 100 or 200 mg/kg/day[dagger] from gestation day 6 to postnatal day (PND) 20, with a 2-day interruption during parturition (Kang et al., 2002). The proportion of pups born alive was significantly reduced at both doses, while the proportion of pups surviving to weaning was significantly reduced at the highest dose. Male reproductive organ weights showed a confusing pattern of significant effects (i.e., increases and decreases), with no consistent relationship with dose or time. Sperm counts in the caudal epididymis and sperm motility were significantly decreased at both doses (see earlier footnote on average propylparaben intake). In female offspring there were no effects on uterus or ovary weights from any dose atany PND. There were no effects on anogenital distance in male or female offspring and a significant effect on vaginal opening at 100 mg/kg, but not at 200 mg/kg.

Finally, a recent study with methyl- and ethylparaben demonstrated no effects on the secretion of sex hormones or male reproductive function following dietary administration to 25-to 27- day-old rats at doses of 0.1 % and 1.0% (Oishi, 2004). Neither compound produced adverse effects on sperm or the weights of the testes, epididymis prostate, seminal vesicles, testosterone, luteinizing hormons (LH), or follicle-stimulating hormons (FSH) at a dose of approximately 1000 mg/kg/day.

As noted in most of the studies just cited that reported a paraben effect on sperm production or a sperm-related parameter, parabens (methyl, ethyl, propyl, and butyl) have been reported to have potent in vitro spermicidal activity (Song et al., 1989, 1991). This activity (i.e., butyl > propyl > ethyl > methyl) has been studied in conjunction with the development of parabens as possible vaginal contraceptive agents, with butylparaben six times more potent than methylparaben in studies with human sperm. Butylparaben is the most potent of the parabens and the most well studied. It appears that butylparaben produces spermicidal effects primarily as a consequence of impairment of sperm membrane function. It is, therefore, biologically plausible that the paraben doses used in the studies reviewed could produce similar in vivo reductions in the various sperm-related parameters as a result of direct toxicity and not as a consequence of an estrogen-mediated mode of action.

As shown in Table 4, notwithstanding potential effects on sperm or sperm-related parameters, to the extent that other effects are reported, virtually all occurred in conjunction with the highest administered butylparaben dose. With the exception of the study by Fisher et al. (1999), none of the studies included an estrogen “control” group. This would have permitted a direct comparison of the in vivo potency of a tested paraben with estrogen (e.g., 17β-estradiol or DES).[double dagger] As noted earlier, the effects on sperm might have been due to direct toxicity and not from an estrogen-mediated mode of action. However, the other reported effects (i.e., changes in some reproductive organ weights and testosterone) could have been the result of an estrogen-mediated mode of action. Consequently, these data (i.e., the lowest doses that produced a nonsperm effect) in conjunction with human paraben exposure data are used later in this review in the section that compares the dose/potency of parabens with either DES or 17β- estradiol. As stressed throughout this review, the only way to assess the potential effects of parabens that might be due to an estrogen-mediated mode of action is to account for both the dose and potency in comparison to the established effects of estrogen.

PHARMACOKINETICS

The pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion) of parabens may influence whether exposure to these compounds might have the capability of acting as EACs in humans. Notwithstanding their substantially lower potency than estrogen, determining the extent to which these compounds can reach potential target organs following exposure will have critical implications in a risk evaluation.

Following oral exposure, all parabens that have been studied are rapidly and almost completely absorbed from the gastrointestinal tract in rats, rabbits, and dogs (CIR, 1994, 1995; Soni et al., 2001, 2002; Jones et al., 1956). Following absorption, parabens are easily hydrolyzed by liver esterases, with phydroxybenzoic acid (PHBA) as the primary metabolite. Other metabolites include p- hydroxyhippuric acid and ester and a variety of conjugated glucuronides. Metabolism is rapid with metabolites appearing in the urine within 0.5 h after ingestion.

The metabolism of parabens (methyl, ethyl, propyl, and butyl) and PHBA was studied in fasted dogs following intravenous (iv) administration of 50 mg/kg or oral administration of 1 g/kg (Jones et al., 1956). Depending on the paraben, recovery in the urine of total administered dose (parent + metabolites) ranged from 40 to 95% suggesting that the majority of these compounds retained their basic phenolic character. In this study, a fasted human was given an oral dose (70 mg/kg) of methylparaben and no detectable parent compound was found in the plasma or urine. Finally, no accumulation was noted in dogs orally administered either methyl- or propylparaben at 1.0 g/ kg/day for 1 year. Following oral administration to rabbits of either 400 or 800 mg/kg isobutylparaben, between 32 and 50% of the parent compound was recovered in the urine as free or conjugated PHBA after 24 h. Only about 0.2-0.9% of the parent compound was detected in the urine as unmetabolized isobutylparaben (CIR, 1995).

The metabolism and excretion of methylparaben (and to a lesser extent propylparaben) has been studied in six preterm infants (four males and two females) as a consequence of their use as preservatives in gentamicin, an antibiotic used to treat sepsis (Hindmarsh et al., 1983). Following intramuscular administration, urine was analyzed by high-performance liquid chromatography (HPLC) to determine the percent of dose excreted over 18-24 h. The percentage of administered methylparaben accounted for in urine was from 13.2 to 88.1%, with the majority in conjugated form. The only metabolite detected was PHBA.

As summarized in Table 3, there is no evidence that methyl-, ethyl-, or propylparaben is estrogenic in vivo in uterotrophic assays following either subcutaneous or oral administration. This is consistent with the observation, from in vitro assays that screen for estrogenic activity, that parabens with shorter or unbranched side chains have less activity than those with longer or branched side chains. While in vitro screening data are useful in assessing activity relative to estrogen, in taking a weight-of-evidence approach, primary emphasis must be placed on in vivo data. Butylparaben and isobutylparaben have been reported to be estrogenic in uterotrophic assays following subcutaneous administration. It is unknown if a similar effect would occur following topical administration. Benzylparaben was positive following topical application albeit with a potency >300,000 times less than estradiol. Unfortunately, there are insufficient data on the potential in vivo uterotrophic effects of butyl-, benzyl-, isopropyl- , and isobutylparaben following both oral and topical exposure to permit a definitive determination of the effect of route of administration on this endpoint. While liver esterases clearly come into play in the metabolism of parabens following oral exposure with first-pass hepatic activity leading to substantial conversion to PHBA and other metabolites, as discussed later, the situation with respect to subcutaneous administration or topical application may not be equivalent to oral administration.

Because most paraben-containing products are topically applied to the skin, dermal absorption is particularly important with respect to estimating doses and potential effects. As described in the following paragraphs, the skin is not an impenetrable barrier, and depending on the specific paraben (i.e., K^sub ow^) and the type of formulation (e.g., aqueous or lipid), some fraction of an applied dose may be absorbed and enter the systemic circulation, although not necessarily as the parent compound.

In an in vitro study using human epidermal membranes, the ability of different vehicles (acetone, ethanol or ointment) to affect the permeability of four parabens (methyl, ethyl, propyl, and butyl) with or without occlusion was determined (Cross and Roberts, 2000). While the skin permeability of the parabens alone was not measured, the results demonstrated that different vehicles, particularly in conjunction with occlusion, enhanced skin permeability. For example, the percentages of butylparaben in ointment, acetone, or ethanol penetrating the skin over a period of 10 h were 39%, 44%, and 57%. These results suggest that parabens formulated into certain skin- care products can penetrate the skin. The determinants of actual dermal permeability are likely to be a complex interaction of individual parabens, partition coefficient (i.e., log K^sub ow^), and the presence of other ingredients in a particular product. The skin permeability of four parabens (methyl, ethyl, propyl and butyl) was studied in an in vitro system using guinea pig skin (Kitagawa et al., 1997). Permeability increased as a function of n-octanol/water partition coefficients (K^sub ow^) in the order butyl > propyl > ethyl > methyl. This was interpreted as demonstrating that these parabens penetrate both human and animal skin via nonpolar stratum corneum lipid lamella. However, neither of these in vitro studies could account for dermal metabolism of parabens as described next.

Butylparaben has also been studied in an in vivo absorption experiment in Wistar rats. After 4 h, almost 50% of the ^sup 14^C- labeled administered dose was recovered in the urine, and 10% was recovered in the skin (Yamashita et al., 1994). Similarly, in an in vitro study with butylparaben, 88% of the applied dose was recovered at the end of the skin diffusion experiments (Koyama et al., 1994). Because both of these studies were based on recovery of ^sup 14^C- radioactivity, it is not possible to determine how much of the recovered compound was parent compound or metabolites.

An important aspect of metabolism pertaining to dermal absorption is provided by several in vitro studies demonstrating substantial enzymatic hydrolysis of parabens in skin by cutaneous esterases. In an in vitro study with rat skin to determine percutaneous penetration of propyl- and butylparaben, fullthickness abdominal skin from male Wistar rats was mounted in a flo\w-through diffusion cell (Bando et al., 1997). Experiments were conducted with and without pretreatment with diisopropyl fluorophosphate (DFP), an irreversible lipophillic inhibitor of cholinesterase. For butylparaben and propylparaben, respectively, without pretreatment with DFP, approximately 96% and 30% from either compound of the total penetrated amount was the primary metabolite PHBA. No PHBA from either compound was detected in receptor fluid following pretreatment with DFP. This study demonstrates the importance of dermal metabolism in reducing the amount of parabens that might enter the systemic circulation.

The enzymatic hydrolysis of parabens (methyl, ethyl, propyl, and butyl) has also been studied in extracts from different layers of human skin, where it was possible to distinguish four carboxyesterases capable of hydrolyzing 4-hydroxybenzoic acid esters (Lobemeier et al., 1996). The anatomic site from which the various esterases were derived (i.e., cutis, keratinocytes, subcutaneous fat, blood) determined their hydrolytic activity. Parabens with shorter side chains (i.e., methylparaben) were the preferred substrate for the subcutaneous esterase I, with decreasing activity as chain length increased. Subcutaneous esterase II demonstrated preferential activity for butylparaben over methylparaben. Butylparaben was the preferred substrate of the esterase III from keratinocytes with less activity as chain length decreased. As noted by Lobemeier et al. (1996), “We conclude from our results that the above mentioned paraben esterase III of keratinocytes is sufficient to completely hydrolyze the traces of parabens that may enter the skin from topically applied ointments” (p. 650). The ultimate determination of how these findings might apply in an in vivo situation must await an appropriate study to confirm these results.

The ability of dermal esterases* to substantially degrade (hydrolyze) topically applied parabens may have important implications with respect to decreasing the potential for endocrine activity for the three parabens that have demonstrated in vivo activity. As already described, PHBA, the major paraben metabolite, is devoid of estrogenic activity as demonstrated by Hossaini et al. (2000), who was unable to confirm the positive uterotropic findings of Lemini et al. (1997) in rats or mice.t To the extent that parabens might be absorbed through the skin suggests that they would be metabolized to PHBA, a nonestrogenic substance. The activity of dermal esterase may also be important in interpreting the results of studies in which paraben test substances are administered subcutaneously, thereby bypassing much (if not all) of likely dermal metabolism. In the only study in which a paraben (i.e., butylparaben) was administered both orally and subcutaneously (Routledge et al., 1998), there were differential effects. Following oral exposure (at doses up to 1200 mg/kg/day), butylparaben was inactive in the immature rat uterotrophic assay; however, a subcutaneous dose of 600 mg/kg/day produced a positive uterotrophic response (increased wet and dry weights). These data suggest that the rapid absorption and metabolism of orally administered butylparaben could account for its lack of uterotrophic activity, while subcutaneous doses may have bypassed or overwhelmed (to an unknown extent) the metabolic capabilities of the skin.

EXPOSURE TO PARABENS

In determining the safety of certain parabens, it is first necessary to ascertain the extent of their use. This information, along with the amounts of various parabens that are formulated into consumer products, can provide an approximation of potential exposures. Based on voluntary registration with the U.S. FDA, Steinberg (2004) compiled the most recent tabulation of preservative use in cosmetic formulations. This tabulation demonstrates that methyl-, propyl-, and ethylparaben are used in 82% of the 17,907 cosmetic formulations containing preservatives listed in the database in 2003. While very weakly estrogenic in some in vitro assays, these three parabens have not demonstrated any estrogenic activity in in vivo assays, suggesting there is no biological basis for including them in an assessment of potential estrogen-mediated risks. The other parabens, butyl-, isobutyl-, isopropyl-, and benzylparaben, were contained in 13%, 1.3%, 0.2%, and 0.02%, respectively, of the cosmetic formulations containing preservatives.

Because of their very limited use in cosmetic formulations, and therefore a limited opportunity for exposure, isobutyl-, isopropyl- , and benzylparaben are not considered in this analysis. However, with butylparaben present in 13% of cosmetic formulations (i.e., >2300 products), there is an opportunity for exposure to this paraben. In a recent survey, the Cosmetic, Toiletry, and Fragrance Association (CTFA) requested its member companies provide the maximum concentration of butylparaben used in FDA cosmetic product categories. The maximum concentrations of use for butylparaben ranged from 0.00004 to 0.5%. Parabens can not be used at higher concentrations as their use is limited by solubility.

Exposure of a 60-kg woman using multiple product categories (bath products, colognes and toilet waters, powders, hairsprays, shampoos, tonics and other hair grooming aids, blushers, foundations, lipstick, makeup bases, bath soaps and detergents, deodorants, skin cleansers, depilatories, face preparations, body moisturizers, skin fresheners, and sun products) was estimated by multiplying estimated product exposure in milligrams per kilogram per day by the reported maximum butylparaben concentration in the product category. This resulted in a total composite butylparaben exposure of 0.307-1.02 mg/ kg/day.

Based on Cross and Roberts (2000), it is reasonable to assume that approximately 40% of butylparaben could be dermally absorbed, which results in a butylparaben dose of approximately 0.12-0.41 mg/ kg/day. It is important to note that this estimate assumes that an individual uses every product in the above list every day (i.e., worst-case assumption). The calculated butylparaben dose of 0.12- 0.41 mg/kg/day also assumes that dermal esterases do not further reduce or completely metabolize this dose to p-hydroxybenzoic acid (PHBA). In the following sections, potential risks from parabens as a consequence of their possible weak estrogenic activity are assessed by comparing the paraben doses required to produce an in vivo effect with total paraben exposure levels (i.e., 0.12-0.41 mg/ kg/day) and contrasting these levels and their estrogenic potency with amounts of estrogen known to produce adverse effects.

EXPOSURE TO PHYTOESTROCENS

A useful approach for providing a perspective on this issue is to compare the estrogen receptor binding affinity of parabens with that of dietary phytoestrogens (i.e., naturally occurring plant estrogens). As a class of structurally diverse and ubiquitous dietary compounds, phytoestrogens can have significant biological activity based primarily on their ability to act as weak estrogens by binding to the estrogen receptor (ER) (Burroughs et al., 1985). More than 300 foods have been shown to contain phytoestrogens. Coumestrol, found in soy protein, sunflower, and many legumes, is the most estrogenic phytoestrogen studied and binds to estrogen receptors with less affinity than 17β-estradiol but with more affinity than other phytoestrogens. Zearalenone is a fungal contaminant of grains such as corn, wheat, barley, and oats, while genistein, which is less potent than coumestrol, is also found in various grains and soybean products. Phytoestrogens are capable of producing a spectrum of biological activity and, depending on the dose, may have estrogenic or antiestrogenic effects (Setchell et al, 1984).

In a comprehensive assessment of the interactions of a number of weakly estrogenic chemicals, including phytoestrogens, with both estrogen receptor a (ERa) and estrogen receptor β (ERβ), Kuiper et al. (1998) compared the relative potency of 17β- estradiol and other natural estrogens with several dietary phytoestrogens (e.g., genistein, coumestrol, zearalenone). These in vitro studies with ERa and ERβ proteins and a transient gene expression assay demonstrate that naturally occurring dietary phytoestrogens have far less binding affinity for either ERa or ERβ than 17β-estradiol. Safford et al. (2003) also assessed the relative estrogen receptor binding affinity of these compounds and 17β-estradiol with ERα and ERβ* Since neither of these studies included parabens in their evaluations, the data on essentially the same endpoint (i.e., binding affinity to ERa and ERβ) from Okubo et al. (2001) are used for comparison. While these three approaches are slightly different, the results illustrate that in vitro, many commonly consumed phytoestrogens have greater binding affinity to estrogen receptors than parabens.

In the case of phytoestrogens, their ubiquitous (and growing) presence in the food supply, and their likely daily intake suggests widespread exposure. A number of studies have demonstrated that peak serum concentrations of daidzein and genistein of 500-1000 nM can be achieved after meals rich in soybeans or soybean protein (Kurzer and Xu, 1997;Lapciketal., 1997). As illustrated in Table 5, phytoestrogens are more potent than parabens with respect to their ability to bind to the ER.

DO HUMAN EXPOSURES TO PARABENS POSE ANY POTENTIAL RISKS DUE TO ENDOCRINE-MODULATING EFFCECTS?

Extensive safety evaluations of parabens have previously been conducted, concluding that they are safe for use in numerous consumer products following either dermal or oral exposure (CIR, 1994, 1995; Soni et al., 2001, 2002). However, none of these assessments explicitly considered potential endocrine activity. Because the estrogen like properties of the parabens are the subject of this review\, this is the focus of the following evaluation of the potential risks to humans that might be associated with these compounds due to an estrogen-mediated mode of action.

TABLE 5

Comparative binding affinity of 17β-estradiol, des, dietary phytoestrogens. and parabens

Despite a lack of consistent regulatory guidelines on assessing potential risks from chemicals identified as endocrine-active compounds, there appears to be a consensus within the scientific community on the broad outlines of how such evaluations should be undertaken. In numerous reviews of this issue, there is general agreement that in evaluating potential endocrine-mediated effects of weakly estrogenic xenobiotic chemicals, potency and dose are critical aspects of a risk assessment process (Baker, 2001; Witorsch, 2002; Degen and Bolt, 2000; Bolt et al., 2001; Ashby, 2000a, 2000b, 2001; Williams et al., 2001). While in vitro screening data can provide useful information about comparative potency, molecular mechanisms involved and hormone receptor activity, in vivo data are afforded more weight than in vitro data because only in vivo data can account for critical pharmacokinetic considerations influencing target organ effects including absorption, distribution, metabolism and excretion. This concept is consistent with a review of this issue by IPCS (2002): “Other chemicals that have shown evidence in vitro of estrogenic activity have not shown similar evidence in in vivo systems, and caution is warranted in interpreting in vitro results without in vivo confirmation” (p. 2412). A common thread that runs through all of these discussions is that simply equating doses without consideration of potency is inappropriate, particularly in comparison with the well established effects of potent estrogens such as DES, ethinyl estradiol, or 17β-estradiol. For example, in reviewing the issue of endocrine active compounds and their effects on the male reproductive system, Williams et al. (2001) concluded that “weak environmental oestrogens are rather unlikely to pose a significant risk to the reproductive system of the developing male unless the compound in question also possesses some other biological activity of relevance” (p. 245).

TABLE 6

Comparative potency of xenoestrogens in the rodent uterotrophic assay

As illustrated in Table 6, comparing effective doses of compounds that produce a positive response in the rodent uterotrophic assay does not give a true picture of their comparative potency. Table 6 also illustrates that common foodstuffs containing naturally occurring phytoestrogens are more potent in producing effects in the rodent uterotrophic assay than parabens. Based on daily intakes of naturally occurring dietary phytoestrogens, it would be unwarranted to simply assume that exposure to less potent parabens would be associated with risks of estrogen-mediated effects.

The relative risk may even be lower considering the two phases of the uterotrophic response to estrogen as reported by Hewitt et al. (2004). In this study, early responses to estrogen included hyperemia and water imbibition, while later responses included DNA synthesis and mitosis of epithelial cells, resulting in real uterine growth. A time-resolved analysis of the uterotrophic response in ovariectomized rats to the weak estrogen genistein revealed that this phytoestrogen mimicked the water imbibition but did not stimulate cellular markers of proliferation (Diel et al., 2004). In other words, weak estrogens may be able to stimulate water imbibition, but are not able to trigger deleterious proliferative responses, which creates an addition margin of safety.

Effects of DES, 17β-Estradiol, and Ethinyl Estradiol in Humans and Animals

As described in this review, there are data showing that some individual paraben compounds have weak activity in a variety of in vitro and in vivo screening assays for estrogenic effects. However, in assessing the likelihood that in utero exposure to these compounds might be etiologically associated with any particular adverse effect, the biological plausibility of such effects must be considered in a comparative approach as part of the evaluation process. This is based on the extensive human and animal data on the effects of pre- and post natal exposure to potent estrogens. In this section, the data on DES, 17β-estradiol (E2), and ethinyl estradiol (EE) are summarized to illustrate the effects in humans and rodents from in utero exposure to these potent estrogens. The subsections compares these data on a dose and potency basis with the paraben potency data reviewed earlier.

DES

Considerable dose-response data, in both humans and experimental animals, demonstrate the effects of in utero exposure to DES on offspring. While the human DES data can be used to judge the likelihood that estrogen-mediated adverse effects might result from in utero exposure to exogenous estrogenic compounds, because of the manner in which DES was used clinically, these data are not useful for assessing the likelihood of adverse effects which might result from postnatal exposures.

DES is a synthetic estrogenic compound which is equal or more potent than 17β-estradiol and hundreds to thousands of times more potent (based primarily on results from in vitro tests) than compounds identified as EACs (McLachlan, 1981; Gaido et al., 1997; Golden et al., 1998). The large difference in potency between DES and parabens can be used to assess the likelihood that in utero exposure to these compounds might be a risk factor for certain adverse health endpoints. Based on extensive human experience, the DES database is widely recognized as the “gold standard” for assessing potential effects from exposure to weakly estrogenic EACs (U.S. EPA, 1997; IPCS, 2002; NAS, 1999). The maternal doses of DES that produce adverse effects in offspring exposed in utero and likely maternal intakes of weakly estrogenic exogenous compounds required to result in approximately comparable estrogenic activity can be directly compared. This approach is the most valid way to address this issue because of the enormous disparity between the estrogenic potency of 17β -estradiol and any EACs identified to date (including the parabens) and also because critical comparative data were derived from studies in humans.

Effects of DES in Humans

There are clinical studies that suggest that some maternal DES dosing regimens were not sufficient to result in certain adverse effects to offspring exposed in utero (Golden et al., 1998). A study conducted on a cohort of males from the Mayo Clinic, which appears to have employed the lowest DES dosing schedule of any clinical center in the United States, demonstrates a mean no effect maternal dose level for adverse effects attributable to in utero DES exposure (Leary et al., 1984). DES did not increase the risk of any urogenital abnormalities, including penile length or diameter, testis length or width, epididymal cysts, or varicocele. There were also no adverse effects on sperm volume, density, motility, morphology, or fertility. In this study, the median total administered maternal dose of DES of 720 mg (range 4-7405 mg; mean = 1429 mg) and a median exposure duration of 101 days (range 2-239 days) were not associated with any of the male reproductive-tract endpoints studied. Assuming a mean total DES intake of 1429 mg represents an approximate daily DES dose of 14 mg/day (approximately 0.3 mg/kg/day for a 50-kg woman). A potential problem with any such studies (whether in humans or animals) is if fetal exposure to DES occurs after the critical period of reproductive-tract development. Records of DES doses and durations of exposure in this cohort reveal that the 25th and 50th percentiles of the first gestational day of exposure were on days 54 and 89 with exposure durations of 28 and 100 days, respectively (Leary et al., 1984). Therefore, the timing of DES exposure is well within the window during which development of the reproductive tract is occurring.

In contrast, at the University of Chicago where mean total maternal DES doses averaged over 11,000 mg with exposure also beginning during the first trimester, numerous adverse effects on the male reproductive tract have been reported in offspring exposed to DES in utero, including microphallus, epididymal cysts, cryptorchidism, testicular hypoplasia, decreased sperm count, and increased incidence of abnormal sperm (Labarthe et al., 1978; Bibbo and Gill, 1977). Most of the women in the treatment group received total DES doses between 11,500 mg and 12,600 mg (Wilcox et al., 1995), and in utero exposure to DES occurred during a critical time of reproductive-tract development. Assuming a total DES intake of 12,000 mg and 28 weeks (196 days) results in an approximate daily DES dose of 50 mg/day or approximately 1 mg/kg/day for a 50-kg woman. Even though this dosing regimen caused a number of male reproductive-tract abnormalities, there was no significant difference in fertility between men exposed in utero to DES and controls (Wilcox et al., 1995). The failure of high maternal doses of DES to adversely affect the fertility of male offspring exposed in utero challenges the notion that in utero exposure to weakly estrogenic compounds might impair male fertility or affect the development of the reproductive tract.

Effects of Estradiol and Ethinyl Estradiol in Rodents

In what is likely the definitive study of the effects of 17β- estradiol (E2) in rodents, Cook et al. (1998) conducted a 90-day, one-generation reproduction study in male and female Crl:CD Br rats with dietary levels of 0, 0.05, 2.5, 10, and 50 ppm. Numerous measurements were made in parental (P^sub 1^) and first-generation (F^sub 1^) male rats, including serum testosterone levels, testicular and epididymal weights, and a variety of sperm parameters. In P^sub 1^ rats, exposure at 10 and 50 ppm decreased testis and epi\didymis weights, while no effects were seen at 2.5 ppm. In F^sub 1^ males epididymis weight was significantly decreased at 2.5 ppm, which remained following a 26-day recovery period. No pups were produced at 10 or 50 ppm. While testes weight was not affected at any dose level, testicular spermatid numbers in F^sub 1^ rats were significantly increased in the 0.05 and 2.5 ppm groups to 135 and 140% of control values, respectively.* Epididymal sperm number was significantly decreased in the 2.5-ppm group, as was the percent sperm with normal morphology, although this later finding was judged biologically insignificant due to the small magnitude of the change which was also within the expected historical range of control values.

O’Connor et al. (1998) conducted a Tier I screening battery to compare responses from exposure to 17β-estradiol in these tests with the results from the study by Cook et al. (1998). The battery in this study included short-term in vivo tests in male and female (ovariectomized) adult rats and an in vitro yeast transactivation system to identify responses to receptor-specific ligands. Doses of 17β-estradiol used in the in vivo tests were 0, 1.0, 2.5, 7.5, and 50 g/kg/day administered by intraperitoneal injection. In the female battery uterine weight was significantly increased at a dose of 2.5 g/kg/day while uterine cell proliferation and cell height was significantly increased at all doses. In the male battery testes and epididymides weights were significantly increased at 50 g/kg/day, while seminal vesicle weight was increased at 7.5 g/kg/day. This study demonstrated that the screening battery in adult rats was as sensitive as the in utero 90-day, one-generation reproduction study in male and female rats described earlier.

Subcutaneous administration of 17β-estradiol to adult male rats at doses of 0.1, 10, 100, 200, 300,400, and 1000 g/kg/day produced a spectrum of effects on the reproductive tract (Gill- Sharma et al., 2001). While there was a significant effect on sperm motility at doses of 0.1-10 g/kg/day, there were no adverse effects on sperm counts or potency or any aspect of pregnancy outcome. At doses of 0.1-10 g/kg/day there were no effects on weights of the testes, seminal vesicles, ventral prostate, or epididymides, and no effects on serum levels of testosterone, LH, or FSH or any gross morphological changes in the testes compared to controls. In another study, subcutaneous administration of 17β-estradiol at a dose of 1 g/day (approximately equivalent to 5 g/kg/day based on a weight of 200 g) for 5 weeks had no effects on testes weight, but produced significant decreases in the weight of the epididymides, seminal vesicle, and ventral prostate, as well as sperm count and motility (Ganguly et al., 1992).

Oral ethinyl estradiol (EE) was administered to adult male Sprague-Dawley rats at doses of 0.1, 0.3, 3, or 10 mg/kg/day for 4 weeks prior to mating to determine potential effects on reproductive function (Iwase et al., 1995). The two highest doses of EE resulted in almost a complete absence of sperm in the epididymides of treated animals, while a dose of 0.3 mg/kg/day caused a significant reduction in sperm count, but had no effect on motility, while the 0.1-mg/kg/day dose had no effect on sperm count or motility. However, the lowest dose (0.1 mg/kg/day) produced a significant reduction in body weight as well as reductions in prostate and seminal vesicle weights relative to body weight and a reduction in absolute (but not relative) testes weight. Reproductive performance was not affected by either of the lowest doses. All of the preceding data illustrate that sufficient doses of estrogen can have deleterious effects on adult male reproductive function and provide a comparative basis for assessing whether exposure to weakly estrogenic substances might have similar effects.

Assessment of Potential Risks from Estrogen-Mediated Effects Following In Utero Exposure to Parabens

Comparisons Based on Human DES Data

Based on the Mayo Clinic data a DES dose of approximately 0.3 mg/ kg/day is a no-observed-effect level (NOEL) for adverse effects on the male reproductive tract. As summarized in Table 4, the two lowest doses of butyl- and propylparaben (which is not positive in the uterotrophic assay) associated with a significant effect on the male reproductive tract (i.e., decreased daily sperm production) were 10 and 12 mg/kg/day, respectively.* These doses are approximately 30-40 times greater than the human DES NOEL of 0.3 mg/ kg/day and approximately 10 times greater than the DES “effect” level of 1 mg/kg/day. As already reviewed, there is considerable uncertainty as to whether any paraben-induced effect on sperm parameters is estrogen-mediated or due to a direct cytotoxicity to developing spermatocytes (Oishi, 2001, 2002a, 2002b; Song et al., 1991). Therefore, it is inappropriate to use these data for comparing the effects of parabens on sperm parameters to the effects of DES on these same parameters. On the other hand, the 2-mg/kg/day subcutaneous dose of butylparaben reported by Fisher et al. (1999) was a NOEL for male reproductive effects, which is 6 times greater than the human DES NOEL of 0.3 mg/kg/day. However, this approximation does not account for the estrogenic potency differences between DES and any of the parabens with demonstrated in vivo estrogenic activity.

As summarized in Table 3, there are only three parabens with demonstrated in vivo activity in the rodent uterotrophic assay (i.e., butyl-, benzyl-, and isobutylparaben), with potencies from approximately 6000 to 3,300,000 less than estradiol. Assuming that DES is equal in potency to 17β-estradiol and applying the most conservative potency estimate to the human DES NOEL suggests that butylparaben is at least 6000-fold below the dose of DES that might cause effects on the male reproductive tract. Based on the estimated maximum total but

Abstract

Ectrodactyly is a rare dominant autosomal malformation with variable expression. Herein we report a case early diagnosed by ultrasound at 15 weeks of gestation of isolated ectrodactyly involving the four limbs. The sonographic findings were bilateral split hands and split foot. Diagnosis of typical isolated ectrodactyly was pathologically confirmed. Clinical forms, pathogenesis, differential diagnosis, and early prenatal diagnosis are discussed.

Keywords: Ectrodactyly, early prenatal diagnosis, ultrasound

Introduction

For centuries, human morphologie anomalies of limbs have been the subject of both public curiosity and scientists’ scrutiny (Paracelso 1536, Saint Hilaire 1818, Ballantyne 1904, Warkany 1971) [I].

The term ectrodactyly refers to a group of congenital malformations characterized by a cleft splitting the hands and feet into two halves due to aplasia and/or hypoplasia of phalanx, metacarpal and/or metatarsal bones of one or more fingers or toes. This anomaly is also referred as split hand and foot syndrome and/ or “lobster claw” deformity.

From a embryological point of view, upper limb buds (primordia) are seen as early as at 5 weeks of gestation, whereas those for lower limbs are noted at 6 weeks. Thereafter, mesenchymal proliferation results in limb bud elongation. Then, the ectoderm covering the tip of each bud becomes thickened, forming the ectodermal apical edge, from which the limb will be developed. Upon the 6th week, completed, mesenchymal condensation forms digital rays on the hand plate. Next, interradial mesenchyma splits, resulting in clefts between digital rays. As tissue programmed death or interdigital degeneration proceeds, fingers and toes are not short and membranous in nature any longer, becoming well differentiated and spaced. Blockade of the aforementioned molecular and cellular process between the 6th and 7th gestational week would cause congenital anomalies such as syndactyly and ectrodactyly [2].

From a sonographic point of view, limb buds can be seen transvaginally at 8 weeks of gestation, and at 11-12 weeks, joints of upper and lower limbs, fingers and toes are visible. We report a case of typical isolated ectrodactyly inherited in an autosomal dominant pattern, diagnosed early by ultrasound at 15 weeks of gestation.

Case report

A 39-year-old secundigravida 14-week pregnant woman was referred to our hospital from a secondary health care center as a routine scan performed transabdominally suggested a malformation of the limbs. Her first pregnancy and delivery were uneventful. Medical records included ectrodactyly in the patient’s father and sister and in the patient herself. History taking ruled out toxic habits and consanguinity. At 15 weeks ultrasound examination revealed an ectrodactyly involving the four limbs with abnormal clefts in hands and feet between the second and fourth metacarpal/metatarsal bones and corresponding soft tissues (Figure 1).

Figure 1. Hand with ectrodactyly showing a central defect between both fingers.

Biometry results matched to gestational age and associated abnormalities were ruled out. After genetic counseling, the parents refused the karyotype analysis and chose to terminate the pregnancy. Postmortem karyotype analysis showed that the fetus was euploid.

The ultrasound diagnosis of isolated typical ectrodactyly was confirmed by postmortem study, an ectrodactyly of all the extremities was found. There were no further internal or external associated abnormalities.

Discussion

Distal limb congenital malformations can be observed either as isolated anomalies involving hands and feet or in the setting of specific syndromes or chromosomal aberrations.

There are two distinctive clinical forms of isolated ectrodactyly: the typical and the atypical forms. The former (incidence rate: 1 in 90,000 births) is a dominant autosomal anomaly and involves lack of both phalangeal and metacarpal bones, which results in a deep V-shaped defect clearly splitting the hand in two halves, one being cubital, the other one radial in nature. The condition is also referred as “lobster claw” deformity because the cubital and radial parts of the hand resemble a claw. However, at times the radial ray aberration may also result in monodactyly with no cleft [3,4]. The atypical form (incidence rate 1 in 150,000 births), involves a much wider cleft resulting from a defect of metacarpal bones of medial fingers/toes [3] with a U-shaped central defect. While ectrodactyly pathogenesis remains to be elucidated, there is evidence suggesting that five loci, in which the mutation resides, may play a role. Candidate chromosomes are the chromosome 7 (critical points at 7qll.2-q21.3) (SHFMl), chromosome X (Xq26) (SHFM2), chromosome 10 (10q24)(SHFM3), chromosome 3 (3q27) (SHFM4), and chromosome 2 (2q31)(SHFM5) [5-7].

Although ectrodactyly can appear either as an isolated malformation or associated with the amniotic band syndrome, most commonly it is a component of the ectrodactylyl-ectodermal dysplasia- cleft lip/palate syndrome (EEC). The EEC syndrome is inherited in a dominant autosomal fashion with incomplete penetrance and variable expression. It involves all four limbs, particularly the hands which present severe deformities. The spectrum of ectodermal defects is broad, including dry skin and impairment of hair, nails, teeth, and nasolacrimal and sweat ducts. Intelligence is most often within normality. Some cases of EEC inherited in a recessive autosomal fashion have been described in the literature [8].

The differential diagnosis of typical isolated ectrodactyly should include other conditions presenting with ectrodactyly, such as Karsch-Neugebauer’s syndrome (hand and foot cleft with congenital nystagmus), Fontaine’s dominant autosomal syndrome (ectrodactyly and syndactyly involving the feet, cleft palate, micrognathia, dysplasic outer ear and, in some cases, mental retardation), ADULT (Acro- Dermato-Ungual-Lacrimal-Tooth) syndrome (ectrodactyly, hypodontia, premature loss of permanent teeth, lacrimal duct obstruction, onychodysplasia, and pigmentary lesions), Apert’s syndrome (craniosynostosis, hypertelorism, and pincer hand), and ectrodactyly with central polydactyly.

In the past, ectrodactyly could be detected only at birth by physical examination. Currently, this condition can be prenatally diagnosed by ultrasound, even in the first half of pregnancy [4]. Therefore, fetuses at risk should be examined as early as possible combining transabdominal and transvaginal routes. Early examination can relieve parents’ anxiety and psychological stress associated with a long wait. Further, early diagnosis gives the parents a chance to terminate the pregnancy in compliance with legal regulations. While patients with ectrodactyly can currently benefit from corrective surgery, many parents think that negative impact due to disability, physical and emotional problems and lack of self- esteem is an excessive burden. These arguments lead the parents to decide the termination of the pregnancy when this condition is prenatally diagnosed. Thus, genetic counselling is the key to prevention. Lifelong prognosis is good for children born with isolated ectrodactyly. Limb function will vary with the severity of the defect present at birth. The newborn with ectrodactyly should be thoroughly evaluated by a multidisciplinary team with the participation of the geneticist, neonatologist, and plastic surgeon. Plastic and reconstructive operations of all defects causing functional impairment is mandatory. Web deepening may be performed alone or in addition to tissue augmentation [9]. New breakthroughs in the knowledge of ectrodactyly will no doubt promote better community integration for these patients.

References

1. Gould GM, PyIe WL. Anomalies and curiosities of medicine. Available: http://www.worldwideschool.org/library/books/tecli/ medicine.

2 Haratz-Rubinstein N, Yeh M-N, Timor-Tritsch IE, et al. Prenatal diagnosis of the split hand anomaly: how early is early. Ultrasound Obstet Gynecol 1996;8:57-61.

3. Barsky AJ. Cleft hand. Classification, incidence, and treatment. J Bone Joint Surg 1964;46:1707-1720.

4. Lapaire O, Schiesser M, Peukert R, et al. Split hand and foot malformation: ultrasound detection in the first trimester. Ultrasound Obstet Gynecol 2002;20:511-512.

5. Sharland M, Patton M, Hill L. Ectrodactyly of hands and feet in a child with a complex translocation including 7q21.2. Am J Med Genet 1991;39:413-414.

6. lanakiev P, Kilpatrick M, Toudjarska I, et al. Split-hand/ splitfoot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet 2000;67:59-66.

7. Crackower MA, Scherer SW, Rommens JM, et al. Characterization of the split hand/split foot malformation locus SHFMl at 7q21.3- q22.1 and analysis of a candidate gene for its expression during limb development. Hum Molec Genet 1996;5:571-579.

8. Jarvik GP, Patton M, Homfray T, et al. Non-mendelian transmission in a human developmental disorder: split hand/ split foot. Am J Hum Genet 1994;55:710-713.

9. Peimer CA, Alexander M. Digital augmentation for ectrodactyly: management and planning. Hand Clin 1990;6(4):607-615.

J. ARBUS1, A. GALINDO1, J.M. PUENTE1, M. GARCA VEGA1, M. HERNNDEZ2, & P. DE LA FUENTE1

1 Ultrasound and Fetal Physiopathology Unit, Department of Obstetrics and Gynecology, Hospital Universit\ario “12 de Octubre”, Madrid, and 2 Department of Pathology, Hospital Universitario “12 de Octubre”, Madrid, Spain

Correspondence: J. Arbus, Department of Obstetrics and Gynecology, Hospital Universitario “12 de Octubre”, Avenida de Crdoba s/no, Madrid 28041, Spain. Tel: 034 1 3908310, Fax: 34 1 3908376. E-mail: [email protected]

Copyright CRC Press Apr 2005

Abstract

Objective. To evaluate the acceptability and endometrial safety of a novel intrauterine drug delivery system, FibroPlant- levonorgestrel (LNG), combined with estrogen therapy (ET) in 150 peri- and postmenopausal women, followed-up for at least 3 years.

Design. This was a prospective, non-comparative study in peri- and postmenopausal women. In the majority of women, treatment with the FibroPlant-LNG intrauterine system (IUS), combined with ET, was initiated during the perimenopausal transitional phase to establish a smooth transition to menopause and suppress the endometrium to prevent endometrial proliferation and bleeding. A 3.5-cm long coaxial fibrous delivery system, delivering approximately 14 g LNG/ day, was used. The calculated duration of release of the system is at least 3 years. The majority of women received percutaneous 17 β-estradiol (Oestrogel), 1.5 mg daily on a continuous basis, which provides sufficient blood levels of estrogen in most women to suppress climacteric symptoms and protect against bone loss.

Outcome measures. To measure acceptability, women were asked, after they had the IUS in place for a minimum of 3 years, if they would like to continue the combined regimen and if they would accept renewal of the IUS. Endometrial safety was evaluated by transvaginal ultrasound examination and endometrial biopsy in a subset of 101 women prior to replacement of the IUS.

Results. Ninety-four insertions were done in perimenopausal and 56 in postmenopausal women aged between 33 and 78 years. Of the total group of 150 women, 132 women (88.0%) accepted replacement of the IUS and ten are waiting for replacement. This group includes nine women who will receive a second replacement. The number of women continuing the method is 142 (94.6%). Histological examinations conducted on endometrial biopsies from 101 postmenopausal women prior to replacement, after an average period of use of the regimen of 40 months (range 25-50 months), showed predominantly inactive endometrium characterized by pseudodecidual reaction of the endometrial stroma with endometrial atrophia, which is in keeping with the effects seen with a progestogenic compound. There were no specimens showing signs of proliferation.

Conclusions. Results suggest that the frameless FibroPlant-LNG IUS is safe, well tolerated, well accepted and effective in suppressing the endometrium during ET. Intrauterine progestogen administration in postmenopausal women can be regarded as fundamentally advantageous compared with systemically applied progestogens, which may have potentially inherent ill side-effects, especially on the breast and cardiovascular system, as reported in the recent literature.

Keywords: Intrauterine drug delivery system, progestogens, progestins, levonorgestrel, hormone therapy, perimenopause, postmenopause

Introduction

The primary role of progestogen in peri- and postmenopausal hormone therapy is endometrial protection to prevent hyperplasia [1]. Prior to the widespread use of combined estrogen-progestogen therapy (EPT), the risk of developing hyperplasia due to unopposed estrogen stimulation was substantial. Endometrial hyperplasia in postmenopausal women with an intact uterus, treated with unopposed oral estrogen, was found in 20% of women during the first year and in 62% after 3 years of estrogen therapy (ET), compared with untreated controls [2]. Hyperplasia is characterized by a proliferation of the endometrial glands. In non-atypical (simple) hyperplasia, the glands are normal but, in atypical hyperplasia, glandular abnormality is present both structurally and at cellular level [3]. Non-atypical hyperplasia rarely progresses to more severe conditions. Atypical adenomatous hyperplasia, on the other hand, has been observed to progress to adenocarcinoma of the uterus in 29% of cases [4]. Progestogens should therefore be added to ET in all postmenopausal women with an intact uterus.

Since the mid-1980s, EPT has increasingly been prescribed. The North American Menopause Society recently reviewed the types of EPT regimen used in the USA and concluded that standard regimens provide adequate endometrial protection [I]. A Cochrane review devoted to this subject also came to the conclusion that the addition of an oral progestin to ET, administered either continuous cyclic or continuous combined, is associated with reduced rates of hyperplasia [5].

An important drawback of postmenopausal EPT is the occurrence of withdrawal or breakthrough bleeding. Withdrawal uterine bleeding occurs in 80% of women using cyclic EPT. Continuous-combined regimens avoid withdrawal bleeding, but breakthrough bleeding has been observed in up to 40% of women during the first 6 months. Most postmenopausal women dislike breakthrough bleeding and this is the commonest reason for discontinuation and non-adherence to the treatment regimen. With EPT, therefore, irregular bleeding should be kept to a minimum.

Depending on the EPT type, dose and route of administration, progestogens may have adverse effects on the cardiovascular system and breast tissue. The Women’s Health Initiative (WHI) reported an increased risk of heart disease, stroke and breast cancer [6]. Since these adverse effect were not observed with ET alone, it is speculated that adding progestogens may diminish the beneficial effects on atherosclerosis, vasodilatation and plasma lipids and may contribute to the increased risk of breast cancer.

Indeed, the WHI suggests that EPT may stimulate breast cancer growth and hinder breast cancer diagnosis due to increased mammographie density when a progestogen is added to ET [7,8]. This was recently confirmed in the Million Women Study and other studies, in particular the Swedish cohort study [9,11].

Intrauterine-administered progestogen, such as levonorgestrel (LNG), delivered to the target cells of the endometrium, has a profound suppressive effect on endometrial growth rendering the endometrium inactive and simultaneously eliminating uterine bleeding [12-14]. Pharmacokinetic studies with an intrauterine system (IUS) releasing 20 g LNG (Mirena; Schering AG, Germany) have shown substantially lower plasma concentrations than those seen with a subdermal LNG implant (Norplant; Wyeth PHARMACEUTICALS Inc, USA), the combined oral contraceptive pill and the mini-pill; moreover, unlike with oral contraceptives, LNG levels with the Mirena IUS do not display peaks and troughs [15]. This is important because the low plasma levels may have a significantly lower impact on organ tissues such as the breast and cardiovascular tissue.

The present study reports the interim results of a continuous- combined estrogen plus low-dose LNGreleasing IUS after more than 3 years of use in periand postmenopausal women, and provides data on the endometrial morphology during use of the IUS to evaluate endometrial safety.

Methods

Description of the FibroPlant-levonorgestrel intrauterine system

The FibroPlant-LNG IUS is an anchored LNG-releasing device. It is a multicomponent system consisting of a non-resorbable thread of which the proximal end is provided with a single knot. Attached thereto is a 3.5-cm long and approximately 1-2-mm wide fibrous delivery system, releasing approximately 14 g LNG/day. The fiber is fixed to the anchoring thread by means of a metal clip 1 cm from the anchoring knot. The anchoring knot is implanted into the myometrium of the uterine fundus using an insertion instrument, so permanently securing the implant in the uterine cavity (Figure 1). The metal clip allows visibility of the system on ultrasound and X-ray, allowing proper location of the IUS in the uterine cavity at insertion and on follow-up (Figure 2). The anchoring knot is also visible on ultrasound. Measuring the distance between the surface of the uterus and the metal clip (S-S distance) indicates whether the FibroPlant system has been properly anchored. In contrast with framed drug delivery systems, such as the T-shaped, LNG-releasing Mirena’ IUS, the FibroPlant-LNG IUS has no frame and so is completely flexible, adapting to cavities of every size and shape.

Based on in vitro study, the rate of LNG release is constant over several years. The duration of release, calculated by extrapolation, is more than 3 years. The fibrous delivery system was developed in cooperation with the Polymer Research Group, Department of Chemistry, University of Ghent, Ghent, Belgium.

Figure 1. The FibroPlant-levonorgestrel intrauterine system after insertion in a uterine model.

Figure 2. Ultrasound visualization of the endometrium in the presence of the FibroPlant- levonorgestrel intrauterine system (Aloka SS3500 with high-resolution, 7-10 MHz broadband vaginal sound).

Admission

Perimenopausal (the perimenopause is defined as the period immediately prior to menopause and the first year after the menopause) and postmenopausal (the postmenopause is the period following the final menstrual period) women who consulted with climacteric symptoms or menstrual problems were enrolled in the study. To minimize the dropout rate, great attention was paid to explaining the advantages and possible disadvantages of the replacement therapy. Women were told they could expect scanty interme\nstrual bleeding during the first weeks or months but that this is a normal side-effect which usually disappears in time and should not be a cause of concern. Use of the study product was approved by the Ethics Committee of the University of Ghent, Belgium and written informed consent was obtained. Prior to the insertion procedure, a medical history was taken and a pelvic examination was carried out, and the patient was checked for any clinical signs of sexually transmitted diseases (STDs). Since women included in the study were at low risk for STDs, no routine chlamydia tests were done. All women were screened for their clinical suitability for insertion of an intrauterine device and compliance with World Health Organization eligibility criteria [16]. Women with the following conditions were excluded: clinical cervicitis or vaginitis (infection should be ruled out); sound length greater than 10 cm; history of pelvic inflammatory disease, genital actinomycosis or chronic pelvic pain; blood clotting disorder and/or undiagnosed genital tract bleeding; known or suspected uterine or cervical malignancy including unresolved, abnormal PAP smear; congenital malformation of the vagina, cervix or uterus; postpartum endometritis or history of infected abortion; leukemia; currently receiving corticosteroid or immunosuppressive therapy; and congenital valvular heart disease. Uterine status was evaluated by transvaginal ultrasound examination prior to insertion of the implant system to exclude uterine abnormalities. In the event that basal and parabasal cells were found on a wet vaginal smear, indicating an atrophie status of the uterus, ET was started immediately and insertion of the FibroPlant system was postponed until the uterus was sufficiently primed and a wet smear showed the absence of parabasal cells (usually 1 month later). All insertions were performed in the majority of women without local or intracervical anesthesia. Following insertion, a transvaginal ultrasound was performed to locate the device in the uterus.

Estrogen was administered as either a percutaneous estrogen- containing gel (Oestrogel; Besins Intern, Belgium) in a dosage of 0.75-1.5 mg/day or a transdermal matrix system (Systen; Janssen- Cilag, Belgium), in a dosage of 50 g/day.

Follow-up and device replacement

Women were followed-up at 1, 3, 6 and 12 months following insertion of the IUS and every 6 months thereafter. They were asked about their bleeding pattern and any side-effects or adverse reactions. A gynecological examination was performed as well as a transvaginal ultrasound to locate the implant and to evaluate the thickness of the endometrium according to Fleischer and colleagues [17].

To measure acceptability, women were asked, after they had the IUS in place for a minimum of 3 years, if they would like to continue estrogen replacement therapy and if they would accept renewal of the IUS. If they accepted, an appointment was scheduled to remove the FibroPlant-LNG IUS and insert a new device immediately.

Endometrial biopsy

To assess the impact of the regimen on the endometrium, an endometrium biopsy was taken with a suction curette (Probet; Gyntics, Belgium) prior to device replacement in at least 100 consecutive women reporting for follow-up, to confirm the transvaginal ultrasound findings. This number was considered sufficient because the effects of LNG on endometrial morphology are well known. The samples were drawn from all parts of the uterus to get a representative picture. The biopsies were placed in phosphate- buffered formaldehyde 4% immediately upon collection and stained with hematoxylin and eosin for examination. They were examined by two pathologists according to the diagnostic categories of Hendrickson and Kempson [18].

Data collection, monitoring and analysis

Data were recorded on standard pre-coded forms at admission, at each scheduled and unscheduled follow-up visit, and upon discontinuation from the study. The cut-off date was 31 August 2003. All data were sent to the data-coordinating center at the Department of Medical Informatics and Statistics, University Hospital Ghent, Belgium, for providing statistical data analysis for the study. The rates of discontinuation for individual reasons and groups of reasons were analyzed using the S-PLUS statistical software package (MathSoft Corp., Cambridge, MA, USA) [19] and the cumulative discontinuation rates were computed using survival analysis methods [20,21].

Results

Between 21 April 1997 and 19 June 2000, the FibroPlant-LNG implant system was inserted in 150 perimenopausal and postmenopausal women. Ninety-four insertions were done in perimenopausal and 56 in postmenopausal women aged between 33 and 78 years (Table I). Insertion was difficult in two postmenopausal women due to cervical stenosis, necessitating sounding and dilatation of the cervical canal. In four perimenopausal women fibroids were present, classified as single or multiple intramural and subserosal fibroids ( > 6 cm) with no evidence of submucosal fibroids.

The events and cumulative gross discontinuation rates are presented in Table II. Of the total group of 150 women, 132 (88.0%) accepted replacement of the IUS and ten are waiting for replacement. This group includes nine women who will receive a second replacement. The total number of women continuing with the method is 142 (94.6%). There were five (3.3%) removals for medical reasons (one for abnormal bleeding, one for pain complaints, one for ‘suspicion’ of pelvic infection by a colleague, one prior to surgery for a para-ovarian tumor and one for weight gain). One woman was released from follow-up due to non-compliance with the study requirements. She had ambiguous feelings about the benefits and risks of EPT although she was symptom-free and had a normal gynecological examination at the time of her last visit.

Table I. Characteristics of the 150 users of the FibroPlant- levonorgestrel intrauterine system: age distribution.

Table II. Events and cumulative gross continuation and discontinuation rates (with standard error in parentheses, expect specified otherwise) per 100 women in 150 users of the FibroPlant- levonorgestrel intrauterine system (IUS).

There were no expulsions of the anchored FibroPlant-LNG IUS. The study, with total number of women-months of use of 6063, was well followed-up. The average number of months with the device in situ was 40 (range 4-70). Only two women (1.3%) were lost from the final analysis.

Histological examinations conducted on endometrial biopsies from 101 postmenopausal women prior to IUS replacement, after an average period of use of the method of 40 months (range 25-50 months), showed predominantly inactive endometrium characterized by pseudodecidual reaction of the endometrial stroma with endometrial atrophy. There were no specimens showing signs of proliferation (Figure 3).

A thin endometrium (

No side-effects of the progestogen (breast tenderness, bloating, headaches, acne, mood swings, depression) were reported. Slight scanty and infrequent bloody discharge requiring no protection, or a small panty liner, occurred in some women during use of the regimen, usually for a very short duration in postmenopausal women and those close to menopause. In a minority of women, this erratic blood- stained discharge lasted longer. However, only one woman requested removal of the IUS for this reason. No serious adverse effects were observed (e.g., pelvic inflammatory disease, perforation). One patient complained of abdominal pain each time she replaced a transdermal patch. There were no expulsions of the IUS recorded.

Figure 3. Photomicrograph showing endometrial atrophy and decidualization of the stroma in a woman using combined estrogen therapy with a low-dose intrauterine levonorgestrel-releasing system (hematoxylin and eosin staining, 20).

Discussion

In 1995, Sarrel described the cardiovascular benefits of ET and how progestins compromise the cardioprotective effect of estrogens [22]. The survey provided evidence that progestins have an anti- estrogenic effect and can potentially counteract the beneficial effects of co-administered estrogens, this effect being dose- and duration-dependent. More recently, several reports on the cardiovascular effects of various types of progestogens, combined with ET, have been published. Following publication of the WHI [6] and Heart and Estrogen/progestin Replacement Study (HERS) [23] reporting significant risks with EPT, it was recommended not to initiate any ET or EPT for primary or secondary prevention of coronary heart disease. The conclusions from the WHI and HERS are in contradiction with earlier observational studies and experiments conducted in humans and animals as reported by Sarrel and others. The approach followed by our group is in line with the recommendations by Sarrel to develop intrauterine systems that deliver a progestin directly to the target structure, the endometrium, to avoid reversal of the potential beneficial effect of systemic ET and to minimize adverse effects. Endometrial studies showed that even 5 g LNG/day is sufficient to suppress the endometrium [24,25].

Previous studies with a FibroPlant-LNG system releasing 14 g/day for the treatment of endometrial hyperplasia suggested that it is an effective method for suppressing the endometrium in women with non- atypical and atypical hyperplasia, indicating the strong anti- proliferative effect on the endometrium of this low-dose, locally applied, potent progestin [26]. In 101 consecutive women in the present study, an endometrial biopsy was performed during treatment. No hyperplasia was detected. A similar low incidence (0%) of hyperplasia in postmenopausal women receiving ET and a low-dose LNG IUS has been observed in other studies [2]. Intrauterine proges\togen delivery, particularly LNG, is probably more effective in postmenopausal women in preventing endometrial proliferation than oral treatment because of the uniform suppression of the endometrium throughout the whole thickness of the mucosa caused by the high tissue concentrations when the hormone is administered locally [24,27,28]. With sequential therapy, however, there may be a higher rate of hyperplasia, including complex and atypical hyperplasia [29,3O]. The duration of the progestogen administration seems more important than the daily dose as far as prevention of endometrial hyperplasia is concerned [31]. Continuous, intrauterine progestin delivery could, therefore, be ideal as the promising results obtained in this study suggest.

The thin endometrium (

The majority of women take hormone therapy to obtain relief from climacteric symptoms rather than for prevention of cardiovascular disease or osteoporosis. Climacteric symptoms are most distressing during the perimenopausal years and, therefore, the uptake of hormone therapy (HT) is highest during the transition to menopause. A large number of women, however, will not continue HT and as many as 60% or more of women taking oral HT will discontinue it after a year [34,36]. Re-initiation of withdrawal bleeding, breakthrough bleeding and hormonal side-effects, caused by systemic progestogen absorption, are the main reasons for discontinuing therapy. With continuous-combined ET plus intrauterine LNG delivery, most women in the perimenopause experience breakthrough bleeding during the first 3 months, which gradually disappears during the months thereafter [37,38]. However, postmenopausal women with absent ovarian function develop an atrophie endometrium and amenorrhea soon after ET combined with insertion of the IUS because the local progestogen reduces the concentration of estrogen receptors and, hence, the local estrogen bioactivity [31,39]. In the present study, virtually all women were bleed-free (occasional infrequent spotting) or had amenorrhea at the end of the first year of EPT, as reported earlier [14], and a high rate of adherence to the treatment regimen was observed that can be ascribed to the absence of bleeding and progestogen-like side-effects.

The results of a recently published cohort study in 29 508 Swedish women, which concluded that both combined systemic estrogen/ progestogen and combined sequential EPT regimens are associated with increased breast cancer risk, is alarming. However, it is reassuring that the study did not find a higher breast cancer risk with estrogen-only therapy, even for longer periods (more than 48 months) [U]. Therefore the authors suggested that estrogen used in combination with a low-dose progestin-releasing IUS could be an attractive option to minimize the impact of the hormone on breast tissue, confirming the viewpoint of the authors of the present study. This opinion is further confirmed by the recently published arm of the WHI that evaluated the long-term benefits of estrogen alone and showed no adverse cardiovascular effects and increase in breast cancer risk. On the contrary, a reduced risk of breast cancer of 23% was found. The risk of myocardial infarction was also reduced (by 9%) but the number of cerebrovascular incidents increased slightly [4O].

Conclusions

The main objective of the present clinical trial was to evaluate an alternative route of progestin administration in peri- and postmenopausal women using ET. The study suggests that continuous- combined ET with intrauterine delivery of a progestogen was highly accepted by the women in the study. The rationale of the development of the FibroPlant-LNG IUS is to minimize the potential adverse effects on cardiovascular and other organ systems. As progestogens are required only to oppose the stimulating effects of estrogens on the endometrium, locally acting progestogens, by definition, could avoid the metabolic effects, as well as effects on other tissues, observed with systemically applied progestogens. Intrauterine LNG delivery with low-dose systems, even though minimal absorption may occur, should be regarded as essentially locally acting.

This regimen also offers important additional benefits that could be exploited, such as high adherence to treatment and the low discontinuation rate because of bleeding problems and progestogen- like side-effects.

In addition, an IUS that adapts to volume changes of the uterus, which reduces in size gradually due to the suppressive effect of the LNG and the falling endogenous estrogen levels, will be optimally tolerated by women.

Acknowledgement

The authors are grateful to Professor Dr G. Van Maele, of the Department of Medical Informatics and Statistics, University Hospital Ghent, Belgium, for analyzing statistical data for the study and Dr Patrick Rowe, Reproductive Health Consultant, Vesancy, France, for reviewing this paper.

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DIRK WILDEMEERSCH1, DIRK JANSSENS2, ETIENNE SCHACHT3, KRIS PYLYSER4, & NATHALIE DE WEVER4

1 Contrel Research, Technology Park Zwijnaarde, Ghent, Belgium, 2 Gynecologische Dienst, Tumhout, Belgium, 3 Polymer Research Group, University of Ghent, Department of Chemistry, Ghent, Belgium, and 4 Dienst Anatomo-pathologie, St. Augustinus Hospital, Veurne, Belgium

Correspondence: D. Wildemeersch, Piers de Raveschootlaan 125, 8300 Knokke, Belgium. Tel: 32 50600900. Fax: 32 50622429. E-mail: [email protected]

Copyright CRC Press Jun 2005

Jul. 29–WASHINGTON — A $30 million physical rehabilitation center for combat veterans will be built at Brooke Army Medical Center in San Antonio, officials announced Thursday.

The public-private venture will be funded by the nonprofit Intrepid Fallen Heroes Fund and designed and managed by the U.S. armed services and the Department of Veterans Affairs.

Officials said the Center for the Intrepid, the National Armed Forces Physical Rehabilitation Center, will be a state-of-the-art facility located at Fort Sam Houston.

“We are committed to building the $30 million Center for the Intrepid as quickly as possible to provide for the critical needs of America’s wounded and disabled military personnel,” said Arnold Fisher, honorary chairman of the Intrepid Fallen Heroes Fund.

The center would be separate from the state-of-the-art regional military medical center already planned for BAMC.

Drawings of the new center were unveiled at a Capitol Hill news conference attended by Veterans Affairs Secretary James Nicholson, Sen. John McCain, R-Ariz., Sen. Hillary Rodham Clinton, D-N.Y., Sen. John Warner, R-Va., and Lt. Gen. Kevin Kiley, the Army surgeon general.

McCain, who spent more than five years as a prisoner of war in Vietnam, said that for veterans, the medical operation is always important, but the rehabilitation is just as vital.

That is particularly true, McCain said, with the types of injuries suffered in the war against terror.

“It’s obvious this kind of warfare we are fighting will go on for a long time,” McCain said.

The lawmakers spoke in praise of the nation’s men and women in the armed services, and those who have paid a sacrifice in the war on terror.

“We have a great obligation to care for them, because they will suffer from their injuries for the rest of their lives,” said Rep. C.W. Bill Young, R-Fla., chairman of the House Appropriations subcommittee on defense.

Clinton said the center would give the “very best America has to offer” when wounded soldiers return from the battlefield.

In San Antonio, officials said the center would enhance BAMC’s role as a specialty center for burns and amputee care and the city’s reputation as a center for military medicine.

“It’s great news. It makes sense to build on a great partnership,” said retired Air Force Brig. Gen. John Jernigan, executive director of the San Antonio Military Missions Task Force.

The rehabilitation center will complement the Pentagon’s $2.4 billion plan, under the base closure process, to establish BAMC and Naval Medical Center in Bethesda, Md., as regional military medical centers.

That plan calls for the closure of Walter Reed military hospital in Washington and Wilford Hall Medical Center in San Antonio. Components of those hospitals would be merged with Naval Medical Center and BAMC.

San Antonio is expected to gain 9,300 jobs as a result of the changes at Fort Sam Houston and BAMC.

About 50 personnel will be employed at the rehabilitation center, officials said.

“It’s one more piece in establishing us as the center of gravity for military medicine,” Jernigan said.

The center will include training areas that include walking and running lanes, stairs, obstacles and climbing surfaces to improve motor skills and prepare injured veterans for everyday life. It also will free up hospital space now being used for amputee patient care.

Two 21-room houses will be built next to the center to accommodate family members of veterans undergoing rehabilitation, Fisher said.

Plans for the center also include a children’s support space to help children understand and manage difficulties associated with a parent’s condition and treatment.

According to the Intrepid Fallen Heroes Fund, more than 15,000 troops have been wounded in combat operations in Iraq and Afghanistan. Some are so severely injured, they require extensive medical care and years of treatment.

Nicholson called the center a “gift of opportunity” for veterans and a “generous gesture for our freedom fighters.”

Kiley said experts from Walter Reed would help design the center.

Construction is scheduled to begin in November, and the facility is expected to open in January 2007.

The Intrepid Fallen Heroes Fund has committed $14 million toward construction. It plans to begin a fundraising effort for the remaining $16 million.

Once the center is opened, it will be handed over to the military with $3.5 million of equipment to maintain, officials said.

—–

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Copyright (c) 2005, San Antonio Express-News

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International nurse migration experts convened on July 9, 2005 at the Rockefeller Foundation Conference Center in Bellagio, Italy to examine the causes and consequences of the global nurse shortage and to consider strategies to mitigate its negative impact on the health of people around the world. The recommendations and presentations from the expert meeting can be found at http://www.academyhealth.org/international/nurses.htm.

Nurses are central to the delivery of care in all countries. Developed countries have come to rely on many more nurses than they produce, and increasingly depend upon nurses recruited from less developed countries. “Approximately 80 percent of nurses immigrating to the United States are from developing countries, however close to 60,000 nurses residing in the U.S. come from Canada, the United Kingdom, Ireland and other developed countries also facing nursing shortages. This contributes to the need for these countries to recruit from developing countries,” says Linda H. Aiken, professor and director of the Center for Health Outcomes and Policy at the University of Pennsylvania. “This exodus of nurses from developing countries impacts the ability of these countries to develop sustainable health care systems, provide appropriate care, and manage disease.”

The expert group’s work was based on guiding principles that advocate countries’ self-sufficiency in their nursing workforce; equitable nursing migration; use of trade and foreign policy to enhance nursing capacity; and the use of partnerships among nursing peers worldwide to advance nursing services.

The group’s recommendations for resolving the global nursing shortage build upon previous successes in developing policies and practices to recruit, build capacity, motivate, and retain nurses. On an international scale, the expert group recommends developing:

A Global Health and Nursing Equity Index including elements such as work conditions, nurse production, inflow/outflow of nurses, nurse/population ratio, and burden of disease. This index can then be used to guide performance assessments, develop practice guidelines, and inform distribution of foreign aid to enhance nurse capacity;

Strategic partnerships and networking to share best practices, promote leadership development, and support cross-national evaluative research;

Appropriate international credentialing to recognize and elevate prestige of nursing work.

On a national scale, the expert group recommends:

Promoting targeted investment in nursing education and work conditions;

Harmonizing curricula and certifications within regions to promote regional self-sufficiency;

Including nurse/bed ratios in hospital accreditation instruments;

Reforming local regulations that discriminate against nurses returning home and recognizing international experience abroad in pay and seniority;

Evaluating strategies for motivating and retaining nurses;

Evaluating the impact of trade agreements on nurse capacity;

Stabilizing visa/work permit quotas offered by destination countries to support effective supply planning in source countries;

Creating a high-level governmental body to coordinate and recommend national and international nursing workforce policies;

Developing oversight of recruitment agencies to align activities with national plans;

Promoting and monitoring immigrant nurses’ rights.

The meeting, organized by AcademyHealth and The University of Pennsylvania, brought together representatives of universities in Canada, the U.K., the U.S., four Sub-Saharan African countries, India, the Philippines, China, and the Caribbean, as well as The World Health Organization, The International Council of Nurses, The Commonwealth Secretariat, and the U.S. Commission on Graduates of Foreign Nursing.

Sponsorship support for this meeting was provided by the Rockefeller Foundation, the International Development Research Centre, Johnson & Johnson, The Robert Wood Johnson Foundation, the Nuffield Trust, the Agency for Healthcare Research and Quality, the Canadian Health Services Research Foundation, the Canadian Nurses Association, and the Joint Committee on Economic and Policy Analysis.

The dialogue on global nursing shortages will continue at the AcademyHealth Health in Foreign Policy Forum, February 8th, 2006 at the Renaissance Washington D. C. Hotel. The 2006 event will bring together domestic and foreign policy experts to explore ways to build health workforce capacity in this country and abroad, and to tailor policies to specific regional situations. For more information on the Forum, visit http://www.academyhealth.org/nhpc/foreignpolicy/

On the Web:

AcademyHealth

GENEVA (Reuters) – Women who take the birth control pill
could increase their risk of cervical and breast cancer,
scientists said on Friday.

A review of research by the International Agency for
Research on Cancer (IARC) in Lyon, France, part of the World
Health Organization, concluded that oral contraceptives
protected against some types of cancer but might trigger
others.

Previously, liver cancer was indicated as a risk for women
who take the pill, IARC said. But the latest research shows
cervical and breast cancer are also possible risks.

The pill can protect against endometrial cancer and ovarian
cancer, IARC said, calling for more research to determine
whether the total net benefits caused by the protective and
carcinogenic effects were positive or negative.

“It is possible that the overall net public health outcome
may be beneficial, but a rigorous analysis is required to
demonstrate this,” the agency said.

“This new information about cancer risks — and also
protection against cancer in the case of oral contraceptives —
makes it important that each woman who uses these hormonal
products discuss the risks and benefits with her doctor,” IARC
said in a statement. At the same time, the IARC working group
of 21 scientists elevated the warning on hormonal menopausal
therapy to “carcinogenic” from “possibly carcinogenic.”

The scientists concluded, based on an expanded study, that
“combined menopausal therapy” increased the risk of breast
cancer and in some cases endometrial cancer.

Worldwide, around 100 million women use oral
contraceptives. In addition, around 20 million women in
developed countries had used hormonal menopausal therapy.

By Patricia Reaney

LONDON (Reuters) – Female circumcision, which is practised
in more than 30 countries and affects 2 million girls each
year, could cause infertility.

Swedish researchers, who examined nearly 300 women in Sudan
where the practice is widespread, said on Friday women who had
undergone circumcision, or female genital mutilation (FGM),
were five to six times more likely to be infertile.

“All sorts of female circumcision, not only the severe
forms, probably cause an increased risk of infertility. This is
a very important argument to be used in areas where this is
practised,” Dr Lars Almroth, a paediatrician and researcher at
the Karolinska Institute in Stockholm, said in an interview.
Despite efforts to stop what human rights campaigners have
described as an atrocity against womanhood, female circumcision
is practised in Africa and is common in some countries in the
Middle East. It involves the removal of part or all of the
female genitalia.

An estimated 135 million women and girls have been
circumcised, according to the human rights group Amnesty
International.

It is considered part of the culture, a tradition or a rite
of passage to adulthood. In some countries it is viewed as a
means of reducing a woman’s sexual desire and of safeguarding
her fertility.

The research, which is published in The Lancet medical
journal, is the first clinical study to show it has the
opposite effect.

“We found that the more extensive form of genital
mutilation, the higher the risk of primary infertility. The
risk is very high — 5 to 6 times higher — than in the other
group,” Almroth said referring to women who had not been not
circumcised.

He and his colleagues believe infertility may be caused by
infection, inflammation, scarring or by the physical
alterations resulting from the circumcision.

In Sudan up to 90 percent of women have had some form of
genital mutilation. The average age of circumcision for women
in the study was 7 but it is performed on girls as young as 4,
according to Almroth.

In some countries crude instruments are used to perform the
circumcision and nothing is given to relieve the girl’s pain.

The researchers examined 99 infertile women and 180 others
who were pregnant for the first time from two hospitals in
Khartoum. They controlled for other factors that could cause
infertility, such as sexually transmitted infections, age and
social and economic conditions.

“It is only female circumcision that stands out,” said
Almroth.

Abstract

Herpes simplex virus (HSV) encephalitis is a life-threatening consequence of HSV infection of the central nervous system. Although HSV encephalitis is rare, mortality rates reach 70 per cent in the absence of therapy and only a minority of individuals return to normal function. Antiviral therapy is most effective when started early, necessitating prompt diagnosis.

A case of atypical HSV encephalitis is reported. The appearance of a strong headache followed by impairment of consciousness and hypertone of arms and legs complicated the post-operative course in a 33-year-old patient who underwent surgical removal of an acoustic neuroma. Several brain magnetic resonance imaging (MRI) and computed tomography scans performed in the first week after onset of symptoms of infection did not establish a proper diagnosis. Diffusion- weighted MRI detected brain abnormalities on the fourth day after onset of symptoms, and polymerase chain reaction identification of HSV 1 DNA confirmed the diagnosis. A positive prognosis was achieved due to the decision to start specific, high-dose antiviral therapy based on clinical suspicion, before a firm diagnosis was established.

Key words: Herpes Simplex; Encephalitis; Acoustic Neuroma

Introduction

The annual estimated incidence of Herpes simplex virus (HSV) encephalitis is one to four cases per million population, and it is the most common nonepidemic cause of viral encephalitis in immunocompetent patients.1 To date, HSV encephalitis complicating the early post-operative course following removal of an acoustic neuroma has not been reported in the literature.

Herpes simplex virus is also the most common cause of sporadic encephalitis throughout the world due to centripetal spread of reactivated virus from cranial nerve ganglia to the brain.

Three possible mechanisms are proposed2 to explain reactivation of HSV in the central nervous system (CNS): (1) reactivation of dormant viral elements located in the sensory ganglia, particularly in the trigeminal nerve ganglion; (2) central spread of a nasal viral infection via the olfactory nerves; and (3) reactivation of latent CNS infection.

Several risk factors for viral infection reactivation have been proposed:3 steroids, radiotherapy, trauma, immunosuppression and stress. Even with adequate treatment, HSV encephalitis infection is associated with a mortality rate of 40 per cent and with a very high incidence of subsequent neurological abnormality among survivors.

We present a case report of atypical HSV encephalitis occurring after surgical removal of an acoustic neuroma, in which early diagnosis and treatment enabled a positive outcome.

Case report

A 33-year-old man was admitted to the ENT clinic of the ‘La Sapienza’ University of Rome for removal of a right acoustic neuroma. The patient’s past medical history (18 months previously) was characterized by right progressive sensorineural hearing loss, tinnitus and dizziness. At the time of admission, the patient had a right pantonal threshold shift of 75 dBHL of hearing loss; the vestibular examination showed a right labyrinthine hyporeflexia with spontaneous nystagmus (third-degree, left-beating) that was reduced by fixation. The neurological assessment ruled out any trigeminal nerve involvement.

Brain magnetic resonance imaging (MRI) detected a 28 33 mm soft- tissue mass in the right cerebellopontine angle.

The patient underwent uneventful tumour resection via a translabyrinthine approach and was then moved to the intensive therapy unit for 24 hours. Post-surgical therapy was: ceftriaxone 2 g twice daily, chloramphenicol 500 mg three times daily, ranitidine 300 mg twice daily, intravenous mannitol 18 per cent 100 cc twice daily and betametasone 4 mg twice daily.

Immediately after surgery, a 4/6 (House-Brackman grading) degree of facial palsy was evident. On the second post-operative day, the patient reported moderate headache and aesthenia and his body temperature was 37C. A blood count showed neutrophilic leukocytosis (23 000 cells/ml) and antibiotic therapy was continued without change. On the seventh post-operative day, the patient complained of a significant worsening of his headache. Brain computed tomography (CT) and MRI scans performed the next day did not detect any significant abnormalities in the brain parenchyma. Ten days after surgery, corresponding to the eighth day after onset of the headache, the patient suddenly developed difficulty talking, somnolence, impairment of consciousness, and hypertone of arms and legs. The body temperature rose to 37.7C and a new blood count showed 20 000/ml leukocytes with a normal differential.

FIG. 1

Magnetic resonance imaging showing hyperintensities at the level of the corpus callosum and corona radiata in (a) FLAIR and (b) diffusion-weighted sequences.

Conventional MRI performed on the 11th post-operative day was negative, whereas fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted sequences showed hyperintensities at the level of the corpus callosum and corona radiata (Figure 1).

Due to suspicion of viral infection, the medical treatment was modified and the patient was commenced on antiviral therapy with high-dose aciclovir (750 mg three times daily intravenous).

FIG. 2

Magnetic resonance imaging showing multiple hyperintense areas of different sizes involving the corpus callosum and corona radiata, associated with bilateral gyral oedema.

A lumbar puncture was performed which detected a slight cerebrospinal fluid (CSF) pleocytosis with 39 cells/ml (28 per cent neutrophils, 32 per cent lymphocytes and 45 per cent monocytes), a normal glucose level (53 mg/dl) and an increased protein level (84.4 mg/dl, with normal rate 15.0-45.0 mg/dl). All bacteriological and fungal cultures of CSF samples obtained during the lumbar puncture were negative, but the results of CSF polymerase chain reaction (PCR) for HSV DNA were positive for HSV type 1 DNA. Finally, brain MRI on the 15th post-operative day showed hyperintense regions of different sizes in multiple areas involving the corpus callosum and corona radiata, associated with bilateral gyral oedema (Figure 2). Based on these findings, the diagnosis of HSV encephalitis was made. The patient underwent therapy for one month and was discharged in good clinical condition. MRI performed three months later excluded the presence of residual infection.

Discussion

Herpes simplex viral encephalitis as a complication of resection of acoustic neuroma has never been described previously, although a cutaneous reactivation of HSV has been reported after manipulation of the facial nerve during surgery for acoustic neuroma.4 In addition, two cases in which fatal HSV encephalitis occurred after a neurosurgical procedure for a high-grade glioma3 and a mcningioma1 have recently been published.

The diagnosis of post-operative HSV encephalitis is difficult because its clinical features can mimic other, more common post- operative complications. Usually, high fever, impairment of consciousness and seizures are the most frequent clinical signs but they are not specific. Brain MRI is the most sensitive imaging modality to detect encephalitis-related cortical changes, especially T2-weighted and FLAIR sequences. In our patient’s MRI, the distribution of cortical lesions (high-intensity signals) shows the well known affinity of HSV for the grey matter of the limbic system.

Our patient’s case displayed many variations from the typical manifestation of HSV encephalitis. The body temperature never reached 38C, seizures were not present, and conventional MRI did detect diffusion abnormalities at the level of the corona radiata and the corpus callosum but only one week after onset of the infection.

According to a very recent study,5 diffusion-weighted MRI should be considered a valuable tool for early detection and diagnosis of HSV encephalitis, whereas contrast-enhanced images are indispensable after the first week.

Polymerase chain reaction identification of HSV 1 DNA has simplified the diagnosis of HSV encephalitis because this method is rapid, sensitive and specific for initial diagnosis and disease monitoring.3 In our patient, the diagnosis of HSV encephalitis was confirmed by the PCR result; however, a positive prognosis was achieved by the decision to start specific, high-dose antiviral therapy based on clinical suspicion, before a firm diagnosis had been established.

* This report documents the clinical course and treatment of a patient developing Herpes simplex virus encephalitis after acoustic neuroma removal

* Diagnosis was by diffusion-weighted MRI and identification of HSV DNA

* Treatment was with high-dose antiviral therapy

References

1 Spuler A, Blaszyk H, Parisi JE, Davis DH. Herpes simplex encephalitis after brain surgery: case report and review of the literature. J Neurol Neurosurg Psychiatry 1999;67:239-42

2 Corey L. Herpes simplex viruses. In: Fauci AS, ed. Harrison’s Principles of Internal Medicine, 14th edn. New York: McGraw-Hill, 1998;1080-6

3 Aldea S, Joly L-M, Roujeau T, Oswald A-M, Devaux B. Postoperative Herpes simplex virus encephalitis after neurosurgery: case report and review of the literature. Clin Infect Dis 2003;36:96- 9

4 Gianoli GJ, Kartush JM. Delayed facial palsy after acoustic neuroma resecti\on: the role of viral reactivation. Am J Otol 1996;96:625-9

5 Kuker W, Nagele T, Schmidt F, Heckl S, Herrlinger U. Diffusion- weighted MRI in herpes simplex encephalitis: a report of three cases. Neuroradiology 2004;46:122-5

ROBERTO FILIPO, MD, GIUSEPPE ATTANASIO, MD, PHD, ELIO DE SETA, MD, MARIKA VICCARO

From the Department of Neurology and Otolaryngology, University ‘La Sapienza’, Rome, Italy.

Accepted for publication: 10 February 2005.

Address for correspondence:

Professor Roberto Filipo,

Dept of Neurology and Otolaryngology,

Viale del Policlinico 155,

Rome 00161, Italy.

E-mail: [email protected]

Professor R Filipo takes responsibility for the integrity of the content of the paper.

Competing interests: None declared

Copyright Royal Society of Medicine Press Ltd. Jul 2005

Jul. 27–DRAPER — For the second time in four months, a major player in Utah’s biomedical industry intends to shut down its manufacturing plant and move hundreds of above-average jobs out of state.

Ballard Medical Products on Tuesday told its 450 employees that the gastroenterology, cardiology and respiratory care devices made in Draper for 27 years would now be produced in Mexico, where labor is cheaper and where parent company Kimberly-Clark already makes 40 percent of such devices.

“Market and competitive pressures have forced all manufacturers to manage costs more efficiently, and Kimberly-Clark Health Care is no exception,” said Joanne Bauer, company president. “We understand that these changes will have a significant impact on our employees at the affected facilities, and we will provide them with maximum support during this time of transition.”

Ballard employees have plenty of company, namely the 750 Hospira workers who learned in March that their employer will strip its Salt Lake City plant and send their jobs to California, Connecticut and Mexico.

Both moves surprised Brian Moss, president of Utah Life Sciences Association. But he does not see either as a sign of big trouble for the state’s biomedical sector. Moss confidently points to other Utah companies — Merit Medical, Becton Dickinson (formerly Deseret Medical) and Cephalon — which plan to create a combined 1,200 jobs in the next few years.

“There’s a big difference between making a highly technical medical device and Kleenex,” Moss said. “I cannot conceive of our very skilled technical jobs being transferred to Mexico . . . and I just don’t see that plant closing down and going away; it will be operated by someone.”

Chris Roybal, Gov. Jon Huntsman Jr.’s senior economic adviser, sees the recent job losses as temporary setbacks.

“It is important to note that Kimberly-Clark [did this] not as a reflection on Utah’s economy, but just that we were caught in the company’s global business plan,” he said.

It was Friday that Dallas-based Kimberly-Clark announced plans to close or sell 20 plants nationwide and slash its work force by 6,000 jobs, or about 10 percent. Ballard, founded in 1978 by late Utah biotechnology entrepreneur Dale H. Ballard, was acquired by Kimberly-Clark in 1999 as part of a $774 million stock deal. On Tuesday, Kimberly-Clark identified the Draper plant, along with a 250-employee facility in Pocatello, Idaho, as among the doomed. The Ogden plant, which makes Huggies and employs 500 workers, will not be affected, company officials said.

John Dodd, head of global manufacturing for Kimberly-Clark, said the company would offer Draper employees job referrals and counseling, along with yet-to-be-detailed severance and benefit packages. The first of the firings won’t take place for at least a month, with the rest staggered out over the next two to three years, he said.

“We’ll begin talking with employees in the next several weeks to let them know what their status will be,” Dodd added, stressing that his company has yet to define a specific work force reduction schedule, though he did confirm Kimberly-Clark would likely discuss the possibility of putting its Draper site up for sale before year’s end.

Roybal cautioned against overreacting to the occasional flow of jobs to Mexico, with which the governor is seeking a trade and commerce pact. “We may, on occasion, lose some jobs but we will gain on a trade basis over time,” he said.

However, nothing is likely to stop the migration of jobs to countries such as Mexico, where manufacturing wages can be a quarter of the cost in the United States.

“This is the ongoing dynamic, especially with the pressure on health care costs,” Richard Davies, managing partner of the Vector Resources biotech consulting firm. “[Hospitals] need to control or reduce their costs, and that puts incredible pressure on the supply side.”

Still, Davies sees medical products development as a strong sector.

“It will continue to be a center of innovation, creation of new and novel devices. We have great minds here,” he said, though adding that outsourcing basic manufacturing abroad for cheaper labor will continue to be a component of the industry.

Brad Bertoch, president of the Wayne Brown Institute and a member of the Utah Technology Industry Council, mused that the lost jobs may find their way back to the Beehive State.

“As companies outsource, they find certain things work well and others don’t. The more technically complicated the job, the less success” of Third World workers meeting stiff regulatory requirements for sales in the United States, he suggested.

“Kimberly-Clark is just bowing to the allure of outsourcing offshore in an effort to improve their bottom line. There could prove to be a lot of problems with that,” Bertoch said.

Meanwhile, Ballard employees, asking to remain unidentified for fear of retribution, took little comfort from the company’s plans to stretch out terminations.

“We knew something was up when corporate and employee assistance people showed up this morning,” one woman said. “We’ve been afraid this would happen.”

Added a male colleague: “A lot of people have been working here a lot of years and really didn’t get much notice this would happen. Now, they are concerned if [Kimberly-Clark] will be true to their word [in phasing jobs out over time].”

Even competitors lamented Ballard Medical’s passing. Fred Lampropoulos, president and CEO of Merit Medical, saw the development as bitter irony, given that “the biomedical industry has been the backbone for this state in the recent recession.”

“It’s a mixed situation for Merit,” he said. “We’re saddened that another company is essentially being shut down. But the positive in this is that many of those employees may become Merit employees as we continue to expand our own operations.”

—–

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Copyright (c) 2005, The Salt Lake Tribune

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

KMB, MMSI, BDX, CEPH,

NEW YORK (Reuters Health) — Shorter men may be more likely than their taller peers to commit suicide — suggesting, researchers say, that various factors related to growth and development also affect suicide risk later in life.

In a study of records for nearly 1.3 million Swedish men, the investigators found that for every 2 inches a man gained in height, his suicide risk dipped by 9 percent. Overall, the shortest men in the study were about twice as likely as the tallest men to commit suicide.

A few previous studies have uncovered a similar height-suicide relationship among men, with some suggestion that income and social class explain the link; children who grow up disadvantaged may have both poorer growth and a higher suicide rates as adults.

But in the current study, neither a man’s education nor his parents’ socioeconomic class significantly affected the link between height and suicide risk.

Still, the findings support the notion that factors in childhood that affect growth and development may be involved in adulthood suicide risk, according to the study authors, led by Dr. Patrik K. E. Magnusson of Uppsala University in Sweden.

The researchers based their findings on records for almost 1.3 million Swedish men who registered for the military draft between 1968 and 1999. The men’s conscription records were linked with public birth, death and census records.

Overall, the researchers found, just over 3,000 men committed suicide, with the risk dipping as a man’s height climbed. Factors such as year of birth, education, parents’ incomes and a record of psychiatric illness at the time of conscription did not explain the height-suicide link.

Magnusson and his colleagues do, however, point to several potential explanations. Psychological stress and a troubled family life, they note, may both impair a child’s growth and raise the risk of suicide later on. There is also some evidence that poor weight gain in infancy is a risk factor for suicide in adulthood.

On the other hand, adulthood factors could also be important. Marriage, the study authors point out, tends to reduce the risk of suicide, and shorter men may be less likely to marry — though in this study, marital status had only a weak effect on the height-suicide relationship.

An alternative explanation, according to Magnusson’s team, is that short men suffer some level of stigmatization or discrimination that makes them more vulnerable to suicidal behavior.

SOURCE: American Journal of Psychiatry, July 2005.

NEW YORK (Reuters Health) – Twins conceived by test tube or
“in vitro fertilization” (IVF) are more likely than twins
conceived through sexual intercourse to be born prematurely and
to be delivered by c-section, a review of previous studies
suggests.

IVF has led to an increase in the number of preterm births
and low birth weight infants, but the mothers of these infants
are typically older and at higher risk of both outcomes,
explain Dr. Sarah McDonald from University of Ottawa, Ontario,
Canada and colleagues in the American Journal of Obstetrics and
Gynecology.

They therefore compared the rate of adverse birth outcomes
for 2303 IVF twins and 2326 spontaneously conceived twins born
to women of similar age.

IVF twins were around 50 percent more likely than
spontaneously conceived twins to be born preterm, the
investigators report, but there were no differences in the
likelihood of having a low birth weight.

IVF twins were also twice as likely to be admitted to the
intensive care unit and 33 percent more likely to undergo
c-section than were spontaneously conceived twins, the report
indicates.

The two groups of twins did not differ in the rates of
stillbirth, very low birth weight, or major complications of
delivery, the researchers note, and there was no difference in
the rate of birth defects.

“IVF twins have worse perinatal outcomes than spontaneously
conceived twins who are matched for maternal age,” the team
concludes.

Possible reasons for the increase in preterm birth “include
a factor inherent to the IVF technology, a history of
infertility itself, or physician or patient anxiety,” the
investigators speculate.

SOURCE: American Journal of Obstetrics and Gynecology, July
2005.

By Pascal Fletcher

CUBAGUA, Venezuela (Reuters) – Those who fear the world’s
economy will crash the day the Earth’s oil reserves run dry can
cite the “pearl island” of Cubagua as a lesson in how not to
exploit a natural resource.

This parched, almost uninhabited, scrub-covered islet off
Venezuela’s eastern coast was once a booming Spanish colonial
trade depot that sent shiploads of glittering pearls to Europe
to adorn the rings, necklaces and robes of monarchs and popes.

Nearly five centuries later, all that remains of one of the
first capitalist export centers of the New World is a dusty and
crumbling patchwork of stone walls, strewn with garbage and
littered with the husks of oysters and other shells.

“These are the ruins of New Cadiz … Now it’s just a
cemetery of sea shells,” said boatman Emilio Suarez, as he
showed visitors around after a bone-jarring one-hour ride
through choppy seas from the nearby island of Coche.

After discovering the Americas in 1492, Christopher
Columbus encountered native Indians wearing strings of pearls
in what is now eastern Venezuela.

Spanish adventurers started using Indian divers to bring up
pearls from the rich oyster banks off Cubagua and founded a
city there, New Cadiz, which was granted its own charter in
1528 by Spain’s King Charles V.

After starting out as a frontier camp of palm thatch huts,
New Cadiz blossomed into a thriving commercial settlement of
1,000 inhabitants, complete with two-story stone houses laid in
a gridiron pattern, a church and a Franciscan monastery.

Such was the fame in Europe of Cubagua’s pearls, reported
to be “the size of hazelnuts,” that Italy’s aristocratic Medici
family even kept a permanent representative there.

But in an orgy of greed and unbridled exploitation lasting
two decades, the Spanish exhausted Cubagua’s pearl banks at the
cost of the lives of hundreds of Indian and black slave divers
who died from fatigue and drowning or were devoured by sharks.

“Cubagua had a fleeting life … By 1540, its production of
pearls had plummeted because of irrational exploitation which
did not allow oysters to reproduce,” said Graziano Gasparini,
one of Venezuela’s leading historians and architects.

DIVINE PUNISHMENT?

In 1541, after the city had survived attacks by pirates and
Indians, a Caribbean hurricane destroyed New Cadiz in what some
contemporary observers saw as divine punishment for the abuses
committed against nature and humanity.

Since then, Cubagua, which has no fresh water source, has
been largely abandoned, populated only by a few fishermen.
Local islanders still sell natural pearls to visitors.

“As the whole city was drowned, no one else has wanted to
settle here,” said Suarez.

He and other locals say a section of the old city of New
Cadiz was submerged under the sea in 1541 and that its outline
can still be made out in the sand and coral.

Gasparini, who took part in one of the first major
excavations of New Cadiz nearly 50 years ago, dismisses this as
a popular myth. “People say you can still hear the bells of the
city ringing underwater … It’s pure fantasy,” he said.

He complained that despite appeals made to successive
Venezuelan governments and local authorities, it had been
impossible to obtain even the most minimal protection for what
was one of the first European cities in the New World.

“It’s little better than a public latrine now,” he said.

While important artifacts like the city shield, seals and
elaborately carved gargoyles have been preserved in museums,
the ruins have suffered heavy pilfering by souvenir-hunters.

“DEVIL’S EXCREMENT”

Archeologists and historians have studied the rise and fall
of New Cadiz as a one of the first documented examples of how
European capitalism, based on a trade monopoly and slave labor,
devastated a natural resource in the Americas.

“It was the most expensive city in the world,” Gasparini
said. Fresh water for Cubagua was fetched by boat from a river
on the mainland and a fort was built to protect this source.
Fruit and vegetables came from the island of Margarita nearby.

“To sustain a city like that, completely artificially, was
only justified by the production of pearls,” Gasparini said.

In their scramble for the pearls, the Spanish adventurers
paid far less attention to a small spring of dark oily liquid
that dribbled into the sea from a tip of the island.

One traveler, Gonzalo Fernandez de Oviedo, said local
inhabitants called the viscous liquid in Latin “stercus
demoniz” (devil’s excrement), or “petrolio.” Fernandez reported
some people said it could be drunk as a cure for gout.

“They didn’t really know what it was … they used it to
caulk their ships,” Gasparini said.

Centuries later, the development by U.S and European
companies of Venezuela’s vast reserves of this “petrolio” has
made it one of the world’s leading crude oil producers.

But that’s another story.