New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate.

BACKGROUND: Hypointense lesions on T1 weighted MRI, referred to as black holes (BH), are a marker of demyelination/axonal loss in multiple sclerosis (MS). There is some evidence that glatiramer acetate (GA) may decrease the conversion of new brain lesions to BH. METHODS: Monthly 3-Tesla brain MRI scans were used for up to 2 years to study the development and evolution of new BH in 75 patients with MS randomised to GA or Interferon beta-1b (IFNbeta1b) in the BECOME study. FINDINGS: Of 1224 newly enhancing lesions (NEL) appearing at baseline through 24 months in 61 patients, 767 (62.7%) showed an acute BH (ABH). The majority of ABH were transient and of similar duration by treatment group. Of 571 ABH in which MRI follow-up scans were available for >or=1 year, 103 (18.8%) were still visible >or=12 months after onset and were considered chronic BH (CBH). Only 12.1% of the 849 NEL with MRI follow-up >or=1 year converted to CBH, 9.8% with IFNbeta1b and 15.2% with GA (p = 0.02). The conversion from ABH to CBH was also lower with IFNbeta1b (15.2%) than with GA (21.4%), of borderline significance (p = 0.06). The majority of patients who developed NEL did not develop CBH; however, about a quarter had conversion rates from ABH to CBH greater than 20%. INTERPRETATION: Only a minority of new brain lesions in patients with MS treated with GA or IFNbeta1b convert to CBH.

Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study.

BACKGROUND: There are no published MRI studies comparing interferon beta 1b (IFNbeta-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS). OBJECTIVE: To compare the efficacy of IFNbeta-1b and GA for suppression of MS disease activity as evidenced on frequent brain MRI. METHODS: A total of 75 patients with relapsing-remitting MS or clinically isolated syndromes were randomized to standard doses of IFNbeta-1b or GA and followed by monthly brain MRI for up to 2 years with a protocol optimized to detect enhancement. The primary outcome was the number of combined active lesions (CAL) per patient per scan during the first year, which included all enhancing lesions and nonenhancing new T2/fluid-attenuated inversion recovery (FLAIR) lesions. Secondary outcomes were the number of new lesions and clinical exacerbations over 2 years. RESULTS: Baseline characteristics were similar between the groups. The primary outcome showed similar median (75th percentile) CAL per patient per scan for months 1-12, 0.63 (2.76) for IFNbeta-1b, and 0.58 (2.45) for GA (p = 0.58). There were no differences in new lesion or clinical relapses for 2 years. Only 4.4% of CAL on monthly MRI scans were nonenhancing new T2/FLAIR lesions. CONCLUSION: Patients with relapsing multiple sclerosis randomized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity.

Leukocytes of exceptionally old persons display ultra-short telomeres.

With a view to understanding the association between leukocyte telomere length and the human lifespan, we performed genome-wide telomere length analyses by the terminal restriction fragment length (TRFL) and single molecule telomere length analysis (STELA) of the X and Y chromosomes in leukocytes of exceptionally old (aged 90-104 yr) and younger (aged 23-74 yr) individuals. We found that the mean TRFL of 82 exceptionally old individuals was within a range projected by age-dependent TRFL attrition of 99 younger individuals. However, compared with the younger individuals, exceptionally old persons exhibited peaking of the TRFL distribution with overrepresentation of ultra-short telomeres. These findings were confirmed by the STELA. Women had longer mean TRFL than men (6.10 vs. 5.86 kb), and exceptionally old women exhibited fewer ultra-short telomeres than exceptionally old men. Our results have implications for gerontological studies of the limitation of lifespan in humans.

Mortality in African-Americans with Type 1 diabetes: The New Jersey 725.

AIM: To determine rates and risk factors for all-cause mortality in African-Americans with Type 1 diabetes from a 3-year observational follow-up study of 725 African-Americans with Type 1 diabetes conducted between 1 January 1999 and 31 December 2001. METHODS: Date of death was ascertained either from telephone contact with the patient's family or from relatives or on line review of the US Social Security death index. RESULTS: Since the initial examination, 131 (18.1%) patients, 60 (20%) men and 71 (17%) women, have died. At the time of death, the mean age of the men was 40.7 +/- 10.6 years and that of the women 39.4 +/- 10.5 years. The median duration of diabetes at the baseline examination was 8.04 years, interquartile range (IQR) 3.76-15.22 years for men and median 10.54, IQR 4.49-18.36 years for women. Three-year mortality rates were 7.1% for women and 10.6% for men. Age-adjusted mortality rates were not significantly different between men and women. Relative to the general US and the New Jersey African-American population, standardized mortality ratios of African-Americans with Type 1 diabetes were 12 and six times greater for women and men, respectively. Older age, low socio-economic status, low body mass index, high diastolic blood pressure, macroangiopathy, proteinuria, severe diabetic retinopathy and heavy alcohol consumption were independent risk factors for all-cause mortality. In patients with microproteinuria at initial examination, the mortality rate for men was twice that of women. CONCLUSION: Microproteinuria and other potentially modifiable factors, including hypertension, macroangiopathy and heavy alcohol consumption, are independent risk factors for mortality in this ethnic group.

Age-dependent telomere attrition as a potential indicator of racial differences in renal growth patterns.

BACKGROUND: Racial differences in the predilection to salt sensitivity may arise from different renal growth patterns. To test this idea, we monitored age-dependent telomere attrition rate, reflecting largely the replicative history of somatic cells, in the outer renal cortex and the inner renal medulla of African Americans and Caucasians. METHODS: Telomere length, determined by the mean length of the terminal restriction fragments (TRF), was measured in specimens from 58 African-American and 63 Caucasian males, ages 1 day to 71 years. RESULTS: In the outer renal cortex, TRF length attrition rate was significantly slower in African Americans (-0.021 +/- 0.0064 kb/year) than in Caucasians (-0.060 +/- 0.0094 kb/year) (p = 0.0007). In both ethnic groups the TRF length attrition rate was slower in the inner medulla than in the outer renal cortex, but without significant racial differences. CONCLUSIONS: The proximal tubule is the most abundant nephron structure in the outer renal cortex. Less proliferative growth of proximal tubular cells in kidneys from African Americans may be one factor explaining the slower age-dependent telomere attrition rate in the outer renal cortex of African Americans than in Caucasians.

Presence and quantification of macrophages in squamous cell carcinoma of the cervix.

Cervical cancer is a major cause of morbidity and mortality in women. The presence of macrophages as well as other inflammatory cells has been noted in many of these tumors. Intratumoral macrophages/monocytes induce anergy to cytokine therapy and cause apoptosis in natural killer(NK) and T cells. The aim of this study was to better evaluate and quantify the presence of macrophages in these tumors. Twenty-four cases of squamous cell carcinoma of the cervix seen at our institution were evaluated. Sections were stained with CD68, a marker for macrophages. Staining was graded microscopically by two reviewers together on a scale of 0-4+, with 4+ representing the greatest number of positive cells. Image analysis was conducted to quantify the percent area stained in a given lesion. For each lesion, 10 fields were evaluated, and a mean percentage area stained was calculated. 4+ staining was observed in five cases, 3+ in zero cases, 2+ in three cases, 1+ in six cases, 1-2+ in one case, and nine cases were negative. Image analysis results correlated well with the light microscopic scoring. Presence of a prominent infiltrate of macrophages did not correlate with tumor grade or with histologic lymph node status, but showed a strong negative correlation with tumor stage. Some squamous cell carcinomas of the cervix show a prominent macrophage component in the tumor-associated inflammatory infiltrate. The presence of this prominent infiltration of macrophages did not correlate with tumor grade or lymph node status, but showed a strong negative correlation with tumor stage. The results suggest that immunotherapy may have a potential role in the treatment of cervical carcinoma. Computerized image analysis appears to be a valid measure to assess macrophage counts in such lesions.

Age dependent aneuploidy and telomere length of the human vascular endothelium.

RATIONALE: Aneuploidy and telomere length are two major parameters that have been associated with cellular senescence in vitro. In order to explore the role of aneuploidy and telomere length in aging of the human vasculature, we studied these two parameters in direct preparations of endothelial cells of the human abdominal aorta. METHODS: Using fluorescent in situ hybridization on 'touch prep' slides, we evaluated aneuploidy of two autosomes (chromosomes 6 and 16) and sex chromosomes in non cultured endothelial cells of the abdominal aorta as a function of the donor's age. RESULTS: We found that the frequency of aneuploidy of vascular endothelial cells significantly increased with age. This was expressed by age-dependent tetrasomy (r(s)=0.56, P=0.006 for chromosome 6; and r(s)=0.54, P=0.008 for chromosome 16), and age dependent loss of the Y chromosome (r(s)=0.85, P=0.0003). In addition, we found that telomere length was inversely correlated with age (r=-0.38, P=0.008). DATA INTERPRETATION: These findings suggest that indicators of cellular senescence, earlier observed in vitro, are also expressed in the human vascular endothelium in vivo. Aneuploidy and telomere attrition might thus play a role in the aging of the human vasculature.

Free fluid on abdominal computed tomography without solid organ injury after blunt abdominal injury does not mandate celiotomy.

BACKGROUND: Mandatory celiotomy has been proposed for all patients with unexplained free fluid on abdominal computed tomography (CT) scanning after blunt abdominal injury. This recommendation has been based upon retrospective data and concerns over the potential morbidity from the late diagnosis of blunt intestinal injury. This study examined the rate of intestinal injury in patients with free fluid on abdominal CT after blunt abdominal trauma. METHODS: This study was a multicenter prospective series of all patients with blunt abdominal trauma admitted to four level I trauma centers over 22 months. Data were collected concurrently at the time of patient enrollment and included demographics, injury severity score, findings on CT scan, and presence or absence of blunt intestinal injury. This database was specifically queried for those patients who had free fluid without solid organ injury. RESULTS: In all, 2,299 patients were evaluated. Free fluid was present in 265. Of these, 90 patients had isolated free fluid with only 7 having a blunt intestinal injury. Conversely, 91% of patients with free fluid did not. All patients with free fluid were observed for a mean of 8 days (95% confidence interval 6.1 to 10.4, range 1 to 131). There were no missed injuries. CONCLUSIONS: Free fluid on abdominal CT scan does not mandate celiotomy. Serial observation with the possible use of other adjunctive tests is recommended.

Human papillomavirus typing in HIV-positive women.

OBJECTIVE: Human papillomavirus (HPV) is the major cause of cervical carcinoma and cervical intraepithelial neoplasia worldwide. Certain HPV types have a strong association with and probably a causative role in the pathogenesis of premalignant cervical lesions. Epidemiologic studies in women infected by the human immunodeficiency virus (HIV) have shown an increased incidence of squamous intraepithelial lesions (SILs), which were predominantly high-grade. Six to 30 per cent of women diagnosed with atypical squamous cells of undetermined significance (ASCUS) on a Papanicolaou (Pap) smear harbor SIL in normal screening populations. This study was undertaken to determine the presence of low-and high-risk HPV types in women infected by HIV and to correlate the results to those of the Pap smear. STUDY DESIGN: HPV DNA typing (low- and high-risk) by Digene (Digene Corporation, Gathesburg, MD) hybrid capture methodology was performed on cervical swabs from 209 HIV-positive women. The results of HPV typing were correlated with those of the Pap smear in a retrospective analysis. RESULTS: One hundred and one women (48%) tested positive for HPV subtypes by DNA typing by the hybrid capture method. Of these, 64 patients (63%) had Pap smears which were read as being normal, having benign cellular changes, or having ASCUS (favor reactive process). Of these, 19 patients tested positive for both high-risk and low-risk subtypes, 32 patients tested positive only for high-risk subtypes, and 13 patients tested positive only for low-risk subtypes. CONCLUSION: HPV subtyping identifies a significant group of HIV-positive women who are at risk for developing cervical intraepithelial neoplasia, although they may not show significant abnormalities on their Pap smears.

Factors associated with age at natural menopause in a multiethnic sample of midlife women.

An unprecedented number of women will experience menopause in the next decade. Although the timing of menopause affects long-term disease risk, little is known about factors that affect this timing. In the present 1995--1997 cross-sectional study, the Study of Women's Health Across the Nation, the relation of demographic and lifestyle factors to age at natural menopause was examined in seven US centers and five racial/ethnic groups. All characteristics were self-reported by women aged 40--55 years (n = 14,620). Cox proportional hazards models were used to estimate the probability of menopause by age. Overall, median age at natural menopause was 51.4 years, after adjustment for smoking, education, marital status, history of heart disease, parity, race/ethnicity, employment, and prior use of oral contraceptives. Current smoking, lower educational attainment, being separated/widowed/divorced, nonemployment, and history of heart disease were all independently associated with earlier natural menopause, while parity, prior use of oral contraceptives, and Japanese race/ethnicity were associated with later age at natural menopause. This sample is one of the largest and most diverse ever studied, and comprehensive statistical methods were used to assess factors associated with age at natural menopause. Thus, this study provides important insights into this determinant of long-term disease risk in women.

Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity.

Chronological age is the primary determinant of stiffness of central arteries. Increased stiffness is an independent indicator of cardiovascular risk. The aim of this study was to determine whether telomere length, a possible index of biological aging, provides a better account than chronological age for variation in arterial stiffness, evaluated by measuring pulse pressure and aortic pulse wave velocity. The study population included 193 French subjects (120 men, 73 women), with a mean age of 56+/-11 years, who were not on any antihypertensive medications. Telomere length was evaluated in white blood cells by measuring the mean length of the terminal restriction fragments. Age-adjusted telomere length was longer in women than in men (8.67+/-0.09 versus 8.37+/-0.07 kb; P=0.016). In both genders, telomere length was inversely correlated with age (P<0.01). Multivariate analysis showed that in men, but not in women, telomere length significantly contributed to pulse pressure and pulse wave velocity variations. In conclusion, telomere length provides an additional account to chronological age of variations in both pulse pressure and pulse wave velocity among men, such that men with shorter telomere length are more likely to exhibit high pulse pressure and pulse wave velocity, which are indices of large artery stiffness. The longer telomere length in women suggests that for a given chronological age, biological aging of men is more advanced than that of women.

Luteal progesterone relates to histological endometrial maturation in fertile women.

To examine the relationship between endometrial histological maturation and reproductive hormones, we studied 11 fertile women, aged 18-37 yr. All participants had had at least 1 previous pregnancy and cycled regularly, every 25-35 days. Women collected daily, first morning voided urine for measurement of estradiol and progesterone metabolite excretion, estrone conjugates (E1c), and pregnanediol glucuronide (Pdg), respectively, throughout the cycle of study. Hormones were normalized for creatinine. Between 7-9 days after home detection of a LH surge (Sure Step), participants underwent an endometrial biopsy using a small bore (Pipelle) catheter. Tissue was prepared for histological and biochemical analyses. The histological analysis is reported herein. Endometrium was dated by 3 authors (N.S., D.H., and S.P.), all of whom were blinded to the participant's identity or timing of biopsy within her cycle. Final dating was agreed upon based upon the method of Noyes et al. E1c and Pdg were integrated throughout the cycle using the trapezoidal rule, and correlations were sought between deviation from expected histology (based upon urinary hormones and LH surge) and integrated hormone values. E1c varied over a 2-fold range in these normal women, from 1196-2040 ng/cycle. Pdg excretion was much more variable, ranging from 22-119 microg/cycle. No relationship could be found between histological lagging of endometrial maturation and lower excretion of E1c. A moderate correlation was observed (Spearman's r = 0.6; P < 0.05) between degree of histological maturation and integrated Pdg. Of two women with evidence of a disparity between gland and stromal development (glands lagging behind stroma by >2 days), one excreted 24 microg Pdg/cycle, the next to lowest value. We conclude that normal fertile women experience a wide range of hormone concentrations in the face of normal endometrial maturation. Progesterone appears to exert a dose-related effect on endometrial maturation, and the techniques we used, although relatively crude clinical measures, appeared to be sufficient to detect this relationship.

Reliability of frozen section of uterine curettings in evaluation of possible ectopic pregnancy.

STUDY OBJECTIVE: To assess the accuracy of frozen section evaluation of uterine curettings to look for chorionic villi and rule out ectopic pregnancy before laparoscopy. DESIGN: Retrospective review (Canadian Task Force classification III). SETTING: Northeastern medical school-affiliated teaching hospital. PATIENTS: Thirty-six women. Intervention. Dilatation and curettage, laparoscopy, and laparotomy. MEASUREMENTS AND MAIN RESULTS: Of 36 cases, 13 showed evidence of intrauterine pregnancy, either chorionic villi or implantation site, on final permanent sections. Five false negatives were identified in which no villi were identified on frozen section, although villi or evidence of an implantation site was noted on permanent sections (sensitivity 62%, 95% CI 0.32, 0.86). CONCLUSION: Frozen section evaluation of uterine curettings can produce false negative diagnoses, and this should be considered in the operative planning of women with suspected ectopic pregnancy.

Prevention of nosocomial bloodstream infections: effectiveness of antimicrobial-impregnated and heparin-bonded central venous catheters.

OBJECTIVES: To examine the effectiveness of antimicrobial-impregnated and heparin-bonded catheters relative to standard central venous catheters in lessening catheter-related bloodstream infections. DATA SOURCES: Articles were identified by computer-assisted searching. STUDY SELECTION: Studies were eliminated from further consideration if they did not contain original data relevant to lessening catheter-related bloodstream infections, were nonrandomized or uncontrolled, described subjects <17 yrs of age, or used animal subjects. DATA ABSTRACTION: From each eligible article, we abstracted the following: a) citation; b) type of control; c) study setting; d) type of experimental catheter; e) catheter-specific complications; f) total numbers of patients and catheters; g) number of experimental catheters used that resulted in a catheter-related bloodstream infection; h) number of control catheters used that resulted in a catheter-related bloodstream infection; i) number of experimental catheters used without catheter-related bloodstream infections; and j) number of control catheters used without infections. We also recorded the duration of catheter use and the types of microbes cultured in association with the catheters and with catheter-related bloodstream infections. DATA SYNTHESIS: Eleven eligible studies were identified. Using meta-analysis, we showed that antimicrobial-impregnated and heparin-bonded central venous catheters significantly decreased catheter-related bloodstream infections by 2.32% (95% confidence interval, 1.04% to 3.61%). CONCLUSIONS: The modest additional cost for the use of these catheters relative to the considerable cost of treating even a single bloodstream infection makes their use cost-effective.

Status of selected nutrients and progression of human immunodeficiency virus type 1 infection.

BACKGROUND: Immune function is highly dependent on nutritional status because the large mass and high rate of cellular turnover of the immune system make it a major user of nutrients. Furthermore, nutrient requirements may be increased during acute and chronic infections, including HIV-1 infection. OBJECTIVE: The current study was designed to assess relations among HIV-1 progression and 11 nutritional and demographic variables. DESIGN: The participants were 106 HIV-infected outpatients and 29 uninfected control subjects (n = 89 men and 46 women; age range: 35-57 y). The HIV-infected subjects represented a broad range of disease progression. RESULTS: We found lower concentrations of plasma and erythrocyte magnesium and of erythrocyte reduced glutathione beginning early in the course of HIV-1 infection. Significantly decreased hematocrit and increased serum copper concentration developed only late in the course of the disease. Statistically significant univariate associations were found between the CD4(+) T lymphocyte count and hematocrit, plasma magnesium concentration, and plasma zinc concentration. The lowest erythrocyte magnesium concentrations occurred in HIV-infected subjects who consumed alcoholic beverages. Independent variables that were significant joint predictors of CD4(+) cell count in multiple regression analyses were hematocrit and plasma free choline and zinc concentrations. These 3 factors together explained 43% of the variability in CD4(+) cell counts. CONCLUSION: The results provide evidence that compromised nutritional and antioxidant status begin early in the course of HIV-1 infection and may contribute to disease progression.

Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosis.

Little is known about the turnover rate (i.e. the rate of replication and death) of cells in the intima and media of human arteries as a function of age and atherosclerosis. One indicator of the replicative history of cells is telomere length. In this work we explored the rate of telomere attrition as a function of age and atherosclerosis in cells of the human abdominal aorta. Telomere length, measured by the terminal restriction fragment using Southern analysis, was determined in the intima and media of the distal (infrarenal) versus proximal (suprarenal) segments of the abdominal aorta. Telomere length was then correlated with age and atherosclerotic grade. The rate of age-dependent telomere attrition was higher in both the intima and media of the distal versus proximal abdominal aorta. In addition, telomere length was negatively correlated with atherosclerotic grade. However, after adjustment for age, this relationship was not statistically significant. The high rate of age-dependent telomere attrition in the distal abdominal aorta probably reflects enhanced cellular turnover rate due to local factors such as an increase in shear wall stress in this vascular segment.

Telomere length inversely correlates with pulse pressure and is highly familial.

There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging.

Emergency department discharge of patients with a negative cranial computed tomography scan after minimal head injury.

OBJECTIVE: To determine the negative predictive value of cranial computed tomography (CT) scanning in a prospective series of patients and whether hospital admission for observation is mandatory after a negative diagnostic evaluation after minimal head injury (MHI). SUMMARY BACKGROUND DATA: Hospital admission for observation is a current standard of practice for patients who have sustained MHI, despite having undergone diagnostic studies that exclude the presence of an intracranial injury. The reasons for this practice are multifactorial and include the perceived false-negative rate of all standard diagnostic tests, the belief that admission will allow prompt diagnosis of occult injuries, and medicolegal considerations about the risk of early discharge. METHODS: In a prospective, multiinstitutional study during a 22-month period at four level I trauma centers, all patients with MHI were evaluated using the following protocol: a standardized physical and neurologic examination in the emergency department, cranial CT scanning, and then admission for observation. MHI was defined as either a documented loss of consciousness or evidence of posttraumatic amnesia and an emergency department Glasgow Coma Scale score of 14 or 15. Outcomes were measured at 20 hours and at discharge and included clinical deterioration, need for craniotomy, and death. RESULTS: Two thousand one hundred fifty-two consecutive patients fulfilled the study protocol. The CT was interpreted as negative for intracranial injury in 1,788, positive in 217, and equivocal in 119. Five patients with CT scans initially interpreted as negative required intervention. There was one craniotomy in a patient whose CT scan was initially interpreted as negative. This patient had facial fractures that required surgical intervention and elevation of depressed intracranial fracture fragments. The negative predictive power of a cranial CT scan based on the preliminary reading of the CT scan and defined by the subsequent need for neurosurgical intervention in the population fully satisfying the protocol was 99.70%. CONCLUSIONS: Patients with a cranial CT scan, obtained on a helical CT scanner, that shows no intracerebral injury and who do not have other body system injuries or a persistence of any neurologic finding can be safely discharged from the emergency department without a period of either inpatient or outpatient observation. Implementation of this practice could result in a potential decrease of more than 500,000 hospital admissions annually.

HIV heterosexual transmission: a hypothesis about an additional potential determinant.

Transmission rates of human immunodeficiency virus (HIV) during heterosexual intercourse vary dramatically around the world. In Asia and South America, they are extraordinarily high, whereas in the United States and Europe, rates are much lower even after a large number of unprotected contacts. The transmission rates in Africa also probably are high, but the available studies unfortunately are weak. In Thailand, female-to-male transmission rates per contact were estimated at.056 (l in 18) compared to.0002 to.0015 (1/5000-1. 5/1000) for male-to-female transmission in the United States and Europe. Male-to-female transmission in Thailand appears to show, as expected, even greater transmission likelihood compared to female-to-male rates. In general, in the United States and Europe, transmission rates within heterosexual couples range from less than 10% to 22%, whereas in Thailand and Brazil, the rates exceed 40%. The much lower transmission rate per contact in the United States and Europe is based on an assumption that HIV transmitters are a homogeneous group. Wiley and colleagues argue that transmitters are likely to be a heterogeneous group with a large percentage of very low frequency transmitters and a small percentage of high frequency transmitters. That hypothesis is given some support by a cluster of cases in rural New York State in which one man appeared to infect 31% of his many contacts.

Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women.

OBJECTIVE: We hypothesized that the increased FSH noted in older reproductive-aged women is due to both decreased inhibin and increased activin A secretion. DESIGN: Comparative clinical study. SETTING: An academic research center. PATIENT(S): Five cycling women, aged 43 to 47, were compared to five midreproductive women, aged 19 to 38. INTERVENTION(S): Specimens taken every 2 to 3 days were assayed for inhibin A and B and activin A. MAIN OUTCOME MEASURE(S): Integrated concentrations of inhibin A, inhibin B, and activin A in the follicular phase, luteal phase, and whole cycle. RESULT(S): Follicular inhibin B was reduced in older versus younger women (504 +/-82 versus 748+/-72 total pg). Luteal inhibin A was reduced in older versus younger women (668 +/-72 versus 1152+/-216 total pg). Activin A was elevated throughout the cycle of older versus younger women, without within-cycle fluctuations (21+/-2 versus 11+/-1 total ng). CONCLUSION(S): Lack of restraint by inhibin A and inhibin B contributes to the FSH rise associated with reproductive aging. This loss of restraint occurs in a tandem fashion, with inhibin B reduction before ovulation and inhibin A reduction after ovulation. Activin A may also play an endocrine role in maintaining elevated FSH in older reproductive-aged women.