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ContextPremutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are frequent in the general population, with estimated prevalences of 1 per 259 females and 1 per 813 males. Several articles have recently described the presence of late-onset neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified syndrome are cerebellar ataxia and intention tremor. Additional documented symptoms include short-term memory loss, executive functional deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction.ObjectiveTo study the penetrance of the fragile X–associated tremor/ataxia syndrome (FXTAS) among premutation carriers.Design, Setting, and ParticipantsFamily-based study of 192 individuals (premutation carriers and controls) whose families belong to the Northern or Southern California Fragile X Associations. Data were collected (March 2002-April 2003) through a survey and a standardized neurological examination, which was videotaped and subsequently scored in a blinded fashion.Main Outcome MeasuresPenetrance of intention tremor and ataxia among adult carriers (aged ≥50 years) of premutation expansions of the FMR1 gene.ResultsData from the survey of 192 individuals demonstrated an age-related penetrance of the combination of reported intention tremor and gait ataxia in male carriers (17%, 38%, 47%, and 75% [lower-bound estimates] for participants aged 50-59, 60-69, 70-79, and ≥80 years, respectively). The male carrier group had an age-adjusted 13-fold increased risk (95% confidence interval, 3.9-25.4; P = .003) of combined intention tremor and gait ataxia when compared with male controls. The clinical examination data from 93 individuals demonstrated that male carriers experienced more difficulties on each of 3 standardized neurological rating scales compared with controls (P

ContextAn imbalance in vasodilating (prostacyclin [PGI2]) and vasoconstricting (thromboxane A2 [TxA2]) eicosanoids may be important in preeclampsia, but prospective data from large studies needed to resolve this issue are lacking. Because most trials using aspirin to reduce TxA2 production have failed to prevent preeclampsia, it is critical to determine whether eicosanoid changes occur before the onset of clinical disease or are secondary to clinical manifestations of preeclampsia.ObjectiveTo determine whether PGI2 or TxA2 changes occur before onset of clinical signs of preeclampsia.Design, Setting, and ParticipantsMulticenter prospective study from 1992 to 1995 of subjects from the placebo arm of the Calcium for Preeclampsia Prevention Trial. Women who developed preeclampsia (n=134) were compared with matched normotensive control women (n=139).Main Outcome MeasuresExcretion of urinary metabolites of PGI2 (PGI-M) and TxA2 (Tx-M) as measured from timed urine collections obtained prospectively before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation.ResultsWomen who developed preeclampsia had significantly lower PGI-M levels throughout pregnancy, even at 13 to 16 weeks' gestation (long before the onset of clinical disease); their gestational age–adjusted levels were 17% lower than those of controls (95% confidence interval [CI], 6%-27%; P=.005). The Tx-M levels of preeclamptic women were not significantly higher overall (9% higher than those of controls; 95% CI, −3% to 23%; P=.14). The ratio of Tx-M to PGI-M, used to express relative vasoconstricting vs vasodilating effects, was 24% higher (95% CI, 6%-45%) in preeclamptic women throughout pregnancy (P=.007).ConclusionsOur results show that reduced PGI2 production, but not increased TxA2 production, occurs many months before clinical onset of preeclampsia. Aspirin trials may have failed because an increase in thromboxane production is not the initial anomaly. Future interventions should make correcting prostacyclin deficiency a major part of the strategy to balance the abnormal vasoconstrictor-vasodilator ratio present in preeclampsia.

ContextPreeclampsia may be caused by an imbalance of angiogenic factors. We previously demonstrated that high serum levels of soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and low levels of placental growth factor (PlGF), a proangiogenic protein, predict subsequent development of preeclampsia. In the absence of glomerular disease leading to proteinuria, sFlt1 is too large a molecule to be filtered into the urine, while PlGF is readily filtered.ObjectiveTo test the hypothesis that urinary PlGF is reduced prior to onset of hypertension and proteinuria and that this reduction predicts preeclampsia.Design, Setting, and PatientsNested case-control study within the Calcium for Preeclampsia Prevention trial of healthy nulliparous women enrolled at 5 US university medical centers during 1992-1995. Each woman with preeclampsia was matched to 1 normotensive control by enrollment site, gestational age at collection of the first serum specimen, and sample storage time at −70°C. One hundred twenty pairs of women were randomly chosen for analysis of serum and urine specimens obtained before labor.Main Outcome MeasureCross-sectional urinary PlGF concentrations, before and after normalization for urinary creatinine.ResultsAmong normotensive controls, urinary PlGF increased during the first 2 trimesters, peaked at 29 to 32 weeks, and decreased thereafter. Among cases, before onset of preeclampsia the pattern of urinary PlGF was similar, but levels were significantly reduced beginning at 25 to 28 weeks. There were particularly large differences between controls and cases of preeclampsia with subsequent early onset of the disease or small-for-gestational-age infants. After onset of clinical disease, mean urinary PlGF in women with preeclampsia was 32 pg/mL, compared with 234 pg/mL in controls with fetuses of similar gestational age (P

ContextA recent meta-analysis found calcium supplementation to be highly effective in preventing preeclampsia but a large National Institutes of Health trial (Calcium for Preeclampsia Prevention [CPEP]) found no risk reduction due to calcium in healthy nulliparous women.ObjectivesTo resolve discrepancies between the results of the meta-analysis and the CPEP trial and to assess the role of effect heterogeneity in the discrepancies.Data SourcesLiterature search of English-language articles published prior to July 10, 1997, the date of publication of the CPEP trial, using MEDLINE and by a manual search of bibliographies of published articles.Study SelectionTrials were included if they reported data on preeclampsia and calcium supplementation. Fourteen trials were systematically evaluated for differences in study design and patient populations. One trial was excluded because its results were reported after publication of the major CPEP results.Data ExtractionThe sample size and number of subjects who developed preeclampsia in the calcium supplementation group vs a control group were recorded and analyzed on an intent-to-treat basis. Each author independently extracted the data.Data SynthesisSubstantial heterogeneity existed across trials (P=.001). After stratifying studies by the presence of a placebo-controlled group and by high-risk and low-risk populations, the conclusions of the meta-analysis of placebo-controlled trials enrolling a low-risk population (relative risk, 0.79; 99% confidence interval, 0.44-1.42; P=.30) were compatible with the conclusions of the CPEP trial that calcium supplementation does not prevent preeclampsia in healthy nulliparous women. In contrast, the data implied a strong beneficial calcium effect (relative risk, 0.19; 99% confidence interval, 0.08-0.46; P=.001) in healthy high-risk subject populations. However, only 225 women were analyzed and because of inconsistent data, these results remain equivocal.ConclusionsFurther studies are needed to establish the efficacy of calcium for preeclampsia prevention in healthy high-risk populations. A single summary measure does not adequately describe the findings of a meta-analysis when the observed effects in individual studies differ substantially. In such settings the primary focus should be to identify and incorporate pertinent covariates that reduce heterogeneity and allow for optimum treatment strategies.

Five hundred eighty-three patients and 451 medical personnel of 15 hemodialysis centers were surveyed for hepatitis B infections. Hepatitis B antigen (HB Ag) was detected in 16.8% of the patients and in 2.4% of the medical staff; specific antibody to HB Ag (HB Ab) was detected in 34.0% and 31.3%, respectively. The cumulative prevalence of HB Ag and HB Ab varied widely among the centers. The prevalence of HB Ag or HB Ab in patients was related to duration of dialysis treatment, but not to blood transfusions. Significant differences in prevalence of serologic indicators of hepatitis B infection among various staff categories were not observed. Sixty-one percent of family contacts of dialysis patients with a history of hepatitis B infection were found to have HB Ag or HB Ab.