Clinical consequences of MRI activity in treated multiple sclerosis.

BACKGROUND: Inflammation on brain MRI is the most sensitive marker of disease activity in multiple sclerosis (MS) but its clinical consequences remain controversial. OBJECTIVE: Here we investigated the clinical consequences of MRI activity in MS subjects treated with two different first line disease modifying agents. METHODS: Seventy-five treatment-naïve subjects with relapsing-remitting MS (N = 61) or clinically isolated syndromes at risk of MS (N = 14) from the BECOME study that had been randomized to interferon beta-1b (N = 39) or glatiramer acetate (N = 36) and followed for up to two years by monthly brain MRI optimized to detect inflammatory activity were studied for the clinical consequences of lack of MRI remission. RESULTS: MRI remission occurred in 46.4% of participants transiently and in 23.2% completely while it was never achieved in 30.4%. There was no difference by treatment in MRI remission, progression of physical disability, or cognitive function. The percentage of relapse-free subjects was 87.5% for the group in complete MRI remission, 47.6% in the group never in remission and 59.4% in the group in transient remission (p = 0.017). Similar differences were observed for six-month-confirmed worsening of ambulatory function as measured by the timed 25 foot walk (p = 0.026) and by Expanded Disability Status Scale (EDSS) (p = 0.10). Cognitive function was lowest at baseline for the group that never reached MRI remission on treatment; this group improved the least upon repeated cognitive testing during the two years of treatment (p < 0.001). CONCLUSIONS: Lack of MRI remission during treatment with interferon beta-1b or glatiramer acetate is associated with higher relapse rate and worsening of physical and cognitive function.

Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths.

In this protocol we describe a method to obtain telomere length parameters using Southern blots of terminal restriction fragments (TRFs). We use this approach primarily for epidemiological studies that examine leukocyte telomere length. However, the method can be adapted for telomere length measurements in other cells whose telomere lengths are within its detection boundaries. After extraction, DNA is inspected for integrity, digested, resolved by gel electrophoresis, transferred to a membrane, hybridized with labeled probes and exposed to X-ray film using chemiluminescence. Although precise and highly accurate, the method requires a considerable amount of DNA (3 µg per sample) and it measures both the canonical and noncanonical components of telomeres. The method also provides parameters of telomere length distribution in each DNA sample, which are useful in answering questions beyond those focusing on the mean length of telomeres in a given sample. A skilled technician can measure TRF length in ∼130 samples per week.

Sex differences in pulse pressure trends with age are cross-cultural.

Sex differences in systolic and diastolic blood pressure levels and trends with age have been consistently observed in both industrialized and unindustrialized populations. However, the impact of sex on pulse pressure, an index of vascular aging, in unindustrialized populations has not been addressed. The objective of this report was to characterize sex differences in aging trends of pulse pressure within unindustrialized populations. Using PubMed and Medline, we identified 60 articles with blood pressure data from unacculturated or partially acculturated populations. Data on 27 populations from 22 articles were included for analysis, on the basis of adequate description of study design and blood pressure measurement. Blood pressure means of adult age groups were modeled by linear and polynomial regression. The pulse pressure levels of women were lower than those of men in early adulthood and higher in older ages. Women had a steeper, steady increase in pulse pressure with age than men (P<0.001), whereas men had a stronger curvilinear upswing in pulse pressure with age (P=0.006). Partially acculturated populations had higher pulse pressures than unacculturated populations. Sex had a stronger effect on pulse pressure than acculturation. Pulse pressure trajectories of unindustrialized populations were slightly attenuated compared with those seen in National Health and Nutritional Examination Surveys III and IV of the US population. A sex effect on pulse pressure trends with age prevails across unacculturated and acculturated populations. Accordingly, the biological principles of arterial aging, as expressed in pulse pressure, are the same in all humans, regardless of demography.

Association of adolescent obesity and lifetime nulliparity--the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: To evaluate whether adolescent obesity is associated with difficulties in becoming pregnant later in life. DESIGN: Cross-sectional analysis of baseline data from a longitudinal cohort. SETTING: Multiethnic, community-based observational study of U.S. women. PATIENT(S): Three thousand one hundred fifty-four midlife women. MAIN OUTCOME MEASURE(S): Lifetime nulliparity and lifetime nulligravidity. RESULT(S): Five hundred twenty-seven women (16.7%) women had never delivered a baby. Participants were categorized by self-reported high school body mass index (BMI): underweight (<18.5 kg/m(2)), normal (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (>30 kg/m(2)). The prevalence of lifetime nulliparity increased progressively across the high school BMI categories: 12.7%, 16.7%, 19.2%, and 30.9%, respectively. Multivariable logistic regression analysis confirmed that women who were obese adolescents had significantly higher odds of remaining childless compared with normal weight women (odds ratio [OR] 2.84; 95% confidence interval [CI], 1.59-5.10) after adjusting for adult BMI, history of nongestational amenorrhea, marital status, ethnicity, study site, and measures of socioeconomic status. Furthermore, adolescent obesity was associated with lifetime nulligravidity (OR = 3.93; 95% CI, 2.12-7.26). CONCLUSION(S): Adolescent obesity is associated with lifetime nulliparity and nulligravidity in midlife U.S. women.

Effect of anti-IFN{beta} antibodies on MRI lesions of MS patients in the BECOME study.

BACKGROUND: Interferon beta (IFNbeta) administered subcutaneously is immunogenic in some patients with multiple sclerosis (MS) and leads to the development of neutralizing antibodies (NAbs). Considerable evidence has accumulated that NAbs diminish or abolish IFNbeta bioactivity, but there is less evidence that NAbs impact clinical efficacy of the drug. METHODS: Because a robust effect of IFNbeta is a decrease in enhancing lesions on brain MRI scans, the Betaseron Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints (BECOME) study, a head-to-head study of IFNbeta-1b vs glatiramer acetate with a primary endpoint of enhancing lesions on MRI, provided an excellent opportunity to determine the effect of NAbs on MRI activity. We measured NAbs and IFNbeta bioactivity by myxovirus resistance protein A gene expression and identified 2 groups of patients: one labeled "bioactivity preserved," with absent NAbs and robust IFNbeta bioactivity (n = 8), and the other labeled "bioactivity lost," with high levels of NAbs and diminished bioactivity (n = 7). The development of enhancing lesions in the groups was then compared. RESULTS: The incidence of NAbs and effect of NAbs on bioactivity were consistent with previous studies. We analyzed MRI outcomes in patients with NAbs at levels high enough to abolish bioactivity relative to patients without NAbs. For the preserved bioactivity group, the enhancing lesion/scan ratio decreased from 7.6 in the pretreatment period to 2.6 in the posttreatment period, a 66% decrease. For the lost bioactivity group, the decrease was 8.5 to 5.8, only a 32% decrease. Thus, lost bioactivity from high levels of NAbs resulted in reduced therapeutic efficacy of IFNbeta as manifested by diminished reductions in enhancing lesions on MRI. CONCLUSIONS: High levels of anti-interferon beta (IFNbeta) antibodies, which result in diminished bioactivity, are correlated with reduced therapeutic efficacy of IFNbeta.

Serum levels of CXCL13 are elevated in active multiple sclerosis.

There is increasing recognition of the important role that B cells play in the pathogenesis of multiple sclerosis (MS). Recently it was reported that the B cell chemokine CXCL13 is elevated in MS serum and cerebrospinal fluid. Here we study whether serum levels of CXCL13 are associated with active MS. We measured serum levels of CXCL13 by enzyme-linked immunosorbent assay in 74 patients with relapsing MS randomized to interferon beta 1b or glatiramer acetate and examined with monthly 3 T brain MRI scans optimized for detection of gadolinium-enhancement for up to 2 years. The median (range) serum levels of CXCL13 pre-treatment were 40 (3-171) pg/ml. Serum levels of CXCL13 were significantly higher at times of active brain MRI scans (p < 0.01). Furthermore, serum levels were higher in patients who never reached MRI remission compared with those in complete (p < 0.01) or partial (p = 0.01) remission. There was a significant positive correlation between the pattern of serum levels of CXCL13 and MRI activity during the first (r = 0.33, p < 0.05) and the full 2 years (r = 0.35, p < 0.01) of the study. Treatment with interferon beta 1b or glatiramer acetate did not affect serum CXCL13. We conclude that the serum levels of the B cell chemokine CXCL13 are associated with active MS.

Association of pathologic diagnoses with clinical findings in chronic endometritis.

OBJECTIVE: To investigate the association of chronic endometritis (CE) with abnormal uterine bleeding, chronic pelvic pain, human immunodeficiency virus (HIV) infection, genital tract infection and salpingitis. STUDY DESIGN: In this retrospective study, specimens obtained from endometrial biopsy, dilatation and curettage or hysterectomy were identified. A total of 123 patients with CE and 177 without CE who were used as controls were included in the study. RESULTS: The patients with CE were younger than controls (p = 0.0001) and were more likely to be premenopausal (p = 0.0004). There was no association of CE with body mass index (p = 0.82), pelvic pain (p = 0.88) or abnormal uterine bleeding (p = 0.80). None of the specimens with CE had atrophic endometrium (p = 0.0018). CE was significantly associated with history of genital tract infection (p = 0.0032), HIV infection (p = 0.0018) and salpingitis (p = 0.0007). CONCLUSION: There was significant association of CE with historical factors, but not with symptomatology.

Longitudinal changes in hypothalamic and ovarian function in perimenopausal women with anovulatory cycles: relationship with vasomotor symptoms.

OBJECTIVE: To determine whether the transition to menopausal status is unidirectional and predictable with aging. DESIGN: Longitudinal evaluation of the menstrual cycle hormone patterns and experience of vasomotor symptoms in an anovulatory, perimenopausal cohort, during cycles that occurred 1 and 2 years after an anovulatory cycle. SETTING: Academic center. PATIENT(S): One hundred fifty-nine of 840 women in the Daily Hormone Study, a substudy of the Study of Women's Health across the Nation (SWAN), had anovulatory cycles. Their menstrual cycle patterns were previously described. This report describes their cycle patterns and vasomotor symptoms in the subsequent 2 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Daily urinary hormone levels of FSH, LH, and estrogen and P metabolites and reports of daily occurrence of vasomotor symptoms. RESULT(S): While a tendency to develop cycles having a loss of negative feedback of estrogen on LH secretion was seen before menopause, there is no clear progression of cycle patterns in anovulatory women. Anovulation did not predict menopause within 2 years. Vasomotor symptoms occur before menopause, as experienced by 73% of the women. Vasomotor symptoms were not related to cycle pattern. CONCLUSION(S): Any cycle pattern may be related to vasomotor symptoms. The best predictor of vasomotor symptoms is a prior history of vasomotor symptoms.

Does the presence of vaginitis on a Pap smear correlate with clinical symptoms in the patient?

OBJECTIVE: To investigate the association of the finding of trichomoniasis, candidiasis or bacterial vaginosis (BV) on Pap smear with possible symptoms, findings on the clinical examination or treatment that the patient received shortly before or shortly after the results of the Pap smear. STUDY DESIGN: Cases were selected from the Department of Pathology, UMDNJ-University Hospital, Newark. Retrospective chart review of patients who had a diagnosis of Trichomonas or Candida infection or bacterial vaginosis on Pap smear was performed. Controls were patients with none of these organisms on Pap smear. RESULTS: We reviewed 761 charts. Of the patients represented, 78 were menopausal, 258 were pregnant and 425 were neither menopausal nor pregnant; 533 (70%) of the patients had an organism associated with vaginitis on their Pap smear. There was a significant association (p <0.001) between a positive Pap smear finding and signs, symptoms or treatment for vaginitis overall. By individual organism, there was a significant association between a positive Pap smear and clinical indicators of Candida and Trichomonas, but not of BV. CONCLUSION: Finding Candida or Trichomonas organisms on a Pap smear is a reliable indicator of vaginitis associated with these organisms. Finding organisms consistent with a shift in vaginal flora (BV) on Pap smear did not correlate with clinical indicators of vaginitis.

Do stillborns with no identifiable pathology have leaner cords than liveborns?

OBJECTIVE: To evaluate whether stillbirths with no explanation found at autopsy have thinner cords than live, gestational-age-matched controls. STUDY DESIGN: Stillbirth autopsies performed at University Hospital, Newark, New Jersey, from January 1995 to October 2002 were reviewed. Cases with no explanation for the death at autopsy had their umbilical cord diameters compared to those in 3 groups of age-matched controls: stillbirths with an identifiable cause of death, liveborns with placentas submitted for pathology evaluation and liveborns from which the placentas were not submitted to pathology. Age-adjusted ANOVAs were performed for comparisons. RESULTS: Of 181 autopsies performed during the review period, 21 cases (11.6%) provided no information at autopsy that would explain or contribute to an understanding of the death. There was no significant difference in cord diameters between either group ofstillbirths or the pathology-submitted controls. Third-trimester placentas from liveborns without placental submission to pathology had significantly greater cord diameters (p = 0.001). CONCLUSION: This study does not support the theory that a cord accident or decreased umbilical blood flow resulting from a leaner umbilical cord can explain a significant number of stillbirths with no other findings at autopsy. However, it supports the literature in that leaner cords appear to be associated with a wide variety of adverse perinatal conditions.

Does histologic chorioamnionitis correspond to clinical chorioamnionitis?

OBJECTIVE: To evaluate the degree to which histologic chorioamnionitis, a frequent finding in placentas submitted for histopathologic evaluation, correlates with clinical indicators of infection in the mother. STUDY DESIGN: A retrospective review was performed on 52 cases with a histologic diagnosis of acute chorioamnionitis from 2,051 deliveries at University Hospital, Newark, from January 2003 to July 2003. Third-trimester placentas without histologic chorioamnionitis (n = 52) served as controls. Cases and controls were selected sequentially. Maternal medical records were reviewed for indicators of maternal infection. RESULTS: Histologic chorioamnionitis was significantly associated with the usage of antibiotics (p = 0.0095) and a higher mean white blood cell count (p = 0.018). The presence of 1 or more clinical indicators was significantly associated with the presence of histologic chorioamnionitis (p = 0.019). CONCLUSION: Histologic chorioamnionitis is a reliable indicator of infection whether or not it is clinically apparent.

Duration of lactation is associated with lower prevalence of the metabolic syndrome in midlife--SWAN, the study of women's health across the nation.

OBJECTIVE: The objective of the study was to evaluate whether lactation duration is associated with lower prevalence of metabolic syndrome (MetSyn) in midlife, parous women. STUDY DESIGN: This was a cross-sectional cohort analysis of 2516 parous, midlife women using multivariable logistic regression to determine the independent association of lactation and lactation duration on prevalence of MetSyn. RESULTS: One thousand six hundred twenty women (64.4%) reported a history of breast-feeding, with average lifetime duration of lactation of 1.16 (+/- 1.04) years. MetSyn was present in 536 women (21.3%). Adjusting for age, smoking history, parity, ethnicity, socioeconomic status, study site, physical activity, caloric intake, and high school body mass index, women with prior lactation had significantly lower odds of MetSyn (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.63 to 0.99). Furthermore, increasing duration of lactation was similarly associated with lower odds of MetSyn (OR 0.88, 95% CI 0.77 to 0.99). CONCLUSION: Duration of lactation is associated with lower prevalence of MetSyn in a dose-response manner in midlife, parous women.

Six-year incidence of visual loss in african americans with type 1 diabetes mellitus: the New Jersey 725.

OBJECTIVE: To report the 6-year incidence of visual loss and associated risk factors in African Americans with type 1 diabetes mellitus. METHODS: African Americans with type 1 diabetes (n=483) who participated in the New Jersey 725 study were reexamined as part of a 6-year follow-up. Best-corrected visual acuity, a structured clinical interview, fundus photographs, and blood pressure measurements were obtained. The biological evaluation included blood and urine assays. Any visual loss was defined as a visual acuity of 20/40 or worse in the better eye, blindness as a visual acuity of 20/200 or worse in the better eye, and doubling of the visual angle (DVA) as the loss of 15 or more letters between the first and second visits. RESULTS: Over 6 years, 19 of 440 patients (4.3%) developed visual loss in the better eye, 3 of 472 patients (0.6%) became blind, 47 of 481 patients (9.8%) developed DVA in the better eye, and 65 of 481 (13.5%) developed DVA in either eye. Baseline older age, high glycosylated hemoglobin level, retinopathy severity, and proteinuria were characteristics significantly (P<.001 for all) and independently associated with DVA in either eye at follow-up. CONCLUSIONS: The 6-year incidence of DVA in either eye (13.5%) is high in African Americans with type 1 diabetes. Baseline poor glycemic control, diabetic retinopathy severity, proteinuria, and older age are predictors of visual loss in this population.

Renal and gastrointestinal potassium excretion in humans: new insight based on new data and review and analysis of published studies.

OBJECTIVES: Little is known about the relationship between the renal and gastrointestinal excretion of potassium in humans. This information is important in light of strong associations of potassium intake with hypertension and occlusive stroke. METHODS: We determined the relationship between fecal and urinary excretion of potassium under both fixed and variable potassium intakes using our unpublished archival data and published data of others. Twenty-five subjects were evaluated. RESULTS: On a fixed, low oral potassium intake (61.2 +/- 4.7 mmol/day; mean +/- SD), there was an inverse relationship between fecal and urinary potassium excretion (r = -0.66, p = 0.040). In studies in which potassium intake varied between 61-135 mmol/day, fecal and urinary potassium excretions were positively correlated (r = 0.58, p = 0.024). Considerable within-and-between-subject variation was observed in the relationship between fecal and urinary potassium excretion. CONCLUSIONS: Inter-individual variation in fecal potassium excretion may arise from both variation in dietary potassium intake and intrinsic individual differences in the renal versus gastrointestinal handling of potassium.

Characteristics of the urinary luteinizing hormone surge in young ovulatory women.

OBJECTIVE: To define characteristics of the luteinizing hormone (LH) surge in urine. DESIGN: Observational study. SETTING: Academic center. PATIENT(S): 46 women aged 20 to 35 years with regular menstrual cycles. INTERVENTION(S): Collected first morning urine daily, throughout one menstrual cycle. MAIN OUTCOME MEASURE(S): Urinary LH, follicle-stimulating hormone (FSH), estrone conjugate (E1C), and pregnanediol-3-glucuronide (PDG). RESULT(S): Three women lacked LH surges. Mean LH surge: start = day 14.5 (+/-3.6 SD) (range: 9-26); peak = 41.2 mIU/mg creatinine (+/-20 SD) (range: 12.1-104.0); fold increase = 7.7 (+/-3.0 SD) (range: 2.5-14.8); duration = 7.6 days (+/-1.5 SD) (range: 5-11). The onset of LH surge was of two types: rapid onset (within 1 day) (42.9%) or gradual onset (2 to 6 days) (57.1%). Configurations of LH surges were of three types: spike (41.9%), biphasic (44.2%), or plateau (13.9%). All LH surges demonstrated a gradual decrease to baseline. Three women (7%) did not have FSH rises coincident with LH surges. All displayed E1C rises during the middle to late follicular phase. CONCLUSION(S): The LH surges that result in ovulation are extremely variable in configuration, amplitude, and duration. The FSH rise does not seem essential for ovulation. However, an E1C rise occurred in all cycles, confirming the critical role of estrogen in induction of the LH surge.

Telomere dynamics in macaques and humans.

In humans, telomere length in proliferating tissues shortens with age--a process accelerated with age-related diseases. Thus, telomere length and attrition with age in the nonhuman primate may serve as a useful paradigm for understanding telomere biology in humans. We examined telomere parameters in tissues of young and old Macaca fascicularis and compared them with several tissues from humans. Macaque telomeres were variable in length and exhibited partial synchrony (equivalence) within animals. They were longer than humans, partially because of longer subtelomeric segments. As skeletal muscle telomere length was unchanged with age, we used it as an internal reference to offset interanimal variation in telomere length. We identified age-dependent telomere attrition in lung, pancreas, skin, and thyroid. Similar to humans, telomerase activity was detected in spleen, thymus, digestive tract, and gonads. We conclude that factors that modify telomere attrition and aging in humans may also operate in the macaque.

Linear derivatives of Saccharomyces cerevisiae chromosome III can be maintained in the absence of autonomously replicating sequence elements.

Replication origins in Saccharomyces cerevisiae are spaced at intervals of approximately 40 kb. However, both measurements of replication fork rate and studies of hypomorphic alleles of genes encoding replication initiation proteins suggest the question of whether replication origins are more closely spaced than should be required. We approached this question by systematically deleting replicators from chromosome III. The first significant increase in loss rate detected for the 315-kb full-length chromosome occurred only after all five efficient chromosomal replicators in the left two-thirds of the chromosome (ARS305, ARS306, ARS307, ARS309, and ARS310) had been deleted. The removal of the inefficient replicator ARS308 from this originless region caused little or no additional increase in loss rate. Chromosome fragmentations that removed the normally inactive replicators on the left end of the chromosome or the replicators distal to ARS310 on the right arm showed that both groups of replicators contribute significantly to the maintenance of the originless chromosome. Surprisingly, a 142-kb derivative of chromosome III, lacking all sequences that function as autonomously replicating sequence elements in plasmids, replicated and segregated properly 97% of the time. Both the replication initiation protein ORC and telomeres or a linear topology were required for the maintenance of chromosome fragments lacking replicators.

Is the presence of Trichomonas on a Pap smear associated with an increased incidence of bacterial vaginosis?

OBJECTIVE: Bacterial vaginosis (BV) is associated with significant morbidity. Bacterial vaginosis is due to an overgrowth of anaerobic organisms in the vagina. It has been postulated that the presence of Trichomonas creates an anaerobic environment that favors BV. Thus, BV should be more frequent in the presence of Trichomonas if Trichomonas is creating a favorable anaerobic environment. MATERIALS AND METHODS: A retrospective review of Pap test reports was performed for a diagnosis of coccobacilli consistent with shift in vaginal flora, that is, the presence of clue cells. Cases were Pap smears with Trichomonas identified. Controls were cases without Trichomonas. Results were analyzed using Fisher exact test. RESULTS: Four hundred cases were reviewed; 200 with and 200 without Trichomonas. The incidence of BV was significantly higher in the Trichomonas group (46.5%) than in group without Trichomonas (24.5%) (p < .0001.). CONCLUSION: The presence of Trichomonas on a Pap smear is associated with an increased incidence of BV. The report of Trichomonas on a Pap smear should prompt clinical consideration that BV may be present.

The F + 0 protocol for diuretic renography results in fewer interrupted studies due to voiding than the F - 15 protocol.

UNLABELLED: Timing of diuretic administration is not universally standardized in renography. Over the past year, our practice has changed from F-15 administration of furosemide to an F + 0 protocol. Therefore, we have retrospectively compared these 2 cohorts to assess if the shorter interval between diuretic administration and study completion in the F + 0 study results in a greater frequency of patients able to complete the subsequent 30-min dynamic acquisition without disruption due to voiding. METHODS: We identified 108 diuretic (99m)Tc-mercaptoacetyltriglycine renograms performed in the previous 18-mo period. Three patients were given furosemide at 30 min after the radiopharmaceutical and were excluded. Twenty studies in children under 3 y of age were excluded from consideration because voiding is neither restricted in this age group nor does voiding into a diaper cause disruption. Forty milligrams of furosemide were administered to adults, whereas 0.5 mg/kg was given to children. In the first cohort of 56 studies, radiopharmaceutical was administered 15 min after furosemide (F-15), whereas, in the second cohort of 29 patients, it was administered immediately thereafter (F + 0). In all cases, patients were asked to void proximal to radiopharmaceutical injection. Dynamic images and renogram curves were inspected for evidence of interruption or voiding midstudy. Statistical significance was determined by a 1-tailed Fisher exact test for proportions, with P < 0.05. RESULTS: The F-15 and F+0 groups of patients were comparable in terms of age, sex, and diuretic amount. In 17 of the F-15 patients, renography was interrupted because of voiding (30%), whereas this occurred in only 3 of the F + 0 patients (10%). This difference was significant at the P = 0.033 level. The mean time of voiding was 18.3 min (range, 12-25 min) for F-15 patients and 16 min (range, 12-19 min) for the F + 0 group. CONCLUSION: The F + 0 renal diuretic protocol is associated with a significantly lower rate of disruption because of voiding than the F-15 protocol, likely due to the shorter period between diuretic administration and study termination, which results in less bladder distention and discomfort. On the basis of these data, the F + 0 protocol appears to be a more tolerable procedure.