Reduced fecundity in HIV-positive women.

STUDY QUESTION: Is HIV associated with increased time to pregnancy (TTP)? SUMMARY ANSWER: HIV-positive women who discontinue a contraceptive method to become pregnant have increased TTP, particularly among those who likely do not know their status. WHAT IS KNOWN ALREADY: HIV-positive women have fewer children on average than their HIV-negative counterparts due to both behavioral and biological factors. There is a need to better describe and quantify fecundity patterns associated with HIV in the general population. STUDY DESIGN, SIZE, DURATION: This cross-sectional study was based on data from 12 Demographic and Health Surveys (DHSs) conducted between 2003 and 2013 in 11 African countries. All studies collected dried blood spot samples for HIV testing and included a retrospective calendar module that recorded women's monthly reproductive status in the 5 years preceding the survey. TTP was measured among 3181 women discontinuing a contraceptive method within 2 years of the survey in order to become pregnant. PARTICIPANTS/MATERIALS, SETTING, METHODS: We use Cox proportional hazard models for discrete survival data to model TTP and estimate fecundability odds ratios (FOR) and 95% CIs for the 12-month period following contraceptive discontinuation. In addition to employing a binary measure of HIV status, we also develop an additional explanatory measure that combines HIV status with information on whether respondents had ever been tested for HIV and received their results (which proxies for knowledge of HIV status) to reduce the threat of confounding from behavioral changes following an HIV diagnosis. MAIN RESULTS AND THE ROLE OF CHANCE: In our sample, 10.3% of women were HIV-positive, and a little more than half (51.8%) of women received test results and likely knew their status. Over a 12-month observation period, HIV-positive women had a 25% average reduction in fecundity compared to HIV-negative women [adjusted FOR (aFOR) = 0.75 (0.62-0.92)] after adjusting for confounders. The 12-month fecundity patterns differed by women's likely knowledge of their status such that results were primarily driven by HIV-positive women who likely did not know their status. Moreover, reductions in fecundity attributable to HIV were not uniform over time. Among women who were still trying for pregnancy after 3 unsuccessful months, HIV-positive women had half the odds of becoming pregnant compared to HIV-negative women [aFOR = 0.50 (0.35-0.71)]. Conversely, there were no significant differences in FORs between HIV-negative and HIV-positive women in the first 3 months. LIMITATIONS REASONS FOR CAUTION: Because dried blood spot samples for HIV testing were collected at the time of the survey but reproductive calendar data were collected retrospectively, it is possible that we introduced misclassification bias, as we have no knowledge if the acquisition of HIV occurred before or after pregnancy attempt. WIDER IMPLICATIONS OF THE FINDINGS: As life expectancy and quality health status improve due to earlier initiation of antiretroviral (ARV) treatment in HIV-positive women, there has been growing awareness that services should also address the fertility desires of HIV-positive women who want children. These findings indicate that if a pregnancy does not occur after 3 months of attempting pregnancy, HIV-positive women and HIV-discordant couples should request access to HIV and reproductive pre-pregnancy counseling and health assessments. STUDY FUNDING/COMPETING INTEREST(S): A.G. was supported by the National Institutes of Health (contract T32-HD007275) during the study. During the conceptualization, data collection and analysis time frame, S.vdP. was supported by WHO/RHR/HRP Special Program in Reproductive Health and Research, Geneva, Switzerland, and HRP (the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction). The authors have no conflicts of interest to declare.

Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines.

PURPOSE: To describe a diagnostic protocol, surveillance and treatment guidelines, genetic counseling considerations and long-term follow-up data elements developed in preparation for X-linked adrenoleukodystrophy (X-ALD) newborn screening in New York State. METHODS: A group including the director from each regional NYS inherited metabolic disorder center, personnel from the NYS Newborn Screening Program, and others prepared a follow-up plan for X-ALD NBS. Over the months preceding the start of screening, a series of conference calls took place to develop and refine a complete newborn screening system from initial positive screen results to long-term follow-up. RESULTS: A diagnostic protocol was developed to determine for each newborn with a positive screen whether the final diagnosis is X-ALD, carrier of X-ALD, Zellweger spectrum disorder, acyl CoA oxidase deficiency or D-bifunctional protein deficiency. For asymptomatic males with X-ALD, surveillance protocols were developed for use at the time of diagnosis, during childhood and during adulthood. Considerations for timing of treatment of adrenal and cerebral disease were developed. CONCLUSION: Because New York was the first newborn screening laboratory to include X-ALD on its panel, and symptoms may not develop for years, long-term follow-up is needed to evaluate the presented guidelines.

Cost-effectiveness of misoprostol to control postpartum hemorrhage in low-resource settings.

OBJECTIVE: To test the cost-effectiveness of training traditional birth attendants (TBAs) to recognize postpartum hemorrhage (PPH) and administer a rectal dose of misoprostol in areas with low access to modern delivery facilities. METHOD: A cost-effectiveness analysis, modeling two hypothetical cohorts of 10,000 women each giving birth with TBAs: one under standard treatment (TBA referral to hospital after blood loss >or=500 ml), and one attended by TBAs trained to recognize PPH and to administer 1000 microg of misoprostol at blood loss >or=500 ml. RESULT: The misoprostol strategy could prevent 1647 cases of severe PPH (range: 810-2920) and save $115,335 in costs of referral, IV therapy and transfusions (range: $13,991-$1,563,593) per 10,000 births. By preventing severe disease and saving money, it dominates the standard approach. CONCLUSION: Training TBAs to administer misoprostol to treat PPH has the potential to both save money and improve the health of mothers in low-resource settings.

Regulation of immune complexes during infection of mice with lactate dehydrogenase-elevating virus: studies with interferon-gamma gene knockout and tolerant mice.

Mice persistently infected with lactate dehydrogenase-elevating virus (LDV) develop circulating IgG-containing hydrophobic immune complexes, with a molecular mass of 150 to 300 kd, which bind to the surfaces of high-capacity enzyme-linked immunosorbent assay (ELISA) plates. LDV infection also stimulates polyclonal B-cell activation and autoimmunity. For this study, interferon-gamma gene knockout (GKO) mice were utilized to study circulating immune complexes and other parameters of LDV infection. The kinetics of LDV viremia, formation of plasma IgG anti-LDV antibodies, and LDV replication in the spleen and liver were essentially normal in GKO mice. Polyclonal activation of B cells, as reflected by increased total plasma IgG concentration during LDV infection, was found to be intact in GKO mice, although at a lower magnitude than in control mice. The plasma concentration of IgG-containing hydrophobic immune complexes was reduced about 75% in LDV-infected GKO mice relative to normal LDV-infected controls. Allogeneic tissue responses were also found to be reduced in LDV-infected GKO mice relative to those in normal LDV-infected controls. These results dissociate specific anti-LDV immunity from formation of hydrophobic immune complexes, show that the IgG anti-LDV response as well as LDV replication in the spleen and liver are insensitive to physiological levels of interferon (IFN)-gamma, and suggest that IgG-containing immune complexes stimulated by LDV infection are a marker for autoimmunity.

Trojan Horse macrophages: studies with the murine lactate dehydrogenase-elevating virus and implications for sexually transmitted virus infection.

Previous studies have suggested that monocytes or macrophages may mediate internal virus spread. For the present study, the tissue distribution and infectious potential of dye-labelled and/or lactate dehydrogenase-elevating virus (LDV)-infected murine macrophages were determined. Murine peritoneal macrophages were labelled with the fluorescent carbocyanine tracking dye Dil, injected into mice, and the tissue distribution of Dil-labelled cells was determined by fluorescence analysis of frozen sections. Mice receiving intravenous (i.v.) or intraperitoneal injections of Dil-labelled macrophages displayed rapid and broad tissue distribution of the labelled cells. Intravaginal injection of Dil-labelled macrophages resulted in penetration into the placentas, but not the fetuses, of pregnant mice. When macrophages were LDV-infected and Dil-labelled prior to i.v. injection into pregnant mice, they homed to various tissues including the placenta, but were not found in fetuses. Intravaginal injection of LDV-infected macrophages resulted in systemic LDV infection, even though the free-virus dose was less than the minimum infectious dose by this route. Neither polyclonal nor monoclonal IgG anti-LDV antibodies protected mice from vaginal infection with cell-associated virus, and LDV-immune complexes were themselves infectious by the vaginal route. These results show that exogenous macrophages are widely distributed following parenteral injection, penetrate locally to placentas after intravaginal injection, and are capable of acting vaginally as relatively efficient virus infection-delivery vehicles. Thus, 'Trojan Horse' macrophages are potentially infectious vehicles both for internal virus spread and for animal-to-animal transmission.

Determination of the viremia threshold for dental cross-infection in a mouse model.

An animal model of dental virus transmission was developed using the lactate dehydrogenase-elevating virus (LDV) of mice to study cross infection. Mouse-to-mouse cross-infection was carried out by scaling the teeth of LDV-infected donor mice with dental instruments, immediately prior to using the contaminated instruments on the teeth of recipient indicator mice. The level of donor viremia was found to correlate with the rate of virus cross-infection, with a viremia threshold level of 10(7.5) ID50/ml observed for dental cross-infection. The blood volume transferred during dental cross-infection was approximately 10(-4) to 10(-5) ml, demonstrating the inefficiency of virus cross-infection, since deposition of about 1000 virions on dental instruments was associated with the threshold limit. Virus transferred during dental cross-infection rapidly entered the blood circulation, showing that dental cross-infection was not dependent on an oral infection. The results from these model studies predict the general inefficiency of dental instrument virus cross-infection, and a further reduced likelihood of dental cross-infection with appropriately cleaned instruments.

Regulation of transplacental virus infection by developmental and immunological factors: studies with lactate dehydrogenase-elevating virus.

Placental and fetal infections with lactate dehydrogenase-elevating virus (LDV) were determined by virus titration, indirect fluorescence antibody (IFA), and in situ hybridization with cDNA probes. Experiments were designed to determine the effects of gestational age, timing of maternal LDV infection, and immunological (antibody and cytokine) factors on mouse placental and fetal LDV infection. Virus infection of the placenta was detected at high levels (almost all placentas infected) within 24 h post-maternal infection (p.m.i.), whereas fetal LDV infection was detected only at a low level by 24 h p.m.i. The percentage of fetuses becoming LDV infected progressively increased between 24 and 72 h p.m.i. When fetal infection was studied at 72 h p.m.i., earlier gestational ages (9-11 days) were associated with fetal resistance to infection, whereas between 12.5 and 15 days of gestation, virus infection was detected in 50-71% of fetuses. Maternal treatment with interferon-gamma (IFN-gamma) or anti-LDV monoclonal antibodies was associated with reduced rates of fetal, but not placental, LDV infection. These results demonstrate that both developmental and immunological factors are important in the regulation of transplacental LDV infection.

Cytokine regulation of lactate dehydrogenase-elevating virus: inhibition of viral replication by interferon-gamma.

The mechanisms which regulate the replication of lactate dehydrogenase-elevating virus (LDV), a persistent murine model virus which infects macrophages, are unclear. For this study, the effects of murine recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) on LDV replication were examined. LDV permissiveness was reduced in macrophages obtained from uninfected mice treated with IFN-gamma prior to cell harvest and in vitro LDV infection. Virus inhibition by IFN-gamma was also observed when neonatal LDV-infected mice were injected with this cytokine prior to macrophage harvest and analysis of LDV replication-positive cells. Persistently LDV-infected mice demonstrated an increase in viremia levels following treatment with TNF-alpha. Neither IFN-gamma nor TNF-alpha had any direct in vitro effect on LDV replication in cultured macrophages, suggesting that the actions of these cytokines required secondary or accessory in vivo events. These results provide evidence for cytokine-mediated regulation of LDV infection and support a role for the immune system in the LDV-host relationship.

Non-micelle forming bile acids increase biliary gentamicin excretion in the rat.

To investigate whether non-micelle forming bile acids are able to increase biliary gentamicin excretion, male Sprague-Dawley rats were anesthetized with pentobarbital and fitted with a biliary fistula. After a control period of 30 min, dehydrocholate, taurodehydrocholate, or norursodeoxycholate were administered iv at doses of 2 or 10 mumol.min-1.kg-1. Taurodehydrocholate increased bile flow and biliary gentamicin clearance similarly in a dose-dependent fashion. Its unconjugated analogue, in contrast, increased gentamicin clearance fourfold, while increasing bile flow only 1.6-fold. This suggests that other than purely osmotic phenomena were involved. This effect was even more marked for the short-chain bile acid, norursodeoxycholate. At a dose of 2 mumol.min-1.kg-1 it increased bile flow by 30%, but gentamicin clearance by 210%; a similar discrepancy between choleresis and gentamicin clearance was observed at the higher dose tested. It may be concluded that conjugated triketo bile acids increase biliary gentamicin clearance by osmotic choleresis. Unconjugated triketo bile acids and nor-bile acids, to an even greater extent, increase gentamicin clearance much more markedly than bile flow; other effects, such as the putative cholahepatic shunt pathway, are responsible for this phenomenon. This novel therapeutic principle might be useful in achieving therapeutic biliary antibiotic concentrations or in treating gentamicin intoxication in patients with renal insufficiency.

A bile alcohol sulfate as a major component in the bile of the small skate (Raja erinacea).

The nature of bile alcohols and bile acids in gall-bladder and hepatic bile from perfused livers of the small skate (Raja erinacea) has been investigated. The main bile alcohol sulfate was isolated by thin-layer chromatography and analyzed by fast atom bombardment mass spectrometry and 13C NMR. Following solvolysis and purification on Lipidex-DEAP, the bile alcohol profile was measured by capillary gas-liquid chromatography-electron impact mass spectrometry. Based on these studies and on comparison with authentic scymmnol sulfate and scymnol, the main bile alcohol was identified as 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 xi,26,27-hexol sulfate. The mean +/- SD concentration in gallbladder bile from five different skates was 24.6 +/- 8.7 mmol/l. Only 0.1 mmol/l of cholic acid and its conjugates was found in a pool of skate bile. The main bile alcohol sulfate in the bile of the small skate seems to be a metabolic end product, present in a concentration comparable to that of bile salts in mammals.

Changes in glomerulotubular dimensions, single nephron glomerular filtration rates and the renin-angiotensin system in hypothyroid rats.

Glomerular diameters (GD) and lengths of attached proximal convoluted tubules (TPL) were measured in nephrons dissected from the superficial (S), intermediate and juxtamedullary (JM) cortex (7-15 each) of acid-macerated kidneys of weight-matched (E) euthyroid and (H) hypothyroid (2-6 months after radioiodine treatment or thyroidectomy) male Sherman-Wistar rats. Incoordination of growth in H rats was evident in a more marked retardation in kidney than in total body growth. A similar incoordination of microstructural growth was evident in maintenance or GD within normal limits with respect to body weight while attached TPL fell 23% on the average below control values relative to body weight. These changes affected the total nephron population uniformly. As a result, GD/TPL in all nephrons increased significantly (p less than 0.01), by 27% in S and by 29% in JM nephrons. The glomerulotubular dimensional imbalance was associated with a marked and uniformly distributed reduction in single nephron glomerular filtration rate (ferrocyanide method), by 36% in S and JM nephrons. Plasma renin activity fell within normal limits while plasma renin substrate was decreased to 56% of control values. These findings are construed as evidence that growth retardation in hypothyroid rats affects the parenchyma of the kidney (and perhaps other viscera) more than the vasculature.

Ellepsis and akairial disproportion in the hypothyroid rat.

Renal structural and functional changes observed in rats during hypothyroidism have been employed to illustrate the concepts of "ellepsis" and "akairia" that have emerged from the work of Cournand and Richards. Ellepsis--the inadequate homeostatic response--is evident in the failure of corrective adjustments in glomerular filtration rate to prevent the excessive natriuresis and detrimental salt loss typical of this disorder in the rat but not in man. A slowing in overall bodygrowth is associated with an inappropriate (akairial) disproportion in the growth of glomeruli and tubules. Comparison of the changes in body weight, glomerular diameters, and tubular lengths in euthyroid and hypothyroid (radioiodine) littermates showed that glomeruli continued to grow in proportion to total body weight following administration of radioiodine while tubular growth almost ceased. Since disproportional failure of pulmonary growth has also been observed in these studies (0.829 +/- SEM 0.040 g in hypothyroid rats as compared with 1.14 +/- 0.034 g in euthyroid weight-matched controls), it may be profitable to look for abnormalities in respiratory homeostasis in the hypothyroid rat.

Infrared remote sounding of the middle atmosphere of venus from the pioneer orbiter.

Orbiter infrared measurements of the Venus atmosphere in the 60- to 140-kilometer region show very small diurnal temperature differences near the cloud tops, increasing somewhat at higher levels. The seasonal (that is, equator to pole) contrasts are an order of magnitude larger, and the temperatures unexpectedly increase with increasing latitude below 80 kilometers. An isothermal layer at least two scale heights in vertical extent is found near the 100-kilometer altitude, where the temperature is about 175 K. Structure is present in the cloud temperature maps on a range of spatial scales. The most striking is at high latitude, where contrasts of nearly 50 K are observed between a cold circumpolar band and the region near the pole itself.