Jane E. Ellis

Signaling through Toll-Like Receptors Triggers HIV-1 Replication in Latently Infected Mast Cells

Evidence that human progenitor mast cells are susceptible to infection with CCR5-tropic strains of HIV-1 and that circulating HIV-1-infected FcεRIα+ cells with a similar progenitor phenotype have been isolated from AIDS patients has led to speculation that mast cells may serve as a potential reservoir for infectious HIV-1. In this study, progenitor mast cells, developed in vitro from CD34+ cord blood stem cells, were experimentally infected with the CCR5-tropic strain HIV-1Bal after 28 days in culture as they reached their HIV-1-susceptible progenitor stage. HIV-1 p24 Ag levels were readily detectable by day 7 postinfection (PI), peaked at 2–3 wk PI as mature (tryptase/chymase-positive) HIV-1 infection-resistant mast cells emerged, and then steadily declined to below detectable limits by 10 wk PI, at which point integrated HIV-1 proviral DNA was confirmed by PCR quantitation in (∼34% of) latently infected mast cells. Stimulation by ligands for Toll-like receptor (TLR) 2, TLR4, or TLR9 significantly enhanced viral replication in a dose- and time-dependent manner in both HIV-1-infected progenitor and latently infected mature mast cells, without promoting degranulation, apoptosis, cellular proliferation, or dysregulation of TLR agonist-induced cytokine production in infected mast cells. Limiting dilution analysis of TLR activated, latently infected mature mast cells indicated that one in four was capable of establishing productive infections in A301 sentinel cells. Taken together, these results indicate that mast cells may serve both as a viral reservoir and as a model for studying mechanisms of postintegration latency in HIV infection.

A Method for Quantitating Motor Deficits in a Nonhuman Primate following MPTP-Induced Hemiparkinsonism and Co-grafting

This report describes a nonhuman primate model of MPTP-induced hemiparkinsonism and the recovery of motor function following co-grafting of adrenal medullary tissue and peripheral nerve into the lesioned area of the brain. A rhesus monkey (Macaca mulatta) trained to perform a complex, discrete-trial, operant task served as the subject. After behavioral performance on the task had stabilized and a high level of accuracy was maintained, 0.4 mg/kg MPTP was infused acutely via the left carotid artery to produce a marked impairment of movement of the right arm. Eighteen weeks later, medullary tissue from the left adrenal gland was grafted along with peripheral nerve into the left caudate nucleus. During the original baseline training condition, right- and left-hand performances were comparable on all dependent measures. However, right-hand performance was severely impaired following unilateral MPTP treatment, and left-hand performance was unaffected. Right-hand performance recovered only after adrenal medullary tissue was transplanted with peripheral nerve into the brain. Neuroanatomical analysis of brain tissue showed the anticipated neuronal loss in the left substantia nigra due to MPTP administration and evidence of adrenal medullary cell survival in the area of the co-graft. The data demonstrate that the rhesus monkey and the behavioral task developed during this study can be efficacious in characterizing the effects of MPTP on psychomotor function and in assessing the outcome of new strategies for treating Parkinsons disease.

Emerging infectious disease outbreaks: old lessons and new challenges for obstetrician-gynecologists.

Objective The purpose of this study was to summarize 3 recent high-profile infectious disease threats that have affected the United States: severe acute respiratory syndrome, West Nile virus, and anthrax. Study design A systematic review was conducted with the use of Medline searches, searches of the Centers for Disease Control and Prevention website, and review by experts at the Centers for Disease Control and Prevention. Results The 3 emerging infectious diseases pose very different threats: Severe acute respiratory syndrome is a newly identified pathogen that caused an international pandemic; the West Nile virus investigation involved an old pathogen that was identified in a new location; and the anthrax attacks involved the intentional introduction of a pathogen. Conclusion All 3 outbreaks highlight the importance of obstetrician-gynecologists keeping current with new information as it emerges. In this global environment, it is likely that novel disease threats will continue to emerge in the United States.

Inhibition of Progenitor Dendritic Cell Maturation by Plasma from Patients with Peripartum Cardiomyopathy: Role in Pregnancy-associated Heart Disease

Dendritic cells (DCs) play dual roles in innate and adaptive immunity based on their functional maturity, and both innate and adaptive immune responses have been implicated in myocardial tissue remodeling associated with cardiomyopathies. Peripartum cardiomyopathy (PPCM) is a rare disorder which affects women within one month antepartum to five months postpartum. A high occurrence of PPCM in central Haiti (1 in 300 live births) provided the unique opportunity to study the relationship of immune activation and DC maturation to the etiology of this disorder. Plasma samples from two groups (n = 12) of age- and parity-matched Haitian women with or without evidence of PPCM were tested for levels of biomarkers of cardiac tissue remodeling and immune activation. Significantly elevated levels of GM-CSF, endothelin-1, proBNP and CRP and decreased levels of TGF- were measured in PPCM subjects relative to controls. Yet despite these findings, in vitro maturation of normal human cord blood derived progenitor dendritic cells (CBDCs) was significantly reduced (p < 0.001) in the presence of plasma from PPCM patients relative to plasma from post-partum control subjects as determined by expression of CD80, CD86, CD83, CCR7, MHC class II and the ability of these matured CBDCs to induce allo-responses in PBMCs. These results represent the first findings linking inhibition of DC maturation to the dysregulation of normal physiologic cardiac tissue remodeling during pregnancy and the pathogenesis of PPCM.

Emerging Infections and Pregnancy: West Nile Virus, Monkeypox, Severe Acute Respiratory Syndrome, and Bioterrorism

As new infectious diseases, such as West Nile virus, monkeypox, and severe acute respiratory syndrome (SARS) are recognized in the United States, there are critical questions about how these infectious diseases will affect pregnant women and their infants. In addition, the implications of bioterrorist attacks for exposed pregnant women need to be considered. In this article, the authors address the following questions for a number of infectious disease threats: (1) does pregnancy affect the clinical course of these novel infectious diseases?, (2) what are the implications for prophylaxis and treatment of exposed or infected pregnant women?, and (3) are these novel infectious diseases transmitted during pregnancy, labor and delivery, or breastfeeding?

Super obesity in pregnancy: difficulties in clinical management

As the obesity pandemic continues in the United States, obesity in pregnancy has become an area of interest. Many studies focus on women with body mass index (BMI) ⩾30 kg m−2. Unfortunately, the prevalence of patients with BMI ⩾50 kg m−2 is rapidly increasing, and there are few studies specifically looking at pregnant women in this extreme category. The purpose of this article is to highlight some of the challenges faced and review the literature available to help guide obstetricians who might encounter such patients.

Fetal development in rhesus monkeys exposed prenatally to cocaine.

Using a timed-breeding protocol, one group of female rhesus monkeys was implanted subcutaneously with osmotic minipumps containing 0.3 mg/kg/h cocaine (N=18) or saline (N=18) from day 24 postconception through gestation. Another group received cocaine (N=12) or saline (N=8) from conception through day 42 of gestation. Mean levels of cocaine in maternal serum were approximately 150 ng/ml during pregnancy. A total of 56 pregnancies were documented in 42 adult monkeys, and 39 pregnancies completed full-term. Maternal food consumption and body weight increased during pregnancy, and there were no significant differences among experimental groups. Although both groups with a history of cocaine exposure had lower survival rates compared to pair-fed controls, of the fetuses that survived, fetal heart rate, fetal biparietal diameter, and mean gestational length were in the normal range for all experimental groups. Similarly, body weight, biparietal diameter, body length, and modified Apgar scores at birth did not differ significantly among experimental groups. The results indicate that surviving fetuses exhibited normal growth.

Pregnancy-Associated Deaths in Rural, Nonrural, and Metropolitan Areas of Georgia.

OBJECTIVE: To characterize pregnancy-associated deaths and examine the relationship between area of residence and pregnancy-associated deaths and pregnancy-related mortality ratios in Georgia from 2010 to 2012. METHODS: The cohort of pregnancy-associated deaths was reviewed and categorized as pregnancy-related or resulting from other medical conditions not related to pregnancy, suicide, drug toxicity, homicide, or motor vehicle accident. Georgia Online Analytical Statistical Information System data were used to calculate pregnancy-related mortality ratio by rural, nonrural, and metropolitan Atlanta area and by race. Causes of death and pregnancy-related mortality ratio were compared by area of residence and race using &khgr;2 tests; a P value <.05 was considered significant. RESULTS: There were 262 pregnancy-associated deaths; 40.1% (n=105) were pregnancy-related. The 2010–2012 pregnancy-related mortality ratio was 26.5 per 100,000 live births and the pregnancy-related mortality ratio did not differ statistically among rural (27.1), nonrural (24.4), and metropolitan Atlanta (27.7) areas (P=.845). Most pregnancy-related deaths were the result of hemorrhage and cardiovascular factors. In aggregate, the pregnancy-related mortality ratio for black women was 49.5 compared with 14.3 for white women (P<.001). The gap in pregnancy-related mortality ratio between black and white women was highest for metropolitan Atlanta (51.6 compared with 12.4, P<.001), less in nonrural areas (50.3 compared with 12.0, P<.001), and comparable in rural areas (39.4 compared with 22.4, P=.281). CONCLUSION: Although the pregnancy-related mortality ratio was similar for rural, nonrural, and metropolitan Atlanta areas, it was significantly higher for black compared with white women living outside of rural areas.

Postpartum contraceptive preferences of HIV-infected women in the era of highly active antiretroviral therapy (HAART) and scheduled cesarean deliveries

BACKGROUND We sought to determine if postpartum tubal ligation among HIV-infected women changed with the introduction of highly active antiretroviral therapy (HAART) and scheduled cesarean delivery. METHODS Retrospective cohort study of HIV-infected women delivered before (Pre-HAART) and after (Post-HAART) the introduction of HAART and scheduled cesarean delivery. Rates of the primary outcome, postpartum tubal ligation (PPTL), were compared by univariable and multivariable analyses. RESULTS We found that 34.5% (60/174) of women in the Post-HAART period chose PPTL, compared to 22.0% (18/82) in the Pre-HAART period [unadjusted OR=1.87 (95% CI 1.02-3.44), p=.04]. When stratified by mode of delivery, rates of PPTL were not significantly different between the two periods. Similarly, in multivariable analysis controlling for confounders, rates of PPTL were not different between the two periods [adjusted OR=1.40 (95% CI=0.66-2.99), p=.39]. CONCLUSIONS HIV-infected women on HAART are overall more likely to have PPTL, but cesarean delivery appears to be the facilitator of this choice.

Adequacy of Prenatal Care Between Hospital-Based, Prepaid, Bundled Program and Traditional Medicaid [28C]

INTRODUCTION:Access to adequate prenatal care (PNC) is a goal of HealthyPeople 2020. However, not all pregnancies in the U.S. are guaranteed this benefit, particularly in States that have not expanded Medicaid or have high concentrations of pregnancies in undocumented women. To address this gap, our