Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure.

A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.

Racial Disparities in Virologic Failure and Tolerability During Firstline HIV Antiretroviral Therapy.

BACKGROUND: Racial/ethnic disparities in HIV outcomes have persisted despite effective antiretroviral therapy. In a study of initial regimens, we found viral suppression varied by race/ethnicity. In this exploratory analysis, we use clinical and socioeconomic data to assess factors associated with virologic failure and adverse events within racial/ethnic groups. METHODS: Data were from AIDS Clinical Trial Group A5257, a randomized trial of initial regimens with either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (each combined with tenofovir DF and emtricitabine). We grouped participants by race/ethnicity and then used Cox-proportional hazards regression to examine the impact of demographic, clinical, and socioeconomic factors on the time to virologic suppression and time to adverse event reporting within each racial/ethnic group. RESULTS: We analyzed data from 1762 participants: 757 self-reported as non-Hispanic black (NHB), 615 as non-Hispanic white (NHW), and 390 as Hispanic. The proportion with virologic failure was higher for NHB (22%) and Hispanic (17%) participants compared with NHWs (9%). Factors associated with virologic failure were poor adherence and higher baseline HIV RNA level. Prior clinical AIDS diagnosis was associated with virologic failure for NHBs only, and unstable housing and illicit drug use for NHWs only. Factors associated with adverse events were female sex in all groups and concurrent use of medications for comorbidities in NHB and Hispanic participants only. CONCLUSIONS: Clinical and socioeconomic factors that are associated with virologic failure and tolerability of antiretroviral therapy vary between and within racial and ethnic groups. Further research may shed light into mechanisms leading to disparities and targeted strategies to eliminate those disparities.

Changes in Waist Circumference in HIV-Infected Individuals Initiating a Raltegravir or Protease Inhibitor Regimen: Effects of Sex and Race.

BACKGROUND: This study investigates the association of clinical and demographic predictors with abdominal fat gain, measured using waist circumference (WC) and self-reported abdominal size. METHODS: We analyzed data from ACTG A5257, a clinical trial that randomized treatment-naïve HIV-infected participants to 1 of 3 antiretroviral regimens: raltegravir (RAL) or the protease inhibitors (PIs) atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. Associations of treatment and baseline/demographic characteristics with 96-week WC change were assessed using repeated-measures models. Ordinal logistic regression was used to examine the associations of predictors with week 96 self-reported abdominal changes. RESULTS: The study population (n = 1809) was 76.0% male and predominantly black non-Hispanic (41.9%) and white non-Hispanic (34.1%). Mean baseline WC was 90.6 cm, with an average 96-week increase of 3.4 cm. WC increases were higher in the RAL arm compared with DRV/r (P = .0130). Females experienced greater increases in WC on RAL vs ATV/r than males (P = .0065). Similarly, a larger difference in WC change was found for RAL vs DRV/r for black vs nonblack individuals (P = .0043). A separate multivariable model found that in addition to the treatment regimen, higher baseline viral load and lower CD4+ were also associated with WC increases. CONCLUSIONS: With antiretroviral therapy initiation, higher WC increases in the RAL arm compared with PIs were more pronounced in female and black participants, and a more advanced baseline HIV disease state was a strong predictor of larger abdominal increases. Understanding factors predisposing individuals to abdominal fat gain could inform health management after therapy initiation.

The Association of Fat and Lean Tissue With Whole Body and Spine Bone Mineral Density Is Modified by HIV Status and Sex in Children and Youth.

BACKGROUND: HIV-infected (HIV-pos) male children/youth showed lower bone mineral density at sexual maturity than HIV-uninfected (HIV-neg) females. It is not known whether complications of HIV disease, including abnormal body fat distribution, contribute to lower bone accrual in male HIV-pos adolescents. METHODS: In a cross-sectional study, we evaluated the relationship between body composition (fat and lean mass) and bone mass in HIV-pos and HIV-neg children/youth and determined if it is modified by HIV status and sex. We used generalized estimating equations to simultaneously model the effect of fat/lean mass on multiple bone outcomes, including total body bone mineral density and bone mineral content and spine bone mineral density. We evaluated effect modification by HIV and sex. RESULTS: The analysis cohort consisted of 143 HIV-neg and 236 HIV-pos, of whom 55% were black non-Hispanic and 53% were male. Ages ranged from 7 to < 25 years. Half of the children/youth were at Tanner stage 1 and 20% at Tanner 5. Fat mass was more strongly positively correlated with bone mass in HIV-neg than HIV-pos children/youth and these relationships were more evident for total body bone than spine outcomes. Within HIV strata, fat mass and bone were more correlated in female than male children/youth. The relationship between lean mass and bone varied by sex, but not by HIV status. CONCLUSIONS: HIV disease diminishes the positive relationship of greater fat mass on bone mass in children/youth. Disruptions in body fat distribution, which are common in HIV disease, may have an impact on bone accretion during pubertal development.

Changes in abdominal fat following antiretroviral therapy initiation in HIV-infected individuals correlate with waist circumference and self-reported changes.

BACKGROUND: We examined whether waist circumference (WC) and self-reported abdominal size changes can estimate visceral adipose tissue (VAT) changes for those initiating antiretroviral therapy (ART). METHODS: Prospectively collected data from ACTG A5257 and its metabolic substudy, A5260s, were used for this analysis. ART-naive HIV-infected participants were randomized to one of three contemporary ART regimens. Changes in abdominal CT-measured VAT and total adipose tissue (TAT) and DXA-measured trunk fat were tested for association with WC changes (by Pearson correlation) and categories of self-reported abdominal size changes (by ANOVA) between entry and week 96. Linear models compared WC and self-reported changes. RESULTS: The study population (n=328) was predominantly male (90%) and White non-Hispanic (44%) with a baseline median age of 36 years and body mass index of 25 kg/m2. At week 96, median WC change was +2.8 cm. Of those reporting at week 96, 53% indicated 'no change/lost', 39% 'gained some/somewhat larger' and 8% 'gained a lot/much larger' as their self-reported changes. Trunk fat, VAT and TAT changes differed across self-reported groups (ANOVA P<0.0001 for all), and the group ordering was as expected. WC changes were strongly correlated with CT and DXA changes (trunk fat: ρ=0.72, p<0.0001; VAT: ρ=0.52, p<0.0001; TAT: ρ=0.62, p<0.0001). While WC changes explained a greater proportion of VAT, TAT and trunk fat variation, self-reported changes remained a significant predictor after controlling for WC (p<0.05). CONCLUSIONS: WC and self-reported abdominal changes each correlated directly with imaging-derived abdominal fat measures, and can be used as reliable, affordable tools for central adiposity assessment.

Metastases from the lung presenting as a parotid lump.

We report a case of a 59-year-old man who presented with a preauricular facial lump that was suspected to be a parotid malignancy based on fine needle aspiration. A chest radiograph and a computed tomogram showed a mass in the lungs and several metastases, and caused a diagnostic dilemma as to the origin of the parotid mass, which was later confirmed to be metastatic disease that had arisen from a carcinoma of unknown origin. Infraclavicular metastasis to the parotid is rare but should not be overlooked particularly in patients who present with coexisting conditions, or when cytological findings are atypical.

Recurrent cystic lymphangioma of the breast: case report and literature review.

Cystic lymphangioma is a rare congenital lymphatic malformation. We report a case of a 37-year-old female with recurrent cystic lymphangioma of the breast which has progressively developed during pregnancy and breast feeding.