Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Non-invasive Predictors of Human Cortical Bone Mechanical Properties: T2-Discriminated 1H NMR Compared with High Resolution X-ray

Recent advancements in magnetic resonance imaging (MRI) have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. To this end, 1H nuclear magnetic resonance (NMR) and high-resolution X-ray signals from human cortical bone samples were correlated with mechanical properties of bone. Results showed that 1H NMR signals were better predictors of yield stress, peak stress, and pre-yield toughness than were the X-ray derived signals. These 1H NMR signals can, in principle, be extracted from clinical MRI, thus offering the potential for improved clinical assessment of fracture risk

Stranger to Familiar: Wild Strepsirhines Manage Xenophobia by Playing

The power of play in limiting xenophobia is a well-known phenomenon in humans. Yet, the evidence in social animals remains meager. Here, we aim to determine whether play promotes social tolerance toward strangers in one of the most basal group of primates, the strepsirhines. We observed two groups of wild lemurs (Propithecus verreauxi, Verreaux's sifaka) during the mating season. Data were also collected on nine visiting, outgroup males. We compared the distribution of play, grooming, and aggressive interactions across three conditions: OUT (resident/outgroup interactions), IN (resident/resident interactions in presence of outgroups) and BL-IN (baseline of resident/resident interactions in absence of outgroups). Play frequency between males was higher in OUT than in IN and BL-IN conditions; whereas, grooming was more frequent in IN than in OUT and BL-IN conditions. Aggression rates between resident and outgroup males were significantly higher than those between residents. However, aggressions between resident and outgroup males significantly decreased after the first play session and became comparable with resident-resident aggression levels. The presence of strangers in a well-established group implies the onset of novel social circumstances, which sifaka males cope with by two different tactics: grooming with ingroup males and playing with outgroup ones. The grooming peak, concurrently with the visit of outgroups, probably represents a social shield adopted by resident males to make their pre-existing affiliation more evident to the stranger “audience”. Being mostly restricted to unfamiliar males, adult play in sifaka appears to have a role in managing new social situations more than in maintaining old relationships. In particular, our results indicate not only that play is the interface between strangers but also that it has a specific function in reducing xenophobia. In conclusion, play appears to be an ice-breaker mechanism in the critical process that “upgrades” an individual from stranger to familiar

Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity

Background\ud The amygdala and medial prefrontal cortex (mPFC) comprise a key corticolimbic circuit that helps shape individual differences in sensitivity to threat and the related risk for psychopathology. Although serotonin (5-HT) is known to be a key modulator of this circuit, the specific receptors mediating this modulation are unclear. The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity. Using a multimodal neuroimaging strategy in 39 healthy volunteers, we determined whether threat-related amygdala reactivity, assessed with blood oxygen level-dependent functional magnetic resonance imaging, was significantly predicted by the interaction between mPFC 5-HT1A and 5-HT2A receptor levels, assessed by positron emission tomography.\ud \ud Results\ud 5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.\ud \ud Conclusions\ud Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC

In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

Cardiac fibroblasts (CFs) are the primary cell type responsible for cardiac fibrosis during pathological myocardial remodeling. Several studies have illustrated that pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) attenuates cardiac fibrosis in different animal models. However, the effects of pirfenidone on cardiac fibroblast behavior have not been examined. In this study, we investigated whether pirfenidone directly modulates cardiac fibroblast behavior that is important in myocardial remodeling such as proliferation, myofibroblast differentiation, migration and cytokine secretion. Fibroblasts were isolated from neonatal rat hearts and bioassays were performed to determine the effects of pirfenidone on fibroblast function. We demonstrated that treatment of CFs with pirfenidone resulted in decreased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen contractility. Boyden chamber assay illustrated that pirfenidone inhibited fibroblast migration ability, probably by decreasing the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1. Furthermore, pirfenidone attenuated the synthesis and secretion of transforming growth factor-β1 but elevated that of interleukin-10. These direct and pleiotropic effects of pirfenidone on cardiac fibroblasts point to its potential use in the treatment of adverse myocardial remodeling

Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies

Type 2 diabetes mellitus (T2DM) influences bone metabolism, but the relation of T2DM with bone mineral density (BMD) remains inconsistent across studies. The objective of this study was to perform a meta-analysis and meta-regression of the literature to estimate the difference in BMD (g/cm2) between diabetic and non-diabetic populations, and to investigate potential underlying mechanisms. A literature search was performed in PubMed and Ovid extracting data from articles prior to May 2010. Eligible studies were those where the association between T2DM and BMD measured by dual energy X-ray absorptiometry was evaluated using a cross-sectional, cohort or case–control design, including both healthy controls and subjects with T2DM. The analysis was done on 15 observational studies (3,437 diabetics and 19,139 controls). Meta-analysis showed that BMD in diabetics was significantly higher, with pooled mean differences of 0.04 (95% CI: 0.02, 0.05) at the femoral neck, 0.06 (95% CI: 0.04, 0.08) at the hip and 0.06 (95% CI: 0.04, 0.07) at the spine. The differences for forearm BMD were not significantly different between diabetics and non-diabetics. Sex-stratified analyses showed similar results in both genders. Substantial heterogeneity was found to originate from differences in study design and possibly diabetes definition. Also, by applying meta-regression we could establish that younger age, male gender, higher body mass index and higher HbA1C were positively associated with higher BMD levels in diabetic individuals. We conclude that individuals with T2DM from both genders have higher BMD levels, but that multiple factors influence BMD in individuals with T2DM

Effect of Citalopram on Emotion Processing in Humans:A Combined 5-HT [C]CUMI-101 PET and Functional MRI Study

A subset of patients started on a selective serotonin reuptake inhibitor (SSRI) initially experience increased anxiety, which can lead to early discontinuation before therapeutic effects are manifest. The neural basis of this early SSRI effect is not known. Presynaptic dorsal raphe neuron (DRN) 5-HT1A receptors are known to play a critical role in affect processing. Thus we investigated the effect of acute citalopram on emotional processing and the relationship between DRN 5-HT1A receptor availability and amygdala reactivity. Thirteen (mean age 48±9 years) healthy male subjects received either a saline or citalopram infusion intravenously (10 mg over 30 min) on separate occasions in a single-blind, random order, cross-over design. On each occasion, participants underwent a block design face-emotion processing task during fMRI known to activate the amygdala. Ten subjects also completed a positron emission tomography (PET) scan to quantify DRN 5-HT1A availability using [(11)C]CUMI-101.Citalopram infusion when compared to saline resulted in a significantly increased bilateral amygdala responses to fearful vs. neutral faces (Left p=0.025; Right p=0.038 FWE-corrected). DRN [(11)C]CUMI-101availability significantly positively correlated with the effect of citalopram on the left amygdala response to fearful faces (Z=2.51, p=0.027) and right amygdala response to happy faces (Z=2.33, p=0.032). Our findings indicate that the initial effect of SSRI treatment is to alter processing of aversive stimuli, and that this is linked to DRN 5-HT1A receptors in line with evidence that 5-HT1A receptors have a role in mediating emotional processing

Human Endometrial CD98 Is Essential for Blastocyst Adhesion

BACKGROUND: Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans. METHODS AND PRINCIPAL FINDINGS: Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate. CONCLUSIONS: These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window