Female sexual dysfunction

Female sexual dysfunction (FSD) is defined as a disorder of sexual desire, arousal, or orgasm, and/or sexual pain, which results in personal distress and has an impact on quality of life and interpersonal relationships. It is a compilation of problems that has both biologic and psychosocial components and is multifactorial in etiology. Improved understanding of the structures and substances involved in normal sexual function, as well as age-related changes, helps practitioners proactively evaluate and appropriately manage women with FSD. Addressing FSD in a clinical setting should begin with an open discussion about relational, situational, and psychological issues. Clinicians should emphasize nonpharmacologic and behavioral therapies with the goal of achieving satisfying and pleasurable experiences. The continued quest to understand female sexual function and dysfunction requires more education and research on treatment of underlying medical conditions and use of pharmacologic therapies.     

Non-bullous neutrophilic dermatosis: an uncommon dermatologic manifestation in patients with lupus erythematosus

BACKGROUND: Rare cases of a non-bullous neutrophilic dermatosis occurring in patients with lupus erythematosus (LE) have been reported, often as the presenting manifestation of the disease. METHODS: We reviewed hematoxylin and eosin-stained slides and obtained clinical information from four additional patients, two of whom had no prior history of LE. RESULTS: All patients were female, aged 16-59 (mean age 37). Clinically, the skin lesions were characterized by widely distributed pruritic papules and plaques. Three patients presented with systemic symptoms, including fever, arthritis and malaise. Histopathologic examination in all cases showed a superficial perivascular and interstitial neutrophilic infiltrate with leukocytoclasis. There was no evidence of vasculitis. Mild focal vacuolar change was a subtle feature seen only in the biopsies of the two patients with a prior history of LE. CONCLUSIONS: It is important to consider LE in the differential diagnosis of non-bullous neutrophilic dermatoses.     

Pulsed High–Intensity-focused US and Tissue Plasminogen Activator (TPA) Versus TPA Alone for Thrombolysis of Occluded Bypass Graft in Swine

PurposeProsthetic arteriovenous or arterial-arterial bypass grafts can thrombose and be resistant to revascularization. A thrombosed bypass graft model was created to evaluate the potential therapeutic enhancement and safety profile of pulsed high–intensity-focused ultrasound (pHIFU) on pharmaceutical thrombolysis.Materials and MethodsIn swine, a right carotid-carotid expanded polytetrafluoroethylene bypass graft was surgically constructed, containing a 40% stenosis at its distal end to induce graft thrombosis. The revascularization procedure was performed 7 days after surgery. After model development and dose response experiments (n = 11), two cohorts were studied: pHIFU with tissue plasminogen activator (TPA; n = 4) and sham pHIFU with TPA (n = 3). The experiments were identical in both groups except no energy was delivered in the sham pHIFU group. Serial angiograms were obtained in all cases. The area of graft opacified by contrast medium on angiograms was quantified with digital image processing software. A blinded reviewer calculated the change in the graft area opacified by contrast medium and expressed it as a percentage, representing percentage of thrombolysis.ResultsCombining pHIFU with 0.5 mg of TPA resulted in a 52% ± 4% increase in thrombolysis on angiograms obtained at 30 minutes, compared with a 9% ± 14% increase with sham pHIFU and 0.5 mg TPA (P = .003). Histopathologic examination demonstrated no differences between the groups.ConclusionsThrombolysis of occluded bypass grafts was significantly increased when combining pHIFU and TPA versus sham pHIFU and TPA. These results suggest that application of pHIFU may augment thrombolysis with a reduced time and dose.     

Prevalence of Hepatitis C Virus Infection in the Veteran Population Undergoing Total Joint Arthroplasty

Many orthopedic surgeons train or are employed at the Department of Veterans Affairs (VA) hospitals. We sought to determine the prevalence of hepatitis C antibody–positive and hepatitis C–viremic patients in the VA population undergoing total joint arthroplasty. In this prospective cohort study, 381 of 408 patients undergoing primary total joint arthroplasty for 22 consecutive months were tested for hepatitis C virus (HCV) infection preoperatively. Thirty-two (8.4%) of 381 patients were positive for hepatitis C virus antibody. Seventeen were actually viremic at the time of total joint arthroplasty (4.5%). The prevalence of detectable hepatitis C antibody in VA patients undergoing total joint arthroplasty is about 6 times the general population (1.3%). Surgeons practicing on populations with a high prevalence of hepatitis C such as this should do all they can to minimize the risk of sharps injury.     

Depression,anxiety, and prevalent diabetes in the Chinese population: Findings from the China Kadoorie Biobank of 0.5 million people

Objective

Despite previous investigation, uncertainty remains about the nature of the associations of major depression (MD) with type 2 diabetes mellitus (T2DM), particularly in adult Chinese, and the relevance of generalized anxiety disorder (GAD) for T2DM.

Methods

Cross-sectional data from the China Kadoorie Biobank Study, a sample of approximately 500,000 adults from 10 geographically defined regions of China, were analyzed. Past year MD and GAD were assessed using the Composite International Diagnostic Inventory. T2DM was defined as either having self-reported physician diagnosis of diabetes at age 30 or later (“clinically-identified” cases) or having a non-fasting blood glucose ≥ 11.1 mmol/L or fasting blood glucose ≥ 7.0 mmol/L but no prior diagnosis of diabetes (“screen-detected” cases). Logistic regression was used to assess the relationship between MD and GAD with clinically-identified and screen-detected T2DM, adjusting for demographic characteristics and health behaviors.

Results

The prevalence of T2DM was 5.3% (3.2% clinically-identified and 2.1% screen-detected). MD was significantly associated with clinically-identified T2DM (odds ratio [OR]: 1.75, 95% confidence interval (CI): 1.47–2.08), but not with screen-detected T2DM (OR: 1.18, 95% CI: 0.92–1.51). GAD was associated with clinically-identified (OR: 2.14, 95% CI: 1.60–2.88) and modestly associated with screen-detected (OR: 1.44, 95% CI: 0.99–2.08) T2DM. The relationship between MD and GAD with T2DM was moderated by obesity.

Conclusion

MD is associated with clinically-identified, but not screen-detected T2DM. GAD is associated with both clinically-identified and screen-detected T2DM. The relationship between MD and T2DM is strongest among those who are not obese.     

Characterization of a monoclonal antibody to a novel glycan-dependent epitope in the V1/V2 domain of the HIV-1 envelope protein,gp120

Recent studies have described several broadly neutralizing monoclonal antibodies (bN-mAbs) that recognize glycan-dependent epitopes (GDEs) in the HIV-1 envelope protein, gp120. These were recovered from HIV-1 infected subjects, and several (e.g., PG9, PG16, CH01, CH03) target glycans in the first and second variable (V1/V2) domain of gp120. The V1/V2 domain is thought to play an important role in conformational masking, and antibodies to the V1/V2 domain were recently identified as the only immune response that correlated with protection in the RV144 HIV-1 vaccine trial. While the importance of antibodies to polymeric glycans is well established for vaccines targeting bacterial diseases, the importance of antibodies to glycans in vaccines targeting HIV has only recently been recognized. Antibodies to GDEs may be particularly significant in HIV vaccines based on gp120, where 50% of the molecular mass of the envelope protein is contributed by N-linked carbohydrate. However, few studies have reported antibodies to GDEs in humans or animals immunized with candidate HIV-1 vaccines. In this report, we describe the isolation of a mouse mAb, 4B6, after immunization with the extracellular domain of the HIV-1 envelope protein, gp140. Epitope mapping using glycopeptide fragments and in vitro mutagenesis showed that binding of this antibody depends on N-linked glycosylation at asparagine N130 (HXB2 numbering) in the gp120 V1/V2 domain. Our results demonstrate that, in addition to natural HIV-1 infection, immunization with recombinant proteins can elicit antibodies to the GDEs in the V1/V2 domain of gp120. Although little is known regarding conditions that favor antibody responses to GDEs, our studies demonstrate that these antibodies can arise from a short-term immunization regimen. Our results suggest that antibodies to GDEs are more common than previously suspected, and that further analysis of antibody responses to the HIV-1 envelope protein will lead to the discovery of additional antibodies to GDEs.     

Quantifying alcohol use among Ecuadorian human immunodeficiency virus positive individuals and assessing alcohol as an independent risk factor for human immunodeficiency virus: A case control study STROBE

Alcohol abuse has been identified as a risk factor for contracting human immunodeficiency virus (HIV) and accelerating disease progression. Our study aims to determine alcohol consumption rates among Ecuadorian HIV positive (HIV+) patients prior to diagnosis to evaluate its impact as an independent risk factor for contracting HIV. Additionally, we will examine post-diagnosis consumption rates among the HIV+ population.We provided anonymous questionnaires to 300 HIV+ patients and 600 internal medicine patients at 3 hospitals in Quito, Ecuador. Questionnaires quantified alcohol usage prior to HIV diagnosis, at time of diagnosis, and post-diagnosis while accounting for other potential HIV risk factors. We then determined frequencies of alcohol consumption and confounding variables. Finally, we performed a multivariable logistic regression controlling for confounders to determine the statistical significance of alcohol consumption as an independent risk factor for HIV.Our results showed increased odds for contracting HIV among those who drank daily (OR 5.3, CI 2.0–14.0) and those who consumed 6 or more alcoholic beverages on days they drank (OR 5.0, CI 3.1–8.2). Through multivariable analysis, we found that abstaining from binge drinking was a protective factor with an OR 0.5 (0.3–0.96). The percentage of HIV+ patients abstaining from alcohol increased from 30% twelve months prior to diagnosis to 57% after diagnosis.Our results show that alcohol abuse significantly increases the risk of contracting HIV. We found that prior to diagnosis, HIV patients consistently drank more frequently and a greater amount than the control group. Alcohol use significantly decreased among HIV+ patients after diagnosis.     

Dimer recognition and secretion by the ESX secretion system in Bacillus subtilis

Protein secretion typically involves translocation of unfolded polypeptides or transport of monomeric folded proteins. Here we provide, to our knowledge, the first experimental evidence for secretion of an intact multimeric complex requiring a signal formed by both members of the complex. Using systematic mutagenesis of a substrate involved in early secretory antigen 6 kDa (ESX) secretion in Bacillus subtilis, we demonstrate that export of the substrate requires two independent motifs. Using mixed dimers, we show that these motifs must form a composite secretion signal in which one motif is contributed by each subunit of the dimer. Finally, through targeted crosslinking we show that the dimer formed in the cell is likely secreted as a single unit. We discuss implications of this substrate recognition mechanism for the biogenesis and quality control of secretion substrates and describe its likely conservation across ESX systems.Protein secretion is critical for protein targeting in any living cell and for its communication with the environment. Bacteria use a wide range of secretion mechanisms to export proteins out of the cytoplasm. Signals for secretion are most commonly primary amino acid sequences, but in some cases also may be formed through interacting surfaces of a substrate and its delivery effector. Some secretion systems unfold their substrates to translocate them across the membrane and cell wall. Other systems export folded proteins, sometimes in complex with bound cofactors. For example, the general secretory machinery (Sec) denatures the tertiary and secondary structure of its substrates to thread the polypeptide through the narrow opening of the integral membrane translocon complex, SecYEG (1). Type III secretion system (T3SS) machinery is thought to unfold the tertiary structure of its substrates, while preserving the secondary structure elements for the substrate recognition (2, 3). In contrast, the twin-arginine transport (Tat) system exports folded substrates (4) and is hypothesized to be able to translocate protein oligomers and complexes via a “hitchhiking” mechanism (5). Overall, these and other secretion types differ in the nature of substrate recognition signal and the mode of substrate translocation.Early secretory antigen 6 kDa (ESX, or type VII) secretion systems are widespread in actinomycetes and Gram-positive bacteria and affect a range of bacterial processes including sporulation, conjugation, and cell wall stability (6–10). In two notorious human pathogens, Mycobacterium tuberculosis and Staphylococcus aureus, ESX secretion was found to be crucial for establishing and maintaining the infection (11–15). Despite the importance of the ESX secretion for human health, the mechanism of this type of secretion is still largely unknown.Recent characterization of the ESX system in Bacillus subtilis confirmed that a functional system is encoded by the yuk/yue operon (16, 17). Importantly, the B. subtilis system codes for a homolog to the prototypical virulence factor substrates from mycobacteria, EsxA and EsxB (18). These proteins all belong to the WXG-100 protein family, which are defined by a conserved WXG amino acid motif that is roughly in the middle of the typically short, otherwise poorly conserved, ∼100-amino-acid polypeptide (Fig. S1A). All characterized WXG proteins share helix-turn-helix hairpin structures where the conserved WXG motif forms a sharp turn between the N- and C-terminal helices (19–23). Two hairpins interact in an antiparallel configuration to form either homo- or heterodimers (Fig. S1B) (19–24). This arrangement places the N and C termini of one subunit in close proximity with the WXG hairpin of the interacting partner. Previous studies have demonstrated that the C-terminal residues and the WXG motif are important for secretion of some mycobacterial substrates but not the others (7, 25, 26). However, dissecting the roles of these motifs has been challenging due to confounding effects, such as their contributions to substrate stability (7, 26, 27). Further complicating the issue, in the mycobacterial system, for example, multiple substrates have been identified and their secretion is codependent (13, 28). There are also multiple closely related ESX systems in mycobacteria that could complicate the analyses (29).Therefore, to investigate the requirements for WXG substrate recognition and the mode of substrate translocation in ESX secretion, we took advantage of the fact that under standard laboratory conditions B. subtilis has a single WXG substrate, YukE (17). Here we report results of a systematic mutagenesis study combined with crosslinking experiments. First, we show that the C-terminal residues of the B. subtilis substrate YukE are important for secretion, suggesting a general mode of recognition of the ESX substrates in firmicutes and actinobacteria. Second, tryptophan and glycine residues of the WXG motif of YukE are required for an efficient transfer of YukE outside of the cell. Third, YukE forms stable homodimers that contain two sites composed by C terminus and WXG turn, but only one intact bipartite site is required for substrate export. Fourth, we present experimental evidence that the ESX system translocates the WXG protein dimers. Together our results show that the ESX system requires a composite signal formed by two folded polypeptides for secretion and exports an intact protein complex that possesses the bipartite signal.