Vortioxetine for major depressive disorder, vasomotor, and cognitive symptoms associated with the menopausal transition.

BACKGROUND: In a preliminary trial, we assessed the efficacy of vortioxetine for major depressive disorder (MDD) during the menopausal transition. Secondary outcomes included hot flashes (HFs), anxiety, and cognitive complaints. METHODS: Perimenopausal and early postmenopausal women with MDD (N = 27) received 8 weeks of open-label, flexible-dose treatment with vortioxetine. The Montgomery-Åsberg Depression Rating Scale (MADRS) was the primary outcome measure. Secondary measures included: HF frequency, the Greene Climacteric Scale (GCS), Menopause-Specific Quality of Life Questionnaire (MEN-QOL), Beck Anxiety Inventory (BAI), Cognitive and Physical Functioning Questionnaire (CPFQ), Digit Symbol Substitution Test (DSST), and Cogstate testing. RESULTS: Of the 27 women, 24 (88.8%) were evaluated (≥1 follow-up), and 21 (77.8%) completed the study; 1 discontinued because of adverse effects. The mean MADRS score decreased significantly (P = .0001) from 31.3 (standard deviation [SD] = 5.5) at pretreatment to 8.1 (SD = 7.8) at posttreatment. The depression response rate (≥50% reduction in MADRS) and remission rate (final MADRS ≤10) were 75% and 70.8%, respectively. GCS, MEN-QOL, BAI, CPFQ, and DSST scores improved significantly (P = .0030, P = .0001, P = .0001, P = .0001, and P = .0133, respectively); Cogstate test scores did not. Frequency and severity of HFs improved significantly (P = .0291 and P = .0299, respectively). CONCLUSIONS: These data support further study of vortioxetine for treating menopausal depression and associated symptoms.

The structure of the cysteine protease and lectin-like domains of Cwp84, a surface layer-associated protein from Clostridium difficile.

Clostridium difficile is a major problem as an aetiological agent for antibiotic-associated diarrhoea. The mechanism by which the bacterium colonizes the gut during infection is poorly understood, but undoubtedly involves a myriad of components present on the bacterial surface. The mechanism of C. difficile surface-layer (S-layer) biogenesis is also largely unknown but involves the post-translational cleavage of a single polypeptide (surface-layer protein A; SlpA) into low- and high-molecular-weight subunits by Cwp84, a surface-located cysteine protease. Here, the first crystal structure of the surface protein Cwp84 is described at 1.4 Šresolution and the key structural components are identified. The truncated Cwp84 active-site mutant (amino-acid residues 33-497; C116A) exhibits three regions: a cleavable propeptide and a cysteine protease domain which exhibits a cathepsin L-like fold followed by a newly identified putative carbohydrate-binding domain with a bound calcium ion, which is referred to here as a lectin-like domain. This study thus provides the first structural insights into Cwp84 and a strong base to elucidate its role in the C. difficile S-layer maturation mechanism.

Super toxins from a super bug: structure and function of Clostridium difficile toxins.

Clostridium difficile, a highly infectious bacterium, is the leading cause of antibiotic-associated pseudomembranous colitis. In 2009, the number of death certificates mentioning C. difficile infection in the U.K. was estimated at 3933 with 44% of certificates recording infection as the underlying cause of death. A number of virulence factors facilitate its pathogenicity, among which are two potent exotoxins; Toxins A and B. Both are large monoglucosyltransferases that catalyse the glucosylation, and hence inactivation, of Rho-GTPases (small regulatory proteins of the eukaryote actin cell cytoskeleton), leading to disorganization of the cytoskeleton and cell death. The roles of Toxins A and B in the context of C. difficile infection is unknown. In addition to these exotoxins, some strains of C. difficile produce an unrelated ADP-ribosylating binary toxin. This toxin consists of two independently produced components: an enzymatic component (CDTa) and the other, the transport component (CDTb) which facilitates translocation of CDTa into target cells. CDTa irreversibly ADP-ribosylates G-actin in target cells, which disrupts the F-actin:G-actin equilibrium leading to cell rounding and cell death. In the present review we provide a summary of the current structural understanding of these toxins and discuss how it may be used to identify potential targets for specific drug design.

Cultivable Bacteria in Urine of Women With Interstitial Cystitis: (Not) What We Expected.

OBJECTIVE: Multiple studies show cultivatable bacteria in urine of most women. The existence of these bacteria challenges interstitial cystitis (IC)/painful bladder syndrome (PBS) diagnosis, which presumes a sterile bladder. The aims of this study were (1) to compare the female bladder microbiomes in women with IC/PBS and unaffected controls and (2) to correlate baseline bladder microbiome composition with symptoms. METHODS: This cross-sectional study enrolled 49 IC/PBS and 40 controls. All provided catheterized urine samples and completed validated questionnaires. A subset of the IC/PBS cohort provided voided and catheterized urine samples. All samples from both cohorts were assessed by the expanded quantitative urine culture (EQUC) protocol; a subset was assessed by 16S rRNA gene sequencing. RESULTS: Of the IC/PBS cohort, 49.0% (24/49) were EQUC positive; in these EQUC-positive samples, the most common urotypes were Lactobacillus (45.8%) and Streptococcus (33.3%). Of the controls, 40.0% were EQUC positive; of these EQUC-positive samples, the most common urotype was Lactobacillus (50.0%). The urotype distribution was significantly different (P < 0.05), as 16% of the IC/PBS cohort, but 0% of controls, were Streptococcus urotype (P < 0.01). Symptom-free IC/PBS participants were less likely to be EQUC positive (12.5%) than IC/PBS participants with moderate or severe symptoms (68.8% and 46.2%) and the control cohort (60%; P < 0.05). CONCLUSION: Lactobacillus was the most common urotype. However, the presence of Lactobacillus did not differ between cohorts, and it did not impact IC/PBS symptom severity. Bacteria were not isolated from most participants with active IC/PBS symptoms. These findings suggest that bacteria may not be an etiology for IC/PBS.

An Electronic Sexual Health Module for Hospitalized Adolescent Girls.

OBJECTIVES: To evaluate the acceptability and feasibility of an electronic sexual health module for inpatient adolescent girls and assess the preliminary effect on uptake of sexual health services. METHODS: We recruited girls 14 to 18 years old admitted to the hospitalist service of 1 academic children's hospital from January 2016 to October 2016. Participants completed an electronic sexual health module that included a sexual health assessment, tailored feedback (randomized for half of the participants only), and a questionnaire to request sexual health services. Participation and completion rates, along with effects of tailored feedback, risk perception, age group, and sexual activity on uptake of services, were examined. RESULTS: Seventy-seven percent of eligible participants who were approached enrolled in the study (n = 66 of 86). The completion rate was 100%. Fifty-three percent (n = 35) requested some form of sexual health service; of these, 83% (n = 29) requested to watch a contraception video. There was no statistically significant difference in the frequency of requests for those who received tailored feedback and for those who did not (57% vs 48%; P = .48). Younger teens and those without sexual experience made requests similar to older and sexually experienced girls except regarding sexually transmitted infection testing, which was significantly higher in the latter populations. CONCLUSIONS: This pilot study demonstrated reasonable feasibility and acceptability of a standardized sexual health module for adolescent girls admitted to the general pediatric wards. Videos focused on adolescent health were of particular interest to this population. Further study should examine the impact of such a module on long-term sexual health behaviors.

Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: Results from a prospective registry of women with psychiatric disorders.

OBJECTIVE: The goal of this analysis was to examine the effect of benzodiazepine use during pregnancy on maternal and neonatal outcomes in a cohort of women with psychiatric disorders. METHODS: 794 evaluable women from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications were followed across pregnancy (N = 144 exposed to benzodiazepines and N = 650 unexposed). Data obtained through maternal report and medical records included maternal outcomes (cesarean section, preeclampsia) and neonatal outcomes (birth weight, breathing difficulty, feeding difficulty, head circumference, 5-minute Apgar score, muscular and/or extrapyramidal symptoms, NICU admission, prematurity). RESULTS: In adjusted analyses, infants exposed to benzodiazepines in utero were more likely to be admitted to the NICU (OR: 2.02, 95% CI: 1.11, 3.66) and to have small head circumferences (OR: 3.89, 95% CI: 1.25, 12.03) compared to unexposed infants. Other neonatal adverse effects such as respiratory distress or muscular symptoms including hypotonia were not observed. There were no significant differences in adverse obstetrical outcomes. CONCLUSIONS: Infants exposed to benzodiazepines during pregnancy had an increased risk of NICU admissions and small head circumferences. Confounding from psychiatric symptoms and other variables cannot be ruled out as contributors to these findings.

Functional significance of active site residues in the enzymatic component of the Clostridium difficile binary toxin.

Clostridium difficile binary toxin (CDT) is an ADP-ribosyltransferase which is linked to enhanced pathogenesis of C. difficile strains. CDT has dual function: domain a (CDTa) catalyses the ADP-ribosylation of actin (enzymatic component), whereas domain b (CDTb) transports CDTa into the cytosol (transport component). Understanding the molecular mechanism of CDT is necessary to assess its role in C. difficile infection. Identifying amino acids that are essential to CDTa function may aid drug inhibitor design to control the severity of C. difficile infections. Here we report mutations of key catalytic residues within CDTa and their effect on CDT cytotoxicity. Rather than an all-or-nothing response, activity of CDTa mutants vary with the type of amino acid substitution; S345A retains cytotoxicity whereas S345Y was sufficient to render CDT non-cytotoxic. Thus CDTa cytotoxicity levels are directly linked to ADP-ribosyltransferase activity.

Molecular features of the sortase enzyme family.

Bacteria possess complex and varying cell walls with many surface exposed proteins. Sortases are responsible for the covalent attachment of specific proteins to the peptidoglycan of the cell wall of Gram-positive bacteria. Sortase A of Staphylococcus aureus, which is seen as the archetypal sortase, has been shown to be essential for pathogenesis and has therefore received much attention as a potential target for novel therapeutics. Being widely present in Gram-positive bacteria, it is likely that other Gram-positive pathogens also require sortases for their pathogenesis. Sortases have also been shown to be of significant use in a range of industrial applications. We review current knowledge of the sortase family in terms of their structures, functions and mechanisms and summarize work towards their use as antibacterial targets and microbiological tools.