Gender Differences in Research Productivity among Academic Psychiatrists in Canada.

OBJECTIVES: Gender inequity in academic medicine persists despite increases in the number of women physicians. We sought to explore gender differences in research productivity for academic psychiatrists in Canada. METHODS: In a cross-sectional study of the 3379 psychiatrists in all 17 university departments of psychiatry in Canada, research productivity, as measured by the h-index and number of publications, was compared between women and men using a negative log binomial regression model to generate relative rates (RRs), adjusted for career duration (aRR). Findings were stratified by academic rank, institution region, and institution size. A subanalysis of those with 10 or more publications was conducted as a proxy for identifying physicians on a research track. RESULTS: Women (43% of the sample) had a lower mean (standard deviation) h-index than men (2.87 [6.49] vs. 5.31 [11.1]; aRR, 0.62; 95% confidence interval [CI], 0.54 to 0.72). Differences were significant only for junior faculty and not for associate and full professors. Comparison by number of publications followed a similar pattern (aRR, 0.46; 95% CI, 0.39 to 0.55). Among those with 10 or more publications (n = 721), differences between men and women were smaller than in the overall cohort for both the h-index (aRR, 0.77; 95% CI, 0.68 to 0.87) and number of publications (aRR, 0.62; 95% CI, 0.53 to 0.72). CONCLUSIONS: Gender differences in research productivity at the national level in academic psychiatry in Canada support a call to adopt a more systematic approach to promoting equitable opportunities for women in research, especially in early career, to improve diversity and enhance future psychiatric research and discovery.

HPV vaccination in male physicians: A survey of gynecologists and otolaryngology surgeons' attitudes towards vaccination in themselves and their patients.

OBJECTIVE: Attitudes and barriers towards HPV vaccination were explored in a population of male surgeons in Gynecology and Otolaryngology in Ontario, Canada. MATERIALS/METHODS: An internet-based survey was distributed to male residents and physicians affiliated with the departments of Obstetrics and Gynecology, and Otolaryngology at six Ontario universities. The survey consisted of 16 questions (3 demographic, 3 workplace exposure, 6 regarding personal vaccination, and 3 regarding patient vaccination). Subgroup analyses examined differences between residents versus staff physicians and gynecologists versus otolaryngologists. RESULTS: Most respondents (51/63, 81.0%) had not been vaccinated against HPV, yet would consider vaccination in the future (41/51, 80.4%). Significantly more residents would consider vaccination compared to staff physicians (p = .03). Personal protection from benign HPV disease was the most common motivating factor (25/59, 42.4%) among participants. A notable barrier to vaccination was "age over recommendations" (9/44, 20.4%). Most participants would recommend the HPV vaccine to both male patients (49/62, 79.0%) and male partners of female patients (47/62, 75.8%). CONCLUSIONS: This study demonstrates male gynecologists and otolaryngologists had largely favorable attitudes towards HPV vaccination though few had received vaccination. These findings may be used to increase HPV vaccine uptake among male health care professionals and their patients.

Aberrant TGFß Signalling Contributes to Dysregulation of Sphingolipid Metabolism in Intrauterine Growth Restriction.

CONTEXT: Sphingolipids function as key bioactive mediators that regulate cell fate events in a variety of systems. Disruptions in sphingolipid metabolism characterize several human pathologies. OBJECTIVE: In the present study we examined sphingolipid metabolism in intrauterine growth restriction (IUGR), a severe disorder complicating 4-7% of pregnancies at increased risk of perinatal morbidity and mortality, which is characterized by placental dysfunction and augmented trophoblast cell death rates. DESIGN, SETTING, AND PARTICIPANTS: Placentae from early severe IUGR with documented abnormal umbilical artery Doppler defined as absence or reverse of end diastolic velocity and a birth weight below the fifth percentile for gestational age were collected (n = 58). Placental tissues obtained from healthy, age-matched preterm and term deliveries (n = 46; TC, n=28) were included as controls. RESULTS: Sphingolipid analysis by tandem mass spectrometry revealed elevated sphingosine and decreased ceramide levels in placentae from pregnancies complicated by IUGR relative to age-matched controls. Sphingosine accumulation was due to accelerated ceramide breakdown via increased acid ceramidase (ASAH1) expression/activity caused by augmented TGFß signalling via the ALK5/SMAD2 pathway. In addition, a marked reduction in sphingosine kinase 1 (SPHK1) expression/activity due to impaired TGFß signalling via ALK1/SMAD1 contributed to the sphingosine buildup in IUGR. Of clinical significance, ALK/SMAD signalling pathways were differentially altered in IUGR placentae. CONCLUSIONS: Altered TGFß signalling in IUGR placentae causes dysregulation of sphingolipid metabolism, which may contribute to the increased trophoblast cell death typical of this pathology.

Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia.

Bioactive sphingolipids including ceramides are involved in a variety of pathophysiological processes by regulating cell death and survival. The objective of the current study was to examine ceramide metabolism in preeclampsia, a serious disorder of pregnancy characterized by oxidative stress, and increased trophoblast cell death and autophagy. Maternal circulating and placental ceramide levels quantified by tandem mass spectrometry were elevated in pregnancies complicated by preeclampsia. Placental ceramides were elevated due to greater de novo synthesis via high serine palmitoyltransferase activity and reduced lysosomal breakdown via diminished ASAH1 expression caused by TGFB3-induced E2F4 transcriptional repression. SMPD1 activity was reduced; hence, sphingomyelin degradation by SMPD1 did not contribute to elevated ceramide levels in preeclampsia. Oxidative stress triggered similar changes in ceramide levels and acid hydrolase expression in villous explants and trophoblast cells. MALDI-imaging mass spectrometry localized the ceramide increases to the trophophoblast layers and syncytial knots of placentae from pregnancies complicated by preeclampsia. ASAH1 inhibition or ceramide treatment induced autophagy in human trophoblast cells via a shift of the BOK-MCL1 rheostat toward prodeath BOK. Pharmacological inhibition of ASAH1 activity in pregnant mice resulted in increased placental ceramide content, abnormal placentation, reduced fetal growth, and increased autophagy via a similar shift in the BOK-MCL1 system. Our results reveal that oxidative stress-induced reduction of lysosomal hydrolase activities in combination with elevated de novo synthesis leads to ceramide overload, resulting in increased trophoblast cell autophagy, and typifies preeclampsia as a sphingolipid storage disorder.

HIV-1 gp120 induces TLR2- and TLR4-mediated innate immune activation in human female genital epithelium.

Although women constitute half of all HIV-1-infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120-TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1-infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.

Where polarity meets fusion: role of Par6 in trophoblast differentiation during placental development and preeclampsia.

Trophoblast cell fusion is a prerequisite for proper human placental development. Herein we examined the contribution of Par6 (Partitioning defective protein 6), a key regulator of cell polarity, to trophoblast cell fusion in human placental development. During early placentation, Par6 localized to nuclei of cytotrophoblast cells but with advancing gestation Par6 shifted its localization to the cytoplasm and apical brush border of the syncytium. Exposure of primary isolated trophoblasts to 3% O(2) resulted in elevated Par6 expression, maintenance of tight junction marker ZO-1 at cell boundaries, and decreased fusogenic syncytin 1 expression compared with cells cultured at 20% O(2). Treatment of choriocarcinoma BeWo cells with forskolin, a known inducer of fusion, increased syncytin 1 expression but decreased that of Par6 and ZO-1. Par6 overexpression in the presence of forskolin maintained ZO-1 at cell boundaries while decreasing syncytin 1 levels. In contrast, silencing of Par6 disrupted ZO-1 localization at cell boundaries and altered the expression and distribution of acetylated α-tubulin. Par6 expression was elevated in preeclamptic placentas relative to normotensive preterm controls and Par6 located to trophoblast cells expressing ZO-1. Together, our data indicate that Par6 negatively regulates trophoblast fusion via its roles on tight junctions and cytoskeleton dynamics and provide novel insight into the contribution of this polarity marker in altered trophoblast cell fusion typical of preeclampsia.

MARCO is required for TLR2- and Nod2-mediated responses to Streptococcus pneumoniae and clearance of pneumococcal colonization in the murine nasopharynx.

Streptococcus pneumoniae is a common human pathogen that accounts for >1 million deaths every year. Colonization of the nasopharynx by S. pneumoniae precedes pulmonary and other invasive diseases and, therefore, is a promising target for intervention. Because the receptors scavenger receptor A (SRA), macrophage receptor with collagenous structure (MARCO), and mannose receptor (MR) have been identified as nonopsonic receptors for S. pneumoniae in the lung, we used scavenger receptor knockout mice to study the roles of these receptors in the clearance of S. pneumoniae from the nasopharynx. MARCO(-/-), but not SRA(-/-) or MR(-/-), mice had significantly impaired clearance of S. pneumoniae from the nasopharynx. In addition to impairment in bacterial clearance, MARCO(-/-) mice had abrogated cytokine production and cellular recruitment to the nasopharynx following colonization. Furthermore, macrophages from MARCO(-/-) mice were deficient in cytokine and chemokine production, including type I IFNs, in response to S. pneumoniae. MARCO was required for maximal TLR2- and nucleotide-binding oligomerization domain-containing (Nod)2-dependent NF-κB activation and signaling that ultimately resulted in clearance. Thus, MARCO is an important component of anti-S. pneumoniae responses in the murine nasopharynx during colonization.