Factors Associated with Poor Mental Health Status Among Homeless Women With and Without Dependent Children

The purpose of this study was to estimate the prevalence of mental health problems among a representative sample of homeless women with and without dependent children and determine if the effects of risk factors for mental health are modified by the presence of dependent children. Homeless women (n = 522) were recruited in 2004–2005 from shelters and meal programs in Toronto, Canada. Linear and logistic regression was performed to identify factors associated with mental health status. Poor mental health was associated with low perceived access to social support, physical/sexual assault in the past 12 months, presence of a chronic health condition, and presence of a drug use problem in the past month. Efforts to improve mental health in this population will need to address the associated problems of victimization, substance abuse, and lack of social supports.     

Psychopathology in bariatric surgery candidates: A review of studies using structured diagnostic interviews

Psychiatric disorders are not uncommon among severely obese patients who present for bariatric surgery. This paper (1) reviews the results of the published studies using the structured interviews to assess psychopathology in bariatric surgery candidates; (2) compares the prevalence rates of psychiatric disorders across these studies with the data from other population samples; and (3) assesses whether sociodemographic variables appear to affect these prevalence rates. We searched online resources, PubMed, PsychINFO and reference lists of all the relevant articles to provide an overview of evidence so far and highlight some details in the assessment and comparisons of different samples in different countries. The prevalence estimates in the non-treatment obese group did not appear to differ substantially from the general population group in the US or the Italian population samples, although they were relatively higher for the German population. However, the rates of psychopathology in the bariatric surgery candidates were considerably higher than the other two population groups in all the samples. Overall, the most common category of lifetime Axis I disorders in all the studies was affective disorders, with anxiety disorders being the most common category of current Axis I disorders. Certain demographic characteristics are also associated with higher rates of psychopathology, such as, female gender, low socioeconomic status, higher BMI. Overall, methodological and sociodemographic differences make these studies difficult to compare and these differences should be taken into account when interpreting the results.     

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.     

Twenty-four-hour intensivist staffing in teaching hospitals: tensions between safety today and safety tomorrow

There is an inherent tension between the training needs of inexperienced clinicians and the safety of the patients for whom they are responsible. Our society has accepted this tension as a necessary trade-off to maintain a competent workforce of physicians year after year. However, recent trends in medical education have diminished resident autonomy in favor of the safety of current patients. One dramatic example is the rapid increase in the number of academic ICUs that provide coverage by attending physicians at all hours. The potential benefits of this staffing model have strong face validity: improved quality and efficiency from the constant involvement of experienced intensivists, increased family and staff satisfaction from the immediate availability of attending physicians, and reduced burn-out among intensivists from reduced on-call responsibilities. Thus, many hospitals have moved toward 24-h coverage by attending intensivist physicians without evidence that these benefits actually accrue and perhaps without full consideration of possible unintended consequences. In this article, we discuss the potential benefits and risks of nocturnal intensivist staffing, considering the needs of current and future patients. Furthermore, we suggest that there remains sufficient uncertainty about these benefits and risks that it is both necessary and ethical to study the effects in earnest.     

Glucocorticoid receptor signaling is essential for mesoderm formation and muscle development in zebrafish

Glucocorticoid receptor (GR) signaling is thought to play a key role in embryogenesis, but its specific developmental effects remain unclear. Cortisol is the primary ligand for GR activation in teleosts, and in zebrafish (Danio rerio), the prehatch embryo content of this steroid is of maternal origin. Using early zebrafish developmental stages, we tested the hypothesis that GR signaling is critical for embryo growth and hatching. In zebrafish, maternal GR mRNA is degraded quickly, followed by zygotic synthesis of the receptor. GR protein is widely expressed throughout early development, and we were able to knockdown this protein using morpholino oligonucleotides. This led to a more than 70% reduction in mRNA abundance of matrix metalloproteinase-13 (mmp13), a glucocorticoid-responsive gene. The GR morphants displayed delayed somitogenesis, defects in somite and tail morphogenesis, reduced embryo size, and rarely survived after hatch. This correlated with altered expression of myogenic markers, including myogenin, myostatin, and muscle-specific myosin heavy chain and troponin genes. A key finding was a 70-90% reduction in the mRNA abundance of bone morphogenetic proteins (BMP), including bmp2a, bmp2b, and bmp4 in GR morphants. Bioinformatics analysis confirmed multiple putative glucocorticoid response elements upstream of these BMP genes. GR morphants displayed reduced expression of BMP-modulated genes, including eve1 and pax3. Zebrafish GR mRNA injection rescued the GR morphant phenotype and reversed the disrupted expression of BMP and myogenic genes. Our results for the first time indicate that GR signaling is essential for zebrafish muscle development, and we hypothesize a role for BMP morphogens in this process.