A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

Gqα/G11α deficiency in dorsomedial hypothalamus leads to obesity resulting from decreased energy expenditure and impaired sympathetic nerve activity.

The G-protein subunits Gqα and G11α (Gq/11α) couple receptors to phospholipase C, leading to increased intracellular calcium. In this study we investigated the consequences of Gq/11α deficiency in the dorsomedial hypothalamus (DMH), a critical site for the control of energy homeostasis. Mice with DMH-specific deletion of Gq/11α (DMHGq/11KO) were generated by stereotaxic injection of adeno-associated virus (AAV)-Cre-green fluorescent protein (GFP) into the DMH of Gqαflox/flox:G11α-/- mice. Compared with control mice that received DMH injection of AAV-GFP, DMHGq/11KO mice developed obesity associated with reduced energy expenditure without significant changes in food intake or physical activity. DMHGq/11KO mice showed no defects in the ability of the melanocortin agonist melanotan II to acutely stimulate energy expenditure or to inhibit food intake. At room temperature (22°C), DMHGq/11KO mice showed reduced sympathetic nervous system activity in brown adipose tissue (BAT) and heart, accompanied with decreased basal BAT uncoupling protein 1 (Ucp1) gene expression and lower heart rates. These mice were cold intolerant when acutely exposed to cold (6°C for 5 h) and had decreased cold-stimulated BAT Ucp1 gene expression. DMHGq/11KO mice also failed to adapt to gradually declining ambient temperatures and to develop adipocyte browning in inguinal white adipose tissue although their BAT Ucp1 was proportionally stimulated. Consistent with impaired cold-induced thermogenesis, the onset of obesity in DMHGq/11KO mice was significantly delayed when housed under thermoneutral conditions (30°C). Thus our results show that Gqα and G11α in the DMH are required for the control of energy homeostasis by stimulating energy expenditure and thermoregulation.NEW & NOTEWORTHY This paper demonstrates that signaling within the dorsomedial hypothalamus via the G proteins Gqα and G11α, which couple cell surface receptors to the stimulation of phospholipase C, is critical for regulation of energy expenditure, thermoregulation by brown adipose tissue and the induction of white adipose tissue browning.

Postoperative atrial fibrillation in patients undergoing non-cardiac non-thoracic surgery: A practical approach for the hospitalist.

New postoperative atrial fibrillation (POAF) is the most common perioperative arrhythmia and its reported incidence ranges from 0.4 to 26% in patients undergoing non-cardiac non-thoracic surgery. The incidence varies according to patient characteristics such as age, presence of structural heart disease and other co-morbidities, as well as the type of surgery performed. POAF occurs as a consequence of adrenergic stimulation, systemic inflammation, or autonomic activation in the intra or postoperative period (e.g. due to pain, hypotension, infection) in the setting of a susceptible myocardium and other predisposing factors (e.g. electrolyte abnormalities). POAF develops between day 1 and day 4 post-surgery and it is often considered a self-limited entity. Its acute management involves many of the same strategies used in non-surgical patients but the optimal long-term management is challenging because of the limited available evidence. Several studies have shown an association between occurrence of POAF and in-hospital morbidity, mortality, and length of stay. Although, traditionally, POAF was considered to have a generally favorable long-term prognosis, recent data have shown an association with an increased risk of stroke at 1 year after hospitalization. It is unknown, however, whether strategies to prevent POAF or for rate/rhythm control when it does occur, lead to a reduction in morbidity or mortality. This suggests the need for future studies to better understand the risks associated with POAF and to determine optimal strategies to minimize long-term thromboembolic risks. In this article, we summarize the current knowledge on epidemiology, pathophysiology, and short- and long-term management of POAF after non-cardiac non-thoracic surgery with the goal of providing a practical approach to managing these patients for the non-cardiologist clinician.

Anemia, chronic heart failure, and the impact of male vs. female gender.

Anemia is common in subjects with chronic heart failure, and correction of anemia improves quality of life and exercise capacity in both men and women. The definition of anemia is sex-specific, but enrollment criteria of studies examining the effects of recombinant human erythropoietin in chronic heart failure to date have not taken sex into account. Indeed, it is unknown whether sex-specific differences of hemoglobin values observed in normal individuals are maintained in subjects with chronic disease and volume overload states. Given the significant treatment implications for sex-specific differences in hemoglobin values, the authors analyzed data for 260 subjects consecutively admitted with decompensated chronic heart failure. In a multivariate regression analysis controlling for serum creatinine and age, female sex was independently associated with lower hemoglobin. When deciding upon initiation of treatment in this population, sex-specific targets should be applied.

[Contraceptive methods used in Istanbul and factors affecting method choice and continuation]. / Istanbul'da kullanilan gebelikten korunma yontemleri, bu yontemlerin tercih ve kullanimini surdurmede etkili faktorler.

PIP: This paper presents and discusses the results of a collaborative research to investigate use of modern versus traditional contraceptive methods in a new settlement area in Istanbul. Two lay interviewers administered a questionnaire to a total of 867 women on current and past contraceptive use. 90% (778) of the 867 currently nonpregnant women of mean age 31.4 years were using a method of contraception at the time of the study. The majority of women practicing contraception (46%) employed withdrawal, alone or in combination, followed by 29% who used an IUD. Among ever-users, withdrawal and IUD remain the two most common methods. The use of these methods was found to be unrelated to age, family size, or education, but there was a negative association of withdrawal use and a positive association of permanent method use with long-term residence in Istanbul. Contraception is widely acknowledged in Turkey. Almost every woman has heard of every method. People believe that there are side effects, and some side effects may actually be occurring, as also supported by the present data. In this community, despite the high failure rate of withdrawal, it appears that convenience and cleanliness of the method also play important roles in the choice. (author's modified)^ieng

Anthropometry as a predictor for mortality among Ugandan children, allowing for socio-economic variables.

Length, height, weight and mid-upper arm circumference (MUAC) were measured in 4320 children aged between 0 and 59 months, and their socio-economic status was assessed, in 31 villages in Southwest Uganda during March-April 1988. A follow-up survey assessed the mortality of the children during the 12 months following anthropometry. Mortality rates were higher in those with low anthropometric indices at the first survey. MUAC was the most sensitive predictor of mortality followed by weight-for-age, height-for-age and weight-for-height. MUAC increased the predictive power of other parameters whereas the other parameters did not increase the predictive power of MUAC. MUAC below 12.5, 11.5 and 10.5 cm predicted 10.9%, 18.7% and 36.5% of the deaths respectively. Nutritional status was worse in the low socio-economic group but the predictive power of anthropometry for mortality was not influenced by socio-economic status. This suggests that nutrition per se has an influence on mortality which is independent of socio-economic status.

Role in vivo for gamma interferon in control of pneumonia caused by Chlamydia trachomatis in mice.

In a model of pneumonia caused by murine Chlamydia trachomatis, depletion experiments with monoclonal antibody to gamma interferon (IFN-gamma) made mice more susceptible. Repletion experiments giving exogenous recombinant murine IFN-gamma were not consistently protective. IFN-gamma may be necessary but not sufficient in host defense against the organism.