Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43

AIMS: T-box factors Tbx2 and Tbx3 play key roles in the development of the cardiac conduction system, atrioventricular canal, and outflow tract of the heart. They regulate the gap-junction-encoding gene Connexin43 (Cx43) and other genes critical for heart development and function. Discovering protein partners of Tbx2 and Tbx3 will shed light on the mechanisms by which these factors regulate these gene programs. METHODS AND RESULTS: Employing an yeast 2-hybrid screen and subsequent in vitro pull-down experiments we demonstrate that muscle segment homeobox genes Msx1 and Msx2 are able to bind the cardiac T-box proteins Tbx2, Tbx3, and Tbx5. This interaction, as that of the related Nkx2.5 protein, is supported by the T-box and homeodomain alone. Overlapping spatiotemporal expression patterns of Msx1 and Msx2 together with the T-box genes during cardiac development in mouse and chicken underscore the biological significance of this interaction. We demonstrate that Msx proteins together with Tbx2 and Tbx3 suppress Cx43 promoter activity and down regulate Cx43 gene activity in a rat heart-derived cell line. Using chromatin immunoprecipitation analysis we demonstrate that Msx1 can bind the Cx43 promoter at a conserved binding site located in close proximity to a previously defined T-box binding site, and that the activity of Msx proteins on this promoter appears dependent in the presence of Tbx3. CONCLUSION: Msx1 and Msx2 can function in concert with the T-box proteins to suppress Cx43 and other working myocardial genes.     

High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis

RATIONALE: High-resolution computed tomography (HRCT) is an integral aspect of the evaluation of patients with suspected idiopathic pulmonary fibrosis (IPF). However, few studies have evaluated its use in a large cohort. OBJECTIVES: To describe HRCT features in patients with mild to moderate IPF, compare diagnostic evaluations by a radiology core (three thoracic radiologists) with those by study-site radiologists, correlate baseline clinical and physiologic variables with HRCT findings, and evaluate their association with mortality. METHODS: We assessed HRCT scans from patients with IPF (n = 315) enrolled in a randomized controlled study evaluating IFN-gamma1b. MEASUREMENTS AND MAIN RESULTS: There was concordance between study-site and core radiologists regarding the diagnosis of IPF in 86% of cases. Diffusing capacity of carbon monoxide (DLCO) was the physiologic characteristic most highly correlated with HRCT findings. Multivariate analysis identified three independent predictors of mortality: a higher extent of fibrosis score increased the risk of death (p < 0.0001), whereas a higher percent-predicted DLCO (p = 0.004) and treatment assignment to IFN-gamma1b rather than placebo (p = 0.04) reduced the risk of death. CONCLUSIONS: A study-site diagnosis of IPF on HRCT was regularly confirmed by core radiologists. Extent of reticulation and honeycombing on HRCT is an important independent predictor of mortality in patients with IPF.     

Monitoring and management of hyperglycemia in patients with advanced diabetic kidney disease

Diabetes mellitus is the leading cause of end-stage renal disease, and uncontrolled hyperglycemia is directly related to the increased mortality in this setting. As kidney function decreases, it becomes more challenging to control blood glucose since the risk of hypoglycemia increases. Decreased appetite, changes in glycaemia homeostasis, along with reduced renal excretion of anti-hyperglycemic drugs tend to facilitate the occurrence of hypoglycemia, despite the paradoxical occurrence of insulin resistance in advanced kidney disease. Thus, in patients using insulin and/or oral anti-hyperglycemic agents, dynamic adjustments with drug dose reduction or drug switching are often necessary. Furthermore, in addition to consider these pharmacokinetics alterations, it is of utmost importance to choose drugs with proven cardio-renal benefits in this setting, such as sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists. In this review, we summarize the indications and contraindications, titration of doses and side effects of the available anti-hyperglycemic agents in the presence of advanced diabetic kidney disease (DKD) and dialysis, highlighting the risks and benefits of the different agents. Additionally, basic renal function assessment and monitoring of glycemic control in DKD will be evaluated in order to guide the use of drugs and define the glycemic targets to be achieved.     

Lifespan and reproduction in Drosophila: New insights from nutritional geometry

Modest dietary restriction (DR) prolongs life in a wide range of organisms, spanning single-celled yeast to mammals. Here, we report the use of recent techniques in nutrition research to quantify the detailed relationship between diet, nutrient intake, lifespan, and reproduction in Drosophila melanogaster. Caloric restriction (CR) was not responsible for extending lifespan in our experimental flies. Response surfaces for lifespan and fecundity were maximized at different protein-carbohydrate intakes, with longevity highest at a protein-to-carbohydrate ratio of 1:16 and egg-laying rate maximized at 1:2. Lifetime egg production, the measure closest to fitness, was maximized at an intermediate P:C ratio of 1:4. Flies offered a choice of complementary foods regulated intake to maximize lifetime egg production. The results indicate a role for both direct costs of reproduction and other deleterious consequences of ingesting high levels of protein. We unite a body of apparently conflicting work within a common framework and provide a platform for studying aging in all organisms.     

Intravenous Nicotine Simulation of Passive Smoking to Estimate Dosage to Exposed Non-Smokers

To estimate nicotine intake from passive smoking, six subjects received slow intravenous infusions of known doses of nicotine at a steady rate over one hour. The plasma and urinary nicotine concentrations produced by the infusions were compared with those found in previous studies of non-smokers exposed to tobacco smoke, in non-smokers in the general population, and in smokers during and after smoking their first cigarette of the day. It was estimated that the average rate of nicotine absorption was 0.23 mg/hr in a group of non-smokers exposed in a poorly ventilated public house, 0.36 mg/hr in non-smokers exposed to more extreme conditions in a smoke-filled unventilated room, and that the average daily-life exposure of a sample of 188 urban non-smokers was 0.014 mg nicotine per hour. In contrast, the dose absorbed by three smokers from their first cigarette of the day averaged 1.4 mg nicotine. The results indicate that when passive exposure of non-smokers results in carbon monoxide intake equivalent to the active smoking of one cigarette, the amount of nicotine absorbed is much less - equivalent to about one third of a cigarette dose. In view of the small samples and various assumptions in deriving these estimates, they can only be viewed as approximate.     

Imaging Findings of Liposuction with an Emphasis on Postsurgical Complications

Liposuction is one of the most frequently performed cosmetic surgeries worldwide for reshaping the body contour. Although liposuction is minimally invasive and relatively safe, it is a surgical procedure, and it carries the risk of major and minor complications. These complications vary from postoperative nausea to life-threatening events. Common complications include infection, abdominal wall injury, bowel herniation, bleeding, haematoma, seroma, and lymphoedema. Life-threatening complications such as necrotizing fasciitis, deep vein thrombosis, and pulmonary embolism have also been reported. In this paper, we provide a brief introduction to liposuction with the related anatomy and present computed tomography and ultrasonography findings of a wide spectrum of postoperative complications associated with liposuction.