Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema

Angioedema occurring in the head and neck region is a rare and sometimes life‐threatening adverse reaction to angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI‐induced angioedema (ACEI‐AE) or ARB‐induced angioedema (ARB‐AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI‐AE, ARB‐AE, and 658 controls) was performed using exome‐enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI‐AE and ARB‐AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89–4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI‐AE or ARB‐AE, P = 2.09 × 10−3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49–3.27, P = 6.30 × 10−9) times the odds of having ACEI‐AE or ARB‐AE. The increased risk due to the common Leiden allele was confirmed in a genome‐wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect‐causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI‐AE or ARB‐AE

Laparoscopic adjustable banded roux-en-y gastric bypass as a primary procedure for the super-super-obese (body mass index > 60 kg/m2)

<p>Abstract</p> <p>Background</p> <p>Currently, there is no consensus opinion regarding the optimal procedure of choice in super-super-morbid obesity (Body mass index, BMI > 60 kg/m2). Roux-en-Y gastric bypass (RYGB) is associated with failure to achieve or maintain 50% excess weight loss (EWL) or BMI < 35 in approximately 15% of patients. Also, percent EWL is significantly less after 1-year in the super-super-obese group as compared with the less obese group and many patients are still technically considered to be obese (lowest post-surgical BMI > 35) following RYGB surgery in this group. The addition of adjustable gastric band (AGB) to RYGB has been reported as a revisional procedure but this combined bariatric procedure has not been explored as a primary operation.</p> <p>Methods</p> <p>In a primary laparoscopic RYGB, an AGB is drawn around the gastric pouch through a small opening between the blood vessels on the lesser curve and the gastric pouch. The band is then fixed by suturing the gastric remnant to the gastric pouch both above and below the band to prevent slippage.</p> <p>Results</p> <p>Between November 2009 and March 2010, 6 consecutive super-super-obese patients underwent a primary laparoscopic adjustable banded Roux-en-Y gastric bypass procedure at our institution. One male patient (21 years, BMI 70 kg/m²) developed a pneumonia postoperatively. No other postoperative complications were observed.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first series of patients that underwent a laparoscopic adjustable banded RYGB as a primary operation for the super-super obese in the indexed literature. With the combined procedure, a sequential action mechanism for weight loss is to be expected. The restrictive, malabsorptive and hormonal working mechanism of the RYGB will induce weight loss from the start reaching a stabilised plateau of weight after 12 - 18 months. At that time, filling of the band can be started resulting in further gastric pouch restriction and increased weight loss. Moreover, besides improving the results of total weight loss, a gradual filling of the band can as well prevent the RYGB patient from weight regain if restriction would fade away with time.</p

Obstructive sleep apnea is underrecognized and underdiagnosed in patients undergoing bariatric surgery

The aim of this study was to evaluate prevalence of obstructive sleep apnea among patients undergoing bariatric surgery and the predictive value of various clinical parameters: body mass index (BMI), neck circumference (NC) and the Epworth Sleepiness Scale (ESS). We performed a prospective, multidisciplinary, single-center observational study including all patients on the waiting list for bariatric surgery between June 2009 and June 2010, irrespective of history or clinical findings. Patients visited our ENT outpatient clinic for patient history, ENT and general examination and underwent a full night polysomnography, unless performed previously. As much as 69.9% of the patients fulfilled the criteria for OSA (mean BMI 44.2 ± SD 6.4 kg/m2); 40.4% of the patients met the criteria for severe OSA. The regression models found BMI to be the best clinical predictor, while the ROC curve found the NC to be the most accurate predictor of the presence of OSA. The discrepancy of the results and the poor statistical power suggest that all three clinical parameters are inadequate predictors of OSA. In conclusion, in this large patient series, 69.9% of patients undergoing BS meet the criteria for OSA. More than 40% of these patients have severe OSA. A mere 13.3% of the patients were diagnosed with OSA before being placed on the waiting list for BS. On statistical analysis, increased neck circumference, BMI and the ESS were found to be insufficient predictors of the presence of OSA. Polysomnography is an essential component of the preoperative workup of patients undergoing BS. When OSA is found, specific perioperative measures are indicated

Physical fitness in morbidly obese patients: effect of gastric bypass surgery and exercise training

Background There is a growing consensus that bariatric surgery is currently the most efficacious and long-term treatment for clinically severe obesity. However, it remains to be determined whether poor physical fitness, an important characteristic of these patients, improves as well. The purpose of this pilot study is to investigate the effect of gastric bypass surgery on physical fitness and to determine if an exercise program in the first 4 months is beneficial. Methods Fifteen morbidly obese patients (BMI 43.0 kg/m(2)) were tested before and 4 months after gastric bypass surgery. Eight of them followed a combined endurance and strength training program. Before and after 4 months the operation, anthropometrical characteristics were measured, and an extensive assessment of physical fitness (strength, aerobic, and functional capacity) was performed. Results Large-scale weight loss through gastric bypass surgery results in a decrease in dynamic and static muscle strength and no improvement of aerobic capacity. In contrast, an intensive exercise program could prevent the decrease and even induced an increase in strength of most muscle groups. Together with an improvement in aerobic capacity, functional capacity increased significantly. Both groups evolved equally with regard to body composition (decrease in fat mass and fat-free mass). Conclusions An exercise training program in the first 4 months after bariatric surgery is effective and should be promoted, considering the fact that physical fitness does not improve by weight loss only

Copper-catalysed selective hydroamination reactions of alkynes

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of ​rivastigmine and the formal synthesis of several other pharmaceutical agents, including ​duloxetine, ​atomoxetine, ​fluoxetine and ​tolterodine.National Institutes of Health (U.S.) (GM58160

Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition

INTRODUCTION Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS). METHODS CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat. RESULTS Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches. CONCLUSIONS Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions