Recent discoveries and emerging therapeutics in eosinophilic esophagitis

Eosinophilic esophagitis(Eo E) is an allergy-mediated disease culminating in severe eosinophilic inflammation and dysfunction of the esophagus. This chronic disorder of the esophagus causes significant morbidity, poor quality of life, and complications involving fibrosis and esophageal remodeling. Overlapping features between EoE and gastroesophageal reflux disease(GERD) pose great challenges to differentiating the two conditions, although the two disorders are not mutually exclusive. Recent findings suggest that the confounding condition proton pump inhibitor- responsive esophageal eosinophilia(PPI-REE) is likely a subset of EoE. Since PPIs have therapeutic properties that can benefit EoE, PPIs should be considered as a therapeutic option for Eo E rather than a diagnostic screen to differentiate GERD, PPIREE, and EoE. Other current treatments include dietary therapy, corticosteroids, and dilation. Immunomodulators and biologic agents might have therapeutic value, and larger trials are needed to assess efficacy and safety. Understanding the pathophysiology of EoE is critical to the development of novel therapeutics.

Atrial Arrhythmias Including Atrial Fibrillation in Congenital Heart Disease:Mechanisms,Substrate Identifi cation and Interventional Approaches

Atrial arrhythmias,including atrial fibrillation,in the setting of congenital heart disease(CHD)are epidemiologically and mechanistically different from those encountered in the general population.These arrhythmias occur at younger ages in patients with CHD,and are frequently degenerative and progressive.The epidemiology,incidence,and prevalence of the spectrum of atrial arrhythmias,including atrial fibrillation,vary according to the specific CHD type,prior treatment,and residual and ongoing structural and functional sequelae.The combined impact of incisional scars,abnormal hemodynamics,atrial chamber dilatation,and increases in atrial wall thickness and distribution of fi brosis results in a highly dynamic and continuously changing atrial substrate that is highly predisposed to arrhythmias.Given the multiple substrates,individualized therapeutic plans can include pharmacologic therapy,catheter-based ablation,and surgical therapies performed concomitantly with primary surgical intervention for hemodynamically significant sequelae of CHD.Advanced imaging with CT or MRI can provide valuable information for decision making and procedural planning.Application of novel therapeutic technologies and pharmacologic agents necessitates special considerations when applied to the CHD population and requires greater study in specific subsets of CHD patients.

Complement Gene Mutation and Ehlers-Danlos Syndrome

Background: Dental complications of Ehlers-Danlos syndrome (EDS) include periodontitis with gum fragility and inflammation, enamel hypoplasia with frequent caries, high palate with dental crowding, TMJ instability, sutural dehiscence or scarring, and insensitivity to anesthetics. Objective: Determine if EDS dental complications always define a specific type and genetic cause or if they can arise as a general consequence of altered inflammatory response in EDS. Method: We compared findings of a 58-year-old female with complement component 1R (C1R) gene mutation (c.1553A > T, p.Asp518Val) found by whole exome sequencing to 43 patients with C1R gene mutations ascertained because of periodontal disease and to 710 EDS patients conventially ascertained because of joint and skin laxity. Result: Female patients ascertained as periodontal EDS showed the expected higher frequency of periodontitis (96% versus 14%) but had similar frequencies of hypermobility (81% versus 90%) and some skin findings (84% versus 92% with skin fragility) as the general group and our female patient who shared their C1R gene change. Her oromandibular bone loss rather than gum disease may reflect the more carboxy-terminal position of her C1R gene mutation compared to those in the patients identified as periodontal EDS. Conclusion: While mutation of the C1R gene may predict more frequent periodontal, skin, and vascular complications, focus on an articulo-autonomic dysplasia process that includes mast-cell activation and altered inflammatory response rather than extreme EDS types will help dentists and other subspecialists identify all EDS patients and anticipate their frequent oral manifestations.

The Polymorphisms in the Vitamin D Receptor Gene and Disease Severity in Sickle Cell Disease

Vitamin D is important in multiple aspects of health and its effects are mediated through the Vitamin D Receptor (VDR). We wanted to test the hypothesis that specific haplotypes of the VDR gene are associated with markers of disease severity, inflammation and bone health in Sickle Cell Disease (SCD). Genotyping was performed on DNA specimens from 1141 study participants in the NIH-funded Silent Infarct Transfusion (SIT) trial. We used the clinical and laboratory data to create separate endothelial dysfunction, vaso-occlusive severity scores and phenotype variables. Seventy-nine Single Nucleotide Polymorphisms (SNP) in the VDR gene and three associated genes—CYP27B1, VD binding protein, retinoid X receptor, were evaluated. The discovery cohort individuals had VDR haplotype information from a prior Genome-Wide Association Study (GWAS). The validation cohort was analyzed for SNPs that were significant in the discovery cohort. The pheno-type data were obtained from the demographic and clinical information of the participants, and were used to create the severity scores, vaso-occlusive score, endothelial dysfunction severity, and overall severity score. Potential gene-gene interactions were analyzed for prediction of disease severity within each severity score. Two SNPs were associated with the overall severity score, 3 SNPs with the endothelial dysfunction severity score and 4 SNPs with the vaso-occlusive severity score. After permutation testing to correct for multiple comparisons, only one of the associations remained significant. SNP rs7965281 was found to be associated with the endothelial dysfunction severity score and remained significant after correcting for multiple comparisons using permutation testing. In the validation cohort, that SNP was again tested for association with each of the severity scores. There was no association with the endothelial or the overall severity score but a trend towards association with the vaso-occlusive severity score (p = 0.02). None of the known functional polymorphisms in the VDR gene were found to have an association with severity in sickle cell disease. Further work analyzing for gene-gene interaction using the same significant SNPs remains to be done in association with inflammatory markers and measure of bone health. Those studies may provide insight on the contribution of VDR polymorphisms to sickle cell disease severity.

男性健康离不开为人父

现代医学已开始逐步了解男性健康现象。“男性健康”这一理念有别于“女性健康”，它往往立足于以下方面存在的性别差异：生殖系统疾病、心血管病等部分受到性激素影响的疾病以及预期寿命（男性〈女性）。本文抓住男性健康的概念，对为人父这一许多男性生活中的重要环节进行了概述。

Is it Possible to Protect the Adolescent Brain with Internal Mechanisms from Repetitive Head Impacts:Results from a PhaseⅡSingle Cohort,Longitudinal,Self-Control Study

Purpose To quantify the effects of an externally worn collar device for mitigating the influence of repetitive head impacts on alterations to diffusion tensor imaging(DTI)metrics of white matter.Methods Fifteen female high-school soccer athletes(age:14.00-16.98 yrs)completed pre-and post-season DTI over two consecutive years,including measures of diffusivity,changes in which may be associated with brain dysfunction.The collar was worn during year 1(Yr1)but not during year 2(Yr2).Athlete exposures(AEs)and head impact exposure were recorded over the competitive seasons.Results There were no significant differences in AEs or head impact exposures between Yr1 and Yr2(P>0.05).In Yr2,there was significant pre-to post-season mean diffusivity and/or axial diffusivity reduction in multiple WM regions(cor-rected P<0.05).Pre-to post-season mean diffusivity,axial diffusivity,and radial diffusivity decreases were 3.04%±2.53%,2.97%±2.19%,and 3.37%±3.34%,respectively,significantly greater than pre-to post-season changes in Yr1(mean dif-fusivity:-0.31%±1.78%,P=0.0014;axial diffusivity:-0.02%±2.25%,P=0.0014;radial diffusivity:-0.63%±2.10%,P=0.0030).Conclusions Mild bilateral compression to athletes'internal jugular vein through collar application may have increased intracranial blood volume and spatially redistributed head-impact-derived brain energy absorption.However,future research is needed to elucidate the potential clinical significance of WM changes of various degrees.Clinical trails registration NCT03014492.