Cardiovascular manifestations of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.

Introduction: Mitral valve prolapse and aortic root dilatation are reported in association with hypermobile Ehlers-Danlos syndrome (hEDS), but the full phenotypic spectrum of cardiovascular complications in this condition has not been studied in the aftermath of updated nosology and diagnostic criteria. Methods: We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm (n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusions: Cardiovascular manifestations in adults with hEDS/HSD, especially females, are typically mild and readily assessed by echocardiography. Since the risk of progression has not yet been defined, adults with hEDS/HSD who are found to have aortic dilatation at baseline should continue ongoing surveillance to monitor for progressive dilatation. Cardiovascular medicine specialists, neurologists, and neurosurgeons should consider hEDS/HSD on the differential for patients with CeAD or SCAD who also have joint hypermobility.

Stroke in first-degree relatives of patients with cervical artery dissection.

BACKGROUND AND PURPOSE: Patients with ischaemic stroke (IS) caused by a spontaneous cervical artery dissection (CeAD) worry about an increased risk for stroke in their families. The occurrence of stroke in relatives of patients with CeAD and in those with ischaemic stroke attributable to other (non-CeAD) causes were compared. METHODS: The frequency of stroke in first-degree relatives (family history of stroke, FHS) was studied in IS patients (CeAD patients and age- and sex-matched non-CeAD patients) from the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) database. FHS ≤ 50 and FHS > 50 were defined as having relatives who suffered stroke at the age of ≤50 or >50 years. FHS ≤ 50 and FHS > 50 were studied in CeAD and non-CeAD IS patients and related to age, sex, number of siblings, hypertension, hypercholesterolemia, smoking and body mass index (BMI). RESULTS: In all, 1225 patients were analyzed. FHS ≤ 50 was less frequent in CeAD patients (15/598 = 2.5%) than in non-CeAD IS patients (38/627 = 6.1%) (P = 0.003; odds ratio 0.40, 95% confidence interval 0.22-0.73), also after adjustment for age, sex and number of siblings (P = 0.005; odds ratio 0.42, 95% confidence interval 0.23-0.77). The frequency of FHS > 50 was similar in both study groups. Vascular risk factors did not differ between patients with positive or negative FHS ≤ 50. However, patients with FHS > 50 were more likely to have hypertension and higher BMI. CONCLUSION: Relatives of CeAD patients had fewer strokes at a young age than relatives of non-CeAD IS stroke patients.

Arterial dissections: Common features and new perspectives.

Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is devastating in its own way. Traditionally they have been studied in isolation, rather than collectively, owing largely to the distinct clinical consequences of dissections in different anatomical locations - such as stroke, myocardial infarction, and renal failure. Here, we review the shared and unique features of these arteriopathies to provide a better understanding of this family of disorders. Arterial dissections occur commonly in the young to middle-aged, and often in conjunction with hypertension and/or migraine; the latter suggesting they are part of a generalized vasculopathy. Genetic studies as well as cellular and molecular investigations of arterial dissections reveal striking similarities between dissection types, particularly their pathophysiology, which includes the presence or absence of an intimal tear and vasa vasorum dysfunction as a cause of intramural hemorrhage. Pathway perturbations common to all types of dissections include disruption of TGF-ß signaling, the extracellular matrix, the cytoskeleton or metabolism, as evidenced by the finding of mutations in critical genes regulating these processes, including LRP1, collagen genes, fibrillin and TGF-ß receptors, or their coupled pathways. Perturbances in these connected signaling pathways contribute to phenotype switching in endothelial and vascular smooth muscle cells of the affected artery, in which their physiological quiescent state is lost and replaced by a proliferative activated phenotype. Of interest, dissections in various anatomical locations are associated with distinct sex and age predilections, suggesting involvement of gene and environment interactions in disease pathogenesis. Importantly, these cellular mechanisms are potentially therapeutically targetable. Consideration of arterial dissections as a collective pathology allows insight from the better characterized dissection types, such as that involving the thoracic aorta, to be leveraged to inform the less common forms of dissections, including the potential to apply known therapeutic interventions already clinically available for the former.

Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome.

Spontaneous cervical artery dissection (CeAD) is a major cause of ischemic stroke in young adults, whose genetic susceptibility factors are still largely unknown. Nevertheless, subtle ultrastructural connective tissue alterations (especially in the collagen fibril morphology) are recognized in a large proportion of CeAD patients, in which recent genetic investigations reported an enrichment of variants in genes associated with known connective tissue disorders. In this regard, COL5A1 variants have been reported in a small subset of CeAD patients, with or without classical Ehlers-Danlos syndrome (cEDS) features. We investigated a 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS. Whole-exome sequencing identified two COL5A1 missense variants in trans configuration: NM_000093.5:c.[1588G>A];[4135C>T], NP_000084.3:p.[(Gly530Ser)];[(Pro1379Ser)]. Functional assays demonstrated a significant decrease of collagen α1(V) chain expression in both heterozygous parents compared to control cells, and an additive effect of these two variants in the proband. Interestingly, both parents manifested very subtle EDS signs, such as atrophic scars, recurrent bone fractures, colonic diverticulosis, varicose veins, and osteoarthritis. Our findings emphasize the involvement of COL5A1 in the predisposition to vascular phenotypes and provide novel insights on the c.1588G>A variant, whose functional significance has not been definitely established. In fact, it was previously reported as both "disease modifying", and as a biallelic causative mutation (with heterozygous individuals showing subtle clinical signs of cEDS). We speculated that the c.1588G>A variant might lead to overt phenotype in combination with additional genetic "hits" lowering the collagen α1(V) chain expression below a hypothetical disease threshold.

Portfolio Decisions and Brain Reactions via the CEAD method.

Decision making can be a complex process requiring the integration of several attributes of choice options. Understanding the neural processes underlying (uncertain) investment decisions is an important topic in neuroeconomics. We analyzed functional magnetic resonance imaging (fMRI) data from an investment decision study for stimulus-related effects. We propose a new technique for identifying activated brain regions: cluster, estimation, activation, and decision method. Our analysis is focused on clusters of voxels rather than voxel units. Thus, we achieve a higher signal-to-noise ratio within the unit tested and a smaller number of hypothesis tests compared with the often used General Linear Model (GLM). We propose to first conduct the brain parcellation by applying spatially constrained spectral clustering. The information within each cluster can then be extracted by the flexible dynamic semiparametric factor model (DSFM) dimension reduction technique and finally be tested for differences in activation between conditions. This sequence of Cluster, Estimation, Activation, and Decision admits a model-free analysis of the local fMRI signal. Applying a GLM on the DSFM-based time series resulted in a significant correlation between the risk of choice options and changes in fMRI signal in the anterior insula and dorsomedial prefrontal cortex. Additionally, individual differences in decision-related reactions within the DSFM time series predicted individual differences in risk attitudes as modeled with the framework of the mean-variance model.

Forced degradation and impurity profiling: recent trends in analytical perspectives.

This review describes an epigrammatic impression of the recent trends in analytical perspectives of degradation and impurities profiling of pharmaceuticals including active pharmaceutical ingredient (API) as well as drug products during 2008-2012. These recent trends in forced degradation and impurity profiling were discussed on the head of year of publication; columns, matrix (API and dosage forms) and type of elution in chromatography (isocratic and gradient); therapeutic categories of the drug which were used for analysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated techniques for the identification and quantification of thresholds of impurities and degradants in different pharmaceutical matrices.

Combining testing gastric juice and serum levels of CA72 - 4、A19 - 9 and CEA for the clinical value of gastric cancer / 重庆医科大学学报

Objective:To explore the clinical value of gastric cancer by combined testing of the gastric juice and serum levels of CA72 - 4,CA19 - 9 and CEA. Methods :The gastric juice and serum levels of CA72 - 4,CA19 - 9 and CEA in 32 cases of all stages of gastric cancer and 20 cases of benign gastric disorders were determined preoperatively using IRMA method. Results: The results showed that the gastric juice, serum levels and the sensitivity rates of CA72 - 4, CA19 ~ 9 and CEA were significantly higher ( P