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Professional Improvement Track to get ready Future Academic Doctors.
Functional properties of the paracellular pathway depend critically on the set of claudins (CLDN) expressed at the tight junction. Two syndromes are causally linked to loss-of-function mutations of claudins hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX) syndrome caused by genetic variations in the CLDN10 gene and familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by genetic variations in the CLDN16 or CLDN19 genes. All three genes are expressed in the kidney, particularly in the thick ascending limb (TAL). However, localization of these claudins in humans and rodents remains to be delineated in detail. We studied the segmental and subcellular expression of CLDN10, CLDN16, and CLDN19 in both paraffin-embedded and frozen kidney sections from the adult human, mouse, and rat using immunohistochemistry and immunofluorescence, respectively. Here, CLDN10 was present in a subset of medullary and cortical TAL cells, localizing to basolateral dom profiles in all species investigated.Cell-associated kidney injury molecule-1 (KIM-1) exerts an anti-inflammatory role following kidney injury by mediating efferocytosis and downregulating the NF-κB pathway. KIM-1 cleavage blunts its anti-inflammatory activities. We reported that mucin 1 (MUC1) is protective in a mouse model of ischemia-reperfusion injury (IRI). As both KIM-1 and MUC1 are induced in the proximal tubule (PT) during IRI and are a disintegrin and metalloprotease 17 (ADAM17) substrates, we tested the hypothesis that MUC1 protects KIM-1 activity. Muc1 knockout (KO) mice and wild-type (WT) littermates were subjected to IRI. KIM-1, MUC1, and ADAM17 levels (and signaling pathways) were assessed by immunoblot analysis. PT localization was assessed by confocal microscopy and an in situ proximity ligation assay. Findings were extended using human kidneys and urine as well as KIM-1-mediated efferocytosis assays in mouse PT cultures. In response to tubular injury in mouse and human kidneys, we observed induction and coexpression of KIM-1 andg IRI and competes with KIM-1 for cleavage by ADAM17. Consequently, MUC1 protects KIM-1 anti-inflammatory activity in the damaged kidney.Background Prior studies have shown an association between myocardial injury after noncardiac surgery (MINS) and all-cause mortality in patients following noncardiac surgery. However, the association between preoperative risk assessments, Revised Cardiac Risk Index and American College of Surgeons National Surgical Quality Improvement Program, and postoperative troponin elevations and long-term mortality is unknown. Methods and Results A retrospective chart review identified 548 patients who had a troponin I level drawn within 14 days of noncardiac surgery that required an overnight hospital stay. Patients aged 40 to 80 years with at least 2 cardiovascular risk factors were included, while those with trauma, pulmonary embolism, and neurosurgery were excluded. Kaplan-Meier survival and odds ratio (OR) with sensitivity/specificity analysis were performed to assess the association between preoperative risk and postoperative troponin elevation and all-cause mortality at 1 year. Overall, 69%/31% were classified asor prognostication, risk reclassification, and initiating therapies such as statins to mitigate long-term risk.Background The relationship between vascular calcification and chronic kidney disease is well known. However, whether vascular calcification affects renal function deterioration remains unclear. We investigated whether kidney function deteriorated more rapidly in individuals with higher vascular calcification indicated by the coronary artery calcium score (CACS). Methods and Results Individuals with a normal estimated glomerular filtration rate (>60 mL/min per 1.73 m2) who underwent cardiac computed tomography in our institution (a tertiary teaching hospital in Cheonan, Korea) from January 2010 to July 2012 were retrospectively reviewed. All participants were aged 20 to 65 years. Among 739 patients, 447, 175, and 117 had CACSs of 0, 1 to 99, and ≥100 units, respectively. The participants were followed for 7.8 (interquartile range, 5.5-8.8) years. The adjusted annual estimated glomerular filtration rates declined more rapidly in patients in the CACS ≥100 group compared with those in the CACS 0 group (adjusted-β, -0.40; 95% CI, -0.80 to -0.03) when estimated using a linear mixed model. The adjusted hazard ratio in the CACS ≥100 group for Kidney Disease Improving Global Outcomes criteria (a drop in estimated glomerular filtration rate category accompanied by a 25% or greater drop in estimated glomerular filtration rate) was 2.52 (1.13-5.61). After propensity score matching, more prevalent renal outcomes (13.2%) were observed in patients with a CACS of ≥100 compared with those with a CACS of 0 (1.9%), with statistical significance (P=0.004). Conclusions Our results showed that renal function declined more rapidly in patients with higher CACSs, suggesting that vascular calcification might be associated with chronic kidney disease progression.Suicide risk screening depends heavily on accurate patient self-report. However, past negative experiences with mental health care may contribute to intentional nondisclosure of suicide risk during screening. This study investigated among 282 men older than age 50 whether likelihood for current explicit risk nondisclosure was associated with previous highest level of mental health care received. This sample was selected post hoc out of a larger sample of participants from higher risk and lower help-seeking populations (i.e., military service members and veterans, men older than age 50, and lesbian gay bisexual, transgender, and queer young adults), however, the other groups were underpowered for analysis. Among these men, history of psychiatric hospitalization was significantly associated with likelihood for explicit nondisclosure of current suicide risk, while history of receiving only outpatient therapy for suicidal thoughts or behaviors was significantly associated with likelihood for full reporting of suicide risk. Severity of suicidal ideation and internalized stigma against mental illness were significant indirect contributors to the effect. Although causality could not be determined, results suggest that a potential cost to consider for psychiatric hospitalization may be future nondisclosure of suicide risk. Conversely, outpatient interventions that appropriately manage suicidal thoughts or behaviors may encourage future full reporting of suicide risk and improve screening detection.
To report a case of 16-month-old boy with a novel variant TSPAN12 gene-presenting as unilateral myopia, pediatric cataract, and heterochromia in a patient with familial exudative vitreoretinopathy.

A 16-month-old otherwise healthy boy was referred to Boston Children's Hospital for evaluation of strabismus. Ocular examination revealed intermittent esotropia, left hypotropia, and limited left eye elevation in both adduction and abduction. Full cycloplegic hyperopic correction of +3.50 diopters (D) over both eyes was given to the patient. Over several months, refraction of the right eye showed progressive myopia (-6.00 D) with new onset iris heterochromia. Fundus examination showed there was a large area of chorioretinal atrophy with abrupt ending of the blood vessels; anterior to the ora serrata there were diffuse vitreous bands and veils that reached the lens anteriorly in direct contact with the lenticular opacity. A novel heterozygous nonsense likely pathogenic variant was identified in the TSPAN12 gene (NM_012338.3) c.315T>A (p.Cys105Ter) confirming the diagnosis of FEVR.

Asymmetric FEVR rarely present with unilateral axial myopia however association with acquired heterochromia and cataract has never been reported. We report a case of FEVR caused by a novel TSPAN12 likely pathogenic nonsense variant presenting as unilateral progressive myopia, acquired heterochromia, and pediatric cataract.
Asymmetric FEVR rarely present with unilateral axial myopia however association with acquired heterochromia and cataract has never been reported. We report a case of FEVR caused by a novel TSPAN12 likely pathogenic nonsense variant presenting as unilateral progressive myopia, acquired heterochromia, and pediatric cataract.There is an urgent need to better understand the micronutrient demands of pregnancy due to the complex physiological adaptations during the gestational period and the importance of micronutrients in maternal-fetal health. Rigorous studies of micronutrients in pregnancy are significantly lacking due to a number of issues including the exclusion of pregnant people in research, methodological barriers to studying micronutrients, and the multidisciplinary expertise required for such studies. Stable isotopes present a unique methodological opportunity to quantify pregnancy-related changes in the absorption, distribution, metabolism, and excretion of micronutrients. We demonstrate here through a rapid review of the published literature that this approach is dramatically underutilized outside of calcium. In this perspective, we discuss the use of stable isotopes to study micronutrient physiology and our experiences in addressing the need for more studies in this area. Finally, we discuss how we might overcome major barriers to move toward a better understanding of micronutrient physiology in pregnancy.Endothelial cell insulin resistance contributes to the development of vascular complications in diabetes. Hypoxia-inducible factors (HIFs) modulate insulin sensitivity, and we have previously shown that a negative regulator of HIF activity, CREB-binding protein/p300 (CBP/p300) interacting transactivator-2 (CITED2), is increased in the vasculature of people with type 2 diabetes. Therefore, we examined whether CITED2 regulates endothelial insulin sensitivity. In endothelial cells isolated from mice with a "floxed" mutation in the Cited2 gene, loss of CITED2 markedly enhanced insulin-stimulated Akt phosphorylation without altering extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation. Similarly, insulin-stimulated Akt phosphorylation was increased in aortas of mice with endothelial-specific deletion of CITED2. Consistent with these observations, loss of CITED2 in endothelial cells increased insulin-stimulated endothelial nitric oxide synthase phosphorylation, Vegfa expression, and cell proliferation. EW & NOTEWORTHY Endothelial cell insulin resistance is a major contributor to the development of diabetic complications. In this study, we have shown that CITED2, a transcriptional coregulator, inhibits endothelial insulin signaling through the PI3K/Akt pathway via repression of HIF-dependent IRS-2 expression, and that deletion of CITED2 enhances insulin signaling. Thus, CITED2 represents a novel and promising target to improve insulin sensitivity in endothelial cells and prevent vascular complications in diabetes.We aimed to determine whether interrupting prolonged sitting improves glycemic control and the metabolic profile of free-living adults with obesity. Sixteen sedentary individuals 10 women/6 men; median [interquartile range (IQR)] age 50 (44-53) yr, body mass index (BMI) 32 (32-35.8) kg/m2 were fitted with continuous glucose and activity monitors for 4 wk. After a 1-wk baseline period, participants were randomized into habitual lifestyle (Control) or frequent activity breaks from sitting (FABS) intervention groups. Glutathione Each day, between 0800 and 1800 h, FABS received smartwatch notifications to break sitting with 3 min of low-to-moderate-intensity physical activity every 30 min. Glycemic control was assessed by oral glucose tolerance test (OGTT) and continuous glucose monitoring. Blood samples and vastus lateralis biopsies were taken for assessment of clinical chemistry and the skeletal muscle lipidome, respectively. Compared with baseline, FABS increased median steps by 744 [IQR (483-951)] and walking time by 10.
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