Elgaardstage0339

An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis.

In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD.

We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). selleck chemicals A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient's mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.

Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear.

Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery.

Ten morbidly obese [BMI (in kg/m2)≥32.5, age 21-50 y] and 10 healthy-weight participants (BMI <25), matched for age (median ∼30 y) but not gender, were infused with [U-13C6] leucine and [2H5] glycerol to quantify leucine and glycerol kinetics. Morbidly obese participants were studied again 6 mo postsurgery. Primary outcomes were kinetic parameters related to BCAA metabolism. link2 Data were analyzed by nonparametric methods and presented as median (IQR).

Participants with obesity had IR with an HOMA-Ithe underlying cause and not the consequence of elevated BCAAs in obesity.

BCAA oxidation is not impaired but elevated in individuals with morbid obesity. Plasma BCAA concentrations are lowered after surgery owing to slower breakdown of body proteins as insulin's ability to suppress proteolysis is restored. These findings suggest that IR is the underlying cause and not the consequence of elevated BCAAs in obesity.

In a sample of dual users of cigarettes and electronic nicotine delivery systems (ENDS; e-cigarettes), we evaluated psychometric properties of ENDS versions of the Nicotine Dependence Syndrome Scale (NDSS), the brief Wisconsin Inventory of Smoking Dependence Motives (WISDM), and the Fagerström Test for Nicotine Dependence (FTND). Using the NDSS, we tested the hypothesis that there would be one common underlying factor of dependence across the cigarette and ENDS scales and other product-specific factors.

Adult dual users (N = 404) completed baseline cigarette and ENDS versions of the NDSS, WISDM, and FTND, and biweekly surveys of their smoking and vaping. Analyses included bifactor modeling, which helps to identify both a general and product-specific factor for each item, and exploratory factor analyses of the combined cigarette and ENDS NDSS items and examinations of concurrent and predictive validity.

The bifactor model was not a good fit, suggesting the lack of one common underlying dependence factor.cific measures may be needed to understand differences in product-specific dependency and predict changes in use of each product over time.

Although the healthy human skin microbiome has been the subject of recent studies, it is not known whether alterations among commensal microbes contribute to surgical site infections (SSIs). The objective of this study was to characterize temporal and spatial variation in the skin microbiota of patients undergoing colorectal surgery and to determine if dysbiosis contributes to SSIs.

Sixty (60) adults scheduled to undergo elective colon or rectal resection were identified by convenience sampling. link3 By analyzing bacterial 16S rRNA gene sequences isolated from clinical samples, we used a culture-independent strategy to monitor perioperative changes in microbial diversity of fecal samples and the skin.

990 samples were analyzed from 60 patients. Alpha diversity on the skin decreased after surgery but later recovered at the postoperative clinic visit. In most patients, we observed a transient postoperative loss of skin commensals (Corynebacterium and Propionibacterium) at the surgical site, which were replacedof SSIs.Neurological soft signs (NSS) are well documented in individuals with schizophrenia (SZ), yet so far, the relationship between NSS and specific symptom expression is unclear. We studied 76 SZ patients using magnetic resonance imaging (MRI) to determine associations between NSS, positive symptoms, gray matter volume (GMV), and neural activity at rest. SZ patients were hypothesis-driven stratified according to the presence or absence of auditory verbal hallucinations (AVH; n = 34 without vs 42 with AVH) according to the Brief Psychiatric Rating Scale. Structural MRI data were analyzed using voxel-based morphometry, whereas intrinsic neural activity was investigated using regional homogeneity (ReHo) measures. Using ANCOVA, AVH patients showed significantly higher NSS in motor and integrative functions (IF) compared with non-hallucinating (nAVH) patients. Partial correlation revealed that NSS IF were positively associated with AVH symptom severity in AVH patients. Such associations were not confirmed for delusions. In region-of-interest ANCOVAs comprising the left middle and superior temporal gyri, right paracentral lobule, and right inferior parietal lobule (IPL) structure and function, significant differences between AVH and nAVH subgroups were not detected. In a binary logistic regression model, IF scores and right IPL ReHo were significant predictors of AVH. These data suggest significant interrelationships between sensorimotor integration abilities, brain structure and function, and AVH symptom expression.

Sofosbuvir is not recommended in persons with estimated glomerular filtration rate (eGFR) <30 mL/min. We report the results of treatment with an off-label 8-week regimen of daclatasvir and half-dose sofosbuvir in patients with acute infection withhepatitis C virus ( HCV) and eGFR <30 mL/min.

Clinic records were searched to identify treatment-naïve, noncirrhotic adults with acute hepatitis C (HCV viremia and a ≥10-fold elevation of serum alanine aminotransferase activity) and eGFR <30 mL/min, who had been treated with a sofosbuvir-based regimen. Treatment response was assessed using serum HCV RNA testing at 4 weeks of treatment, end of the 8-week treatment and 12 weeks after stopping treatment.

Of the 31 patients with acute hepatitis C, 27 [median age (range) 36 (18-74) years; 20 (74%) male] were started on treatment with 200 mg sofosbuvir and 60 mg daclatasvir daily for 8 weeks, irrespective of HCV genotype. All the 27 completed the planned 8-week treatment. One patient died 10 weeks after completing the treatment of an unrelated cause. All the 27 patients had undetectable HCV RNA after 4 weeks of and at the end of treatment. At 12 weeks after completion of treatment, only one tested HCV RNA positive and 25 were negative, with sustained virological response rate of 25/27 (92.6%) and 25/26 (96.2%) on intention-to-treat and per-protocol basis, respectively.

Eight-week course of daclatasvir and half-dose sofosbuvir is effective for acute hepatitis C in patients with eGFR <30 mL/min and could be a useful alternative to costly, kidney-safe anti-HCV oral drugs in resource-constrained settings.

Eight-week course of daclatasvir and half-dose sofosbuvir is effective for acute hepatitis C in patients with eGFR  less then 30 mL/min and could be a useful alternative to costly, kidney-safe anti-HCV oral drugs in resource-constrained settings.The aim of this guideline is to provide an update on evidence-based recommendations for treatment of adult patients with PsA. The previous BSR guidelines for PsA were published in 2012 and since that time, there have been many new advanced therapies licensed for PsA. This update will provide practical guidance for clinicians on the optimal selection of advanced therapies taking into account different domains of PsA (arthritis, enthesitis, dactylitis, axial disease and psoriasis) and key associated comorbidities. It will also update guidance on treatment strategy including the use of a treat-to-target approach. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines Our Protocol. (1) This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Obesity accelerates age-related cognitive decline, which is partly mediated by vascular dysfunction.

The aim was to test the hypothesis that supplementation with fish oil and curcumin can enhance cognitive performance by improving cerebral circulatory function in overweight or obese middle-aged to older adults.

In a 16-wk double-blind, placebo-controlled intervention trial, adults [50-80 y; BMI (kg/m2) 25-40] were randomly assigned to either fish oil (2000 mg/d DHA+400 mg/d EPA), curcumin (160 mg/d), or a combination. Effects on cerebrovascular function (primary outcome) and cardiovascular risk factors were reported previously. Effects on cognitive performance and cerebrovascular responsiveness (CVR) to cognitive stimuli are reported herein. One-factor ANOVA with post hoc analyses was conducted between groups in the whole cohort and in males and females separately. Two-factor ANOVA was conducted to assess independent effects of fish oil and curcumin and a potential interaction. Correlations between outclementation is warranted. This trial was registered at the Australian and New Zealand Clinical Trial Register at https//www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370788 as ACTRN12616000732482p.

Improvements in processing speed following fish-oil supplementation in middle-aged to older males might be mediated by improvements in circulatory function. Mechanisms underlying the cognitive benefit seen with curcumin are unknown. As cognitive benefits were found in males only, further evaluation of sex differences in responsiveness to supplementation is warranted. This trial was registered at the Australian and New Zealand Clinical Trial Register at https//www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370788 as ACTRN12616000732482p.