Genetic and Epigenetic Determinants of Low Dysferlin Expression in Monocytes

Dysferlinopathies are autosomal recessive inherited muscular dystrophies caused by mutations in the gene DYSF. Dysferlin is primarily expressed in skeletal muscle, cardiac muscle, and peripheral blood monocytes. Expression in skeletal muscle and monocytes strongly correlates in healthy and disease states. We evaluated the efficiency of the monocyte assay to detect carriers and to determine the carrier frequency of dysferlinopathies in the general population. We enrolled 149 healthy volunteers and collected peripheral blood samples for protein analysis. While 18 of these individuals with protein levels in the range of 40%–64% were predicted to be carriers by the monocyte assay, subsequent DYSF sequencing analysis in 14 of 18 detected missense variants in only four. Analysis of DNA methylation patterns at the DYSF locus showed no changes in methylation levels at CpG islands and shores between samples. Our results suggest that: (1) dysferlin expression can also be regulated by factors outside of the dysferlin gene, but not related to DNA methylation; (2) carrier frequency and therefore the number of affected individuals could be higher than previously estimated; and (3) although reliable for evaluating dysferlinopathies, the monocyte assay cannot be used to determine the carrier status; for this, a molecular analysis of DYSF must be performed.     

Monitoring of direct alcohol markers in alcohol use disorder patients during withdrawal treatment and successive rehabilitation

Direct and indirect biomarkers are widely applied for the determination of alcohol consumption. They help to assess past or present alcohol consumption. Depending on the window of detection and sensitivity of the investigated marker, punctual alcohol consumption may remain undetected. In this study, different sampling strategies for the intermediary long‐term marker phosphatidylethanol (PEth) are evaluated and compared to the determination of the short‐term markers ethyl glucuronide (EtG) and ethyl sulfate (EtS) in urine. Samples from 19 patients undergoing alcohol use disorder treatment were collected during the withdrawal treatment and successive rehabilitation (33 ± 26 days (range: 3–74 days)). With liquid chromatography–tandem mass spectrometry (LC–MS/MS) EtG and EtS in urine, PEth in blood, PEth in dried blood spot (DBS) from venous blood, and PEth in DBS from capillary blood were quantified and compared. The use of volumetric capillary DBS, prepared from 20 μL of blood, provided the same results as the use of venous DBS (95% ± 10%, R² 0.9899 for PEth 16:0/18:1). Capillary DBS sampling has the advantage that it can be performed without venipuncture. The use of PEth in DBS proved to prevent post‐sampling degradation, providing a longer detection in comparison to PEth in liquid blood, which only showed 67% ± 24% of the PEth DBS 16:0/18:1 concentration. When compared with EtG and EtS in urine, PEth monitoring proved to be advantageous for the detection of relapse situations, as the accumulation of PEth in blood prolongs the detectability. In conclusion, volumetric capillary DBS sampling for PEth is a simple and useful tool for compliance monitoring, and avoids hematocrit issues.     

Ileal intussusception due to a parasite egg: A case report

Ileal intussusception is the invagination of the small intestine within itself and accounts for 1% of cases of acute obstruction. However, physicians do not initially consider intussusception as a possible diagnosis of obstruction due to its rarity in adults. Herein, we report the case of a 22-year-old male who was admitted to the Emergency Department with continuous abdominal pain. Ultrasonography and computed tomography revealed an ileal intussusception. The patient underwent surgical removal of the segment of the small bowel. Unexpectedly, pathology revealed that the invagination occurred due to a parasite egg, with features suggestive of Schistosoma species. Schistosomiasis, although considered a parasitic disease in tropical countries, is not absent from Europe and though it is highly improbable, it may be responsible for cases of intussusception in adults.     

A multicentre observational study of the effectiveness,safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice

International Journal of Clinical Pharmacy - Background Immunotherapy has become a standard treatment for lung cancer; however, the high cost makes it necessary to assess health outcomes. Objective...     

An Automated Telephone Nutrition Support System for Spanish-Speaking Patients With Diabetes

In the United States, Spanish-speaking patients with diabetes often receive inadequate dietary counseling. Providing language and culture-concordant dietary counseling on an ongoing basis is critical to diabetes self-care. To determine if automated telephone nutrition support (ATNS) counseling could help patients improve glycemic control by duplicating a successful pilot in Mexico in a Spanish-speaking population in Oakland, California. A prospective randomized open-label trial with blinded endpoint assessment (PROBE) was performed. The participants were seventy-five adult patients with diabetes receiving care at a federally qualified health center in Oakland, California. ATNS, a computerized system that dialed patients on their phones, prompted them in Spanish to enter (via keypad) portions consumed in the prior 24 hours of various cultural-specific dietary items, and then provided dietary feedback based on proportion of high versus low glycemic index foods consumed. The control group received the same ATNS phone calls 14 weeks after enrollment. The primary outcome was hemoglobin A1c % (A1c) 12 weeks following enrollment. Participants had no significant improvement in A1c (–0.3% in the control arm, –0.1% in the intervention arm, P = .41 for any difference) or any secondary parameters. In our study, an ATNS system did not improve diabetes control in a Spanish-speaking population in Oakland.     

Left atrial function is impaired in cirrhosis: a speckle tracking echocardiographic study

Purpose

Abnormalities in left ventricular systolic and diastolic function have been described in patients with cirrhosis. There are no studies on left atrial (LA) function in these patients. We aimed to evaluate LA function in cirrhosis patients using myocardial deformation imaging.

Methods

We included 111 hospitalized and ambulatory patients with cirrhosis and 18 healthy controls. A comprehensive echocardiographic evaluation was performed; LA strain was assessed using velocity vector imaging.

Results

Peak atrial longitudinal strain at the end of ventricular systole was lower in patients [41.9 % (34.4–51.0) vs. 48.0 % (42.0–57.1), p = 0.02]. No differences were found in atrial strain before atrial contraction in patients and controls [17.5 % (14.3–22.4) vs. 20.7 % (14.1–26.3), p = 0.14]. On multivariate linear regression analysis, E′ velocity was the only variable independently associated with peak atrial longitudinal strain (R ² = 47 %). No correlation was found between the LA volume index (LAVI) and peak atrial longitudinal strain (r = ?0.136, p = 0.219). Peak atrial longitudinal strain performed better than LAVI in identifying patients with elevated filling pressures (AUC = 0.81 vs. 0.52).

Conclusions

Patients with cirrhosis have abnormal atrial reservoir function, which may be related to the same factors associated with impaired ventricular relaxation. LA enlargement in cirrhosis may not reflect elevated filling pressures and should not be used as an isolated marker of diastolic dysfunction. The atrial “pump” function does not seem to be affected in cirrhosis patients.     

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients

AIM:To assess,in a routine practice setting,the sus-tained virologic response(SVR) to telaprevir(TPV) or boceprevir(BOC) in hepatitis C virus(HCV) nullresponders or relapsers with severe liver fibrosis.METHODS:One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon(peg-INF) α2a + ribavirin(PR) according to standard treatment schedules without randomization.These patients were treated in routine practice settings in 10 public or private health care centers,and the data were prospectively collected.Only patients with severe liver fibrosis(Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography),genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.RESULTS:The Metavir fibrosis scores were F3 in 35(28%) and F4 in 90(72%) of the patients.In total,62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy.The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%.The SVR was 65.9% in the TPV group and 44.1% in the BOC group.Independent predictive factors of an SVR included a response to previous treatment,relapsers vs null-responders [OR = 3.9;(1.4,10.6),P = 0.0084],a rapid virological response(RVR) [OR 6.9(2.6,18.2),P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2(2.3,29.5),P = 0.001].During treatment,63 patients(50.8%) had at least one severe adverse event(SAE) of grade 3 or 4.A multivariate analysis identified two factors associated with SAEs:female gender [OR = 2.4(1.1,5.6),P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3(2.3,12.4),P ≤ 0.001].CONCLUSION:More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting.The SVR rate was influenced by the response to previous PR treatment,the RVR and liver stiffness.     

Simulation of Waveforms of a Ferrite Inductor with Saturation and Power Losses

We propose a model of an equivalent electrical circuit specifically designed for a ferrite indAuctor excited by a sinusoidal waveform. The purpose of this model is its use in a circuit simulator. We calculate the model parameters by means of Finite Elements in 2D which leads to significant computational advantages over the 3D model. We carry out the validation for a toroidal ferrite inductor by comparing the experimental results and computed ones. We consider the saturation and power losses in the core. In addition, we have tested the model for the case of square waveform in order to generalize the results. We find excellent agreement between the experimental data and the results obtained by numerical calculations.