The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype

neurogenetics - Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from...     

Anticoagulation Strategies in Patients With Cancer: JACC Review Topic of the Week

Patients with active cancer are at an increased risk of arterial and venous thromboembolism (VTE) and bleeding events. Historically, in patients with cancer, low molecular weight heparins have been preferred for treatment of VTE, whereas warfarin has been the standard anticoagulant for stroke prevention in patients with atrial fibrillation (AF). More recently, direct oral anticoagulants (DOACs) have been demonstrated to reduce the risk of venous and arterial thromboembolism in large randomized clinical trials of patients with VTE and AF, respectively, thus providing an attractive oral dosing option that does not require routine laboratory monitoring. In this review, we summarize available clinical trial data and guideline recommendations, and outline a practical approach to anticoagulation management of VTE and AF in cancer.     

Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.     

Diminution in Kerosene-Mediated Induction of Drug Metabolizing Enzymes by Asbestos in Rat Lungs

Abstract: In order to determine the pulmonary toxicity of kerosene and its ignition product (soot) in asbestos exposed subjects, the activities of phase I and phase II drug metabolizing enzymes in rat lungs after single intratracheal coexposure to Indian chrysotile asbestos and kerosene or its soot and Indian chrysotile were assayed. Exposure to kerosene or its soot resulted in a significant increase in the level of microsomal cytochrome P-450 and the activity of P-450 dependent monooxygenase, benzo(a)pyrene hydroxylase, as well as in the activities of microsomal epoxide hydrase and cytosolic glutathione-S-transferase (GST). However, in chrysotile exposed animals a reverse pattern in these parameters was recorded. The co-exposure to chrysotile and kerosene or chrysotile and soot led to a significant depletion in cytochrome P-450 level and a decrease in the activities of benzo(a)pyrene hydroxylase, epoxide hydrase and GST when compared to kerosene and soot controls, respectively. These results suggest that asbestos by altering the pulmonary drug metabolizing enzyme system may increase the toxic potential of kerosene and its ignition product in the respiratory system.     

The physiological regulation of toll-like receptor expression and function in humans

Eleven mammalian toll-like receptors (TLRs 1–11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14⁺ monocytes following activation with specific TLR ligands was greater ( P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34°C). Strenuous exercise resulted in a decrease ( P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14⁺ monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14⁺ monocytes following activation with specific TLR ligands was decreased ( P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.     

Reduced susceptibility to dextran sulphate sodium-induced colitis in the interleukin-2 heterozygous (IL-2) mouse

Summary Mice homozygous for an inactivation of the interleukin-2 (IL-2) gene develop a T-cell dependent colitis. Heterozygous (IL-2+/-) mice are clinically healthy but have been shown to express reduced levels of IL-2 in the colon. Splenocytes from the IL-2+/- mice had a poorer proliferative response to polyclonal T-cell activation and these mice have reduced numbers of intestinal regulatory T cells (CD4+ CD25+ cells) when compared to wild type mice. When exposed to dextran sulphate sodium (DSS) IL-2+/- mice showed a markedly reduced susceptibility to DSS-induced colitis. While DSS treatment caused a marked increase in both CD4+ and CD8+ colonic T cells expressing increased levels of IL-2, IL-4, and IL-10 in wild type mice none of these changes were seen in IL-2+/- mice. On the contrary, cytokine expression in intestinal T cells of IL-2+/- mice was actually reduced after DSS treatment. These results suggest that reduced levels of IL-2 leads to attenuated activation and function of intestinal T cells in IL-2+/- mice and a failure to react adequately to DSS exposure.     

Cross-cultural adaptation,validity and reliability of Turkish version of Oxford Ankle Foot Questionnaire for children with congenital talipes equinovarus

BackgroundThe purpose of the study was to evaluate the reliability and validity of the Turkish version of the Oxford Ankle Foot Questionnaire (OxAFQ) to provide cultural adaptation.MethodsThis study involved translation, back translation, and cross-cultural adaptation. Forty-nine patients with congenital talipes equinovarus were evaluated using the Turkish version of OxAFQ. Turkish version of the Childhood Health Assessment Questionnaire (CHAQ) was used as a gold standard to validate the Turkish version of the OxAFQ. The validation was assessed with Spearman correlation analysis by using CHAQ. The reliability of the questionnaire was assessed with Cronbach alpha (internal consistency) and exploratory factor analysis.ResultsHigh validity was found between OxAFQ and CHAQ (r = -0.422?0.292) (p < 0.01). Reliability analysis showed that OxAFQ had a high level of Cronbach alpha (α = 0.88?0.96) and internal consistency (ICC = 0.90?0.96).ConclusionThe Turkish version of OxAFQ is a valid, reliable and useful quality of life questionnaire in patients with congenital talipes equinovarus and it is proper for use by health professionals and researchers.