Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design

Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway

Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of chordoma. In view of the reported association of chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT

Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: A retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database

Aims Oral glucose-lowering medications are associated with excess risk of heart failure (HF). Given the absence of comparative data among drug classes, we performed a retrospective study in 32 Health Services of 16 Italian regions accounting for a population of 18 million individuals, to assess the association between HF risk and use of sulphonylureas, DPP-4i, and glitazones. Methods and results We extracted data on patients with type 2 diabetes who initiated treatment with DPP-4i, thiazolidinediones, or sulphonylureas alone or in combination with metformin during an accrual time of 2 years. The endpoint was hospitalization for HF (HHF) occurring after the first 6 months of therapy, and the observation was extended for up to 4 years. A total of 127 555 patients were included, of whom 14.3% were on DPP-4i, 72.5% on sulphonylurea, 13.2% on thiazolidinediones, with average 70.7% being on metformin as combination therapy. Patients in the three groups differed significantly for baseline characteristics: age, sex, Charlson index, concurrent medications, and previous cardiovascular events. During an average 2.6-year follow-up, after adjusting for measured confounders, use of DPP-4i was associated with a reduced risk of HHF compared with sulphonylureas [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.62-0.97; P = 0.026]. After propensity matching, the analysis was restricted to 39 465 patients, and the use of DPP-4i was still associated with a lower risk of HHF (HR 0.70; 95% CI 0.52-0.94; P = 0.018). Conclusion In a very large observational study, the use of DPP-4i was associated with a reduced risk of HHF when compared with sulphonylureas

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Proceedings of the 24th Paediatric Rheumatology European Society Congress: Part three

From Springer Nature via Jisc Publications Router.Publication status: PublishedHistory: collection 2017-09, epub 2017-09-0

Wavelet Energy and the Usefulness of its Powers in Motion Detection

The potential for the usage of energy exponents in motion detection from video sequences is explored. The wavelet domain was chosen for the research due to the optimality of Hilbert's space for energy calculations and Parseval's equation for energy equivalence between domains. Five algorithms were considered: wavelet energy motion detection algorithm based on wavelet pairs and buffer, listed in the references, and four which are the contributions of this paper: modification by the application of different wavelet pairs, a modified algorithm without buffer, a modified algorithm without buffer and pairs, newly developed algorithms for energy exponents with and without buffer, but with wavelet pairs. The considered algorithms are background subtraction algorithms modified not to use pixels values, but rather energy/energy exponent backgrounds and the current situation models. These models are described by wavelet descriptors, the introduction of which is the contribution of this paper. They are compared by standard statistical criteria and execution time. The results suggest that an increase in the energy exponent decreases precision, recall and F-measure. However, the percentage of correct classifications remains almost constant. Higher exponentials reduce noise, but are more susceptible to shadows, the waving tree effect and similar abnormalities. Algorithms without buffers are less robust to illumination changes

The effects of satureja hortensis l. Extract on cisplatin-induced behavioral alterations in the tail suspension test

In order to evaluate the effects of Satureja hortensis L. extract on cisplatin-induced behavioral alterations in the tail suspension test (TST), we included 35 male Wistar albino rats in this study, divided into 7 equal groups. Cisplatin was administered (single dose of 7.5 mg/kg, i.p., on the fifth day) alone, and in groups with orally administered (for 10 days) Satureja hortensis L. extract (50, 100, and 200 mg/kg), and silymarin (100 mg/kg) in individual groups. The behavioral testing was performed in TST, and the following parameters were obtained: the latency to the first immobility, the number of immobility episodes, and the total duration of immobility. Cisplatin application increased the latency to the first immobility, but decreased the number of immobility episodes and the total duration of immobility. Oral administration of Satureja hortensis L. extract in a dose of 100 mg/kg attenuated cisplatin-induced alterations, and those effects were similar to silymarin group. The extract in a dose of 200 mg/kg diminished cisplatin-induced effect only for the total duration of immobility, while in a dose of 50 mg/kg, the extract had no impact on cisplatin effects. Although common use of this methodology would lead to a conclusion that cisplatin produced antidepressant effect, comparison with certain literature data allows the conclusion that this action of cisplatin may be attributed to its anxiogenic action that was attenuated by antioxidant supplementation (Satureja hortensis L.) in an adequate dose (100 mg/kg)

Specific regulation of ACTH secretion under the influence of low and high ambient temperature-The role of catecholamines and vasopressin

The response of hypothalamo-pituitary-adrenocortical (HPA) axis to different stressors depends on numerous stimulatory and inhibitory signals gathering from various parts of the brain to the hypothalamic nuclei. The present study was aimed at determining whether catecholamines (CA) and vasopressin (VP) play the role in the specific regulation of adrenocorticotropic hormone (ACTH) secretion under the influence of thermal stressors, cold (+4 degrees C) and heat (+38 degrees C), applied acutely for 1 h or repeatedly during 7 and 14 day (1 h daily). The results showed that following acute exposure to those stressors, hypothalamic dopamine (DA), noradrenaline (NA) and adrenaline (ADR) concentrations were significantly decreased as compared to non stressed controls. The prolonged exposure to either of the two stressors left hypothalamic CA concentration unaffected. The amount of pituitary VP significantly increased only under the influence of acute heat stress. Prolonged exposure to both stressors induced significant decrease in the pituitary VP content. Unlike the heat, the cold-caused changes in circulating VP did not follow those in the pituitary. The applied stressors significantly increased the amount of the pituitary V1b receptor (V1bR) mainly present at the surface of corticotrophs, depending on both duration of exposure and nature of stressor. Additionally, both cold and heat specifically induced an increase in blood ACTH. In conclusion, this studys results suggest that the role of VP in the regulation of the ACTH secretion in response to cold and heat depends on the type of stressor, whereas the role of the CA depends on the manner of exposure. (C) 2012 Elsevier Ltd. All rights reserved