Current status of gene therapy research in polyglutamine spinocerebellar ataxias

Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients.Foundation (FCT) project (ALG-01-0145-FEDER-29480)info:eu-repo/semantics/publishedVersio

Different ventilatory responses to progressive maximal exercise test performed with either the arms or legs

OBJECTIVE: This study aimed to compare respiratory responses, focusing on the time-domain variability of ventilatory components during progressive cardiopulmonary exercise tests performed on cycle or arm ergometers. METHODS: The cardiopulmonary exercise tests were conducted on twelve healthy volunteers on either a cycle ergometer or an arm ergometer following a ramp protocol. The time-domain variabilities (the standard deviations and root mean squares of the successive differences) of the minute ventilation, tidal volume and respiratory rate were calculated and normalized to the number of breaths. RESULTS: There were no significant differences in the timing of breathing throughout the exercise when the cycle and arm ergometer measurements were compared. However, the arm exercise time-domain variabilities for the minute ventilation, tidal volume and respiratory rate were significantly greater than the equivalent values obtained during leg exercise. CONCLUSION: Although the type of exercise does not influence the timing of breathing when dynamic arm and leg exercises are compared, it does influence time-domain ventilatory variability of young, healthy individuals. The mechanisms that influence ventilatory variability during exercise remain to be studied

Mutant Ataxin-2 expression in aged animals aggravates neuropathological features associated with Spinocerebellar Ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.info:eu-repo/semantics/publishedVersio

On the effect of the wall slip boundary conditon

This work describes the implementation and assessment of the wall slip boundary condition in a 3D numerical modelling code, based on the finite volume method, that is being developed by the research team. Several phenomenological models relating the velocity and the shear stress at the wall were implemented. The capabilities of the new numerical code are illustrated with three case studies where the wall slip boundary conditions play an important role, namely the flow in a smooth contraction, the stick-slip phenomenon an the flow in a profile extrusion die. The results obtained are qualitatively in accordance with the theoretical expectations and evidence the importance of wall slip

Effect of polymer melt wall slip on the flow balance of profile extrusion dies

This work describes the implementation of the wall slip boundary condition in an in-house developed 3D numerical code based on the Finite Volume Method. For this purpose, several phenomenological models relating the velocity and the shear stress at the wall were implemented. This new feature is verified using a simple case study, by comparing the numerical results with those obtained through the corresponding analytical solution. Then, the potentialities of the new code are illustrated performing flow simulations of a polymer melt in a complex flow channel. The results obtained show that the slip at the wall influences the flow distribution at the die flow channel outlet. Therefore, and to assess the relevance of slippage in the optimal die geometry, the automatic optimization of a die flow channel, required for the production of a specific thermoplastic profile, is performed using both the no-slip and slip boundary conditions, together with two alternative optimization strategies. It is shown that slip favors the flow balance of the dies and also other issues of its performance.The authors gratefully acknowledge funding from Fundação para a Ciência e Tecnologia, FCT (COMPETE Program) under the projects FCOMP-01-0124 - FEDER-010190 (Ref. PTDC / EME - MFE/102729/2008) and FCOMP-01-0124-FEDER-015126 (Refª. FCT PTDC/EME-MFE/113988/2009), and FEDER, via FCT, under the PEst-C/CTM/LA0025/2011 (Strategic Project - LA 25 - 2011-2012)

Medial dorsal cutaneous nerve entrapment following inversion ankle sprain

The medial dorsal cutaneous nerve is one of the terminal branches of the superficial peroneal nerve that provides sensory innervation to the dorsum of the foot. It may be prone to injury by direct blow, iatrogenic surgical lesion or in rare situations secondary to ankle sprains. The authors report a case of persistent ankle pain in a female patient caused by a post- traumatic compressive neuropathy of the medial dorsal cutaneous nerve secondary to an ankle sprain which was successfully surgically treated with complete resolution of the symptoms

Is Bilateral Hallux Valgus Chevron Osteotomy a Safe Procedure for Ambulatory Surgery?

Introduction: Several osteotomies of the first metatarsal have been described for treatment of hallux valgus but chevron osteotomy is one of the most common and well-established procedure for treating this deformity. Although there is a trend towards considering bilateral surgery there is lack of publications addressing bilateral treatment in ambulatory units. The aim of this study is to analyze results of bilateral and unilateral distal chevron osteotomies associated with lateral soft tissue release as ambulatory procedures. Materials and methods: A retrospective review was made about the patients treated at our ambulatory unit over a period of five years. Initially, general information as patient's satisfaction's rate and return to normal activity's time and evaluation of standardized follow-up charts and records made by the surgeon were recorded. Secondly, the hallux metatarsophalangeal interphalangeal scale developed by the American Orthopedic Foot & Ankle Society was used. Results: A total of 194 patients with 230 feet operated were included in this study. We found 29 patients that didn't meet the inclusion criteria and were excluded. The unilateral group was composed by 139 feet and the bilateral group by 52 feet. The improvement between preoperative and discharge clinical and radiographic results was significant independently in both groups. A total of 14% of complications were found in our study, 19% in the unilateral group and 12% at the bilateral group. None of them required revision surgery. Conclusion: Bilateral distal chevron osteotomies, associated with lateral soft tissue release, are safe and effective ambulatory procedures. It was found a satisfactory deformity correction in moderate HV. Both patients that underwent unilateral and bilateral procedures had similar clinical and radiological outcomes with no increase in complications or return to normal activity time. With this study it was demonstrated that bilateral chevron osteotomies can be performed as ambulatory procedures.info:eu-repo/semantics/publishedVersio

Viagem à Índia para prospecção de tecnologias sobre mamona e pinhão manso.

Viagem á Índia para prospecção de tecnologias sobre mamona e pinhão manso ; Introdução; Roteiro; Detalhamento; Sardar Krushinagar Dantiwada University; Pesquisas com mamona; Pesquisas com pinhão manso; Outras oleaginosas ; Indústria de extração de óleo de mamona ; Mercado de leilões para comercialização de produtos agrícolas ; Mini-usina de biodiesel de pinhão manso; 4º Seminário Internacional sobre semente e óleo de mamona e produtos de valor agregado ; Visita à Secretaria de Agricultura do Estado de Tamil Nadu ; Projeto MGR jatropha biodiesel ; Loco Works - Empresa operadora de ferrovias ; Exposição sobre a mini-usina de biodiesel da Empresa Loco Works ; Considerações finais; Pinhão manso ; Mamona.bitstream/CNPA/18319/1/DOC153.pd