Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics.

Machado-Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an abnormal expansion of the triplet CAG at exon 10 within the ATXN3 gene. The gene encodes for ataxin-3, which is a deubiquitinating protein that is also involved in transcriptional regulation. In normal conditions, the ataxin-3 protein polyglutamine stretch has between 13 and 49 glutamines. However, in MJD/SCA3 patients, the size of the stretch increases from 55 to 87, contributing to abnormal protein conformation, insolubility, and aggregation. The formation of aggregates, which is a hallmark of MJD/SCA3, compromises different cell pathways, leading to an impairment of cell clearance mechanisms, such as autophagy. MJD/SCA3 patients display several signals and symptoms in which the most prominent is ataxia. Neuropathologically, the regions most affected are the cerebellum and the pons. Currently, there are no disease-modifying therapies, and patients rely only on supportive and symptomatic treatments. Due to these facts, there is a huge research effort to develop therapeutic strategies for this incurable disease. This review aims to bring together current state-of-the-art strategies regarding the autophagy pathway in MJD/SCA3, focusing on evidence for its impairment in the disease context and, importantly, its targeting for the development of pharmacological and gene-based therapies.

Chronic axillary wounds in cats: what do we know and how should we manage them?

PRACTICAL RELEVANCE: Axillary wounds most often occur in outdoor cats that wear a collar, typically after having been missing. These wounds are commonly chronic and indolent in nature, and although there is so far no consensus on an explanation for this, it is likely that there are several factors involved. CLINICAL CHALLENGES: Axillary wounds are often difficult to manage due to the frequent presence of infection, their histopathological characteristics and their location, where there is excessive tension and movement of the axillary tissues. Initial surgical treatment has a high reported incidence of failure and complications in the literature, with wound breakdown reported most commonly. Giving due consideration to the difficulties of managing these wounds, however, will help practitioners to decrease the occurrence of complications and the need for multiple procedures, and therefore improve the outcome. EQUIPMENT: Initial approach and surgical management can be achieved using standard medical equipment and surgical kit available to general practitioners. EVIDENCE BASE: This review discusses the surgical techniques reported in the literature to have successfully treated chronic axillary wounds and recommendations are also provided based on the authors' clinical experience.

Control of single-joint movements with a reversal.

We studied the kinematic and electromyographic (EMG) patterns during single-joint elbow flexion movements with a reversal and tested two hypotheses. First, that the amplitude of the second phase of the movement (M(2)) will be controlled by two different means, a drop in the second flexor burst for a small M(2) and an increase in the integral of the extensor burst for larger M(2). Second, based on the muscle stretch-shortening cycle (SSC), that movements reversing without a delay will show a larger extensor burst, as compared to movements that reverse after a delay. Changes in EMG patterns with M(2) amplitude supported the first hypothesis and could be interpreted within the framework of the equilibrium-point hypothesis. The observations also corroborate a hypothesis that discrete movements represent outcomes of an oscillatory control process stopped at a particular phase. In Experiment-2, even the shortest delay at the target led to a significantly larger extensor burst. However, there were no differences in the peak velocity of M2 with and without the delay. These observations do not support a major role of stretch reflexes in the SSC effects during such movements. However, they are compatible with the idea of peripheral factors, such as peripheral muscle and tendon elasticity, playing a major potentiating role in the SSC.