Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders.

BACKGROUND: Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive. METHODS: We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations. RESULTS: Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration. CONCLUSIONS: This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs

Guidelines for management of ischaemic stroke and transient ischaemic attack 2008

This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation

Examining potential contraindications for prolonged exposure therapy for PTSD

Contains fulltext : 126430.pdf (publisher's version ) (Open Access)Although prolonged exposure (PE) has received the most empirical support of any treatment for posttraumatic stress disorder (PTSD), clinicians are often hesitant to use PE due to beliefs that it is contraindicated for many patients with PTSD. This is especially true for PTSD patients with comorbid problems. Because PTSD has high rates of comorbidity, it is important to consider whether PE is indeed contraindicated for patients with various comorbid problems. Therefore, in this study, we examine the evidence for or against the use of PE with patients with problems that often co-occur with PTSD, including dissociation, borderline personality disorder, psychosis, suicidal behavior and non-suicidal self-injury, substance use disorders, and major depression. It is concluded that PE can be safely and effectively used with patients with these comorbidities, and is often associated with a decrease in PTSD as well as the comorbid problem. In cases with severe comorbidity, however, it is recommended to treat PTSD with PE while providing integrated or concurrent treatment to monitor and address the comorbid problems

Characteristics and Surgical Treatment of Dolichoectatic and Fusiform Aneurysms

Dolichoectatic and fusiform aneurysms represent a small subset of cerebral aneurysms and are often among the most difficult to treat. A consecutive series of 40 patients with 41 of these two types of aneurysms is presented, including their clinical characteristics and surgical treatments. Common to all aneurysms was the pathological involvement of a length of blood vessel with separate inflow and outflow sites (nonsaccular). However, dolichoectatic aneurysms have markedly different symptoms and surgical treatments dependent on their location in either the anterior or posterior circulation. Anterior circulation aneurysms involved the petrous internal carotid artery (ICA) in one, the supraclinoid ICA in three, the middle cerebral artery in 13, and the anterior cerebral artery in four patients. Posterior circulation aneurysms involved the basilar artery in 13, the vertebral artery in six, and the posterior inferior cerebellar artery in one patient. Various surgical procedures were performed, including direct clipping, trapping with bypass, proximal occlusion, resection with reanastomosis, transposition, aneurysmorrhaphy with thrombectomy, and wrapping. There was no surgical mortality in the patient series, and treatment was effective in many patients. Overall, outcome at late follow up was good (Glasgow Outcome Scale scores 1-2) in 78% of patients. Patients with anterior circulation aneurysms had better outcomes than patients with posterior circulation aneurysms, with good outcomes in 90% and 65% of the cases, respectively. Dolichoectatic and giant serpentine aneurysms may develop from smaller fusiform aneurysms and represent a spectrum of the same pathological entity. Arterial dissection may also play a role in the initial development of these aneurysms