Low frequency of GCH1 and TH mutations in Parkinson's disease

BackgroundThe causes of Parkinson's disease (PD) are unknown in the majority of patients. The GCH1 gene encodes GTP-cyclohydrolase I, an important enzyme in dopamine synthesis. Co-occurrence of dopa-responsive dystonia (DRD) and a PD phenotype has been reported in families with GCH1 mutations. Recently, rare coding variants in GCH1 were found to be enriched in PD patients, indicating a role for the enzyme in the neurodegenerative process.MethodsTo further elucidate the contribution of GCH1 mutations to sporadic PD, we examined its coding exons in a targeted deep sequencing study of 509 PD patients (mean age at onset 56.7 ± 12.0 years) and 230 controls. We further included the tyrosine hydroxylase gene TH, also known to cause DRD. Gene dose assessments were performed to screen for large copy number variants in a subset of 48 patients with early-onset PD.ResultsNo putatively pathogenic GCH1 mutations were found. The frequency of rare heterozygous variants in the TH gene was 0.69% (7/1018) in the patient group and 0.22% (1/460) in the control group (p = 0.45).ConclusionsPrevious studies have found that coding variants in the GCH1 gene may be considered a risk factor for PD. Our study indicates that mutations in GCH1 are rare in late-onset PD. Several patients carried heterozygous variants in the TH gene that may affect protein function. Our study was not designed to determine with certainty if any of these variants play a role as risk factors for late-onset PD.     

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

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Impact of ultra-low dose CT acquisition on semi-automated RECIST tool in the evaluation of malignant focal liver lesions

PurposeTo compare the evaluation of malignant focal liver lesions (FLLs) using a semi-automated RECIST tool with a standard and an ultra-low dose (ULD) computed tomography (CT) protocol.Materials and methodsThirty-four patients with malignant FLLs underwent two abdominal-pelvic CT examinations one using a standard protocol and one using an ULD protocol. There were 23 men and 11 women with a mean age 64.3 ± 14.4 (SD) years (range: 22–91 years). Dosimetric indicators were recorded, and effective dose was calculated for both examinations. Mean malignant FLL attenuation, image noise and contrast-to-noise-ratio (CNR) were compared. The largest malignant FLL per patient was evaluated using the semi-automated RECIST tool to determine longest axis length, longest orthogonal axis length, volume and World Health Organisation area.ResultsDosimetric values were significantly reduced by −56% with ULD compared to standard protocol. No differences in mean malignant FLL attenuation values were found between the two protocols. Image noise was significantly increased for all locations (P < 0.05) with ULD compared to standard protocol, and CNR was significantly reduced (P < 0.05). On the 34 malignant FLLs analyzed, six semi-automated shapes non-concordant with radiologist's visual impression were highlighted with the software, including one FLL (1/34; 3%) with standard CT acquisition only, three FLLs (3/34; 9%) with ULD CT acquisition only and two FLLs (2/34; 6%) with both CT acquisitions. After manual editing, the concordance of the values of the studied criteria between both acquisitions was good and no significant difference was reported.ConclusionSemi-automated RECIST tool demonstrates good performances using ULD CT protocol. It could be used in routine clinical practice with a ULD protocol for follow-up studies in patients with known malignant FLL.     

A new role for downstream Toll-like receptor signaling in mediating immediate early gene expression during focal cerebral ischemia

To better understand the role of downstream Toll-like receptor (TLR) signaling during acute cerebral ischemia, we performed cDNA microarrays, on brain RNA, and cytokine arrays, on serum, from wild type (WT), MyD88−/− and TRIF-mutant mice, at baseline and following permanent middle cerebral artery occlusion (pMCAO). The acute stress response pathway was among the top pathways identified by Ingenuity Pathway Analysis of microarray data. We used real-time polymerase chain reaction to confirm the expression of four immediate early genes; EGR1, EGR2, ARC, Nurr77, in this pathway, and insulin degrading enzyme (IDE). Compared to WT, baseline immediate early gene expression was increased up to10-fold in MyD88−/− and TRIF-mutant mice. However, following pMCAO, immediate early gene expression remained unchanged, from this elevated baseline in these mice, but increased up to 12-fold in WT. Furthermore, expression of IDE, which also degrades β-amyloid, decreased significantly only in TRIF-mutant mice. Finally, sE-Selectin, sICAM, sVCAM-1, and MMP-9 levels were significantly decreased only in MyD88−/− compared with WT mice. We thus report a new role for downstream TLR signaling in immediate early gene expression during acute cerebral ischemia. We also show that the TRIF pathway regulates IDE expression; a major enzyme that clears β-amyloid from the brain.     

3D-Quantitative evaluation of a rigid seating system and dynamic seating system using 3D movement analysis in individuals with dystonic tetraparesis

To improve postural stability in individuals with dystonic cerebral palsy, the concept of a dynamic seat has been suggested as a potential solution. An experimental set-up for the acquisition of movement during extensor thrusts while sitting on a seating system was defined and applied on a group of dystonic individuals, to compare a dynamic versus a rigid seat system, using quantitative movement analysis. The seating system in dynamic configuration is able to reduce the extensor thrust experienced by the consumers, as well as to increase range of motion in the anterior–posterior direction, limiting the sliding down of trunk and showing better upper limb smoothness during extensor thrusts. The procedures used in this study appear to provide a useful tool for better understanding how the concept of a dynamic back in a seat system may affect and influence position and stability of individuals with dystonia on the seat system.     

Sphingomyelin changes in rat cerebral cortex during focal ischemia

Abstract

To better define the sphingolipid metabolism during focal brain ischemia, levels of ceramide, sphingomyelin, cerebroside and gangliosides were determined in rat cerebral cortex during focal ischemia produced by occlusion of the middle cerebral artery. Sphingomyelin began to decrease at 2 hours of ischemia and continued to decrease for 96 hours. In contrast, ceramide increased at 6 hours and increased to 4.2-fold at 96 hours after ischemia, and the fatty acid composition of ceramide was solely nonhydroxylated fatty acid similar to sphingomyelin. Hydroxylated fatty acid-linked cerebroside decreased at 6 hours of ischemia, whereas any significant decrease of nonhydroxylated fatty acid-linked cerebroside didn't occur for 96 hours of ischemia. There were no measurable changes in the levels of gangliosides. These results suggested that ceramide was produced in the cerebral cortex by the breakdown of sphingomyelin during early ischemia. [Neurol Res 1996; 18: 337-341]     

局灶节段性肾小球硬化患者常见并发症的分析

目的:观察局灶节段性肾小球硬化(FSGS)患者急性肾损伤(AKI)、感染及血栓栓塞的发生率,探讨并发症发生的危险因素。方法:观察70例经临床及肾脏病理确诊的特发性FSGS患者的AKI、感染及血栓栓塞的发生率,分析并发症的临床特征及高危因素。结果:(1)70例特发性FSGS中,34例(48.6%)并发AKI、14例(20.0%)合并感染、11例(15.7%)出现血栓栓塞。(2)AKI以男性多见,其尿蛋白水平较高,血白蛋白水平较低,小管间质损伤更重,小管急性损伤的程度与AKI的分期有关;随访过程中AKI患者完全缓解率及有效率显著低于未合并AKI者。(3)感染以呼吸道感染多见,院内感染占50%;与非感染组相比,感染组患者的尿蛋白水平更高,血白蛋白、球蛋白、IgG水平则较低;随住院时间延长,感染发生率升高,院内感染所占比例增加;Logistic回归分析显示白蛋白低于20g/L和住院时间延长是感染的独立危险因素。(4)血栓栓塞包括颅内静脉窦血栓2例、颈内静脉血栓1例、右肾静脉血栓1例、股静脉血栓2例、腘静脉血栓2例和肺栓塞3例;血栓栓塞患者的循环内皮细胞计数(CECs)、血管性血友病因子(vWF)高于未合并血栓栓塞者,Logistic回归分析显示CECs和血红蛋白水平升高与血栓栓塞独立相关。结论:FSGS患者肾小管损伤、低白蛋白血症和住院时间延长、血管内皮细胞损伤和血液浓缩分别在AKI、感染、血栓栓塞的发生中起重要作用。     

Focal adhesion kinase: a promising target for anticancer therapy

Focal adhesion kinase (FAK) is a protein tyrosine kinase acting as an early modulator of the integrin signalling cascade, thus regulating various basic cellular functions. In transformed cells, upregulation of FAK protein expression and uncontroled signalling were held responsible for the promotion of malignant phenotypic characteristics, as well as resistance to chemotherapy and radiotherapy. Direct FAK targeting resulted in the inhibition of the malignant phenotype of cancer cells, whereas increased apoptotic rates of cancer cells, either used alone or in combination with conventional chemotherapeutic agents, radiotherapy or hormonal therapy. Furthermore, drugs used in cancer chemotherapy, besides their basic mode of action, were also shown to act through altering FAK signalling. Finally, positive results were noted by the transfection of cancer cells with fak mutants or genes that suppress FAK expression or activity, such as phosphatase and tensin homolog deleted on chromosome Ten (PTEN), ribonucleotide reductase M1 polypeptide (RRM1) and melanoma differentiation-associated gene-7 (mda-7). The purpose of this article is a comprehensive review of the existing data on the possible use of FAK targeting in anticancer therapy.     

The many faces of hemifacial spasm: Differential diagnosis of unilateral facial spasms

Hemifacial spasm is defined as unilateral, involuntary, irregular clonic or tonic movement of muscles innervated by the seventh cranial nerve. Most frequently attributed to vascular loop compression at the root exit zone of the facial nerve, there are many other etiologies of unilateral facial movements that must be considered in the differential diagnosis of hemifacial spasm. The primary purpose of this review is to draw attention to the marked heterogeneity of unilateral facial spasms and to focus on clinical characteristics of mimickers of hemifacial spasm and on atypical presentations of nonvascular cases. In addition to a comprehensive review of the literature on hemifacial spasm, medical records and videos of consecutive patients referred to the Movement Disorders Clinic at Baylor College of Medicine for hemifacial spasm between 2000 and 2010 were reviewed, and videos of illustrative cases were edited. Among 215 patients referred for evaluation of hemifacial spasm, 133 (62%) were classified as primary or idiopathic hemifacial spasm (presumably caused by vascular compression of the ipsilateral facial nerve), and 4 (2%) had hereditary hemifacial spasm. Secondary causes were found in 40 patients (19%) and included Bell's palsy (n = 23, 11%), facial nerve injury (n = 13, 6%), demyelination (n = 2), and brain vascular insults (n = 2). There were an additional 38 patients (18%) with hemifacial spasm mimickers classified as psychogenic, tics, dystonia, myoclonus, and hemimasticatory spasm. We concluded that although most cases of hemifacial spasm are idiopathic and probably caused by vascular compression of the facial nerve, other etiologies should be considered in the differential diagnosis, particularly if there are atypical features. © 2011 Movement Disorder Society