Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.

Diagnosis and management of Guillain-Barré syndrome in ten steps.

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

Short-term effects of non-invasive ventilation on cerebral blood flow and cognitive function in COPD.

OBJECTIVES: Investigate the acute effects of non-invasive ventilation (NIV) on cerebral blood flow (CBF) and on cognitive functions in COPD. METHODS: Nine non-hypercapnic stable COPD and twelve healthy controls were enrolled. CBF (transcranial Doppler), cognitive tests and cardiorespiratory response were performed at baseline, during one hour of NIV and after 30 min. RESULTS: Both groups had an increase in tidal volume and reduction in respiratory rate during NIV, but only controls showed PaCO2 reductions (41.2 ±â€¯4.6 to 36.5 ±â€¯7.3 in controls vs. 40.9 ±â€¯4.5 to 42.9 ±â€¯5.9 in COPD). During NIV CBF was significantly reduced in healthy controls and COPD, although this effect was less pronounced in the latter. At the same time, healthy controls demonstrated an improvement in cognitive executive function compared to COPD in the Trail Making Test part B (90.5 vs. 180s; respectively). CONCLUSION: NIV application for one hour reversibly reduced CBF in healthy controls and non-hypercapnic stable COPD patients, despite no significant reductions of the PaCO2 in the latter group. It was associated with minor cognitive improvements in the executive function in healthy volunteers, but not in COPD.

Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy.

Dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) was associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase, in two large unrelated Bulgarian and US pedigrees and one sporadic case. Here for the first time we describe the clinical, neurophysiological and histopathological features, and phenotypic differences between these two DI-CMTC families. Twenty-one affected individuals from the US family and 27 from the Bulgarian family were evaluated. The mean age of onset in US subjects was 10.7 years in men and 7.3 years in women, while in the Bulgarian participants it was 18.2 years in men and 33.7 years in women. The course was slowly progressive. Extensor digitorum brevis atrophy was uniform. Atrophy and/or weakness of upper and lower limb muscles were found in over 50 % of the subjects. Nerve conduction studies (NCS) were abnormal in all US adults and five of six children and all Bulgarian patients except one asymptomatic 25-year-old man. Median motor NCS were in the range of 29.5-45.6 m/s in the US family and 24.7-57.8 m/s in the Bulgarian family. Sural sensory nerve action potentials were absent in 14/21 and 4/12 NCS from adult US and Bulgarian participants, respectively. Analysis of sural nerve biopsies from US patients revealed age-dependent morphological changes of axonal degeneration, absence of onion bulbs, and <10 % fibers with segmental remyelination. Our findings provide further insights into the diagnosis and pathology of intermediate CMT. They also extend the phenotypic spectrum of peripheral neuropathies associated with aminoacyl-tRNA synthetase mutations.

Rehabilitation of the upper extremity and basic activities of daily living in the first month after ischemic stroke: an international cohort comparison study.

Inpatient rehabilitation has been traditionally employed in developed countries, while in developing countries, outpatient rehabilitation is the rule. The purpose of this study was to compare the patterns of recovery of upper extremity (UE) function, global impairment and independence in activities of daily living (ADL) during the first month after ischemic stroke in inpatient (United States) and outpatient (Brazil) rehabilitation settings.This is a prospective cohort comparison study. Twenty patients from each country were selected using identical inclusion criteria.The study measures employed were the UE portion of the Fugl-Meyer scale, the Action Research Arm test, the National Institutes of Health Stroke Scale and Barthel Index. Changes from baseline to the end of treatment, efficiency and effectiveness of each treatment were compared.Both populations exhibited significant improvement between the first and second evaluations in the four outcome scales (p<0.0001). There were no differences between the two rehabilitation settings on any of the four dependent measures (p>0.05).Substantially different treatment approaches after ischemic stroke led to similar results in UE function, global impairment and ADL. Further studies in larger populations should be performed in order to confirm the present results.

Bilateral nephrectomy delays gastric emptying of a liquid meal in awake rats.

AIMS: This study evaluates the effect of bilateral nephrectomy on the gastric emptying of a liquid meal. METHODS: Male rats were submitted under anesthesia to cervical vessels cannulation and bilateral lumbar incision, followed or not by nephrectomy. Next day, they were gavage fed (1.5 mL) with phenol red (0.5gmL(-1)) in 5% glucose solution and sacrificed 0,10, 20,30 or 45 min later. A blood sample was obtained for biochemical analysis while gastric dye retention was determined by spectrophotometry. Data (mean +/- SEM) were compared by ANOVA and Student-Newman-Keuls tests. RESULTS: Gastric emptying values from nephrectomy group at 10,20,30 and 45 min were lower (P < 0.05) than those of sham-operated animals (22.0 +/- 4.0 vs. 38.9 +/- 6.1%, 34.1 +/- 1.4 vs. 66.9 +/- 1.3%, 45.5 +/- 6.1 vs. 64.9 +/- 5.4% and 59.7 +/- 2.4 vs. 81.5 +/- 4.0%, respectively). Mean arterial pressure, blood volume, serum osmolarity, urea, creatinine and potassium values were higher (P < 0.05) in nephrectomy group than in sham-operated animals (143.3 +/- 2.7 vs. 100.5 +/- 4.1 mmHg, 15.7 +/- 0.9 vs. 8.9 +/- 1.1 mL 100 g(-1), 344.0 +/- 10.8 vs. 299.4 +/- 1.3 mOsm KgH2O(-1), 344.0 +/- 33.7 vs. 47.0 +/- 2.8mg dL(-1), 3.6 +/- 0.3 vs. 1.1 +/- 0.1 mg dL(-1), 6.4 +/- 0.7 vs. 3.7 +/- 0.2 mEq L(-1), respectively). The plasmatic Na+ values did not change (139.3 +/- 2.0 in sham-operation vs. 123.0 +/- 7.5 mEq L(-1) in nephrectomy). CONCLUSION: Acute loss of kidney function markedly delays the gastric emptying rates, which could be involved in gastrointestinal dysmotility complaints seen after renal failure.

Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome 1p34-p35.

Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a genetic and phenotypic variant of classical CMT, characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. We report two unrelated families with intermediate CMT linked to a novel locus on chromosome 1p34-p35 (DI-CMTC). The combined haplotype analysis in both families localized the DI-CMTC gene within a 6.3-cM linkage interval flanked by markers D1S2787 and D1S2830. The functional and positional candidate genes, Syndecan 3 (SDC3), and lysosomal-associated multispanning membrane protein 5 (LAPTM5) were excluded for pathogenic mutations.