Prevalence and causes of thrombocytopenia in an academic state sector laboratory in Soweto, Johannesburg, South Africa

Background: Causes of thrombocytopenia range from laboratory errors to life-threatening pathological conditions. To establish the cause, appropriate laboratory investigation is required.Objectives: To determine the prevalence and causes of platelet counts <100 × 109/L in state health facilities in Johannesburg, South Africa, as well as the quality of the subsequent laboratory work-up in this setting.Methods: Full blood counts (FBCs) performed on 7 randomly selected days at the National Health Laboratory Service laboratory at Chris Hani Baragwanath Academic Hospital were retrospectively reviewed. Samples with platelet counts <100 × 109/L were identified, and pertinent information was extracted from the laboratory database.Results: Of 4 456 FBCs included, 381 (8.6%) had a platelet count of <100 × 109/L. Thrombocytopenia prevalence rates were high in haematology/oncology wards (34.4%), intensive care units (20.5%) and medical wards (18.7%) and among neonatal inpatients (16.5%), and were lowest in outpatient clinics (1 - 2%). A cause was apparent in ~60% of patients, the commonest causes being chemotherapy and sepsis (each comprising >20% of the recognised causes). Spurious thrombocytopenia, disseminated tuberculosis, aplastic anaemia, immune thrombocytopenia and malignant marrow infiltration each accounted for 5 - 10% of the causes, while malaria, thrombotic thrombocytopenic purpura, HIV effect and liver disease were each identified in <5% of cases. HIV status was documented in ~70% of the patients, of whom ~50% tested positive. The quality of the laboratory work-up showed differences between specialties within the hospital setting, and was poorest in the primary healthcare clinic sector.Conclusion: Thrombocytopenia is common in hospitalised patients in the Johannesburg academic state sector. Differences in the quality of the laboratory work-up emphasise the need for a standardised approach to thrombocytopenia investigation and increased awareness among clinicians

Mutations that alter the regulation of the chb operon of Escherichia coli allow utilization of cellobiose

Wild-type strains of Escherichia coli are normally unable to metabolize cellobiose. However, cellobiose-positive (Cel+) mutants arise upon prolonged incubation on media containing cellobiose as the sole carbon source. We show that the Cel+ derivatives carry two classes of mutations that act concertedly to alter the regulation of the chb operon involved in the utilization of N,N'-diacetylchitobiose. These consist of mutations that abrogate negative regulation by the repressor NagC as well as single base-pair changes in the transcriptional regulator chbR that translate into single-amino-acid substitutions. Introduction of chbR from two Cel+ mutants resulted in activation of transcription from the chb promoter at a higher level in the presence of cellobiose, in reporter strains carrying disruptions of the chromosomal chbR and nagC. These transformants also showed a Cel+ phenotype on MacConkey cellobiose medium, suggesting that the wild-type permease and phospho-β-glucosidase, upon induction, could recognize, transport and cleave cellobiose respectively. This was confirmed by expressing the wild-type genes encoding the permease and phospho-β-glucosidase under a heterologous promoter. Biochemical characterization of one of the chbR mutants, chbRN238S, showed that the mutant regulator makes stronger contact with the target DNA sequence within the chb promoter and has enhanced recognition of cellobiose 6-phosphate as an inducer compared with the wild-type regulator

Force dysmetria in spinocerebellar ataxia 6 correlates with functional capacity

Spinocerebellar ataxia type 6 (SCA6) is a genetic disease that causes pure cerebellar degeneration affecting walking, balance, and coordination. One of the main symptoms of SCA6 is dysmetria. The magnitude of dysmetria and its relation to functional capacity in SCA6 has not been studied. Our purpose was to quantify dysmetria and determine the relation between dysmetria and functional capacity in SCA6. Ten individuals diagnosed and genetically confirmed with SCA6 (63.7 ± 7.02yrs) and nine age-matched healthy controls (65.9 ± 8.5yrs) performed goal-directed isometric contractions with the ankle joint. Dysmetria was quantified as the force and time error during goal-directed contractions. SCA6 functional capacity was determined by ICARS and SARA clinical assessments. We found that SCA6 participants exhibited greater force dysmetria than healthy controls (P < 0.05), and reduced time dysmetria than healthy controls (P < 0.05). Only force dysmetria was significantly related to SCA6 functional capacity, as measured with ICARS kinetic score (R2 = 0.63), ICARS total score (R2 = 0.43), and SARA total score (R2 = 0.46). Our findings demonstrate that SCA6 exhibit force dysmetria and that force dysmetria is associated to SCA6 functional capacity. Quantifying force and time dysmetria in individuals with SCA6 could provide a more objective evaluation of the functional capacity and disease state in SCA6

Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

OBJECTIVE: Friedreich's ataxia (FRDA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FRDA. We investigated the safety and efficacy of omaveloxolone in patients with FRDA. METHODS: We conducted an international, double-blind, randomized, placebo-controlled parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FRDA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150 mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. RESULTS: 155 patients were screened and 103 were randomly assigned to receive omaveloxolone (n=51) or placebo (n=52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96; p=0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. INTERPRETATION: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FRDA. This article is protected by copyright. All rights reserved

C9orf72 repeat expansions as genetic modifiers for depression in spinocerebellar ataxias

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142479/1/mds27258.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142479/2/mds27258_am.pd

Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology

Abstract Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer’s disease (AD) and Parkinson’s disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.https://deepblue.lib.umich.edu/bitstream/2027.42/152173/1/40478_2019_Article_818.pd

Analysis of Nigerians with Apparently Sporadic Parkinson Disease for Mutations in LRRK2, PRKN and ATXN3

Several genetic variations have been associated with Parkinson disease in different populations over the past few years. Although a considerable number of worldwide populations have been screened for these variants, results from Sub-Saharan populations are very scarce in the literature. In the present report we have screened a cohort of Parkinson disease patients (n = 57) and healthy controls (n = 51) from Nigeria for mutations in the genes PRKN, LRRK2 and ATXN3. No pathogenic mutations were found in any of the genes. Hence, common pathogenic mutations in these genes, observed in several different populations, are not a frequent cause of Parkinson disease in Nigeria

Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report

Background: Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although Parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity), namely on what concerns genetic variation in Parkinson's disease (PD) associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNAGln T4336C). Case presentation: Patient 1 is a 40 year-old female (onset at 30 years of age), initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother). Patient 2 is a 38 year-old male (onset at 33 years of age), presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father). Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients. Conclusions: The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD

International Perspectives on the Legal Environment for Selection

Perspectives from 22 countries on aspects of the legal environment for selection are presented in this article. Issues addressed include (a) whether there are racial/ethnic/religious subgroups viewed as "disadvantaged,” (b) whether research documents mean differences between groups on individual difference measures relevant to job performance, (c) whether there are laws prohibiting discrimination against specific groups, (d) the evidence required to make and refute a claim of discrimination, (e) the consequences of violation of the laws, (f) whether particular selection methods are limited or banned, (g) whether preferential treatment of members of disadvantaged groups is permitted, and (h) whether the practice of industrial and organizational psychology has been affected by the legal environmen