Prospective Cohort Study on Performance of Cerebrospinal Fluid (CSF) Xpert MTB/RIF, CSF Lipoarabinomannan (LAM) Lateral Flow Assay (LFA), and Urine LAM LFA for Diagnosis of Tuberculous Meningitis in Zambia.

Tuberculous meningitis (TBM) is a devastating infection of the central nervous system lacking an adequate point-of-care diagnostic test. We conducted a prospective cohort study of 550 Zambian adults with suspected TBM to determine the diagnostic accuracy of cerebrospinal fluid (CSF) Xpert MTB/RIF, CSF lipoarabinomannan (LAM), urine LAM, CSF total protein, and CSF glucose compared with the gold standard of CSF culture. We categorized patients with a positive CSF tuberculosis (TB) culture as definite TBM. We also assessed inpatient and 1-year mortality on definite TBM patients when CSF Xpert MTB/RIF results were available in real time to treating physicians relative to a historical comparison cohort in whom Xpert results were not available in real time. Of the 550 patients, 474 (86.2%) were HIV-infected and 105/550 (19.1%) had definite TBM based on a positive CSF culture. The sensitivity/specificity of the diagnostic tests were CSF Xpert MTB/RIF, 52.9%/94.2%; CSF LAM, 21.9%/94.2%; urine LAM, 24.1%/76.1%; and CSF glucose 100 mg/dl, 66.3%/90%. A model including CSF Xpert MTB/RIF, CSF LAM, CSF glucose, and CSF total protein demonstrated an area under the receiver operating curve of 0.90. The inpatient and 1-year mortality for definite TBM was 43% and 57%, respectively. There was low sensitivity for the diagnosis of TBM across all diagnostics tests. CSF Xpert MTB/RIF and CSF LAM are highly specific for the diagnosis of TBM. Despite the use of Xpert MTB/RIF for diagnostic purpose in real time, TBM was still associated with a high mortality in Zambian patients

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Experimental simulation of Prkinson's sydndrome and comprehensive pathogenetic therapy thereof

Available from VNTIC / VNTIC - Scientific & Technical Information Centre of RussiaSIGLERURussian Federatio

HIV infection, hypercoagulability and ischaemic stroke in adults at the University Teaching Hospital in Zambia: a case control study

Abstract Background In Zambia, 14.2% of adults have HIV/AIDS. There has been a substantial and significant increase in patients hospitalized for ischaemic stroke with co-existing HIV infection. However, little is known about the mechanism of stroke in these HIV + ve patients let alone studied in our region. The aim of this pilot study was to explore the association of hypercoagulability state in HIV + ve patients with ischaemic stroke. This was achieved by comparing hypercoagulability state markers between HIV + ve ischaemic stroke patients with HIV-ve and HIV + ve patients with and without ischaemic stroke respectively. Methods A matched case control study in which a total of 52 HIV + ve patients with ischaemic stroke were prospectively compared with control groups for the presence of protein S, protein C deficiencies and hyperhomocysteinaemia. The control groups comprised an equal number of consecutively matched for age and sex HIV-ve and HIV + ve patients with and without ischaemic stroke respectively. Data was analysed in contingency tables using Paired t- test, Chi square and conditional logistic regression. Results Ischaemic stroke of undetermined aetiology occurred more frequently in HIV + ve compared to HIV-ve patients (p < 0.001). In addition, protein S deficiency and Hyperhomocysteinaemia were more prominent in HIV + ve than HIV-ve ischaemic stroke patients (P = 0.011). There was no difference in the presence of hyperhomocysteinaemia or protein S deficiency in HIV + ve patients with or without ischaemic stroke. Protein C deficiency was not noted to be significantly different between the cases and the two control arms. Conclusion Protein S deficiency and hyperhomocysteinaemia were associated with HIV infection, but not stroke in our study population. However, this is an area that requires extensive research and one that we cannot afford to ignore as it is an important bridge to all cardiovascular and cerebrovascular diseases

The cost of implementing a nationwide program to decrease the epilepsy treatment gap in a high gap country

Healthcare systems in many low income countries have evolved to provide services for acute, infections and are poorly structured for the provision of chronic, non-communicable diseases which are increasingly common. Epilepsy is a common chronic neurologic condition and antiepileptic drugs are affordable, but the epilepsy treatment gap remains &gt;90% in most African countries. The World Health Organization has recently released evidence-based guidelines for epilepsy care provision at the primary care level. Based upon these guidelines, we estimated all direct costs associated with epilepsy care provision as well as the cost of healthcare worker training and social marketing. We developed a model for epilepsy care delivery primarily by primary healthcare workers. We then used a variety of sources to develop cost estimates for the actual implementation and maintenance of this program being as comprehensive as possible to include all costs incurred within the health sector. Key sensitivity analyses were completed to better understand how changes in costs for individual aspects of care impact the overall cost of care delivery. Even after including the costs of healthcare worker retraining, social marketing and capital expenditures, epilepsy care can be provided at less than $25.00 per person with epilepsy per year. This is substantially less than for drugs alone for other common chronic conditions. Implementation of epilepsy care guidelines for patients receiving care at the primary care level is a cost effective approach to decreasing the epilepsy treatment gap in high gap, low income countries

Clinical and genetic analysis of spinocerebellar ataxia type 7 (SCA7) in Zambian families

Background: To date, 43 types of Spinocerebellar Ataxias (SCAs) have been identified. A subset of the SCAs are caused by the pathogenic expansion of a CAG repeat tract within the corresponding gene. Ethnic and geographic differences are evident in the prevalence of the autosomal dominant SCAs. Few descriptions of the clinical phenotype and molecular genetics of the SCAs are available from the African continent. Established studies mostly concern the South African populations, where there is a high frequency of SCA1, SCA2 and SCA7. The SCA7 mutation in South Africa (SA) has been found almost exclusively in families of indigenous Black African ethnic origin. Objective: To present the results of the first clinical description of seven Zambian families presenting with autosomal dominant SCA, as well as the downstream molecular genetic analysis of a subset of these families. Methods: The study was undertaken at the University Teaching Hospital in Lusaka, Zambia. Ataxia was quantified with the Brief Ataxia Rating Scale derived from the modified international ataxia rating scale. Molecular genetic testing for 5 types of SCA (SCA1, SCA2, SCA3, SCA6 and SCA7) was performed at the National Health Laboratory Service at Groote Schuur Hospital and the Division of Human Genetics, University of Cape Town, SA. The clinical and radiological features were evaluated in seven families with autosomal dominant cerebellar ataxia. Molecular genetic analysis was completed on individuals representing three of the seven families. Results: All affected families were ethnic Zambians from various tribes, originating from three different regions of the country (Eastern, Western and Central province). Thirty-four individuals from four families had phenotypic features of SCA7. SCA7 was confirmed by molecular testing in 10 individuals from 3 of these families. The age of onset of the disease varied from 12 to 59 years. The most prominent phenotypic features in these families were gait and limb ataxia, dysarthria, visual loss, ptosis, ophthalmoparesis/ophthalmoplegia, pyramidal tract signs, and dementia. Affected members of the SCA7 families had progressive macular degeneration and cerebellar atrophy. All families displayed marked anticipation of age at onset and rate of symptom progression. The pathogenic SCA7 CAG repeat ranges varied from 47 to 56 repeats. Three additional families were found to have clinical phenotypes associated with autosomal dominant SCA, however, DNA was not available for molecular confirmation. The age of onset of the disease in these families varied from 19 to 53 years. The most common clinical picture in these families included a combination of cerebellar symptoms with slow saccadic eye movements, peripheral neuropathy, dementia and tremor. Conclusion: SCA is prevalent in ethnic Zambian families. The SCA7 families in this report had similar clinical presentations to families described in other African countries. In all families, the disease had an autosomal dominant pattern of inheritance across multiple generations. All families displayed anticipation of both age of onset and the rate of disease progression. Further clinical and molecular investigations of the inherited ataxias in a larger cohort of patients is important to understand the natural history and origin of SCAs in the Zambian population

Association of the APOE, MTHFR and ACE genes polymorphisms and stroke in Zambian patients

The aim of the present study was to investigate the association of <em>APOE</em>, <em>MTHFR</em> and <em>ACE</em> polymorphisms with stroke in the Zambian population. We analyzed 41 stroke patients and 116 control subjects all of Zambian origin for associations between the genotype of the <em>APOE</em>, <em>MTHFR</em> and <em>ACE</em> polymorphisms and stroke. The <em>APOE</em> ε2ε4 genotype showed increased risk for hemorrhagic stroke (P&lt;0.05) and also a high risk for ischemic stroke (P=0.05). There was complete absence of the <em>APOE</em> ε2ε2 and the <em>MTHFR</em> TT genotypes in the Zambian population. The difference between cases and controls was not significant for the other genetic variants when analyzed for relationship between stroke, stroke subtype and genotype. We show that genetic variation at the <em>APOE locus</em> affects susceptibility to stroke. No detectable association were observed for the <em>MTHFR</em> and <em>ACE</em> genotypes and stroke in the Zambian population