Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa

Background. Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA.Objective. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/ LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy.Methods. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results.Results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p<0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 - 114.25) compared with males.Conclusion. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA

Oesophageal cancer in Area 2 of Kwazulu-Natal: predictors of late presentation.

BACKGROUND: There are limited prospective data sets on clinical characteristics, stage of presentation and treatment of patients with Oesophageal Squamous Cell Carcinoma (OSCC) in South Africa. This study aimed to assess the frequency and severity of clinical characteristics associated with late presentation of patients with OSCC presenting to a cancer referral centre in KwaZulu-Natal, South Africa. METHODS: A prospective consecutive series of patients presenting with confirmed OSCC treated at Greys Hospital in 2016/2017 were enrolled. Data collected included: age, gender, home language, referral centre, clinical and laboratory characteristics: dysphagia score, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index (BMI), serum albumin, tumour pathology and treatment administered. RESULTS: One hundred patients were analysed. Ninety four percent spoke isiZulu. The mean age was 61 with a male to female ratio of 1.5:1 Ninety percent had palliative treatment as their overall assessment precluded curative treatment. Five patients underwent curative treatment. The age standardised incidence (ASR) was 25.2 per 100 000. The factors associated with late presentation and their frequency were: advanced dysphagia grade ( </=2 in 68%), malnutrition (BMI <18.5kg/m2 in 49%), hypoalbuminaemia (serum albumin < 35 g/l in 70%), poor performance status (ECOG</=2 in 50% ) and moderate to poor tumour differentiation in 95% of patients. CONCLUSION: OSCC in Kwazulu-Natal has double the ASR of South Africa and places a significant burden on the region's health care system. Factors associated with late presentation occur in the majority and alone or in combination preclude curative therapies. The frequency of these factors serve as a benchmark for comparison, and reduction in their frequency may indicate effectiveness of interventions designed to improve awareness and access to proper care

High Field fMRI Reveals Thalamocortical Integration of Segregated Cognitive and Emotional Processing in Mediodorsal and Intralaminar Thalamic Nuclei

Thalamocortical loops, connecting functionally segregated, higher order cortical regions, and basal ganglia, have been proposed not only for well described motor and sensory regions, but also for limbic and prefrontal areas relevant for affective and cognitive processes. These functions are, however, more specific to humans, rendering most invasive neuroanatomical approaches impossible and interspecies translations difficult. In contrast, non-invasive imaging of functional neuroanatomy using fMRI allows for the development of elaborate task paradigms capable of testing the specific functionalities proposed for these circuits. Until recently, spatial resolution largely limited the anatomical definition of functional clusters at the level of distinct thalamic nuclei. Since their anatomical distinction seems crucial not only for the segregation of cognitive and limbic loops but also for the detection of their functional interaction during cognitive–emotional integration, we applied high resolution fMRI on 7 Tesla. Using an event-related design, we could isolate thalamic effects for preceding attention as well as experience of erotic stimuli. We could demonstrate specific thalamic effects of general emotional arousal in mediodorsal nucleus and effects specific to preceding attention and expectancy in intralaminar centromedian/parafascicular complex. These thalamic effects were paralleled by specific coactivations in the head of caudate nucleus as well as segregated portions of rostral or caudal cingulate cortex and anterior insula supporting distinct thalamo–striato–cortical loops. In addition to predescribed effects of sexual arousal in hypothalamus and ventral striatum, high resolution fMRI could extent this network to paraventricular thalamus encompassing laterodorsal and parataenial nuclei. We could lend evidence to segregated subcortical loops which integrate cognitive and emotional aspects of basic human behavior such as sexual processing

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa

Background. Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA.Objective. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy.Methods. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results.Results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p&lt;0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 - 114.25) compared with males.Conclusion. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA

Frequency locking of modulated waves

We consider the behavior of a modulated wave solution to an $\mathbb{S}^1$-equivariant autonomous system of differential equations under an external forcing of modulated wave type. The modulation frequency of the forcing is assumed to be close to the modulation frequency of the modulated wave solution, while the wave frequency of the forcing is supposed to be far from that of the modulated wave solution. We describe the domain in the three-dimensional control parameter space (of frequencies and amplitude of the forcing) where stable locking of the modulation frequencies of the forcing and the modulated wave solution occurs. Our system is a simplest case scenario for the behavior of self-pulsating lasers under the influence of external periodically modulated optical signals

Available data sources for monitoring non-communicable diseases and their risk factors in South Africa.

BACKGROUND: Health information systems for monitoring chronic non-communicable diseases (NCDs) in South Africa (SA) are relatively less advanced than those for infectious diseases (particularly tuberculosis and HIV) and for maternal and child health. NCDs are now the largest cause of premature mortality owing to exposure to risk factors arising from obesity that include physical inactivity and accessible, cheap but unhealthy diets. The National Strategic Plan for the Prevention and Control of Non-Communicable Diseases 2013 - 17 developed by the SA National Department of Health outlines targets and monitoring priorities. OBJECTIVES: To assess data sources relevant for monitoring NCDs and their risk factors by identifying the strengths and weaknesses, including usability and availability, of surveys and routine systems focusing at national and certain sub-national levels. METHODS: Publicly available survey and routine data sources were assessed for variables collected, their characteristics, frequency of data collection, geographical coverage and data availability. RESULTS: Survey data sources were found to be quite different in the way data variables are collected, their geographical coverage and also availability, while the main weakness of routine data sources was poor quality of data. CONCLUSIONS: To provide a sound basis for monitoring progress of NCDs and related risk factors, we recommend harmonising and strengthening available SA data sources in terms of data quality, definitions, categories used, timeliness, disease coverage and biomarker measurement