Intronic variants in the long non-coding RNA CDKN2B-AS1 are strongly associated with the risk of coronary artery disease in the Northern Tribes of Tanzania

Introduction: Sub-Saharan Africa (SSA) is facing a rising epidemic of non-communicable diseases including the coronary artery disease (CAD) ranking at the top of the list. Chromosome locus 9p21.3 containing CDKN2B antisense RNA 1 (CDKN2B-AS1), identified in many genome-wide association studies for coronary artery disease (CAD), encompasses multiple single nucleotide polymorphisms (SNPs). This study aimed to conduct the first genetic study evaluating the common polymorphisms in 9p21.3 locus in Tanzanian CAD patients from different regions of Tanzania and their associations with CAD risk factors. Material and Methods: A total of 90 patients from Northern region (N-CAD) of Tanzania and 65 patients from other regions (South, East, West and Central) (R-CAD) were included in the study. Further the biochemical analysis the genotyping of common variants was performed with the LightSNiP typing assay using qRT-PCR method.  Results: Our analyses revealed that both genotype and allele frequencies of rs10757274, rs10757278 and rs10811656 were significantly different between the groups (p<0.05, respectively). We identified that one previously undescribed three-marker haplotype (rs1333049, rs10757274 and rs10757278) encompassing CDKN2B-AS1 was overrepresented (G-G-G, the risk haplotype, p<0.05) in N-CAD group compared to R-CAD group. The AUC of a risk model based on non-genetic factors was 0.730 (0.654-0.797) and the combination with genetic risk factors improved the AUC to 0.784 (95%CI=0.713-0.844, p<0.0001). Conclusion: Our results identified the presence of a novel three-marker haplotype having a significant association with CAD in Northern Tanzania. Moreover, combination of the nongenetic and genetic risk models were demonstrated to indicate good diagnostic accuracy for CAD in Northern Tanzania

Are we prepared for emerging and re-emerging diseases? Experience and lessons from epidemics occurred in Tanzania during the last five decades

This paper reviews preparedness for containing and controlling emerging and re-emerging diseases drawing lessons from disease events that occurred in animal and human populations in the last five decades (1961-2011). A comprehensive analysis based on retrieval and analysis of grey and published literature as well as reported cases was carried out to document type and trend of occurrence of emerging and re-emerging infectious diseases in different parts of Tanzania. Overall, the majority of diseases reported in the country were viral in nature followed by bacterial diseases. The trend for the occurrence shows a number of new emerging diseases as well as re-occurrence of old diseases in both animal (domestic and wild) and human populations. In humans, the major disease epidemics reported in the last five decades include cholera, influenza A H1N1, plague and rubella. In animals, the major epidemic diseases reported were Contagious Bovine Pleuropneumonia, Contagious Caprine Pleuropneumonia, Peste des petits ruminants and Giraffe Ear and Skin Diseases. Some epidemics have been reported in both human and animal populations including Rift Valley fever and anthrax.  The emergence of the ‘fit-for purpose’ approaches and technologies such as the discipline of One Health, use of participatory epidemiology and disease surveillance and mobile technologies offers opportunity for optimal use of limited resources to improve early detection, diagnosis and response to disease events and consequently reduced impact of such diseases in animal and human populations

Effect of α+-thalassaemia on episodes of fever due to malaria and other causes: a community-based cohort study in Tanzania

It is controversial to what degree α(+)-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium. In Tanzania, in children aged 6-60 months and height-for-age z-score < -1.5 SD (n = 612), rates of fevers due to malaria and other causes were compared between those with heterozygous or homozygotes α(+)-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child. The overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α(+)-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α(+)-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes. In this population, the association between α(+)-thalassaemia and malaria depends on age. Our data suggest that protection by α(+)-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity

TBX 5 gene mutation analysis among Tanzanian children with congenital heart diseases using high-resolution melting assays

Early cardiac development is governed by transcription factor genes. TBX5, a T-box transcription factor gene, plays an important role in the development&nbsp; of the second heart field during cardiac septation by promoting cell cycle progression through the enhancement of Cdk6 and hedgehog signaling&nbsp; pathways. TBX5 binds to the promoter region of genes, enhancing the expression of alpha cardiac myosin heavy chain 6 (MYH6), which is a predominant&nbsp; isoform found in human cardiac tissue. TBX5 gene mutations are postulated to cause congenital heart diseases. A casecontrol TBX5 mutational analysis&nbsp; was performed to provide insight into the etiology of sporadic congenital heart diseases in our setting. We used a magnetic induction cycler (mic-PCR),&nbsp; which is a next-generation tool for polymerase chain reaction-high resolution melting assays, to detect mutations in children with sporadic isolated&nbsp; congenital heart diseases. A retrospective casecontrol study was conducted at the Jakaya Kikwete Cardiac Institute. The peripheral blood samples were&nbsp; collected, and DNA was extracted using the Quick-DNA Miniprep Kit. The primers were designed using Primer 3 software, validated using the program&nbsp; BLAST, and checked for hairpin and homo-hetero-dimerization using the IDT oligo analyzer. Real-time polymerase chain reaction (PCR)-high-resolution&nbsp; melting assays for screening TBX5 gene mutations were done using a magnetic induction cycler. We found two (2) TBX5 mutations in exon 5, among&nbsp; patients with Atrial-Ventral Septal Defects (ASVD) and Atrial-Septal Defects (ASD) and none among controls. TBX5 exon 5 is a molecular hotspot for&nbsp; isolated congenital heart diseases.&nbsp

Effect of Preventive Supplementation with Zinc and other Micronutrients on Non-Malarial Morbidity in Tanzanian Pre-School Children: A Randomized Trial.

The efficacy of preventive zinc supplementation against diarrhea and respiratory illness may depend on simultaneous supplementation with other micronutrients. We aimed to assess the effect of supplementation with zinc and multiple micronutrients on diarrhea and other causes of non-malarial morbidity. Rural Tanzanian children (n = 612) aged 6-60 months and with height-for-age z-score < -1.5 SD were randomized to daily supplementation with zinc (10 mg) alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Children were followed for an average of 45 weeks. During follow-up, we recorded morbidity episodes. We found no evidence that concurrent supplementation with multi-nutrients influenced the magnitude of the effect of zinc on rates of diarrhea, respiratory illness, fever without localizing signs, or other illness (guardian-reported illness with symptoms involving skin, ears, eyes and abscesses, but excluding trauma or burns). Zinc supplementation reduced the hazard rate of diarrhea by 24% (4%-40%). By contrast, multi-nutrients seemed to increase this rate (HR; 95% CI: 1.19; 0.94-1.50), particularly in children with asymptomatic Giardia infection at baseline (2.03; 1.24-3.32). Zinc also protected against episodes of fever without localizing signs (0.75; 0.57-0.96), but we found no evidence that it reduced the overall number of clinic visits. We found no evidence that the efficacy of zinc supplements in reducing diarrhea rates is enhanced by concurrent supplementation with other micronutrients. By reducing rates of fever without localizing signs, supplementation with zinc may reduce inappropriate drug use with anti-malarial medications and antibiotics. ClinicalTrials.gov NCT00623857

Alterations in early cytokine-mediated immune responses to Plasmodium falciparum infection in Tanzanian children with mineral element deficiencies: a cross-sectional survey

BACKGROUND: Deficiencies in vitamins and mineral elements are important causes of morbidity in developing countries, possibly because they lead to defective immune responses to infection. The aim of the study was to assess the effects of mineral element deficiencies on early innate cytokine responses to Plasmodium falciparum malaria. METHODS: Peripheral blood mononuclear cells from 304 Tanzanian children aged 6-72 months were stimulated with P. falciparum-parasitized erythrocytes obtained from in vitro cultures. RESULTS: The results showed a significant increase by 74% in geometric mean of TNF production in malaria-infected individuals with zinc deficiency (11% to 240%; 95% CI). Iron deficiency anaemia was associated with increased TNF production in infected individuals and overall with increased IL-10 production, while magnesium deficiency induced increased production of IL-10 by 46% (13% to 144%) in uninfected donors. All donors showed a response towards IL-1beta production, drawing special attention for its possible protective role in early innate immune responses to malaria. CONCLUSIONS: In view of these results, the findings show plasticity in cytokine profiles of mononuclear cells reacting to malaria infection under conditions of different micronutrient deficiencies. These findings lay the foundations for future inclusion of a combination of precisely selected set of micronutrients rather than single nutrients as part of malaria vaccine intervention programmes in endemic countries

Effect of nutrient deficiencies on in vitro Th1 and Th2 cytokine response of peripheral blood mononuclear cells to Plasmodium falciparum infection

BACKGROUND: An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies. METHODS: Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum-parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status. RESULTS: The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-gamma response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-gamma production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status. CONCLUSIONS: The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status

Training in the art and science of facilitation to scale research mentor training in low and middle income countries

Advancing biomedical research in low and middle income countries (LMICs) to expand the capacity for LMICs to integrate biomedical research into their health care systems and education has been the focus of many programs in global health over the past two decades. Central to the success of these programs is effective research mentoring, characterized by academic, career and psychosocial support through culturally appropriate practices. Research mentoring is a learned skill, developed through training, mutual discussions, practice and feedback. The majority of extant training programs are designed and delivered by US partners, so the next stage in building capacity is to train facilitators within the LMIC partner institutions to contextualize and advance mentoring specifically within their cultural and institutional norms by co-developing, delivering and evaluating semi-annual research mentoring training. To this end, we describe the development, delivery and outcome evaluation of a 5-week course in the art and skill of facilitation. Care was taken to explicitly distinguish between concepts of “teaching” and “facilitation,” since “teaching” is closely connected to a transmission or banking model of education, which is characterized by “top-down,” hierarchical relationship. The course discussed power and positionality, themes that resonate with partners in Nigeria and Tanzania. These themes provided unique entry into deeper conversations core to advancing mentoring practice away from the traditional dyadic power structure that remains from colonization. Evaluation findings indicate significant advances in awareness of differences between teaching and facilitating, increased confidence in facilitation skills, especially in the area of structured planning and organization, as well as improved communication and interpersonal skills. All respondents felt that students in Nigeria and Tanzania would respond well to the facilitation approach conveyed during the course and they found value in participating in the course as a cohort

Defining malaria burden from morbidity and mortality records, self treatment practices and serological data in Magugu, Babati District, northern Tanzania

Malaria morbidity and mortality data from clinical records provide essential information towards defining disease burden in the area and for planning control strategies, but should be augmented with data on transmission intensity and serological data as measures for exposure to malaria. The objective of this study was to estimate the malaria burden based on serological data and prevalence of malaria, and compare it with existing self-treatment practices in Magugu in Babati District of northern Tanzania. Prospectively, 470 individuals were selected for the study. Both microscopy and Rapid Diagnostic Test (RDT) were used for malaria diagnosis. Seroprevalence of antibodies to merozoite surface proteins (MSP-119) and apical membrane antigen (AMA-1) was performed and the entomological inoculation rate (EIR) was estimated. To complement this information, retrospective data on treatment history, prescriptions by physicians and use of bed nets were collected. Malaria prevalence in the area was 6.8% (32/470). Of 130 individuals treated with artemisinin combination therapy (ACT), 22.3 % (29/130) were slide confirmed while 75.3% (98/130) of them were blood smear negative. Three of the slides confirmed individuals were not treated with ACT. Fever was reported in 38.2% of individuals, of whom 48.8 % (88/180) were given ACT. Forty-two (32.3%) of those who received ACT had no history of fever. About half (51.1%) of those treated with ACT were childre