Haptoglobin, alpha-thalassaemia and glucose-6-phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania.

Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co-inheritance in SCA of alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co-inheritance of these polymorphisms on CBFv in 601 stroke-free Tanzanian SCA patients aged <24 years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (β-coefficient -16·1 cm/s, P = 0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha-thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR] = 0·53 [95% confidence interval (CI):0·35-0·8] & RRR = 0·43 [95% CI:0·23-0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR = 0·38 [95% CI:0·17-0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co-inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha-thalassaemia in reducing risk of abnormal CBFv

Transcranial Doppler and Magnetic Resonance in Tanzanian Children With Sickle Cell Disease

Background and Purpose: We determined prevalences of neurological complications, vascular abnormality, and infarction in Tanzanian children with sickle cell disease. // Methods: Children with sickle cell disease were consecutively enrolled for transcranial Doppler; those with slightly elevated (>150 cm/s), low (150 cm/s was associated with frequent painful crises and low hemoglobin level. Absent/low CBFv was associated with low hemoglobin level and history of unilateral weakness. In 49 out of 67 children with low/absent/elevated transcranial Doppler undergoing magnetic resonance imaging, 43% had infarction, whereas 24 out of 48 (50%) magnetic resonance angiographies were abnormal. One had hemorrhagic infarction; none had microbleeds. Posterior circulation infarcts occurred in 14%. Of 11 children with previous seizure undergoing magnetic resonance imaging, 10 (91%) had infarction (5 silent) compared with 11 out of 38 (29%) of the remainder ( P=0.003). Of 7 children with clinical stroke, 2 had recurrent stroke and 3 died; 4 out of 5 had absent CBFv. Of 193 without stroke, 1 died and 1 had a stroke; both had absent CBFv. // Conclusions: In one-third of Tanzanian children with sickle cell disease, CBFv is outside the normal range, associated with frequent painful crises and low hemoglobin level, but not hemolysis. Half have abnormal magnetic resonance angiography. African children with sickle cell disease should be evaluated with transcranial Doppler; those with low/absent/elevated CBFv should undergo magnetic resonance imaging/magnetic resonance angiography

A ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania

Background: Africa has the highest burden of Sickle cell disease (SCD) but there are few large, systematic studies providing reliable descriptions of the disease spectrum. Tanzania, with 11,000 SCD births annually, established the Muhimbili Sickle Cell program aiming to improve understanding of SCD in Africa. We report the profile of SCD seen in the first 10 years at Muhimbili National Hospital (MNH). Methods: Individuals seen at MNH known or suspected to have SCD were enrolled at clinic and laboratory testing for SCD, haematological and biochemical analyses done. Ethnicity was self-reported. Clinical and laboratory features of SCD were documented. Comparison was made with non-SCD population as well as within 3 different age groups (< 5, 5-17 and ≥ 18 years) within the SCD population. Results: From 2004 to 2013, 6397 individuals, 3751 (58.6%) SCD patients, were enrolled, the majority (47.4%) in age group 5-17 years. There was variation in the geographical distribution of SCD. Individuals with SCD compared to non-SCD, had significantly lower blood pressure and peripheral oxygen saturation (SpO2). SCD patients had higher prevalence of severe anemia, jaundice and desaturation (SpO2 < 95%) as well as higher levels of reticulocytes, white blood cells, platelets and fetal hemoglobin. The main causes of hospitalization for SCD within a 12-month period preceding enrolment were pain (adults), and fever and severe anemia (children). When clinical and laboratory features were compared in SCD within 3 age groups, there was a progressive decrease in the prevalence of splenic enlargement and an increase in prevalence of jaundice. Furthermore, there were significant differences with monotonic trends across age groups in SpO2, hematological and biochemical parameters. Conclusion: This report confirms that the wide spectrum of clinical expression of SCD observed elsewhere is also present in Tanzania, with non-uniform geographical distribution across the country. Age-specific analysis is consistent with different disease-patterns across the lifespan

Characterization of MTAP gene expression in breast cancer patients and cell lines

MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors\ub4 MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNB