Gestational Age, Birth Weight, and Neurocognitive Development in Adolescents in Tanzania.

OBJECTIVES: To investigate the association between gestational age, birthweight, and birthweight adjusted for gestational age, with domains of neurocognitive development and behavioral problems in adolescents in Tanzania. STUDY DESIGN: Data from a long-term follow-up of adolescents aged 11-15 years born to women previously enrolled in a randomized controlled trial of prenatal multiple micronutrient supplementation in Dar es Salaam, Tanzania, were used. A battery of neurodevelopmental tests were administered to measure adolescent general intelligence, executive function, and behavioral problems. The INTERGROWTH-21st newborn anthropometric standards were used to derive birthweight for gestational age z-scores. We assessed the shape of relationships using restricted cubic splines and estimated the associations of gestational age, birthweight, and birthweight for gestational age z-score with adolescent development using multivariable linear regressions. RESULTS: Among adolescents studied (n = 421), higher gestational age (per week), birthweight (per 100 grams), and birthweight for gestational age z-score (per SD) were linearly associated with higher intelligence score (adjusted standardized mean difference, 0.05 SD [95% CI, 0.01-0.09], 0.04 SD [95% CI, 0.02-0.06], and 0.09 SD [95% CI, 0.01-0.17], respectively). Birthweight and birthweight for gestational age z-score, but not gestational age, were also associated with improved executive function. Low birthweight (<2500 g) was associated with lower intelligence and executive function scores. Associations between birthweight and executive function were stronger among adolescents born to women with higher education. CONCLUSIONS: The duration of gestation and birthweight were positively associated with adolescent neurodevelopment in Tanzania. These findings suggest that interventions to improve birth outcomes may also benefit adolescent cognitive function.

Effect of zinc supplementation on duration of hospitalization in Tanzanian children presenting with acute pneumonia.

BACKGROUND: Zinc supplementation prevents incident pneumonia in children; however, the effect for pneumonia treatment remains unclear. METHODS: A randomized, double-blind, placebo-controlled trial of zinc supplements (daily 25 mg) adjunct to antibiotic treatment of radiology-confirmed acute pneumonia was conducted among hospitalized children (6-36 months) in Dar es Salaam, Tanzania. RESULTS: The trial was stopped early due to low enrollment, primarily owing to exclusion of children outside the age range and >3 days of prior illness. Among children enrolled (n = 94), zinc supplementation indicated no beneficial effect on the duration of hospitalization (IRR: 0.69; 95% CI 0.45-1.06; p = 0.09) or the proportion of children who were hospitalized for <3 days (RR: 0.85; 95% CI: 0.57-1.25; p = 0.40) or <5 days (RR: 1.01; 95% CI: 0.83-1.23; p = 0.92) (IRRs and RRs >1.0 favor zinc). CONCLUSIONS: Although underpowered, this randomized trial provided no evidence for a beneficial effect of zinc supplementation adjunct to antibiotics for hospitalized children.

Risk factors for mortality among Tanzanian infants and children.

BACKGROUND: During the era of the Millennium Development Goals, under 5 mortality rates decreased significantly worldwide; however, reductions were not equally distributed. Children in sub-Saharan Africa still account for more than 50% of the world's annual childhood deaths among children under 5 years of age. Understanding upstream risk factors for mortality among children may reduce the large burden of childhood mortality in sub-Saharan Africa. Our objective was to identify risk factors for mortality among infants and children in Tanzania. METHODS: We conducted a secondary analysis of data pooled from two randomized-controlled micronutrient supplementation trials. A total of 4787 infants were enrolled in the two trials (n = 2387 HIV-exposed and n = 2400 HIV-unexposed). Predictors of mortality were assessed using unadjusted and adjusted hazard ratios (aHRs). RESULTS: There were 307 total deaths, 262 (11%) among children who were HIV-exposed and 45 (2%) among children who were HIV-unexposed (P < 0.001). The most common cause of death was respiratory diseases (n = 109, 35.5%). Causes of death did not significantly differ between HIV-exposed and HIV-unexposed children. In adjusted regression analyses, children with birth weight <2500 g (aHR 1.75, 95% CI 1.21-2.54), Apgar score of ≤7 at 5 min (aHR 2.16, 95% CI 1.29-3.62), or who were HIV-exposed but not infected (aHR 3.35, 95% CI 2.12-5.28) or HIV-infected (aHR 27.56, 95% CI 17.43-43.58) had greater risk of mortality. CONCLUSIONS: Infection with HIV, low birthweight, or low Apgar scores were associated with higher mortality risk. Early identification and modification of determinants of mortality among infants and children may be the first step to reducing such deaths.

Complementary Feeding and Diarrhea and Respiratory Infection Among HIV-Exposed Tanzanian Infants.

OBJECTIVE: To examine the association between complementary feeding and risks of diarrhea and acute respiratory infection (ARI) among HIV-exposed infants aged 6-24 months. DESIGN: We prospectively used an Infant and Child Feeding Index (ICFI) to measure complementary feeding practices (breastfeeding status, food consistency, dietary diversity, food group frequency, and meal frequency). We determined the association of ICFI and each of its components with the risk of diarrhea and ARI. Generalized estimating equations were used to estimate the relative risks for morbidity episodes. SETTING: Dar es Salaam, Tanzania. SUBJECTS: A total of 2092 HIV-exposed infants followed from 6 months of age to 24 months of age. RESULTS: The ICFI score ranged from 0 to 9; the median score was 6 (interquartile range = 4-7). Low ICFI scores were likely associated with increased risk of dysentery [low vs. high tertile risk ratio (RR): 1.40; 95% confidence interval (CI): 0.93 to 2.10; P for trend = 0.02] and respiratory infection (low vs. high tertile RR: 1.16; 95% CI: 0.96 to 1.41; P for trend = 0.01). Low dietary diversity scores were likely associated with higher risk of dysentery (low vs. high tertile RR: 1.47; 95% CI: 0.92 to 2.35; P for trend = 0.03) and respiratory infection (low vs. high tertile RR: 1.41; 95% CI: 1.13 to 1.76; P for trend = 0.01). Low food consistency scores were associated with higher risk of respiratory infection (RR: 1.77; 95% CI: 1.40 to 2.26; P < 0.01). CONCLUSIONS: In this setting, low ICFI, dietary diversity, and food consistency scores were likely associated with increased risk of diarrhea and ARI among HIV-exposed infants.

Experimental treatment of human neuroblastoma using live-attenuated poliovirus.

Neuroblastoma, originated from neural crest cells, is the most common extracranial solid tumor in childhood. In the present study, we evaluated in vitro the oncolytic effect of live-attenuated poliovirus on human neuroblastoma cell lines, and in vivo its therapeutic efficacy in human neuroblastoma-bearing athymic mice. Live-attenuated poliovirus killed 27 (93%) of 29 established neuroblastoma cell lines in vitro. It induced cleavage of eukaryotic translation initiation factor 4G, leading to cell death through a mechanism involving activation of caspase-9, caspase-3 and poly(ADP-ribose)polymerase. For the in vivo experiments, an animal model was established using athymic mice xenotransplanted with SJ-N-JF neuroblastoma cells on both flanks. Inoculation of live-attenuated poliovirus into one of the two tumors caused a dramatic and complete regression of both the inoculated and contralateral tumors. Live-attenuated poliovirus has potent oncolytic activity against human neuroblastomas in vitro and in vivo and it may be useful for the treatment of advanced and refractory neuroblastomas, however, further studies are necessary to evaluate the safety of method.

Multivitamin supplementation improves haematologic status in children born to HIV-positive women in Tanzania.

INTRODUCTION: Anaemia is prevalent among children born to HIV-positive women, and it is associated with adverse effects on cognitive and motor development, growth, and increased risks of morbidity and mortality. OBJECTIVE: To examine the effect of daily multivitamin supplementation on haematologic status and mother-to-child transmission (MTCT) of HIV through breastfeeding. METHODS: A total of 2387 infants born to HIV-positive women from Dar es Salaam, Tanzania were enrolled in a randomized, double-blind, placebo-controlled trial, and provided a daily oral supplement of multivitamins (vitamin B complex, C and E) or placebo at age 6 weeks for 24 months. Among them, 2008 infants provided blood samples and had haemoglobin concentrations measured at baseline and during a follow-up period. Anaemia was defined as haemoglobin concentrations <11 g/dL and severe anaemia <8.5 g/dL. RESULTS: Haemoglobin concentrations among children in the treatment group were significantly higher than those in the placebo group at 12 (9.77 vs. 9.64 g/dL, p=0.03), 18 (9.76 vs. 9.57 g/dL, p=0.004), and 24 months (9.93 vs. 9.75 g/dL, p=0.02) of follow-up. Compared to those in the placebo group, children in the treatment group had a 12% lower risk of anaemia (hazard ratio (HR): 0.88; 95% CI: 0.79-0.99; p=0.03). The treatment was associated with a 28% reduced risk of severe anaemia among children born to women without anaemia (HR: 0.72; 95% CI: 0.56-0.92; p=0.008), but not among those born to women with anaemia (HR: 1.10; 95% CI: 0.79-1.54; p=0.57; p for interaction=0.007). One thousand seven hundred fifty three infants who tested HIV-negative at baseline and had HIV testing during follow-up were included in the analysis for MTCT of HIV. No association was found between multivitamin supplements and MTCT of HIV. CONCLUSIONS: Multivitamin supplements improve haematologic status among children born to HIV-positive women. Further trials focusing on anaemia among HIV-exposed children are warranted in the context of antiretroviral therapy.

Health professions educators as agents of change in Tanzania: creativity to implement new curricula.

Muhimbili University of Health and Allied Sciences (MUHAS) strives to instill in its graduates skills and competencies appropriate to serving the Tanzanian population well. MUHAS leadership, working in collaboration with educators from the University of California San Francisco (UCSF), selected and trained an interdisciplinary group of faculty members to promote effective teaching. We describe the development of this group of faculty change agents - now known as the Health Professions Educators Group (HPEG). The HPEG invigorated the education environment at MUHAS by: engaging many colleagues in special training events that introduced new methods for teaching and assessment; encouraging innovation; and developing strong mentoring relationships. HPEG members piloted courses in education to prepare all postgraduate students as peer educators, teaching assistants, and as candidates for faculty future appointments. Creation of a 'teaching commons' reinforces the new focus on innovative teaching as faculty members share experiences and gain recognition for their contributions to quality education.

Curricular transformation of health professions education in Tanzania: the process at Muhimbili University of Health and Allied Sciences (2008-2011).

Tanzania requires more health professionals equipped to tackle its serious health challenges. When it became an independent university in 2007, Muhimbili University of Health and Allied Sciences (MUHAS) decided to transform its educational offerings to ensure its students practice competently and contribute to improving population health. In 2008, in collaboration with the University of California San Francisco (UCSF), all MUHAS's schools (dentistry, medicine, nursing, pharmacy, and public health and social sciences) and institutes (traditional medicine and allied health sciences) began a university-wide process to revise curricula. Adopting university-wide committee structures, procedures, and a common schedule, MUHAS faculty set out to: (i) identify specific competencies for students to achieve by graduation (in eight domains, six that are inter-professional, hence consistent across schools); (ii) engage stakeholders to understand adequacies and inadequacies of current curricula; and (iii) restructure and revise curricula introducing competencies. The Tanzania Commission for Universities accredited the curricula in September 2011, and faculty started implementation with first-year students in October 2011. We learned that curricular revision of this magnitude requires: a compelling directive for change, designated leadership, resource mobilization inclusion of all stakeholders, clear guiding principles, an iterative plan linking flexible timetables to phases for curriculum development, engagement in skills training for the cultivation of future leaders, and extensive communication.

Expression of short-form caspase 8 correlates with decreased sensitivity to Fas-mediated apoptosis in neuroblastoma cells.

Disruption of apoptotic death signal transduction pathways may be responsible for tumor formation, progression and resistance to treatment in neuroblastoma. Caspase 8, one of the initiator caspases, plays an important role in the Fas-Fas ligand pathway. This caspase signals through the formation of a death-inducing signaling complex in response to Fas activation by its ligand. In this study, we evaluated the sensitivity of a series of human neuroblastoma cell lines to membrane-bound Fas ligand induced-cell death, as well as the expression of Fas, caspase 3 and caspase 8. Sensitivity to Fas-mediated cell death did not correlate with the expression of Fas in neuroblastoma cells, but was directly associated with the pattern of caspase 8 protein expression. We found that the majority of neuroblastoma cell lines we evaluated lacked caspase 8 expression, and these cell lines were invariably resistant to Fas-mediated cell death. In contrast, cell lines expressing normal caspase 8 protein were quite sensitive to Fas-mediated cell death. More interestingly, a group of cell lines expressing a distinct short form of caspase 8 with splicing out of exon 3 consistently showed moderate sensitivity to Fas-mediated cell death. These results indicate that the profile of caspase 8 expression is an important determinant of the response of neuroblastoma cells to Fas-mediated cell death.

Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells. We investigated TRAIL sensitivity and the TRAIL-induced apoptosis signalling pathway in a panel of B-lymphocytic leukaemia cell lines. Depending upon TRAIL sensitivity, leukaemia cells could be divided into three groups: highly sensitive, moderately sensitive and resistant. TRAIL receptor-2 (DR5) plays an important role in transducing apoptosis signals. DR5 was internalized into the cytoplasm where it recruited FAS-associated death domain protein (FADD) under TRAIL stimulation in both sensitive and resistant cells. However, the active form of caspase-8 was recruited to FADD and only sensitive cells showed increased caspase-8 activity upon TRAIL stimulation. The caspase-8 specific inhibitor, Z-IETD, impaired caspase-8 activation and completely abrogated TRAIL-induced apoptosis. These results suggest that TRAIL resistance in B-lymphocytic leukaemia cells is due to negative regulation at the level of caspase-8 activation and that caspase-8 activation is an indispensable process in TRAIL-induced apoptosis. However, FADD-like interleukin-1 beta-converting enzyme inhibitory protein (c-FLIPL) was similarly expressed and down-regulated after TRAIL stimulation in both sensitive and resistant cells. Interestingly, in some cell lines, TRAIL sensitivity and caspase-8 activity was enhanced or restored with the treatment of cycloheximide (CHX). In addition, X-linked inhibitor of apoptosis (XIAP) levels decreased significantly and rapidly following treatment with CHX. Down-regulation of XIAP may be responsible for enhancement or restoration of TRAIL sensitivity after CHX treatment in B-lymphocytic leukaemia cells.

Impairment of IL-12-dependent STAT4 nuclear translocation in a patient with recurrent Mycobacterium avium infection.

We examined the immunological abnormality in a patient with recurrent Mycobacterium avium infection. T cells from the patient showed decreased ability both to produce IFN-gamma and to proliferate in response to IL-12. Despite decreased expression of IL-12R beta1 and beta2 chains in the patient's PHA-activated T cells, there was no difference in IL-12-induced tyrosine and serine phosphorylation of STAT4 in PHA-activated T cells between the patient and healthy subjects, suggesting that IL-12R signals are transmitted to STAT4 in the patient's PHA-activated T cells. Using EMSA, confocal laser microscopy, and Western blotting, we demonstrated that the nuclear translocation of STAT4 in response to IL-12 is reduced in PHA-activated T cells from the patient when compared with those from healthy subjects. Leptomycin B was used to examine whether nuclear export of STAT4 is increased in the patient's T cells. However, leptomycin B treatment did not reverse impaired IL-12-induced nuclear accumulation of STAT4. Although the exact mechanism responsible for the impaired STAT4 nuclear translocation in this patient remains unclear, the absence of mutation in the IL-12Rbeta1, IL-12Rbeta2, STAT4, and STAT4-binding sequence of the IFN-gamma gene and preservation of STAT4 tyrosine and serine phosphorylation suggest the existence of a defective STAT4 nuclear translocation. This defect is likely responsible for the impaired STAT4 nuclear translocation in IL-12-stimulated T cells, leading to impairment of both IFN-gamma production and cell proliferation. To the best of our knowledge, this is the first report of a patient with atypical mycobacterial infection associated with impairment of STAT4 nuclear translocation.