Influence of candidate susceptibility genes on tuberculosis in a high endemic region

Genetic susceptibility towards clinical tuberculosis has been proposed in several population studies. We investigated whether polymorphisms in the candidate genes encoding solute carrier 11a1 protein (SLC11A1 formerly NRAMP1), mannose-binding lectin (MBL2) and Vitamin D receptor (VDR) were associated with tuberculosis in an East-African setting. Four hundred and forty-three culture positive pulmonary tuberculosis patients and 426 controls from Mwanza district in the northern part of Tanzania were prospectively included. Polymorphisms in the candidate genes were detected by different PCR-based techniques. A significant association between pulmonary tuberculosis and a microsatellite marker in the 5'(CA)n locus in the SLC11A1 gene compared with controls (38% versus 30% odds ratio 1.45, 95% CI: 1.06-1.9, P=0.014) was observed. The association was apparent only in HIV negative tuberculosis patients. No association with tuberculosis was seen with 3 other SLC11A1 loci investigated, which previously have been associated with tuberculosis in other populations or with MBL2 and VDR polymorphisms. The tuberculosis associated microsatellite marker was situated on different SLC11A1 haplotypes. In this cohort a microsatellite marker in the 5'(CA)n locus situated in the SLC11A1 gene was associated with tuberculosis. The observed association was seen only in HIV negative patients suggesting that this genetic susceptibility for tuberculosis may be surpassed by co-infections.     

Thiamine (vitamin B1) status of boarding school students in the Southern Region of Papua New Guinea

Thiamine pyrophosphate (TPP) is the major biologically active form of thiamine (vitamin B1). This cross-sectional study assessed whole-blood thiamine pyrophosphate concentration (WBTPPC) in boarding school students in the Southern Region of Papua New Guinea. Sample size for each of the five boarding schools was calculated using the 'proportionate to population size' cluster sampling technique. The 'Clin-Rep' reagent kit was used for the extraction of thiamine pyrophosphate from whole blood. Reverse phase high performance liquid chromatography with post-column derivatization was used to determine the thiamine pyrophosphate concentration. Informed consent was obtained from 468 students, mean age 17.7 +/- 1.5 years. The gender distribution of these students was 274 (58.5%) males and 194 (41.5%) females. The median and interquartile range of WBTPPC for all students was 95.41 microg/l (82.27-113.55). Severe to marginal status of thiamine deficiency was present in 6.4% of all the students. The mean WBTPPC for female students was significantly lower than that for the male students (p < 0.001), with a mean difference of 14.17 microg/l (95% CI of the difference: 9.85-18.50). Severe to marginal status of thiamine deficiency was present in 9.8% of female students and 4.0% of male students. The data strongly support the need for effective implementation and monitoring of food fortification legislation in Papua New Guinea. Withdrawal of fortification or suboptimal thiamine fortification of rice and other cereal products in Papua New Guinea would have serious negative public health implications, especially among students in boarding schools.     

Identification of a novel Twinkle mutation in a family with infantile onset spinocerebellar ataxia by whole exome sequencing

Whole exome sequencing combined with homozygosity mapping comprises a genetic diagnostic tool to identify genetic defects in families with multiple affected members, compatible with presumed autosomal recessively inherited neurometabolic/neurogenetic disease. These tools were applied to a family with two individuals manifesting ataxia, associated with peripheral sensory neuropathy, athetosis, seizures, deafness, and ophthalmoplegia. A novel homozygous missense mutation c.1366C>G (L456V) in C10orf2 (the Twinkle gene) was identified, confirming infantile onset spinocerebellar ataxia in the probands. Signs in infantile onset spinocerebellar ataxia follow a fairly distinct pattern, affecting early development, followed by ataxia and loss of skills. However, this very rare disease was previously reported only in Finland. We suggest that infantile onset spinocerebellar ataxia should be more frequently considered in the differential diagnosis of neurometabolic diseases in childhood. Next-generation sequencing and its use along with homozygosity mapping offer highly promising techniques for molecular diagnosis, especially in small families affected with very rare neurometabolic disorders such as infantile onset spinocerebellar ataxia.     

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40-85 years, and with disease duration ≤3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 ± 7.0 versus 15.5 ± 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 ± 1.0 at baseline to 4.6 ± 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 ± 4,477 ng/mL at baseline to 3,250 ± 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.     

HIV and parasitic co-infections in tuberculosis patients: a cross-sectional study in Mwanza, Tanzania

A cross-sectional study was conducted in Mwanza, Tanzania, to determine the burden of HIV and parasitic co-infections among patients who were confirmed or suspected cases of pulmonary tuberculosis (PTB). Of the 655 patients investigated, 532 (81.2%) had been confirmed as PTB cases, by microscopy and/or culture (PTB+), whereas the other 123 (18.8%) were only suspected cases, on the basis of other clinical criteria (PTB-). Hookworm and Schistosoma mansoni infections were common in the patients, with prevalences of 18% and 34%, respectively. Malarial, Ascaris lumbricoides, Trichuris trichiura and Strongyloides stercoralis infections were less common, each recorded at a prevalence of <5%. The PTB+ patients were less likely to be HIV-positive than the PTB- patients (43.6% v. 62.6%; P<0.0001). Among the PTB+ patients, the HIV-positive had a significantly lower prevalence (12.1% v. 25%; P<0.0001) and mean intensity (49 v. 123 eggs/g; P=0.003) of hookworm infection than the HIV-negative. The PTB patients in the study area were, however, still frequently co-infected with HIV and with parasitic infections that may increase morbidity and accelerate the progression of HIV disease.     

Outcome of acute peritoneal dialysis in northern Tanzania

Data on the burden of acute kidney injury (AKI) in resource-poor countries such as Tanzania are minimal because of a lack of nephrology services and an inability to recognize and diagnose AKI with any certainty. In the few published studies, high morbidity and mortality are reported. Improved nephrology care and dialysis may lower the mortality from AKI in these settings. Hemodialysis is expensive and technically challenging in resource-limited settings. The technical simplicity of peritoneal dialysis and the potential to reduce costs if consumables can be made locally, present an opportunity to establish cost-effective programs for managing AKI. Here, we document patient outcomes in a pilot peritoneal dialysis program established in 2009 at a referral hospital in Northern Tanzania.     

High prevalence of distal sensory polyneuropathy in antiretroviral-treated and untreated people with HIV in Tanzania

Objectives To describe the prevalence of distal sensory polyneuropathy (DSP), a complication of both advanced HIV disease and of antiretroviral therapy (ART), amongst Tanzanians with HIV, on and off ART (including stavudine) with CD4 counts above and below 200 cells/μl. Methods We recruited participants attending ART clinic into four groups: >6 months ART exposure and (i) CD4 < 200 cells/μl or (ii) CD4 > 200 cells/μl (ART/CD4 < 200 and ART/CD4 > 200, respectively); ART‐naïve and (iii) CD4 < 200 cells/μl or iv)CD4 > 200 cells/μl (noART/CD4 < 200 and noART/CD4 > 200, respectively). Primary outcome was DSP, as defined by presence of at least one symptom and one sign. Results Of 326 evaluable participants, 81 (32 men, median age 38 years, median CD4 142 cells/μl) were enrolled in the ART/CD4 < 200 group, 78 (17 men, median age 37 years, median CD4 345 cells/μl) in ART/CD4 > 200, 81 (30 men, median age 37 years, median CD4 128 cells/μl) in noART/CD4 < 200 and 86 (22 men, median age 33 years, median CD4 446 cells/μl) in noART/CD4 > 200. Numbness was the most commonly reported symptom. DSP prevalence ranged from 43.2% in ART/CD4 < 200 to 20.9% in noART/CD4 > 200. DSP was more common among men (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.2–3.3) and older participants (aOR 2.7, 95% CI 1.1–6.2 for age 40 + vs. <30 years). Conclusion Distal sensory polyneuropathy is common amongst those attending this clinic, even those with no ART exposure and a CD4 count above 200 cells/μl. Stavudine and didanosine expose HIV‐infected patients to an additional avoidable risk of DSP. Access to non‐neurotoxic ART regimes as well as earlier HIV diagnosis and initiation of ART is needed.     

The ultrasonographic diagnosis of bleeding into a pancreatic pseudocyst

Bleeding into a pancreatic pseudocyst is a rare but life-threatening entity. Early diagnosis is crucial in its management. There are reports suggesting that computed tomography (CT), scintigraphy, endoscopic retrograde cholangiopancreatography (ERCP), and angiography could be the diagnostic maneuvers. In this report, we present a case of arterial bleeding into a pancreatic pseudocyst, which was diagnosed by the turbulent echo-currents seen in real-time ultrasonography.     

Evaluation of the efficacy of the crude extracts of Capsicum frutescens, Citrus limon and Opuntia vulgaris against Newcastle disease in domestic fowl in Tanzania

Prophylactic and therapeutic efficacy of a combination of Capsicum frutescens (red pepper), Citrus limon (lemon) and Opuntia vulgaris (prickly pear) against Newcastle disease (ND) in domestic fowl were evaluated. Eighty-eight broiler chickens were divided into five groups. Birds from three groups were inoculated with velogenic ND virus strain, whereas birds from two groups were left as controls. Two groups received a mixture of the plant extract three days prior to inoculation and birds from one group were given the plant extract for two days following development of clinical signs. Blood samples were collected for haemaglutination inhibition tests (HI) for detection of ND virus antibodies. Body weights were monitored during the experiment. Three birds died from the group that was inoculated with ND virus and treated with the plant extract; two died from the group that received the plant extract as a prophylaxis and inoculated with ND virus; and one bird died from the group that was inoculated with ND virus but not given the plant extract. No death was observed in any of the birds in the control groups. Antibody titers for ND virus rose four-fold in the inoculated birds but remained low in the un-inoculated groups. Mean body weights of birds in group B declined markedly compared to the other groups. The results indicated that there was no prophylactic or therapeutic value of the plant extract against ND. The plant extract showed a negative effect on body weights in birds with ND.