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Objective: Studies on phenotypes of diabetes in Africa are inconsistent. We assessed the role of β-cell dysfunction and insulin resistance on pre-diabetes and diabetes., Methods: We included 1890 participants with mean age of 40.6 (SD11.9) years in a cross-sectional study among male and female adults in Tanzania during 2016 to 2017. Data on C-reactive protein (CRP), alpha-acid glycoprotein (AGP), HIV, oral glucose tolerance test (OGTT), body composition and insulin were collected. Insulinogenic index and HOMA-IR were used to derive an overall marker of β-cell dysfunction and insulin resistance which was categorised as follows: normal β-cell function and insulin sensitivity, isolated β-cell dysfunction, isolated insulin resistance, and combined β-cell dysfunction and insulin resistance. Pre-diabetes and diabetes were defined as 2-hour OGTT glucose between 7.8-11.0 and ≥ 11.1 mmol/L, respectively. Multinomial regression assessed the association of β-cell dysfunction and insulin resistance with outcome measures., Results: β-cell dysfunction, insulin resistance, and combined β-cell dysfunction and insulin resistance were associated with higher pre-diabetes risk. Similarly, isolated β-cell dysfunction (adjusted relative risk ratio (aRRR) 4.8 (95% confidence interval (CI) 2.5, 9.0), isolated insulin resistance (aRRR 3.2 (95% CI 1.5, 6.9), and combined β-cell dysfunction and insulin resistance (aRRR 35.9 (95% CI 17.2, 75.2) were associated with higher diabetes risk. CRP, AGP and HIV were associated with higher diabetes risk, but fat mass was not. 31%, 10% and 33% of diabetes cases were attributed to β-cell dysfunction, insulin resistance, and combined β-cell dysfunction and insulin resistance, respectively., Conclusions: β-cell dysfunction seemed to explain most of diabetes cases compared to insulin resistance in this population. Cohort studies on evolution of diabetes in Africa are needed to confirm these results., (© 2021 John Wiley & Sons Ltd.)

Objectives: To assess the prevalence and clinical importance of previously unrecognised tuberculosis (TB) and isolation of non-tuberculous mycobacteria (NTM) among HIV-infected individuals in a teaching hospital in Ghana., Methods: Intensified mycobacterial case finding was conducted among HIV-positive individuals before initiation of antiretroviral therapy (ART). Data were collected on socio-demographic characteristics, medical history and TB-related signs and symptoms, and participants were followed for six months to determine treatment and vital status. Two sputum samples were obtained and examined for mycobacteria with smear microscopy, culture and Xpert MTB/RIF assay. NTM species were identified with the GenoType Mycobacterium CM/AS or sequence analysis of 16S rRNA gene., Results: Of 473 participants, 60 (12.7%) had confirmed pulmonary TB, and 38 (8.0%) had positive cultures for NTM. Mycobacterium avium complex was identified in 9/38 (23.7%) of NTM isolates. Participants with NTM isolated were more likely to have CD4 cell count< 100 cells/μL (aOR 2.37; 95% CI: 1.10-5.14), BMI<18.5kg/m(2) (aOR 2.51; 95% CI: 1.15-5.51) and fever ≥2 weeks (aOR 2.76; 95% CI: 1.27-6.03) at baseline than participants with no mycobacteria. By six months, 76 (16.1%) participants had died; 20 (33.3%) with confirmed TB and 9 (23.7%) with NTM-positive culture. Mortality at six months was independently associated with TB diagnosis at enrolment (aHR 1.97; 95% CI 1.09-3.59), but not with NTM isolation after controlling for age, sex, CD4 cell count, BMI, prolonged fever and ART initiation., Conclusions: Intensified mycobacterial screening of HIV-infected individuals revealed a high burden of unrecognised pulmonary TB before ART initiation, which increased risk of death within six months. NTM were frequently isolated and associated with signs of poor clinical status but not with increased mortality., (© 2016 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Objective: Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment., Methods: A total of 1250 Tanzanian TB patients were followed prospectively during TB treatment with sputum culture after 2 and 5 months. Survival status was assessed at least 1 year after initiation of treatment. At baseline, all participants underwent testing for diabetes and HIV, and the serum concentration of the acute phase reactant alpha-1 glycoprotein (AGP) was determined., Results: There were no differences between participants with and without diabetes regarding the proportion of positive cultures at 2 (3.8% vs. 5.8%) and 5 (1.3% vs. 0.9%) months (P > 0.46). However, among patients with a positive TB culture, relatively more patients with diabetes died before the 5-month follow-up. Within the initial 100 days of TB treatment, diabetes was associated with a fivefold increased risk of mortality (RR 5.09, 95% CI 2.36; 11.02, P < 0.001) among HIV uninfected, and a twofold increase among HIV co-infected patient (RR 2.33 95% CI 1.20; 4.53, P = 0.012), while diabetes was not associated with long-term mortality. Further adjustment with AGP did not change the estimates., Conclusion: Diabetes considerably increases risk of early mortality during TB treatment. The effect may not be explained by increased severity of TB, but could be due to impaired TB treatment response. Research is needed to clarify the mechanism and to assess whether glycaemic control improves survival., (© 2013 Blackwell Publishing Ltd.)

Objective: Diabetes is associated with pulmonary tuberculosis (TB), possibly due to impaired immunity, and diabetes may exacerbate the clinical manifestations of TB. Our aim was to assess the role of diabetes in the clinical manifestations of TB., Methods: We studied 1250 patients with pulmonary TB in an urban population in a cross-sectional study in Tanzania. All participants were tested for diabetes and HIV co-infection, and TB culture intensity was assessed. Levels of white blood cells, haemoglobin, acute phase reactants, CD4 count and HIV viral load were measured, and a qualitative morbidity questionnaire was used to identify the prevalence of disease-related symptoms., Results: Tuberculosis patients with diabetes had a higher neutrophil count (B 0.5 × 10(9) cells/l, 95% CI 0.2; 0.9, P = 0.001) than non-diabetic TB patients. Serum C-reactive protein (B 18.8 mg/l, CI 95% 8.2; 29.4, P = 0.001) and alpha-1-acid glycoprotein (B 0.2 g/l, CI 95% 0.03; 0.3, P = 0.02) were similarly higher in patients with diabetes. Diabetes did not affect culture intensity or HIV status, but self-reported fever was three times higher among participants with diabetes than in those without diabetes (OR 2.9, CI 95% 1.5; 5.7, P = 0.002)., Conclusion: Diabetes is associated with small changes in the manifestations of TB, but may have little clinical significance., (© 2012 Blackwell Publishing Ltd.)

Interleukin-12 receptor deficiency is a well-described cause of human susceptibility to infection with low-virulent mycobacteria and Salmonella species. We identified a male patient presenting in his late forties with severe gastroenteropathy because of outbred infestation by a previously unknown mycobacterium. In addition to selective IgA deficiency, the patient was found to carry a not previously described R283X homozygous mutation in his IL12RΒ1 gene. Two of his sisters, a brother, and his four children were healthy, heterozygous carriers of the mutation. In this patient, the combination of two deficiencies could promote illness. Even though the IgA deficiency in itself does not predispose to mycobacterial disease, the lack of secreted IgA may have disturbed the intestinal homoeostasis and increased the susceptibility to the low-virulent mycobacterium that the patient was not able to clear because of his IL12R deficiency. Antimycobacterial chemotherapy and interferon-γ treatment for 2 years significantly improved his condition. This is the first description of IL12RΒ1 deficiency combined with another immunodeficiency, and we suggest that combinatory defects may circumvent the otherwise low penetrance of IL12RB1 deficiency., (© 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.)

Objective: The aim of the study was to assess the effects of micronutrient supplementation on culture conversion in tuberculosis (TB) patients., Design: The study was a randomized, double-blind placebo-controlled 2 x 2 trial of zinc and multi-micronutrient (MMN) supplementation in pulmonary TB patients in Tanzania., Results: A total of 499 pulmonary TB patients were included in the trial after being confirmed sputum-positive by microscopy or culture. At 8 weeks, 25% were sputum-smear positive but only 11% were culture-positive (P<0.0001). No significant differences were observed in culture conversion rate among those allocated to MMN or placebo (89.5 vs. 86.2%, P=0.29) at 8 weeks, although at week 4 those allocated to MMN had a slightly reduced culture conversion rate (42.8 vs. 52.8%, P=0.058). Zinc had no effects on culture conversion. MMN increased weight gain by 0.78 kg [95% confidence interval (CI): 0.12--1.43] at week 8, while zinc supplementation had no effect. The effects of MMN and zinc did not interact and neither MMN nor zinc interacted with human immunodeficiency virus status, sex and culture-intensity at baseline., Conclusion: Neither zinc nor MMN supplementation had significant effects on culture conversion, but MMN supplementation increased weight gain in TB patients.

Inherited deficiency of mannan-binding lectin (MBL) has been shown to predispose to infections. Conversely, it has also been suggested that MBL might facilitate the uptake of certain intracellular microbes. The aim of this study was to investigate whether MBL plays a role in the HIV and tuberculosis epidemics in Africa. Thus, the authors determined the MBL serum concentration in 173 HIV infected patients (150 with concomitant tuberculosis), 94 patients with tuberculosis without being HIV infected, and 113 controls from Tanzania. The frequency of MBL deficiency was significantly increased in HIV infected patients compared with controls (12.1% and 3.5%, respectively). The frequency of patients deficient of MBL did not differ between controls and HIV negative patients with tuberculosis. However, HIV negative patients with tuberculosis had significantly higher MBL levels than both controls and HIV infected patients with or without tuberculosis. These results indicate that low levels of MBL are associated with increased risk of sexually transmitted HIV infection in Africans. By contrast, high levels of MBL may be involved in the pathogenesis of tuberculosis in immunocompetent individuals.

Nine monoclonal antibodies were raised against purified protein derivative (PPD) of tuberculin in mice previously treated with Bacilli Calmette Guérin (BCG). The antibodies also reacted with a culture filtrate from Mycobacterium tuberculosis strain H37Rv. In immunoblotting after SDS-PAGE the reaction with PPD was seen as a diffuse smear, whereas ammonium sulphate-precipitated proteins from H37Rv gave well-defined bands ranging from 10 to 65 kDa. Enzyme immunoassay showed that both PPD and H37Rv antigens were able to inhibit binding of the antibodies to PPD coated microtitre wells, suggesting that the antibodies reacted with continuous epitopes. A 12 kDa protein purified by immunoaffinity chromatography from H37Rv antigens was tested intradermally in M. tuberculosis MNC3 sensitized guinea pigs and gave a delayed type hypersensitivity reaction.

We have developed monoclonal antibodies (MoAb) reactive with a protein from Mycobacterium tuberculosis of apparent molecular mass 24 kDa. This protein was shown to be identical with MPB 64 (Harboe et al.,) MoAb bound to four different epitopes of which two were restricted to the 'tuberculosis complex' and two were also found in mycobacteria not belonging to the 'tuberculosis complex'. The cross-reactive MoAb demonstrate that MPB 64 is present in more mycobacterial species than previously assumed. MPB 64 was shown to induce strong delayed type hypersensitivity (Dth) reactions in outbred guinea pigs immunized with M. tuberculosis and M. bovis bacille Calmette-Guérin (BCG). No reaction was observed in animals immunized with mycobacteria not belonging to the 'tuberculosis complex'. The Dth-inducing capacity of MPB64 was compared with that of another 24 kDa protein purified from M. tuberculosis and of the previously described 38 kDa protein. The Dth responses to these three antigens were further analysed in four inbred guinea pig strains. A genetic restriction of the ability of the animals to respond to MPB 64 as well as to the 38 kDa protein was observed.

We have examined the immunological activity of five affinity-purified protein antigens from Mycobacterium tuberculosis in seven inbred and one outbred guinea pig strains. The test systems were measurements of delayed-type hypersensitivity (Dth) responses, lymphocyte stimulation assays (LS), and antibody response measurements. The results showed significant differences in the immunogenicity of the single-protein antigens and, when the antigens were considered separately, highly significant guinea pig strain differences. The outbred guinea pig strain behaved as a Dth high responder to all antigens studied. The order of magnitude of the Dth responses was not usually correlated with that of the corresponding antibody responses for the individual guinea pig strain-antigen combinations. In particular, when compared with the other strains, strain 2 guinea pigs generally gave the lowest Dth, but the highest antibody responses. A 38,000 molecular weight protein, possessing M. tuberculosis complex-specific B-cell determinants, appeared immunodominant in 5 out of 7 strains. Our Dth data in the inbred strains further suggest the presence of an M. tuberculosis-specific T-cell epitope. A T-cell line, 11D9, derived from the high-responder guinea pig strain 13 reactive to this protein, was shown to be able to confer a tuberculin-like skin reaction in vivo. LS assays with recombinant 38-kDa protein and truncated versions of the protein mapped the 11D9-defined T-cell epitope to the middle part of the molecule.

MPB 70 is a protein found in large quantities in the culture filtrate (CF) of the Tokyo and some other strains of Mycobacterium bovis BCG, and it has a remarkable degree of specificity for these strains. We estimated the molecular weight of MPB 70 to 22,000 by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). SDS-PAGE and immunoblotting showed that MPB 70 was present in high quantities in CF from BCG Tokyo, that it could be also demonstrated in BCG Copenhagen, and that it was absent in CF from M. tuberculosis H37Rv. When the purified MPB 70 preparation used in the present study was run in SDS-PAGE, blotted and stained with a polyclonal rabbit or a monoclonal mouse anti-MPB 70 antibody, several bands in addition to the main 22 kDa band were seen, indicating a tendency of the MPB 70 molecules and/or fragments thereof to form very stable aggregates with themselves. The biological activity of MPB 70 was studied in groups of guinea pigs sensitized with live BCG of the Tokyo and Copenhagen strains. Guinea pigs from both groups developed reactivity to tuberculin PPD as assessed by skin tests and lymphocyte stimulation tests with peripheral blood or lymph node lymphocytes. In addition, a strong and persistent reactivity to MPB 70 was demonstrated in the BCG Tokyo group with both methods. Guinea pigs sensitized with the Copenhagen strain were only weakly reactive to MPB 70. Skin reactions in guinea pigs that had been repeatedly tested with MPB 70 and tuberculin were compared with reactions in animals tested only once. Reactions to MPB 70 in BCG Tokyo sensitized guinea pigs were suppressed by repeated tests, whereas tuberculin reactions were boosted by the interim tests. The levels of specific anti-MPB 70 antibodies were higher in BCG Tokyo- than in BCG Copenhagen-sensitized guinea pigs. MPB 70 has a high degree of specificity and is a strongly immunogenic protein, which may prove useful in studies of mycobacterial immunology.