| 1. |
- Cooke, Graham S, et al.
(författare)
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Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis
- 2006
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 174:3, s. 339-343
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Interferon-gamma (IFN-gamma) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN-gamma signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear. METHODS: A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN-gamma and its receptor subunits (IFNG, IFNGR1, and IFNGR2). RESULTS: Within the IFNG gene, two promoter variants showed evidence of novel disease association: -1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11-2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09-1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89-1.51; p = 0.25). In addition, novel disease association was also found with the -56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57-0.99; p = 0.041). No disease association was seen with the IFNGR2 locus. CONCLUSIONS: These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN-gamma production and responsiveness influences the risk of developing tuberculosis.
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| 2. |
- Gustafson, Per, et al.
(författare)
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Risk factors for positive tuberculin skin test in Guinea-Bissau
- 2007
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Ingår i: Epidemiology. - : Ovid Technologies (Wolters Kluwer Health). - 1531-5487 .- 1044-3983. ; 18:3, s. 340-347
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Tidskriftsartikel (refereegranskat)abstract
- Background: The tuberculin skin test is used for tracing of tuberculosis transmission and identifying individuals in need of prophylactic treatment. Methods: Using a case-control study design, we recruited 220 smear-positive tuberculosis cases and 223 randomly selected healthy community controls in Bissau, Guinea-Bissau, during 1999-2000. Tuberculin skin tests were performed on family members of cases and controls (n = 1059 and n = 92 1, respectively). Induration of 10 mm or greater was considered positive. Risk factors were calculated for children (< 15 years) and adults separately in multivariate logistic regression analysis. Results: The prevalence of positive tuberculin skin test was 41% in case-contacts compared with 22% in control-contacts, resulting in a prevalence ratio of 1.48 (95% confidence interval = 1.37-1.60). Positive skin tests among case-contacts increased with age for children, as well as with proximity to a case during the night, for both children and adults. A Bacille Calmette Guerin scar increased the likelihood of having a positive tuberculin skin test for adults in case households, but not in other categories of contacts. Among control-contacts the prevalence of positive skin test was associated with older age in children, history of tuberculosis in the family, and a positive tuberculin skin test of the control person. Conclusions: Risk factors for a positive tuberculin skin test among case- and control-contacts are closely related to tuberculosis exposure. Having a BCG scar did not increase the risk of positive skin test in unexposed individuals. Tuberculin skin testing remains a useful tool for diagnosing tuberculosis infection.
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| 3. |
- Smythe, Wynand, et al.
(författare)
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A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients
- 2012
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 56:4, s. 2091-2098
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Tidskriftsartikel (refereegranskat)abstract
- The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters.h(-1) at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction.
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| 4. |
- Smythe, Wynand, et al.
(författare)
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Evaluation of Initial and Steady-State Gatifloxacin Pharmacokinetics and Dose in Pulmonary Tuberculosis Patients by Using Monte Carlo Simulations
- 2013
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 57:9, s. 4164-4171
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Tidskriftsartikel (refereegranskat)abstract
- A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of >= 125 for the area under the concentration time curve to infinity (AUC(0-infinity)) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC(0-infinity) of 41.2 mu g.h/ml decreased on average by 14.3% (90% confidence interval [CI], -90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of >= 125 only when the MIC was <0.125 mu g/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.)
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| 5. |
- Tosh, Kerrie, et al.
(författare)
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Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa
- 2006
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 103:27, s. 10364-10368
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Tidskriftsartikel (refereegranskat)abstract
- The sst1 locus has been identified in a mouse model to control resistance and susceptibility of Mycobacterium tuberculosis infection. Subsequent studies have now identified Ipr1 (intracellular pathogen resistance 1) to be the gene responsible. Ipr1 is encoded within the sst1 locus and is expressed in the tuberculosis lung lesions and macrophages of sst1-resistant, but not sst1-susceptible mice. We have therefore examined the closest human homologue of Ipr1, SP110, for its ability to control susceptibility to M. tuberculosis infection in humans. In a study of families from The Gambia we have identified three polymorphisms that are associated with disease. On examination of additional families from Guinea-Bissau and the Republic of Guinea, two of these associations were independently replicated. These variants are in strong linkage disequilibrium with each other and lie within a 31-kb block of low haplotypic diversity, suggesting that a polymorphism within this region has a role in genetic susceptibility to tuberculosis in humans.
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| 6. |
- Vasiliu, Anca, et al.
(författare)
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Tuberculosis incidence in foreign-born people residing in European countries in 2020
- 2023
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Ingår i: Eurosurveillance. - : European Centre for Disease Prevention and Control (ECDC). - 1025-496X .- 1560-7917. ; 28:42
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Tidskriftsartikel (refereegranskat)abstract
- Background: European-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.Aim: We aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.Methods: The Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.Results: Data on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.Conclusions: Country of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.
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