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Rationale: Contact tracing is an important component of tuberculosis (TB) control programs. Standardization of contact investigation protocols can make them more efficient., Objectives: To develop a model to select contact subjects for screening., Methods: We prospectively collected standardized data on 325 TB index cases and their 2,009 contacts. Factors that independently influenced the risk of TB infection were included in the model, which was then validated in a second prospective cohort of 88 cases of TB and their 618 contacts., Measurements and Main Results: A total of eight independent risk factors were identified (odds ratio; 95% confidence interval): age, with three subgroups: 6-14 years (3.6; 1.6-8.0); 15-29 years (3.7; 1.8-7.7); > or =30 years (4.1; 2.0-8.5); cavitation on the index case's chest radiograph (1.6; 1.1-2.2); an index case sputum smear with 100 or more acid-fast bacilli per field (1.8; 1.2-2.8); household contact at night (2.1; 1.3-3.2); first-degree family relationship with the index case (2.1; 1.3-3.3); active smoking by the contact (1.6; 1.1-2.4); free health care (2.0; 1.2-3.2); and birth in a country with TB incidence rate higher than 25 of 100,000 (2.2; 1.5-3.2). Predictive probabilities were chosen to ensure false-negative rates lower than estimated TB infection background. The number of contacts to be investigated was reduced by 26% while maintaining a false-negative rate of 8%., Conclusions: This study provides a standardized contact screening model which reduces resources required without negatively affecting disease control.

Primary immunodeficiencies are typically seen as rare monogenic conditions associated with detectable immunologic abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional primary immunodeficiencies, we describe nonconventional primary immunodeficiencies as Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or more virulent microbes. Conventional primary immunodeficiencies are suspected on the basis of a rare, striking, clinical phenotype and are defined on the basis of an overt immunologic phenotype, often leading to identification of the disease-causing gene. Nonconventional primary immunodeficiencies are defined on the basis of a more common and less marked clinical phenotype, which remains isolated until molecular cloning of the causal gene reveals a hitherto undetected immunologic phenotype. Similar concepts can be applied to primary immunodeficiencies presenting other clinical features, such as allergy and autoimmunity. Nonconventional primary immunodeficiencies thus expand the clinical boundaries of this group of inherited disorders considerably, suggesting that Mendelian primary immunodeficiencies are more common in the general population than previously thought and might affect children with a single infectious, allergic, or autoimmune disease.

Five disease-causing genes, including the IL12RB1 gene that encodes the beta 1 chain of the receptor for interleukin (IL)-12 (IL-12R beta 1), are known to be associated with the syndrome of Mendelian susceptibility to mycobacterial diseases. Some IL-12R beta 1-deficient patients present with tuberculosis as the only clinical phenotype. A comprehensive genetic study of IL12RB1 was conducted among 101 Moroccan families, including 157 offspring (age, >15 years) who had culture-positive pulmonary tuberculosis (PTB). The promoter, exons, and flanking intron regions of IL12RB1 in 40 randomly selected patients with PTB were entirely sequenced, leading to the detection of 19 variants (including 10 novel mutations). Blood cells obtained from individuals who were homozygous for any of the 13 most common variants responded to IL-12, indicating that these polymorphisms were not loss-of-function mutations. By use of a family-based study, 2 promoter polymorphisms that were in strong linkage disequilibrium were found to be associated with PTB, especially -2C-->T (odds ratio for CT or TT vs. CC, 2.69 [95% confidence interval, 1.19-6.09]). This result suggests that IL12RB1 polymorphisms might influence the risk of development of PTB in adults.

Sarcoidosis is known to be a systemic granulomatous disorder characterized by a cell-mediated Th1-type inflammatory response. To identify a key genetic factor in the pathogenesis of sarcoidosis, we investigated single nucleotide polymorphisms within 10 candidate genes involved in type 1 immune process ( IFNA17, IFNB, IFNG, IFNGR1, IFNGR2, IL12B, IL12RB1, IL12RB2, ETA-1, and NRAMP1) in an association-based study of 102 Japanese patients with sarcoidosis, 114 with tuberculosis, and 110 control subjects. After correction for multiple testing, an IFNA17 polymorphism (551T-->G) was found to be associated with susceptibility to sarcoidosis (odds ratio 3.27 [95% CI: 1.44-7.46], P=0.004, P(c)=0.04), but not to tuberculosis. We observed no significant associations with the other polymorphisms of the Th1-related genes. We further typed another IFNA polymorphism ( IFNA10 60T-->A) and confirmed two major haplotypes of the IFNA gene, viz., allele 1: IFNA10 [60T]- IFNA17 [551T] and allele 2: IFNA10 [60A]- IFNA17 [551G], in the Japanese population. In healthy subjects, IFNA allele 2, which is over-represented in patients with sarcoidosis, was significantly associated with increased IFN-alpha and IL-12p70 production induced by Sendai virus in vitro. This study suggests that possession of the IFNA allele with higher levels of IFN-alpha significantly increases the risk of sarcoidosis.

Objective: To evaluate the prevalence and patterns of drug resistance of Mycobacterium tuberculosis isolates collected from patients with chronic tuberculosis in Casablanca, Morocco., Methods: Between February 1996 and September 2001, 122 isolates were recovered from 112 different patients. The male to female ratio was 2.4., Results: From February 1996 to May 1997, 77.5% of isolates were multidrug-resistant (MDR-TB), compared to 69.4% from February 1999 to May 2000 and 78.7% from June 2000 to September 2001. The prevalence of MDR-TB is similar from the initial to the last period of this study. Analysis of the 69 bp hypervariable region of the rpoB gene by DNA sequencing on 42 M. tuberculosis isolates (37 resistant, 5 sensitive) showed nine different types of mutations on codons rpoB 513, rpoB 516, rpoB 522, rpoB 523 and rpoB 526. A new point mutation was observed on codon rpoB 523 on one isolate. No mutation was detected on this rpoB region for four resistant isolates., Conclusion: The high rate of MDR-TB illustrates a serious problem. The public health authorities have introduced a new regimen protocol consisting of 3 months of kanamycin, ofloxacin, pyrazinamide and ethionamide, followed by 18 months of ofloxacin, pyrazinamide and ethionamide (3KOZEA/18OZEA) for this category of patients, and it is hoped that the additional use of ofloxacin during the intensive phase of treatment will reduce the rate of resistance.

It has been well established that the host genetic background is an important modulator of tuberculosis susceptibility. The NRAMP1 (alias SLC11A1) gene has been associated with tuberculosis susceptibility in several ethnic groups. Here we studied the association and linkage of NRAMP1 with tuberculosis in 116 nuclear families, comprising 211 affected offspring, from Casablanca, Morocco. All enrolled tuberculosis cases were culture-positive. No evidence was found of linkage or association of NRAMP1 with tuberculosis. These findings suggest heterogeneity in the genetic control of tuberculosis susceptibility.

There is increasing interest in and understanding of the role of human genetic factors controlling susceptibility/resistance to infectious diseases. This is of particular importance for the two most common mycobacterial infections, tuberculosis and leprosy, because this will allow a genetic dissection of antimycobacterial immunity and should open new fields of preventive and therapeutic measures. In this review we will initially discuss various methods of genetic epidemiology that have been and are being developed to identify human genes controlling infectious diseases, and then illustrate the findings obtained in the numerous studies performed in tuberculosis and leprosy. Although the most convincing results were observed for HLA-DR2 and NRAMP1 (or a closely linked gene) in pulmonary tuberculosis and leprosy subtypes and for a 10p13 locus in paucibacillary leprosy, the molecular basis of their effects remains to be established.

Mendelian susceptibility to poorly virulent mycobacteria such as bacillus Calmette-Guerin (BCG) and environmental nontuberculous mycobacteria is a clinically heterogeneous syndrome. The clinical features of affected children cover a continuous spectrum from disseminated lethal bacillus Calmette-Guerin infection to local recurrent nontuberculous mycobacterial infection. Different types of mutations in four genes (IFNGR1, IFNGR2, IL12B, IL12RB1) have revealed both allelic and nonallelic heterogeneity and result in eight different disorders whose common pathogenic pathway is impaired interferon gamma (IFNgamma) mediated immunity. The severity of the clinical phenotype depends on the genotype. Complete IL-12 p40 and IL-12 receptor beta1 deficiencies and partial IFNgamma receptor 1 (IFNgammaR1) and IFNgammaR2 deficiencies generally lead to curable infections at various ages, and antibiotics supplemented with IFNgamma if required are likely to be effective. Complete IFNgammaR1 and IFNgammaR2 deficiencies predispose to overwhelming infection in early childhood, which may respond to antibiotics but relapse when antibiotics are discontinued. Rapid discrimination between complete IFNgammaR1 and IFNgammaR2 deficiency and other defects, therefore, is an important diagnostic step for planning clinical management.

Body composition and organ weights were determined in male mice sampled from 4 different lines of a selection experiment: DU-6P (selected for high protein amount), DU-6 (selected for high body weight), DU-6 + LB (selected for an index combining body weight and endurance fitness) and DU-K (unselected control line). Selection was carried out under the conditions of ad libitum feeding and standardization of litter size at birth. In all 3 selection lines a significant direct selection response was shown. While fat in lines DU-6P and DU-6 + LB remained normal, it increased after selection for body weight (DU-6) significantly. Up to generation 13 the average increase of fat was 0.32% per generation. Investigations on 28 to 80 days old mice showed, that males of this line were fatter before, at and after the age of selection (42 days). After 9 generations the body weight of selected mice was significantly increased by 23 to 29%. The absolute organ weights of hearts, livers and kidneys were also significantly higher, while the relative weights of hearts and kidneys decreased. The relative liver weights were in the selected lines higher, but only the difference DU-6 vs. DU-K was significant.

The object of the present study was to characterize the selection-conditioned differentiation of the biological performance of laboratory mice having been selected for 13 generations at the age of 6 weeks to body mass (Du-6) as well as simultaneously to body mass and high physical capacity (Du-6 + LB) by parameters of fat metabolism. The improved physical capacity with unchanged body composition (Du-6 + LB) coincides with increasing activity of dehydrogenases supplying NADPH (glucose-6-phosphate-dehydrogenase, 6-phosphate-gluconate-dehydrogenase, NADP-malate-dehydrogenase, NADP-isocitrate-dehydrogenase) in the liver. The doubling of the fat content of the body (Du-6) was accompanied by a significant increase of the G-6-PDH- and fatty-acid synthetase activity in the fatty tissue. Furthermore, the growth-selected animals showed an intensified transformation of 14C-glucose substrate in the lipids of the epididymal fatty tissues occurring especially at the selection age (42nd day) as well as at the earlier date of ontogenesis (32nd day). The insulin stimulation capacity of the fat cells as to the glucose incorporation, however, remained unchanged.