Impact of HIV on tuberculosis in Zambia: a cross sectional study.

OBJECTIVE--To examine the contribution of HIV infection to the apparently increasing incidence of tuberculosis in central Africa. DESIGN--Cross sectional study. SETTING--Outpatient clinic in teaching hospital, Lusaka, Zambia. PATIENTS--346 Adult patients with tuberculosis. RESULTS--Overall, 206 patients (60%; 95% confidence interval 54% to 65%) were positive for HIV--in one or both assays used. The peaks for both tuberculosis and HIV infection were among men aged 25-34 years and women aged 14-24 years. Of patients with confirmed pulmonary tuberculosis, 73/149 (49%; 41% to 57%) were positive for HIV; 67/83 (81%; 70% to 89%) patients with pleural disease and 16/19 (84%; 60% to 97%) patients with pericardial disease were positive. HIV positive patients with positive sputum culture were less likely to have had a positive sputum smear, and their chest x ray films less often showed classic upper zone disease or cavitation. Of 72 patients who fulfilled clinical criteria for AIDS, 17 were negative for HIV. CONCLUSIONS--The high prevalence of HIV in patients with tuberculosis suggests that an epidemic of reactivating tuberculosis is arising in those who are infected with HIV. The redirection of public health priorities towards tuberculosis would focus on a major treatable and preventable complication of the AIDS epidemic.     

The role of pleiotropy vs signaller-receiver gene epistasis in life history trade-offs: dissecting the genomic architecture of organismal design in social systems

Traditional life history theory ignores trade-offs due to social interactions, yet social systems expand the set of possible trade-offs affecting a species evolution--by introducing asymmetric interactions between the sexes, age classes and invasion of alternative strategies. We outline principles for understanding gene epistasis due to signaller-receiver dynamics, gene interactions between individuals, and impacts on life history trade-offs. Signaller-receiver epistases create trade-offs among multiple correlated traits that affect fitness, and generate multiple fitness optima conditional on frequency of alternative strategies. In such cases, fitness epistasis generated by selection can maintain linkage disequilibrium, even among physically unlinked loci. In reviewing genetic methods for studying life history trade-offs, we conclude that current artificial selection or gene manipulation experiments focus on pleiotropy. Multi-trait selection experiments, multi-gene engineering methods or multiple endocrine manipulations can test for epistasis and circumvent these limitations. In nature, gene mapping in field pedigrees is required to study social gene epistases and associated trade-offs. Moreover, analyses of correlational selection and frequency-dependent selection are necessary to study epistatic social system trade-offs, which can be achieved with group-structured versions of Price's (1970) equation.     

Impoundment effects on the thermal regimes of Kootenay Lake,the Arrow Lakes Reservoir and Upper Columbia River

Hydrobiologia - The Arrow Lakes Reservoir and Kootenay Lake are comparable large reservoirs formed by the addition of storage onto natural lakes. Both have significant storage reservoirs upstream...     

Expenditure freeze: the metabolic response of small mammals to cold environments

There is renewed focus on the ecological determinants of animal metabolism and recent comparative analyses support the physiological expectation that the field metabolic rate (FMR) of homeotherms should increase with declining ambient temperature. However, sustained elevation of FMR during prolonged, seasonal cold could be prevented by intrinsic limits constraining FMR to some multiple of basal metabolic rate (BMR) or extrinsic limits on resource abundance. We analysed previous measures of mammalian FMR and BMR to establish the effect of ambient temperature on both traits and found no support for intrinsic limitation. We also measured the FMR of a northern population of red squirrels (Tamiasciurus hudsonicus) exposed to ambient temperatures much colder than all but one previous study of mammal FMR. These measurements revealed levels of energy expenditure that are, unexpectedly, among the lowest ever recorded in homeotherms and that actually decrease as it gets colder. Collectively, these results suggest the metabolic niche space of cold climate endotherms may be much larger than previously recognized.     

Multilevel and sex‐specific selection on competitive traits in North American red squirrels

Individuals often interact more closely with some members of the population (e.g., offspring, siblings, or group members) than they do with other individuals. This structuring of interactions can lead to multilevel natural selection, where traits expressed at the group‐level influence fitness alongside individual‐level traits. Such multilevel selection can alter evolutionary trajectories, yet is rarely quantified in the wild, especially for species that do not interact in clearly demarcated groups. We quantified multilevel natural selection on two traits, postnatal growth rate and birth date, in a population of North American red squirrels (Tamiasciurus hudsonicus). The strongest level of selection was typically within‐acoustic social neighborhoods (within 130 m of the nest), where growing faster and being born earlier than nearby litters was key, while selection on growth rate was also apparent both within‐litters and within‐study areas. Higher population densities increased the strength of selection for earlier breeding, but did not influence selection on growth rates. Females experienced especially strong selection on growth rate at the within‐litter level, possibly linked to the biased bequeathal of the maternal territory to daughters. Our results demonstrate the importance of considering multilevel and sex‐specific selection in wild species, including those that are territorial and sexually monomorphic.     

Does ozone increase ABA levels by non‐enzymatic synthesis causing stomata to close?

Reactive oxygen species (ROS) are widely recognized as important regulators of stomatal aperture and plant gas exchange. The pathways through which stomata perceive ROS share many common linkages with the well characterized signalling pathway for the hormone abscisic acid (ABA), a major driver of stomatal closure. Given reports that ABA receptor mutants have no stomatal response to ozone‐triggered ROS production, as well as evidence that all steps in the ABA biosynthetic pathway can be non‐enzymatically converted by ROS, here we investigated the possibility that ozone closes stomata by directly converting ABA precursors to ABA. In plants where stomata were responsive to ozone, we found that foliar ABA levels rapidly increased upon exposure to ozone. Recovery of gas exchange post‐exposure occurred only when ABA levels declined. Our data suggest that stomatal closure in response to ozone exposure occurs as a result of direct oxidation of ABA precursors leading to ABA production, but the importance of this ROS interaction remains uncertain under normal photosynthetic conditions.     

CD209 genetic polymorphism and tuberculosis disease

Background

Tuberculosis causes significant morbidity and mortality worldwide, especially in sub-Saharan Africa. DC-SIGN, encoded by CD209, is a receptor capable of binding and internalizing Mycobacterium tuberculosis. Previous studies have reported that the CD209 promoter single nucleotide polymorphism (SNP)-336A/G exerts an effect on CD209 expression and is associated with human susceptibility to dengue, HIV-1 and tuberculosis in humans. The present study investigates the role of the CD209 -336A/G variant in susceptibility to tuberculosis in a large sample of individuals from sub-Saharan Africa.

Methods and Findings

A total of 2,176 individuals enrolled in tuberculosis case-control studies from four sub-Saharan Africa countries were genotyped for the CD209 -336A/G SNP (rs4804803). Significant overall protection against pulmonary tuberculosis was observed with the -336G allele when the study groups were combined (n = 914 controls vs. 1262 cases, Mantel-Haenszel 2x2 χ² = 7.47, P = 0.006, odds ratio = 0.86, 95%CI 0.77–0.96). In addition, the patients with -336GG were associated with a decreased risk of cavitory tuberculosis, a severe form of tuberculosis disease (n = 557, Pearson''s 2×2 χ² = 17.34, P = 0.00003, odds ratio = 0.42, 95%CI 0.27–0.65). This direction of association is opposite to a previously observed result in a smaller study of susceptibility to tuberculosis in a South African Coloured population, but entirely in keeping with the previously observed protective effect of the -336G allele.

Conclusion

This study finds that the CD209 -336G variant allele is associated with significant protection against tuberculosis in individuals from sub-Saharan Africa and, furthermore, cases with -336GG were significantly less likely to develop tuberculosis-induced lung cavitation. Previous in vitro work demonstrated that the promoter variant -336G allele causes down-regulation of CD209 mRNA expression. Our present work suggests that decreased levels of the DC-SIGN receptor may therefore be protective against both clinical tuberculosis in general and cavitory tuberculosis disease in particular. This is consistent with evidence that Mycobacteria can utilize DC-SIGN binding to suppress the protective pro-inflammatory immune response.     

Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells

The inducible costimulatory (ICOS) molecule is expressed by activated T cells and has homology to CD28 and CD152. ICOS binds B7h, a molecule expressed by APC with homology to CD80 and CD86. To investigate regulation of ICOS expression and its role in Th responses we developed anti-mouse ICOS mAbs and ICOS-Ig fusion protein. Little ICOS is expressed by freshly isolated mouse T cells, but ICOS is rapidly up-regulated on most CD4(+) and CD8(+) T cells following stimulation of the TCR. Strikingly, ICOS up-regulation is significantly reduced in the absence of CD80 and CD86 and can be restored by CD28 stimulation, suggesting that CD28-CD80/CD86 interactions may optimize ICOS expression. Interestingly, TCR-transgenic T cells differentiated into Th2 expressed significantly more ICOS than cells differentiated into Th1. We used two methods to investigate the role of ICOS in activation of CD4(+) T cells. First, CD4(+) cells were stimulated with beads coated with anti-CD3 and either B7h-Ig fusion protein or control Ig fusion protein. ICOS stimulation enhanced proliferation of CD4(+) cells and production of IFN-gamma, IL-4, and IL-10, but not IL-2. Second, TCR-transgenic CD4(+) T cells were stimulated with peptide and APC in the presence of ICOS-Ig or control Ig. When the ICOS:B7h interaction was blocked by ICOS-Ig, CD4(+) T cells produced more IFN-gamma and less IL-4 and IL-10 than CD4(+) cells differentiated with control Ig. These results demonstrate that ICOS stimulation is important in T cell activation and that ICOS may have a particularly important role in development of Th2 cells.     

Either B7 costimulation or IL-2 can elicit generation of primary alloreactive CTL

B7-1 and B7-2 are important costimulatory molecules in the activation of T cell immunity. We have used mice made genetically deficient in either or both B7 molecules to determine the role of B7 molecules in activation of primary alloreactive CTL. The absence of either B7-1 or B7-2 did not alter generation of CTL from unfractionated lymphocytes, but the absence of B7-2 greatly decreased CTL generation from purified CD8+ responder cells. However, if B7-1 was induced on the stimulating cells then CTL generation was restored to wild-type levels. Absence of both B7-1 and B7-2 from MLR using whole splenocytes resulted in a profound reduction in generation of CTL. This could completely be reversed by the addition of IL-2. B7 molecules could directly costimulate CD8+ cells, as purified CD8+ cells developed into mature CTL when stimulated with wild-type APC, but not with B7-deficient APC. Again, IL-2 could drive CTL generation from purified CD8+ cells, even in the absence of B7 molecules. Taken together, these results demonstrate an important role for B7 costimulation in CTL generation.