Publications

RATIONALE

Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome.

OBJECTIVES

To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort.

METHODS

Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome.

MEASUREMENTS AND MAIN RESULTS

Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not.

CONCLUSIONS

This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.

OBJECTIVE

We examined the short-term and long-term associations of serum albumin with mortality and cardiovascular disease among HIV-infected veterans.

DESIGN

Retrospective cohort analysis using a national database of US veterans with HIV infection.

METHODS

This analysis evaluated all HIV-infected veterans in the Department of Veterans Affairs HIV Clinical Case Registry (CCR), a national database consisting of demographic, clinical, laboratory, pharmaceutical, and viral status data. There were 25 522 patients enrolled between 1986 and 2007. We evaluated the associations of baseline and time-updated serum albumin levels with all-cause mortality, atherosclerotic cardiovascular disease, and heart failure by multivariate proportional hazards models.

RESULTS

Over 21 years, there were 10 869 deaths; the cumulative mortality was 73.2 per 1000 person-years. After multivariate adjustment for covariates measured at baseline, the lowest category of serum albumin (<2.5 g/dl) was associated with a higher mortality risk compared with the highest category (>4 g/dl; hazard ratio 3.00; 2.67-3.37). When analyzed as a time-dependent model, the association strengthened substantially (15.1; 14.0-16.4). Findings were similar for atherosclerotic cardiovascular disease and heart failure. We stratified the baseline mortality model by year of follow-up and found that albumin was more strongly associated with deaths that occurred within 1 year of baseline (9.29; 7.85-11.0) than in the second (1.66; 1.18-2.33) or third (1.22; 0.77-1.96) year after measurement.

CONCLUSION

Among ambulatory HIV-infected patients, lower serum albumin levels are strongly predictive of mortality risk, particularly within 1 year.

BACKGROUND

The genes FTO and GNB3 are implicated in essential hypertension but their interaction remains to be explored. This study investigates the role of interaction between the two genes in the pathophysiology of essential hypertension.

METHODS/PRINCIPAL FINDINGS

In a case-control study comprising 750 controls and 550 patients, interaction between the polymorphisms of FTO and GNB3 was examined using multifactor dimensionality reduction (MDR). The influence of interaction on clinical phenotypes like systolic and diastolic blood pressure, mean arterial pressure and body mass index was also investigated. The 3-locus MDR model comprising FTO rs8050136C/A and GNB3 rs1129649T/C and rs5443C/T emerged as the best disease conferring model. Moreover, the interacted-genotypes having either 1, 2, 3, 4 or 5 risk alleles correlated with linearly increasing odds ratios of 1.91 (P = 0.027); 3.93 (P = 2.08E-06); 4.51 (P = 7.63E-07); 7.44 (P = 3.66E-08) and 11.57 (P = 1.18E-05), respectively, when compared with interacted-genotypes devoid of risk alleles. Furthermore, interactions among haplotypes of FTO (H1-9) and GNB3 (Ha-d) differed by >1.5-fold for protective-haplotypes, CTGGC+TC [H2+Ha] and CTGAC+TC [H4+Ha] (OR = 0.39, P = 0.003; OR = 0.22, P = 6.86E-05, respectively) and risk-haplotypes, AAAGC+CT [H3+Hc] and AAAGC+TT [H3+Hd] (OR = 2.91, P = 9.98E-06; OR = 2.50, P = 0.004, respectively) compared to individual haplotypes. Moreover, the effectiveness of gene-gene interaction was further corroborated with a 1.29-, 1.25- and 1.38-fold higher SBP, MAP and BMI, respectively, in patients having risk interacted-haplotype H3+Hc and 2.48-fold higher SBP having risk interacted-haplotype H3+Hd compared to individual haplotypes.

CONCLUSION

Interactions between genetic variants of FTO and GNB3 influence clinical parameters to augment hypertension.

OBJECTIVE

We examined associations between neighborhood socioeconomic disadvantage, perceived neighborhood safety and cardiometabolic risk factors, adjusting for health behaviors and socioeconomic status (SES) among African Americans.

METHODS

Study participants were non-diabetic African Americans (n = 3,909) in the baseline examination (2000-2004) of the Jackson Heart Study. We measured eight risk factors: the metabolic syndrome, its five components, insulin resistance and cardiovascular inflammation. We assessed neighborhood socioeconomic disadvantage with US Census 2000 data. We assessed perceived neighborhood safety, health behaviors and SES via survey. We used generalized estimating equations to estimate associations with a random intercept model for neighborhood effects.

RESULTS

After adjustment for health behaviors and SES, neighborhood socioeconomic disadvantage was associated with the metabolic syndrome in women (PR 1.13, 95% CI 1.01, 1.27). Lack of perceived safety was associated with elevated glucose (OR 1.36, 95% CI 1.03, 1.80) and waist circumference (PR 1.06, 95% CI 1.02, 1.11) among women, and with elevated glucose (PR 1.30, 95% CI 1.02, 1.66) and insulin resistance (PR 1.25, 95% CI 1.08, 1.46) among men.

CONCLUSIONS

Neighborhood socioeconomic disadvantage and perceived safety should be considered as targets for intervention to reduce cardiometabolic risks among African Americans.

Epidemic community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is associated with more severe and acute forms of osteomyelitis than healthcare-associated (HA-) MRSA. Although S. aureus is now recognized as a facultative intracellular pathogen, the contribution of osteoblast invasion by CA-MRSA to the pathogenesis of osteomyelitis is unknown. Using an ex vivo model of intracellular infection of human osteoblasts, we demonstrated that CA-MRSA strains of diverse lineages share an enhanced ability to kill infected osteoblasts compared to HA-MRSA. Cytotoxicity comparisons of CA-MRSA isogenic deletion mutants revealed that phenol-soluble modulins (PSMs), a class of membrane-damaging exoproteins that are expressed at higher levels in CA-MRSA than in HA-MRSA, are involved in this osteoblast killing, whereas other major CA-MRSA virulence determinants, the Panton-Valentine leukocidin and alpha-toxin, are not involved. Similarly, functional agr and sarA regulators, which control the expression of PSMs and alpha-toxin, were required for the expression of the intracellular cytotoxic phenotype by CA-MRSA, whereas the saeRS regulator, which controls the expression of alpha-toxin but not PSMs, had no impact on cytotoxicity. Finally, PSM transcript levels determined by quantitative reverse-transcriptase PCR were significantly higher in CA-MRSA than in HA-MRSA strains and associated with cell damage in MRSA-infected osteoblasts. These findings provide new insights into the pathogenesis of severe CA-MRSA osteomyelitis and unravel a novel virulence strategy of CA-MRSA, based on the invasion and subsequent killing of osteoblasts by PSMs acting as intracellular toxins.

Treating drug-resistant tuberculosis (DR-TB) is particularly challenging in high human immunodeficiency virus (HIV) prevalence settings. Neither antiretroviral resistance testing nor viral load monitoring is widely available in sub-Saharan Africa, and antiretroviral resistance can complicate the clinical management for DR-TB/HIV coinfected patients. We describe six cases of antiretroviral resistance in DR-TB patients with HIV coinfection in Lesotho. Two patients died before or immediately after antiretroviral resistance was detected by genotyping; the remaining four patients were switched to effective antiretroviral therapy (ART) regimens. Favorable DR-TB treatment outcomes in coinfected patients require successful management of their HIV infection, including treatment with an effective ART regimen. Coinfected patients undergoing DR-TB treatment may require closer monitoring of their response to ART, including routine viral load testing, to ensure that they receive an effective ART regimen concurrent with DR-TB treatment.