Publications

Changes in extracellular [Ca2+] modulate the function of bone cells in vitro via the extracellular Ca2+-sensing receptor (CaR). Within bone microenvironments, resorption increases extracellular [Ca2+] locally. To determine whether enhanced CaR signaling could modulate remodeling and thereby bone mass in vivo, we generated transgenic mice with a constitutively active mutant CaR (Act-CaR) targeted to their mature osteoblasts by the 3.5 kb osteocalcin promoter. Longitudinal microcomputed tomography of cancellous bone revealed reduced bone volume and density, accompanied by a diminished trabecular network, in the Act-CaR mice. The bone loss was secondary to an increased number and activity of osteoclasts, demonstrated by histomorphometry of secondary spongiosa. Histomorphometry, conversely, indicates that bone formation rates were unchanged in the transgenic mice. Constitutive signaling of the CaR in mature osteoblasts resulted in increased expression of RANK-L (receptor activator of nuclear factor-kappaB ligand), the major stimulator of osteoclast differentiation and activation, which is the likely underlying mechanism for the bone loss. The phenotype of Act-CaR mice is not attributable to systemic changes in serum [Ca2+] or PTH levels. We provide the first in vivo evidence that increased signaling by the CaR in mature osteoblasts can enhance bone resorption and further propose that fluctuations in the [Ca2+] within the bone microenvironment may modulate remodeling via the CaR.

Management of airway infections caused by Pseudomonas aeruginosa is a serious clinical challenge, but little is known about the microbial ecology of airway infections in intubated patients. We analyzed bacterial diversity in endotracheal aspirates obtained from intubated patients colonized by P. aeruginosa by using 16S rRNA clone libraries and microarrays (PhyloChip) to determine changes in bacterial community compositions during antibiotic treatment. Bacterial 16S rRNA genes were absent from aspirates obtained from patients briefly intubated for elective surgery but were detected by PCR in samples from all patients intubated for longer periods. Sequencing of 16S rRNA clone libraries demonstrated the presence of many orally, nasally, and gastrointestinally associated bacteria, including known pathogens, in the lungs of patients colonized with P. aeruginosa. PhyloChip analysis detected the same organisms and many additional bacterial groups present at low abundance that were not detected in clone libraries. For each patient, both culture-independent methods showed that bacterial diversity decreased following the administration of antibiotics, and communities became dominated by a pulmonary pathogen. P. aeruginosa became the dominant species in six of seven patients studied, despite treatment of five of these six with antibiotics to which it was sensitive in vitro. Our data demonstrate that the loss of bacterial diversity under antibiotic selection is highly associated with the development of pneumonia in ventilated patients colonized with P. aeruginosa. Interestingly, PhyloChip analysis demonstrated reciprocal changes in abundance between P. aeruginosa and the class Bacilli, suggesting that these groups may compete for a similar ecological niche and suggesting possible mechanisms through which the loss of microbial diversity may directly contribute to pathogen selection and persistence.

Understanding human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T-lymphocyte responses is important for the development of vaccines and therapies. We describe a novel method for the rational selection of peptides that target stable regions of the HIV-1 genome, rich in epitopes specifically recognized by the study population. This method will be of particular use under resource/sample-limited conditions.

BACKGROUND

End-stage renal disease disproportionately affects black Americans. However, the impact of residential segregation by race-a prominent feature of many U.S. cities--on outcomes of patients receiving dialysis and on facility performance has not been evaluated.

OBJECTIVE

To examine the relationship among racial composition of ZIP codes in metropolitan areas, outcomes of patients receiving dialysis, and characteristics of dialysis facilities.

DESIGN

Retrospective cohort study of patients receiving dialysis and cross-sectional study of dialysis facilities.

SETTING

U.S. metropolitan ZIP codes with differing percentages of black residents.

PATIENTS

Black and non-Hispanic white patients who initiated long-term dialysis between 1 January 1995 and 31 December 2002 (n = 399,424) and dialysis facilities in operation in December 2004 (n = 3244).

MEASUREMENTS

Mortality and time to transplantation among patients receiving dialysis, and performance of dialysis facilities on the basis of quality indicators (anemia management, dialysis adequacy, and facility-level mortality rates).

RESULTS

Most black patients (50.3%) but few white patients (5%) lived in the 3% (n = 769) of ZIP codes in which most residents were black. In analyses adjusted for patient and ZIP code characteristics, mortality rates were higher among white patients but not among black patients living in areas with a higher percentage of black residents (adjusted hazard ratio for ZIP codes with > or =75% black residents vs. <10% black residents, 1.14 [95% CI, 1.07 to 1.21] for white patients and 1.02 [CI, 0.99 to 1.06] for black patients). Time to transplantation was longer among both black and white patients (adjusted hazard ratio for ZIP codes with > or =75% black residents vs. <10% black residents, 0.84 [CI, 0.78 to 0.92] and 0.63 [CI, 0.57 to 0.71] for black patients and white patients, respectively). Dialysis facilities located in areas with a higher percentage of black residents were more likely to have higher-than-expected mortality rates and were less likely to meet performance targets.

LIMITATIONS

Patient-level analyses were restricted to black and non-Hispanic white patients. Patient-level and facility-level analyses focused only on the percentage of black residents in each ZIP code.

CONCLUSIONS

The racial composition of urban residential areas is associated with time to transplantation and dialysis facility performance on standard quality measures. Closer scrutiny of care provided to patients receiving dialysis who live in predominantly black residential areas and to dialysis facilities operating in these areas may be warranted.

BACKGROUND

The prolonged effectiveness of antiretroviral therapy (ART) in a developing country is not well established.

METHODS

An observational database was established at the HIV clinic of the Almenara Hospital in Lima, Peru in 1996. All 564 initially antiretroviral-naive HIV-infected persons (mean CD4 count of 91 cells/mm3) who received combination ART were followed over time.

RESULTS

The overall survival rate was 96% at year 2, 94% at year 4, and 91% at year 5. Among persons who initiated therapy with CD4 counts <100 cells/mm3, the overall survival rate at 3 years was 95%. Opportunistic infections while on ART occurred in 20% of persons. Patients who received 2 reverse transcriptase (RT) inhibitors plus a protease inhibitor had slightly better survival rates and less opportunistic disease in the first year of therapy as compared with those receiving 2 RT inhibitors and a nonnucleoside reverse transcriptase inhibitor or 3 RT inhibitors.

CONCLUSIONS

This study demonstrates the long-term effectiveness of ART in a developing country urban setting. It provides evidence of the importance of continuing global financing initiatives to provide widespread HIV therapy for countries in the developing world.