Publications

Effector T cells control intracellular infection by secreting cytokines and through contact-dependent cytolysis. Because cytokines can diffuse and act at a distance, we determined whether cytokine diffusion is sufficient to control Mycobacterium tuberculosis or whether direct recognition of infected cells by CD4 T cells is required. Using MHC class II (MHC II) mixed bone marrow chimeras, we compared the bacterial burdens in lung myeloid cells that were capable (MHC II(+/+)) or not (MHC II(-/-)) of being recognized by CD4 T cells. MHC II(+/+) cells had lower bacterial burdens than did MHC II(-/-) cells. CD4 T cell depletion increased the number of bacteria associated with MHC II(+/+)cells but not MHC II(-/-) cells, indicating that direct recognition of infected cells by CD4 T cells is required for control of intracellular M. tuberculosis. These results show that the effector mechanisms required for CD4 T cell control of distinct intracellular pathogens differ and that long-range cytokine diffusion does not contribute to control of M. tuberculosis.

BACKGROUND

Additional drugs are needed for the treatment of cytomegalovirus (CMV) infection. Artesunate is an antimalarial drug that has activity against CMV in vitro and in a rodent model. Only a small number of case reports are available describing the clinical effects of artesunate on CMV infection, and these yielded inconsistent results.

OBJECTIVE

To evaluate the effect of artesunate on CMV infection, using blood samples collected from children who participated in malaria treatment trials.

STUDY DESIGN

Quantitative CMV DNA PCR was performed on dried blood spots collected from 494 Ugandan children, who were randomized either to artesunate plus amodiaquine or sulfadoxine-pyrimethamine plus amodiaquine for acute malaria infection. Poisson regression was used to compare treatment regimens with respect to the change in the frequency and quantity of CMV detected that occurred before and after treatment.

RESULTS

CMV was detected in 11.4% of children immediately prior to treatment and 10.7% 3 days later (p=0.70). The average quantity of CMV was 0.30 log10 copies per million cells higher on day 3 than at treatment initiation (95% CI 0.01-0.58, p=0.041). There was no measurable difference in either the frequency or quantity of CMV detected in blood between children randomized to the two treatment arms.

CONCLUSIONS

A standard 3-day artesunate-containing antimalarial regimen had no detectable effect on CMV viremia in children with malaria. Longer treatment courses and/or higher doses of artesunate than those routinely used for malaria may be required for effective treatment of CMV infection.

BACKGROUND

Obesity is a growing public health concern and is becoming an epidemic among veterans in the post-deployment period.

OBJECTIVE

To explore the relationship between body mass index (BMI) and posttraumatic stress disorder (PTSD) in a large cohort of Iraq and Afghanistan veterans, and to evaluate trajectories of change in BMI over 3 years.

DESIGN

Retrospective, longitudinal cohort analysis of veterans' health records

PARTICIPANTS

A total of 496,722 veterans (59,790 female and 436,932 male veterans) whose height and weight were recorded at the Department of Veterans Affairs (VA) healthcare system at least once after the end of their last deployment and whose first post-deployment outpatient encounter at the VA was at least 1 year prior to the end of the study period (December 31, 2011).

MAIN MEASURES

BMI, mental health diagnoses.

KEY RESULTS

Seventy-five percent of Iraq and Afghanistan veterans were either overweight or obese at baseline. Four trajectories were observed: "stable overweight" represented the largest class; followed by "stable obese;" "overweight/obese gaining;" and "obese losing." During the 3-year ascertainment period, those with PTSD and depression in particular were at the greatest risk of being either obese without weight loss or overweight or obese and continuing to gain weight. Adjustment for demographics and antipsychotic medication attenuated the relationship between BMI and certain mental health diagnoses. Although BMI trajectories were similar in men and women, some gender differences were observed. For example, the risk of being in the persistently obese class in men was highest for those with PTSD, whereas for women, the risk was highest among those with depression.

CONCLUSIONS

The growing number of overweight or obese returning veterans is a concerning problem for clinicians who work with these patients. Successful intervention to reduce the prevalence of obesity will require integrated efforts from primary care and mental health to treat underlying mental health causes and assist with engagement in weight loss programs.

CKD and its complications are associated with substantial morbidity and mortality. Studies have highlighted significant deficiencies in resident knowledge and awareness of CKD and its complications. There is a need to improve CKD education through medical school and residency. There is also a need to provide alternatives to traditional teaching methods to meet the challenges of learning in the context of work-hour restrictions and increasing workload among residents and fellows. Internet-based learning resources offer various educational tools, including websites, kidney blogs, online modules, and smartphone applications, which could potentially and efficiently advance CKD knowledge among medical trainees. In this review, we describe several online resources for CKD education that could be useful for medical students, residents, and fellows. Increased awareness of these tools and their utilization may significantly influence and hopefully improve the recognition and management of patients with CKD. Future studies may help evaluate the effectiveness of these online learning methods and their effect on CKD patient outcomes. In addition, in light of increased concern about nephrology workforce issues, the potential for these online tools to augment interest in nephrology careers should be investigated.

OBJECTIVE

Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin.

METHODS

This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1.

RESULTS

The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin.

CONCLUSION

Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.

BACKGROUND

Combined pulmonary fibrosis and emphysema (CPFE) is increasingly recognized, but its prevalence and prognosis remain unclear. We sought to determine the prevalence, clinical features, and prognosis of CPFE in idiopathic pulmonary fibrosis (IPF), using a standardized and reproducible definition.

METHODS

Patients with IPF were identified from two ongoing cohorts. Two radiologists scored emphysema and fibrosis severity on high-resolution CT (HRCT) scans. CPFE was defined as ≥10% emphysema on HRCT scan. Clinical characteristics and outcomes of patients with CPFE and IPF and those with non-CPFE IPF were compared with unadjusted analysis and then analysis after adjustment for HRCT fibrosis score. Mortality was compared using competing risks regression to handle lung transplantation. Sensitivity analyses were performed using Cox proportional hazards, including time to death (transplantation censored) and time to death or transplant.

RESULTS

CPFE criteria were met in 29 of 365 patients with IPF (8%), with high agreement between radiologists (κ=0.74). Patients with CPFE had less fibrosis on HRCT scans and higher FVC, but greater oxygen requirements (P≤.01 for all comparisons). Findings were maintained with adjustment for fibrosis severity. Inhaled therapies for COPD were used by 53% of patients with CPFE. There was no significant difference in mortality comparing patients with CPFE and IPF to those with non-CPFE IPF (hazard ratio, 1.14; 95% CI, 0.61-2.13; P=.69).

CONCLUSIONS

CPFE was identified in 8% of patients with IPF and is a distinct, clinical phenotype with potential therapies that remain underutilized. Patients with CPFE and IPF and those with non-CPFE IPF have similar mortality.