Publications

The beneficial effects of high-density lipoprotein (HDL) on atherosclerosis have largely been attributed to its major protein, apolipoprotein A-I (apoA-I). Used as a therapeutic intervention, apoA-I is a large protein that requires venous administration, and is both difficult and expensive to manufacture. Because of these problems with apoA-I, the generation of smaller, easier to manufacture apoA-I mimetic peptides has become a target for pharmacologic development in the therapeutic management of human atherosclerosis. A potent apoA-I mimetic peptide, 4F, was found to have significant activity in various inflammatory states in both mice and monkeys. The anti-inflammatory and antiatherogenic effects of 4F include increased pre-beta HDL formation, increased cholesterol efflux, the conversion of pro-inflammatory HDL to anti-inflammatory HDL, and reduced lipoprotein oxidation. In addition, improved arterial vasoreactivity is another important function of 4F. In a rat model of diabetes, D-4F increased arterial concentrations of heme oxygenase-1 (HO-1) and superoxide dismutase, decreased superoxide levels, reduced levels of circulating endothelial cells, decreased endothelial cell fragmentation, and restored arterial vasoreactivity to normal. In a mouse model of systemic sclerosis, D-4F functioned to improve vasodilation and angiogenic potential, while reducing myocardial inflammation and oxidative stress. With respect to mouse models of heart transplant-associated atherosclerosis, D-4F induced HO-1. In addition, D-4F was shown to improve cognitive performance in low-density lipoprotein-receptor null mice with Western diet-induced cognitive decline. D-4F also reduced the kidney content of oxidized phospholipids in a mouse model of hyperlipidemia-induced renal inflammation. In early human studies in patients with significant cardiovascular risk, a single dose of oral D-4F was found to safely improve the anti-inflammatory index of HDL. L-4F is also being studied in clinical trials as a potential treatment modality for obesity and the metabolic syndrome.

SUMMARY

In response to acute infections or vaccines, naive antigen-specific CD8(+) T cells proliferate and differentiate into effector cytotoxic lymphocytes that acquire the ability to kill infected cells. While the majority of differentiated effector cells die after pathogen clearance, a small number evade terminal differentiation, downregulate active effector functions, and survive as long-lived, self-renewing memory T cells. Our understanding of how effector CD8(+) T cells adopt these different cell fates has grown greatly in recent years. In this review, we discuss the transcriptional regulators that are known to support general effector differentiation, terminal effector differentiation, and memory cell formation. We propose that the diversity of activated CD8(+) T-cell differentiation states is achieved via gradients of activity or expression of transcriptional regulators that are regulated by the level of inflammation and antigenic signaling the T cells experience during infection.

A prospective cohort design was used to measure the association between daily cotrimoxazole-prophylaxis and infection with Plasmodium falciparum containing mutations associated with antifolate resistance among persons infected with human immunodeficiency virus (HIV) in Tororo and Busia District, in eastern Uganda. Of 149 cases of P. falciparum parasitemia diagnosed, 147 (99%) (smears from participants taking prophylaxis = 91 and smears from those not taking cotrimoxazole prophylaxis = 56) were successfully assessed for mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutations associated with antifolate resistance. Prevalences of the dhfr pure triple mutant (74% and 70%; P = 0.71), the dhps pure double mutant (95% and 88%; P = 0.21), and the dhfr/dhps pure quintuple mutant (73% and 64%; P = 0.36), were not significantly different between those taking and those not taking cotrimoxazole-prophylaxis, respectively. The overall prevalence of the pure quintuple mutant in this study was 69%, which is among the highest in Africa. Although resistance rates of P. falciparum to antifolate drugs are high, cotrimoxazole-prophylaxis in HIV-infected persons was not associated with a higher prevalence of mutations associated with antifolate resistance.

Earlier recognition of chronic kidney disease (CKD) could slow progression, prevent complications, and reduce cardiovascular-related outcomes. However, current estimates of CKD awareness indicate that both patient- and provider-level awareness remain unacceptably low. Many of the factors that are possibly associated with CKD awareness, which could help guide implementation of awareness efforts, have yet to be fully examined. Also, little is known regarding whether increased patient or provider awareness improves clinical outcomes, or whether there are possible negative consequences of awareness for CKD patients. Further research is necessary to continue to design and refine awareness campaigns aimed at both patients and providers, but there is an immediate need for dissemination of basic CKD information, given both the high prevalence of CKD and its risk factors and the low estimated awareness of CKD.

PURPOSE OF REVIEW

To provide a brief review of methods used in genetic epidemiology studies, an update of recent significant findings in genome-wide studies of kidney disease, and a discussion of the clinical implications of these findings.

RECENT FINDINGS

Recent developments in genetic epidemiology methodologies, specifically the use of genome-wide panels of single nucleotide polymporphisms (SNPs) for association analyses, have yielded exciting insights into the underlying pathogenesis of chronic kidney disease and its progression. The two most notable and promising genetic discoveries are those of MYH9 and UMOD, both of which have been replicated in separate populations.

SUMMARY

Genomic studies have the potential to yield exciting new areas of biological research, potential targets for treatment, and ultimately markers of disease risk. This review addresses recent genetic studies and their implications in chronic kidney disease care.

BACKGROUND

Previously, we found that mast cell tryptases and carboxypeptidase A3 (CPA3) are differentially expressed in the airway epithelium in asthmatic subjects. We also found that asthmatic subjects can be divided into 2 subgroups ("T(H)2 high" and "T(H)2 low" asthma) based on epithelial cell gene signatures for the activity of T(H)2 cytokines.

OBJECTIVES

We sought to characterize intraepithelial mast cells (IEMCs) in asthma.

METHODS

We performed gene expression profiling in epithelial brushings and stereology-based quantification of mast cell numbers in endobronchial biopsy specimens from healthy control and asthmatic subjects before and after treatment with inhaled corticosteroids (ICSs). We also performed gene expression and protein quantification studies in cultured airway epithelial cells and mast cells.

RESULTS

By means of unsupervised clustering, mast cell gene expression in the airway epithelium related closely to the expression of IL-13 signature genes. The levels of expression of mast cell genes correlate positively with lung function improvements with ICSs. IEMC density was 2-fold higher than normal in subjects with T(H)2-high asthma compared with that seen in subjects with T(H)2-low asthma or healthy control subjects (P = .015 for both comparisons), and these cells were characterized by expression of tryptases and CPA3 but not chymase. IL-13 induced expression of stem cell factor in cultured airway epithelial cells, and mast cells exposed to conditioned media from IL-13-activated epithelial cells showed downregulation of chymase but no change in tryptase or CPA3 expression.

CONCLUSION

IEMC numbers are increased in subjects with T(H)2-high asthma, have an unusual protease phenotype (tryptase and CPA3 high and chymase low), and predict responsiveness to ICSs. IL-13-stimulated production of stem cell factor by epithelial cells potentially explains mast cell accumulation in T(H)2-high asthmatic epithelium.

A major source of air pollution exposure in the developing world is smoke due to inefficient cooking with biomass fuels in poorly ventilated homes. Biomass fuel refers to any recently living plant- and/or animal-based material that is deliberately burned by humans as fuel, including wood, crop residues, and animal dung. The levels of exposure to particulate matter in such homes are often at least an order of magnitude higher than the highest concentrations that occur in the ambient air of the developed world. Because roughly half the world's population cooks daily with unprocessed biomass fuel, the potential public health impact is huge. The World Health Organization has estimated that indoor air pollution from solid fuel use is responsible for 2.6% of the total global burden of disease and between 1.5 and 2 million deaths each year, primarily due to acute lower respiratory infection in young children and chronic obstructive pulmonary disease in adult women. Major limitations of the existing epidemiologic literature include lack of actual exposure measurements, lack of longitudinal studies, inadequate exposure-response information, and few intervention studies. Ongoing research in Guatemala is attempting to address these data gaps.

Twenty-four-hour dietary recalls are used frequently to study homebound older adults' eating behaviors. However, the reliability and predictive validity of this method have not been established in this population. The purpose of this study was to examine whether homebound older adults provide reliable and valid measures of total energy intake in 24-hour dietary recalls. Two hundred thirty homebound older adults were interviewed in their homes using a questionnaire to assess eating behaviors and factors that could affect those behaviors. Participants completed three 24-hour dietary recalls at baseline and again at 6-month follow-up. Two subsamples were identified for analyses. For participants who were not hospitalized during the 6-month interval and had their weight measured at both assessments (n=52), sufficient test-retest reliability of energy intake was observed (r=0.59), but energy intake deficiencies relative to estimated energy requirements did not predict actual weight loss (r=0.08). When this sample was supplemented with 91 participants who experienced any adverse event (weight loss of 2.5% or more, hospitalization, institutionalization, or mortality) in the 6-month period (n=143), adverse events were more likely to occur for those with insufficient energy intake (odds ratio 3.49, P=0.009), and in white participants compared to African-American participants (odds ratio 3.13, P=0.016). Adequate test-retest reliability of the 24-hour dietary recall was demonstrated, but additional research with larger samples and longer follow-up intervals is needed to better evaluate the predictive validity of energy intake measures for this population.