Publications

People with HIV infection have metabolic abnormalities that resemble metabolic syndrome (hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance), which is known to predict increased risk of cardiovascular disease (CVD). However, there is not one underlying cause for these abnormalities and they are not linked to each other. Rather, individual abnormalities can be affected by the host response to HIV itself, specific HIV drugs, classes of HIV drugs, HIV-associated lipoatrophy, or restoration to health. Furthermore, one component of metabolic syndrome, increased waist circumference, occurs less frequently in HIV infection. Thus, HIV infection supports the concept that metabolic syndrome does not represent a syndrome based on a common underlying pathophysiology. As might be predicted from these findings, the prevalence of CVD is higher in people with HIV infection. It remains to be determined whether CVD rates in HIV infection are higher than might be predicted from traditional risk factors, including smoking.

The pro-opiomelanocotin (POMC) plays a key role in body weight regulation, where its derived peptides mediate leptin action via the hypothalamic melanocortin 4 receptor (MC4R). The pathogenic effects of POMC mutations have been challenged in obesity. Our aim was to assess the relevance of POMC mutations in a cohort of French obese and nonobese children. Direct sequencing of the POMC gene was performed in 322 obese and 363 control unrelated children. Functional studies for the novel Phe144Leu mutation included the response to alpha-melanocyte stimulating hormone (alphaMSH) and a competitive binding assay. POMC mutations were identified in 3.72% of obese [95% confidence interval (CI): 1.66-5.80] and 2.20% of control (95% CI: 0.69-3.71) subjects. The novel mutation located in the alphaMSH region of the POMC gene (Phe144Leu) was found in one obese child and was transmitted by the obese father. Functional studies showed that MC4R activation in response to Leu144alphaMSH was almost completely abolished due to a dramatically altered binding of Leu144alphaMSH to MC4R. The frequency of POMC mutations is not significantly different between obese and control children in our cohort. The novel heterozygous mutation Phe144Leu leading to the absence of melanocortin signaling was associated with early-onset obesity suggesting its pathogenic role.

Expression of the autoimmune regulator (Aire) protein in mice and humans is thought to be restricted to the medullary epithelial and monocyte-dendritic cells of the thymus. There it mediates expression and presentation of a large variety of proteins, including those that are peripheral organ-specific and are not expressed by other thymocytes. In this way, self-reactive T lymphocytes that would attack peripheral cells producing these proteins are confronted with the self-Ags and, as a consequence, are deleted. In this study, we show that Aire mRNA is also expressed in the testis--another tissue with promiscuous gene expression. Aire protein, however, is expressed only sporadically in spermatogonia and spermatocytes. Transcription of genes that are under Aire control in the thymus is unaffected by Aire in the testis. However, in mice with a disrupted Aire gene, the scheduled apoptotic wave of germ cells, which is necessary for normal mature spermatogenesis, is reduced, and sporadic apoptosis in adults is increased. Because Rag-1 deficiency does not abolish the effect, the adaptive immune system is not involved. We suggest that there is a link between the scheduled and sporadic apoptotic processes and propose that scheduled apoptosis provides a counterselection mechanism that keeps the germline stable.

BACKGROUND

We examined the potential clinical utility of using a cytomegalovirus (CMV)-specific T cell immunoassay to determine the risk of developing new-onset CMV retinitis (CMVR) in patients with acquired immunodeficiency syndrome (AIDS).

METHODS

CMV-specific T cell assays were performed by multiparameter flow cytometry using stored peripheral blood mononuclear cells that had been obtained in an observational study 2-6 months before new-onset CMVR was diagnosed in case patients (at a study visit during which a dilated ophthalmologic examination revealed no evidence of CMVR) and at the same study visit in control subjects (matched by absolute CD4(+) T cell count at entry) who did not subsequently develop retinitis during 1-6 years of study follow-up.

RESULTS

There were no significant differences in CMV-specific CD4(+) or CD8(+) T cell interferon-gamma or interleukin-2 expression in peripheral blood mononuclear cells from case patients and control subjects. Although there were trends toward lower percentages and absolute numbers of CMV-specific, cytokine-expressing CD8(+) T cells with a "late memory" phenotype (CD27(-)CD28(-)) as well as with an "early memory" phenotype (CD27(+)CD28(+)CD45RA(+)) in case patients than in control subjects, these differences were not statistically significant.

CONCLUSIONS

Many studies have reported that CMV-specific CD4(+) and CD8(+) T cell responses distinguish patients with active CMVR (i.e., who lack CMV-protective immunity) from those with inactive CMVR after immune restoration by antiretroviral treatment (i.e., who have CMV-protective immunity). However, the multiple CMV-specific immune responses we measured do not appear to have clinical utility for predicting the risk for patients with AIDS of developing new-onset CMVR with sufficient accuracy to be used in guiding therapeutic management.

OBJECTIVE

To determine complications and neurologic outcomes associated with dexamethasone administration to dogs with surgically treated thoracolumbar intervertebral disk herniation, compared with dogs not receiving dexamethasone.

DESIGN

Retrospective case series.

ANIMALS

161 dogs with surgically confirmed thoracolumbar disk herniation.

PROCEDURES

Medical records from 2 hospitals were used to identify dogs that had received dexamethasone < 48 hours prior to admission (dexamethasone group dogs), dogs that received glucocorticoids other than dexamethasone < 48 hours prior to admission (other-glucocorticoid group dogs), and dogs that received no glucocorticoids (nontreatment group dogs). Signalment, neurologic injury grade, laboratory data, and complications were extracted from medical records.

RESULTS

Dexamethasone group dogs were 3.4 times as likely to have a complication, compared with other-glucocorticoid or nontreatment group dogs. Dexamethasone group dogs were 11.4 times as likely to have a urinary tract infection and 3.5 times as likely to have diarrhea, compared with other-glucocorticoid or nontreatment group dogs. No differences in neurologic function at discharge or recheck evaluation were detected among groups.

CONCLUSIONS AND CLINICAL RELEVANCE

Results indicated that treatment with dexamethasone before surgery is associated with more adverse effects, compared with treatment with glucocorticoids other than dexamethasone or no treatment with glucocorticoids, in dogs with thoracolumbar intervertebral disk herniation. In this study population, no difference in outcome was found among groups. These findings suggest that the value of dexamethasone administration before surgery in dogs with thoracolumbar disk herniation should be reconsidered.

BACKGROUND

Innate immune system stimuli, such as endotoxin, seem to affect allergy risk. Previously, we described gene-environment interactions between the endotoxin receptor polymorphism C-260T of the CD14 gene and endotoxin exposure on total serum IgE level; however, the mechanism of this interaction is not known.

OBJECTIVE

To examine whether this gene-environment interaction affects early CD4(+)Foxp3(-) or CD4(+)Foxp3(+) lymphocyte numbers.

METHODS

Participating children were part of a birth cohort in the Detroit metropolitan area. Participants were genotyped for the CD14 C-260T polymorphism. Endotoxin exposure was estimated from dust measured in the home when children were 6 months old. Intracellular Foxp3 protein expression, a regulatory T-cell marker, was used to characterize CD4(+) lymphocytes in blood samples collected at the age of 12 months; total serum IgE level was also measured at this time. Because race/ethnicity may confound or modify genetic associations, all analyses were stratified by race/ethnicity.

RESULTS

We observed a significant gene-environment interaction between CD14 C-260T genotype and endotoxin exposure on CD4(+) lymphocyte numbers, particularly CD4(+)Foxp3(-) lymphocytes. Stratified analyses suggest effect modification by race/ ethnicity on CD4(+)Foxp3(+) lymphocyte numbers, with a significant interaction in African American children but not in white children. The interaction between CD14 C-260T genotype and endotoxin exposure on total IgE levels was opposite that observed for CD4(+) lymphocyte numbers, suggesting reciprocal relationships.

CONCLUSIONS

A gene-environment interaction between endotoxin and CD14 C-260T genotype on IgE levels may be the result of an upstream, opposing effect on CD4(+)Foxp3(+) and CD4(+)Foxp3(-) lymphocyte numbers. Race/ethnicity may affect which of these cell populations is affected by this gene-environment interaction.

Small heat shock proteins (sHSPs), or alpha-crystallins, are low-molecular weight proteins found in every kingdom and nearly every species examined to date. Many, if not all, sHSPs act as molecular chaperones. Several also have functions independent of their chaperone activity, and at least a few are expressed in specific spatiotemporal patterns during embryonic and/or juvenile stages, suggesting specific roles during development. To date, however, no one has systematically characterized the expression patterns of all of the sHSPs during development in any organism. We have characterized the normal heat shock-induced expression patterns of all 13 zebrafish sHSPs during development. Seven of the sHSPs are expressed in a tissue-specific manner during development, and five are upregulated by heat shock. The results of these studies provide a foundation for analysis of sHSP function during normal development and their roles in protecting cells from the effects environmental stressors.