Publications

Antigen receptor signaling in lymphocytes has been clearly implicated in the pathogenesis of the rheumatic diseases. Here, we review evidence from mouse models in which B-cell and T-cell signaling machinery is perturbed as well as data from functional studies of primary human lymphocytes and recent advances in human genetics. B-cell receptor hyper-responsiveness is identified as a nearly universal characteristic of systemic lupus erythematosus in mice and humans. Impaired and enhanced T-cell receptor signaling are both associated with distinct inflammatory diseases in mice. Mechanisms by which these pathways contribute to disease in mouse models and patients are under active investigation.

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8 x 10(-5)), establishing a novel phenotype for this genetic variant.

Histone deacetylase (HDAC) inhibitors are a novel class of anti-tumor agents with a potential role in the treatment of breast cancer. In ER-positive cells, treatment with selective and non-selective HDAC inhibitors has been associated with a transcriptional down-regulation (and possibly protein modification via the HSP90 chaperone function) of ER and its response genes. In ER-negative cell lines, HDAC inhibitors have been shown to re-establish ER expression. In addition, HDAC inhibitors have been reported to modulate the progesterone receptor. Despite the opposing effects in ER-positive and ER-negative breast cancer cells, the addition of an HDAC inhibitor potentiated and restored the efficacy of anti-estrogen therapy in preclinical models. This has led to the initiation of several clinical trials combining HDAC inhibitors with anti-estrogen therapy. In this review, we will summarize the relationship between estrogen signaling and HDACs, examine how HDAC inhibitors impact this relationship and synergize with anti-estrogens to inhibit tumor growth, and discuss the clinical possibilities and potential of this new approach.

BACKGROUND

Obesity is an established and modifiable risk factor for urinary incontinence, but conclusive evidence for a beneficial effect of weight loss on urinary incontinence is lacking.

METHODS

We randomly assigned 338 overweight and obese women with at least 10 urinary-incontinence episodes per week to an intensive 6-month weight-loss program that included diet, exercise, and behavior modification (226 patients) or to a structured education program (112 patients).

RESULTS

The mean (+/-SD) age of the participants was 53+/-11 years. The body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) and the weekly number of incontinence episodes as recorded in a 7-day diary of voiding were similar in the intervention group and the control group at baseline (BMI, 36+/-6 and 36+/-5, respectively; incontinence episodes, 24+/-18 and 24+/-16, respectively). The women in the intervention group had a mean weight loss of 8.0% (7.8 kg), as compared with 1.6% (1.5 kg) in the control group (P<0.001). After 6 months, the mean weekly number of incontinence episodes decreased by 47% in the intervention group, as compared with 28% in the control group (P=0.01). As compared with the control group, the intervention group had a greater decrease in the frequency of stress-incontinence episodes (P=0.02), but not of urge-incontinence episodes (P=0.14). A higher proportion of the intervention group than of the control group had a clinically relevant reduction of 70% or more in the frequency of all incontinence episodes (P<0.001), stress-incontinence episodes (P=0.009), and urge-incontinence episodes (P=0.04).

CONCLUSIONS

A 6-month behavioral intervention targeting weight loss reduced the frequency of self-reported urinary-incontinence episodes among overweight and obese women as compared with a control group. A decrease in urinary incontinence may be another benefit among the extensive health improvements associated with moderate weight reduction. (ClinicalTrials.gov number, NCT00091988.)

To determine whether pigment type determines differences in epidermal function, we studied stratum corneum (SC) pH, permeability barrier homeostasis, and SC integrity in three geographically disparate populations with pigment type I-II versus IV-V skin (Fitzpatrick I-VI scale). Type IV-V subjects showed: (i) lower surface pH (approximately 0.5 U); (ii) enhanced SC integrity (transepidermal water loss change with sequential tape strippings); and (iii) more rapid barrier recovery than type I-II subjects. Enhanced barrier function could be ascribed to increased epidermal lipid content, increased lamellar body production, and reduced acidity, leading to enhanced lipid processing. Compromised SC integrity in type I-II subjects could be ascribed to increased serine protease activity, resulting in accelerated desmoglein-1 (DSG-1)/corneodesmosome degradation. In contrast, DSG-1-positive CDs persisted in type IV-V subjects, but due to enhanced cathepsin-D activity, SC thickness did not increase. Adjustment of pH of type I-II SC to type IV-V levels improved epidermal function. Finally, dendrites from type IV-V melanocytes were more acidic than those from type I-II subjects, and they transfer more melanosomes to the SC, suggesting that melanosome secretion could contribute to the more acidic pH of type IV-V skin. These studies show marked pigment-type differences in epidermal structure and function that are pH driven.

Neutralization of stratum corneum (SC) adversely impacts key epidermal functions, including permeability barrier homeostasis and SC integrity. Conversely, acidification of SC improves these functions in developmentally impaired (neonatal or aged) skin, and enhances function in normal skin. Hence, we hypothesized that acidification could alter the course of inflammatory dermatoses, which invariably exhibit an increased SC pH. Maintenance of a low pH by topical applications of the polyhydroxyl acid, lactobionic acid, during the repeated-challenge phase inhibited the development of oxazolone-induced atopic dermatitis (AD). Neither gross/histological dermatitis nor altered barrier function developed, and emergence of epidermal hyperplasia was prevented; however, cytokine generation decreased. Acidification also largely normalized the development of hapten-induced changes in eosinophil/mast cell densities, density of chemoattractant receptor-homologous molecule expressed on TH2-positive lymphocytes, and serum IgE levels. The pH-induced improvement in barrier function most likely accounts for the anti-inflammatory activity, which could be further attributed to normalization of both lamellar body secretion and lamellar bilayer formation. Acidification of SC alone substantially prevents development of barrier abnormalities and downstream immune abnormalities during the elicitation phase of murine AD. These results provide direct evidence for the "outside-inside" pathogenesis of AD and further suggest that maintenance of an acidic SC pH could prevent the emergence of AD in humans.

BACKGROUND

The aim of this paper is to highlight emerging data on occupational attributable risk in asthma. Despite well documented outbreaks of disease and the recognition of numerous specific causal agents, occupational exposures previously had been relegated a fairly minor role relative to other causes of adult onset asthma. In recent years there has been a growing recognition of the potential importance of asthma induced by work-related exposures

METHODS

We searched Pub Med from June 1999 through December 2007. We identified six longitudinal general population-based studies; three case-control studies and eight cross-sectional analyses from seven general population-based samples. For an integrated analysis we added ten estimates prior to 1999 included in a previous review.

RESULTS

The longitudinal studies indicate that 16.3% of all adult-onset asthma is caused by occupational exposures. In an overall synthesis of all included studies the overall median PAR value was 17.6%.

CONCLUSION

Clinicians should consider the occupational history when evaluating patients in working age who have asthma. At a societal level, these findings underscore the need for further preventive action to reduce the occupational exposures to asthma-causing agents.