Publications

BACKGROUND

Isocyanates remain a leading cause of work-related asthma (WRA).

METHODS

Two independent data systems were analyzed for the period 1993-2008: (1) State-based WRA case surveillance data on persons with isocyanate-induced WRA from four states, and (2) Occupational Safety and Health Administration (OSHA) Integrated Management Information System (IMIS) isocyanate air sampling results.

RESULTS

We identified 368 cases of isocyanate-induced WRA from 32 industries and 678 OSHA isocyanate air samples with detectable levels from 31 industries. Seventeen industries were unique to one or the other dataset.

CONCLUSION

Isocyanate-induced WRA continues to occur in a wide variety of industries. Two data systems uncovered industries with isocyanate exposures and/or illness. Improved control measures and standards, including medical surveillance, are needed. More emphasis is needed on task-specific guidance, spill clean-up procedures, skin and respiratory protection, and targeted medical monitoring to mitigate the hazards of isocyanate use.

The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. Significance statement: The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids.

Novel targeted cancer therapies, especially kinase inhibitors, have revolutionized the treatment of many cancers and have dramatically improved the survival of several types of malignancies. Because kinases not only are important in cancer development and progression, but also play a critical role in the cardiovascular (CV) system and metabolic homeostasis, important CV and metabolic sequelae have been associated with several types of kinase inhibitors. This paper reviews the incidences and highlights potential mechanisms of vascular and metabolic perturbations associated with 3 classes of commonly used kinase inhibitors that target the vascular endothelial growth factor signaling pathway, the ABL kinase, and the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathway. We propose preventive, screening, monitoring, and management strategies for CV care of patients treated with these novel agents.

IMPORTANCE

Smoke-free laws are associated with a lower prevalence of smoking.

OBJECTIVE

To quantify the effect of 100% smoke-free laws on the smoking behavior of adolescents and young adults in a longitudinal analysis.

DESIGN, SETTING, AND PARTICIPANTS

Pooled logistic regression and zero-inflated negative binomial regression analysis of participants in the National Longitudinal Survey of Youth 1997 (data from 1997 to 2007), with complete data on initiation of smoking (n = 4098) and number of days respondents reported smoking in the past 30 days (n = 3913).

EXPOSURES

Laws for 100% smoke-free workplaces, laws for 100% smoke-free bars, and state cigarette taxes.

MAIN OUTCOMES AND MEASURES

Smoking initiation (first report of smoking cigarette), current (for 30 days) smoking, and number of days respondents reported smoking in the past 30 days among current smokers.

RESULTS

Laws for 100% smoke-free workplaces, but not bars, were associated with significantly lower odds of initiating smoking (odds ratio, 0.66 [95% CI, 0.44-0.99]). Laws for 100% smoke-free bars were associated with lower odds of being a current smoker (odds ratio, 0.80 [95% CI, 0.71-0.90]) and fewer days of smoking (incidence rate ratio, 0.85 [95% CI, 0.80-0.90]) among current smokers. Taxes were associated with a lower percentage of new smokers but not current smokers among adolescents and young adults. The effect of smoke-free workplace laws on smoking initiation is equivalent to a $1.57 (in 2007 dollars) tax increase. Smoke-free bar laws are associated with lower rates of current smoking, as well as a decrease in the number of days reported smoking among current smokers.

CONCLUSIONS AND RELEVANCE

Smoke-free laws are an important tobacco control tool. They not only protect bystanders from secondhand smoke but also contribute to less smoking among adolescents and young adults.

BACKGROUND

Prognosis associated with metastatic renal cell carcinoma (mRCC) can vary widely.

METHODS

This study used pretreatment nephrectomy specimens from a randomized phase III trial. Expression levels of candidate genes were determined from archival tumors using the OpenArray® platform for TaqMan® RT-qPCR. The dataset was randomly divided at 2:1 ratio into training (n = 221) and testing (n = 103) sets to develop a multigene prognostic signature.

FINDINGS

Gene expressions were measured in 324 patients. In the training set, multiple models testing 424 candidate genes identified a prognostic signature containing 8 genes plus MSKCC clinical risk factors. In the testing set, the time dependent (td) AUC for a prognostic model containing the 8 genes with and without MSKCC risk factors were 0.72 and 0.69, respectively. The tdAUC for the clinical risk factors alone was 0.61. Additional primary mRCCs from patients with mRCC (n = 12) were sampled in multiple sites and standard deviations of gene expressions within a tumor were used as a measure of heterogeneity. All 8 genes in the final prognostic model met our criteria for minimal heterogeneity.

CONCLUSIONS

A molecular prognostic signature based on 8 genes was developed and is ready for external validation in this patient population and other related settings such as nonmetastatic RCC.

To examine the T cell receptor structure in the absence of B cells, the TCR β CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V-J combinations, derived from both productive and non-productive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cell receptor contained significantly fewer deletions and insertions in V, D, and J gene segments, differences intrinsic to the V(D)J recombination process and not due to peripheral T cell selection. XLA CDR3s demonstrated fewer charged amino acid residues, more sharing of CDR3 sequences, and almost completely lacked a population of highly modified Vβ gene segments found in control DNA, suggesting both a skewed and contracted T cell repertoire in XLA.