Publications

BACKGROUND

Psychosocial working conditions are likely to contribute to work-related musculoskeletal disorders (WRMSDs), but a lack of standardized measurement tools reflects both the theoretical and methodological limitations of current research.

METHODS

An interdisciplinary team including biomedical, behavioral, and social science researchers used an iterative process to adapt existing instruments for an interviewer-administered questionnaire assessing psychosocial workplace exposure related to musculoskeletal disorders.

RESULTS

The resulting questionnaire included measures of psychosocial workplace factors based on two theoretical models (the demand-control-support and the effort-reward imbalance models), supplemented by the additional constructs of "emotional demands," and "experiences of discrimination." Other psychosocial and physical measures selected for questionnaire inclusion address physical workload, sociodemographic and anthropometric characteristics, social relations and life events, health behaviors, and physical and psychological health.

CONCLUSION

Using an interdisciplinary approach facilitated the development of a comprehensive questionnaire inclusive of key measures of psychosocial factors that may play a role in the complex mechanisms leading to WRMSDs.

Sweat collection patches are used for drug abuse monitoring. We investigated the effect of sweat patch location (back and shoulder) on cocaine levels after controlled intravenous cocaine exposure (210 mg/70 kg) in 12 subjects (Experiment 1). Gas chromatographic-mass spectrometric analyses show cocaine and metabolites levels in Pharmchek trade mark patches were eightfold higher on the back than those on the shoulders. To assess the mechanisms for possible loss of cocaine from patches during wear, 48 sweat patches with a small amount of cocaine-d(5) (100 ng as base/patch) were placed on the backs of eight cocaine-naive volunteers for up to 72 h (Experiment 2). Drug-free patches were applied over eight of the cocaine-d(5) (100 ng) containing patches to measure loss through the patch. Cocaine levels in spiked patches declined over time (p = 0.002), with levels at 48 h postapplication 30% less than control, consistent with possible drug reabsorption. Cocaine was detectable (> 2 ng/patch, LOQ) in four of eight initially cocaine-free patches placed on top of the cocaine-containing patches, indicating transfer through the patch outer membrane. Conversion to benzoylecgonine was detectable but at low levels (< 2%). Reabsorption (back transfer), degradation or hydrolysis, and loss of cocaine to the environment may account for substantial loss of cocaine from skin sweat collection patches during patch wear.

Infections caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are emerging as a major public health problem. CA-MRSA has been associated previously with skin and soft-tissue infection (SSTI) and with carriage of staphylococcal cassette chromosome mec (SCCmec) type IV and the Panton-Valentine leucocidin (PVL) virulence factor. To assess the clonal distribution of PVL-carrying strains and the association with SSTI in the San Francisco Bay area, we surveyed six collections of S. aureus isolates-671 isolates in all-collected between 1997 and 2002 originating from inpatient and outpatient clinical specimens and from a community-based sampling. Isolates were genotyped by pulsed-field gel electrophoresis, multilocus restriction fragment typing, and multilocus sequence typing and assayed for the PVL virulence factor. The S. aureus populations showed a high proportion of PVL-carrying strains, with frequencies ranging up to 70% in MRSA isolated from jail inmate patients and 69% in MRSA from patients receiving surgical treatment at an outpatient clinic specializing in treating SSTIs. PVL-carrying isolates were identified in nine clonal groups, but 88.5% of the PVL-carrying MRSA isolates belonged to only two clonal groups. These two clonal groups carried the SCCmec type IV resistance determinant and were more likely than other clonal groups to be recovered from SSTI sites than from other sites (P < 0.0001). There is evidence of clonal replacement over the period from 1999 to 2002, with one of these two clonal groups being supplanted by the other.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the U.S. Because cigarette smoking is so importantly implicated in the pathogenesis of COPD and because mucus hypersecretion plays such an important role in COPD, understanding of the mechanisms of smoking-induced mucus hypersecretion could lead to new therapies for COPD. Cigarette smoke causes mucin overproduction via EGF receptor (EGFR) in airway epithelial cells, but the cellular mechanism remains unknown. Airway epithelial cells contain EGFR proligands on their surfaces, which can be cleaved by metalloprotease and subsequently bind to EGFR resulting in mucin production. We hypothesize that TNF-alpha-converting enzyme (TACE) is activated by cigarette smoke, resulting in increased shedding of EGFR proligand, leading to EGFR phosphorylation and mucin induction in human airway epithelial (NCI-H292) cells. Here we show that cigarette smoke increases MUC5AC production in NCI-H292 cells, an effect that is prevented by an EGFR-neutralizing antibody and by specific knockdown of transforming growth factor-alpha (TGF-alpha) using small interfering RNA (siRNA) for TGF-alpha, implicating TGF-alpha-dependent EGFR activation in the responses. Cigarette smoke increases TGF-alpha shedding, EGFR phosphorylation, and mucin production, which are prevented by metalloprotease inhibitors (GM-6001 and TNF-alpha protease inhibitor-1) and by specific knockdown of TACE with TACE siRNA, implicating TACE in smoking-induced responses. Furthermore, pretreatment with antioxidants prevents smoking-induced TGF-alpha shedding and mucin production, suggesting that reactive oxygen species is involved in TACE activation. These results implicate TACE in smoking-induced mucin overproduction via the TACE-proligand-EGFR signal pathway in NCI-H292 cells.

BACKGROUND

HIV replication, HIV-specific T-cell responses and T-cell activation each contributes to disease outcome during untreated HIV infection. The interaction of these factors is not well understood, particularly in the setting of antiretroviral therapy.

METHODS

This is a longitudinal study of antiretroviral-treated patients with plasma HIV RNA levels < 1000 copies/ml. Patients were divided into three groups: suppressed viremia, intermittent viremia ('blips') and persistent low-level viremia. HIV-specific immunity was measured using interferon-gamma ELISPOT. T-cell activation was defined by CD38 and HLA-DR co-expression. Drug resistance was quantified using a phenotypic susceptibility assay.

RESULTS

The breadth and the magnitude of the HIV-specific CD8 T-cell response was greater in patients with either intermittent or persistent viremia compared to patients with suppressed viremia. In contrast, T-cell activation was significantly elevated only in those patients with persistent viremia. Patients with persistent low-level viremia had moderate levels of phenotypic antiretroviral drug resistance that increased over time. Virologic failure (confirmed increase in viral load > 1000 HIV RNA copies/ml) was primarily observed in the persistently viremic group.

CONCLUSIONS

Antiretroviral-treated individuals with intermittent viremia appear to mount an effective HIV-specific T-cell response while not experiencing increases in the level of immune activation. This may limit viral evolution and emergence of drug resistance. In contrast, antiretroviral-treated individuals with persistent low-level viremia exhibit significant increases in overall immune activation and a substantial risk of subsequent treatment failure. It is likely that higher viremia and stronger immune activation act synergistically to accelerate the development of systemic drug resistance.