Publications

The objectives of this study were to evaluate whether there were higher rates of primary congenital hypothyroidism (PCH) or elevated concentrations of thyroid-stimulating hormone (TSH) in a community where perchlorate was detected in groundwater wells. The adjusted PCH prevalence ratio and 95% confidence interval (CI) comparing the study community to San Bernardino and Riverside counties combined was 0.45 (95% CI=0.06-1.64). The odds ratios for elevated TSH concentration were 1.24 (95% CI=0.89-1.68) among all newborns screened and 0.69 (95% CI=0.27-1.45) for newborns whose age at screening was 18 hours or greater. Age of the newborn at time of screening was the most important predictor of the TSH level. These findings suggest that residence in a community with potential perchlorate exposure has not impacted PCH rates or newborn thyroid function.

AIM

Recent data suggests that LDL particle concentration, as determined by Nuclear Magnetic Resonance (NMR) spectroscopy, may be associated with cardiovascular risk. We sought to determine the effect of randomization to pravastatin therapy on LDL particle concentration-NMR, among a primary prevention population.

METHODS AND RESULTS

LDL particle concentration-NMR, LDL size-NMR, and standard chemical lipid parameters were measured at baseline and after 12 weeks among 500 individuals without overt coronary disease randomly allocated to pravastatin 40mg (n=256) or placebo (n=244). Randomization to pravastatin therapy caused a 19% reduction in median LDL particle concentration-NMR at 12 weeks, as compared to a 4.2% increase among those randomized to placebo (P<0.001 for pravastatin group compared to placebo). Pravastatin therapy caused a median 24.9% reduction in LDL cholesterol measured chemically compared to a 0.9% increase in the placebo group (P<0.001). Pravastatin therapy did not cause a significant change in median LDL size-NMR (0.5% increase in pravastatin group vs 0.0% in placebo group; P=0.25). The change in LDL particle concentration with pravastatin correlated inversely with baseline LDL size (r=-0.24; P<0.001) such that the largest reduction in LDL particle concentration-NMR was among those with the smallest LDL size-NMR at baseline (median% change =21.4% for tertile 1 of LDL size, 19.9% for tertile 2, and 16.5% for tertile 3; P=0.03). In contrast, pravastatin-induced changes in LDL cholesterol did not correlate with baseline LDL size-NMR (r=-0.05; P=0.47).

CONCLUSION

Among individuals without overt hyperlipidemia or known coronary artery disease, randomized allocation to pravastatin (40mg) therapy for 12 weeks caused a reduction in LDL particle concentration-NMR, the magnitude of which was dependent on baseline LDL size-NMR.

Atrial fibrillation (AF) is a difficult and growing problem in the population. While medical therapy controls symptoms in many patients, a proportion of individuals with this common arrhythmia cannot be optimally managed with drugs alone. However, truly curative therapy for AF has always been one of the "holy grails" of electrophysiology. The surgical maze procedure was the first to offer permanent maintenance of sinus rhythm in patients with AF but subjected the patient to open heart surgery; a catheter-based translation of the maze procedure served as proof of concept that a catheterization technique could be used to treat AF. Subsequent experience has narrowed the electrophysiologist's attention to ablation of triggers of AF, most often residing in the pulmonary veins, rather than requiring more extensive ablation lines to control the arrhythmia. The following discussion deals with the development and current status of techniques for catheter ablation of atrial fibrillation, focusing on determination of appropriate target sites for ablation.

Transforming growth factor-beta1 (TGF-beta1) and the renin-angiotensin-aldosterone system are key mediators in kidney fibrosis. Integrin alphavbeta6, a heterodimeric matrix receptor expressed in epithelia, binds and activates latent TGF-beta1. We used beta6 integrin-null mice (beta6(-/-)) to determine the role of local TGF-beta1 activation in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Obstructed kidneys from beta6(-/-) mice showed less injury than obstructed kidneys from wild-type (WT) mice, associated with lower collagen I, collagen III, plasminogen activator inhibitor (PAI-1), and TGF-beta1 mRNA levels and lower collagen content. Infusion with either angiotensin II (Ang II) or aldosterone (Aldo) or combination in beta6(-/-) UUO mice significantly increased collagen contents to levels comparable to those in identically treated WT. Active TGF-beta protein expression in beta6(-/-) mice was less in UUO kidneys with or without Ang II infusion compared to matched WT mice. Activated Smad 2 levels in beta6(-/-) obstructed kidneys were lower than in WT UUO mice, and did not increase when fibrosis was induced in beta6(-/-) UUO mice by Ang II infusion. Anti-TGF-beta antibody only partially decreased this Ang II-stimulated fibrosis in beta6(-/-) UUO kidneys. In situ hybridization and immunostaining showed low expression of PAI-1 mRNA and protein in tubular epithelium in beta6(-/-) UUO kidneys, with increased PAI-1 expression in response to Ang II, Aldo, or both. Our results indicate that interruption of alphavbeta6-mediated activation of TGF-beta1 can protect against tubulointerstitial fibrosis. Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed beta6(-/-) mice by Ang II suggests the existence of a TGF-beta1-independent pathway of induction of fibrosis through angiotensin.

Carboxypeptidase A (CPA) is a metalloprotease, residing in the mast cell secretory granules together with chymases and tryptases. Little information is available with respect to the mechanisms that maintain or regulate the levels of stored proteases in the mast cell secretory granules. In this study we examined whether cathepsins C and S may be involved in the control of the levels of mast cell proteases. Mast cells cultured from bone marrow of cathepsin C- or S-null mice expressed higher levels of CPA protein and activity than cells from wild-type mice. Similar increases in protein were observed for the mouse chymase, mast cell protease-5 (mMCP-5), but not for the tryptase, mMCP-6. Steady-state levels of CPA and mMCP-5 mRNA were similar in wild-type and cathepsin C-null mast cells, indicating that post-transcriptional mechanisms explain the observed cathepsin C-dependence of CPA and mMCP-5 expression. The present study thus indicates novel roles for cathepsins C and S in regulating the levels of stored proteases in the mast cell secretory granules.

There is accumulating evidence that the workplace environment contributes significantly to the general burden of asthma. The purpose of this review is to explore the respiratory health and socioeconomic consequences of work-related asthma by addressing a series of controversial issues: 1) what is the natural history of occupational asthma and in what ways does ongoing exposure to the causal agent impact clinical outcomes?; 2) how does the natural history of irritant-induced asthma differ in its health outcomes from immunologically-mediated occupational asthma?; 3) do working conditions have a significant impact on asthma regardless of the aetiology of the disease?; 4) what is the scope of work disability from work-related-asthma in social and economic terms?; 5) what is the clinician's role in reducing the respiratory health consequences of work-related asthma? 6) to what extent do existing compensation and other social insurance schemes successfully address occupational asthma and work-aggravated asthma?

BACKGROUND

Gas stoves release respiratory irritants, such as nitrogen dioxide and other combustion by-products. Adults with asthma may be susceptible to the effects of gas stove exposure because of their underlying airway hyperresponsiveness, but this association has been difficult to establish.

AIMS

To examine the association between gas stove use and respiratory health.

METHODS

The analysis used data from the US Third National Health and Nutrition Examination Survey among 445 adults with asthma (representing 4.8 million persons with the condition).

RESULTS

Nearly half of the adults with asthma had a gas stove in their home (47.1%). There was no association between gas stove use and FEV1 (mean change 146 ml; 95% CI -50 to 342 ml), FVC (0 ml; 95% CI -151 to 152 ml), or FEF25%-75% (357 ml; 95% CI -7 to 722 ml). There was also no relation between gas stove use and the risk of self reported cough (OR 0.8; 95% CI 0.4 to 1.7), wheeze (OR 1.5; 95% CI 0.7 to 3.2), or other respiratory symptoms. Controlling for sociodemographic, smoking, housing, and geographic factors did not appreciably affect these results.

CONCLUSIONS

Among adults with asthma, there was no apparent impact of gas stove use on pulmonary function or respiratory symptoms. These results should be reassuring to adults with asthma and their health care providers.

Upper-respiratory-tract symptoms (nasal irritation, congestion and rhinorrhea) are prevalent complaints in so-called "problem buildings." In epidemiologic studies, symptom reporting is associated with selected subject characteristics, including younger age, female gender, and the presence of allergic rhinitis. The physiologic correlates of these differential reporting patterns, however, are largely unknown. Using dilute chlorine gas as a model upper-respiratory-tract irritant, we studied 52 otherwise healthy volunteers in a sample stratified on age (18-69 yr), gender, and allergy status. In a single-blinded crossover study, subjects had their nasal airway resistance measured preexposure, immediately postexposure, and 15 min postexposure to both filtered air and chlorine (1.0 ppm in air) for 15 min. Allergic rhinitic subjects showed a significantly greater net (chlorine minus air) congestive response at 15 min postexposure than did nonrhinitic controls (p <.01). Advancing age also predicted a greater response immediately post-exposure (p <.01). No gender effect was observed. Significant interindividual variability was evident in the nasal congestive response to irritant (chlorine) provocation. The rhinitis effect was consistent with prior observations, whereas the effect of advancing age was opposite to that hypothesized.

Noxious stimuli activate neuroendocrine axes, inhibiting inflammation, an effect that is powerfully attenuated by ongoing activity in subdiaphragmatic vagal afferents. To evaluate whether this inhibitory effect of vagal afferent activity is mediated by descending antinociceptive control, we tested whether antagonizing descending antinociceptive controls: (i) enhances the inhibition of inflammation produced by spinal nicotine (which stimulates central terminals of nociceptors) and (ii) occludes the enhancing effect of subdiaphragmatic vagotomy, in the rat. Spinal intrathecal co-administration of the alpha-adrenergic receptor antagonist phentolamine and the non-selective opioid receptor antagonist naloxone, and acute subdiaphragmatic vagotomy each produced enhancement, with similar magnitude, of nicotine-induced inhibition of plasma extravasation, produced by the potent inflammatory mediator, bradykinin. The combination of subdiaphragmatic vagotomy and intrathecal receptor antagonists, however, produced no further enhancement compared to each treatment alone. These findings support the suggestion that activity in descending antinociceptive controls modulates noxious stimulus-induced inhibition of inflammation and the vagal modulation of noxious stimulus-induced inhibition of inflammation is mediated by descending antinociceptive controls.