Edward L. Peterson

Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors.

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.

Smoking cessation in young adults: age at initiation of cigarette smoking and other suspected influences.

OBJECTIVES Previous research has suggested that early smoking initiation predicts longer duration of smoking, heavier daily consumption, and increased chances of nicotine dependence. This report set out to estimate the relationship between smoking cessation and age of initiation, as well as nicotine dependence, sex, race, and education. METHODS A sample of 1007 young adults was randomly selected from a large health maintenance organization in southeast Michigan. Hazard ratios of quitting associated with age at smoking initiation were estimated among 414 persons who smoked daily for 1 month or more. RESULTS With potential confounders controlled for, the likelihood of cessation was significantly higher in smokers who initiated smoking after age 13. The hazard ratio for quitting associated with smoking initiation at ages 14 to 16 was 1.6 and with initiation at or after age 17 was 2.0, compared with initiation at or before 13 years of age. Factors that decreased the likelihood of cessation were nicotine dependence and low education. CONCLUSIONS Public policy to discourage early smoking, if it succeeds in delaying the initiation of smoking, might contribute to the reduction of smoking-related mortality and morbidity by increasing the potential for quitting.

The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living

We assessed exposure to pesticides, farming, well water use, and rural living as risk factors for Parkinsons disease (PD) in a population-based case-control study consisting of men and women ≥50 years of age who had primary medical care at Henry Ford Health System in metropolitan Detroit. Enrolled PD patients (n = 144) and control subjects (n = 464) were frequency-matched for age, race, and sex. When adjusted for these variables and smoking status, there was a significant association of occupational exposure to herbicides (odds ratio [OR], 4.10; 95% CI, 1.37, 12.24) and insecticides (OR, 3.55; 95% CI, 1.75, 7.18) with PD, but no relation was found with fungicide exposure. Farming as an occupation was significantly associated with PD (OR, 2.79; 95% CI, 1.03, 7.55), but there was no increased risk of the disease with rural or farm residence or well water use. The association of occupational exposure to herbicides or insecticides with PD remained after adjustment for farming. The association of farming with PD was maintained after adjustment for occupational herbicide exposure and was of borderline significance after adjustment for occupational insecticide exposure. These results suggest that PD is associated with occupational exposure to herbicides and insecticides and to farming and that the risk of farming cannot be accounted for by pesticide exposure alone.

A second look at comorbidity in victims of trauma: the posttraumatic stress disorder-major depression connection.

BACKGROUND We examine whether traumatic events increase the risk for major depression independent of their effects on posttraumatic stress disorder (PTSD). METHODS Data come from the Epidemiologic Study of Young Adults in southeast Michigan (N = 1007). Retrospective and prospective data were used to estimate the risk of major depression in persons with PTSD and persons exposed to trauma with no PTSD, compared with persons who did not experience a trauma. National Comorbidity Survey data were used to evaluate the influence of trauma type. RESULTS In the retrospective lifetime data, hazard ratios were, for first-onset major depression in exposed persons with PTSD, 2.8 and, in exposed persons with no PTSD, 1.3 (not significant), as compared with persons who were not exposed. Corresponding estimates from the prospective data were 11.7 and 1.4 (not significant). The difference in the risk for depression associated with PTSD versus exposure without PTSD is unlikely to be due to differences in trauma type. CONCLUSIONS The findings of a markedly increased risk for major depression in persons with PTSD, but not in exposed persons without PTSD, do not support the hypothesis that PTSD and major depression in trauma victims are influenced by separate vulnerabilities.

Motor Activity Assessment Scale: A valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit

OBJECTIVE To establish the validity and reliability of a new sedation scale, the Motor Activity Assessment Scale (MAAS). DESIGN Prospective, psychometric evaluation. SETTING Sixteen-bed surgical intensive care unit (SICU) of a 937-bed tertiary care, university-affiliated teaching hospital. PATIENTS Twenty-five randomly selected, adult, mechanically ventilated, nonneurosurgical patients who were admitted to the SICU > or = 12 hrs after surgery and were not receiving neuromuscular blockers. INTERVENTION Four hundred assessments (eight per patient) were completed consecutively but independently, in pairs, at standardized times (both day and night) by two nurses who were preselected for each assessment from a pool of 32 pretrained SICU nurses. MEASUREMENTS AND MAIN RESULTS To estimate validity, paired assessments (four/patient) compared the MAAS result with the subjective assessment using a 10-cm visual analog sedation scale, the percent change in blood pressure and heart rate from the previous 4-hr baselines, and the number of recent agitation-related sequelae. To estimate reliability, paired assessments (four/patient) measured correlation between assessments of the same type (e.g., MAAS-MAAS). Generalized estimating equations, which accounted for the four repeated measures in each patient, supported MAAS validity by finding a linear trend between MAAS and the visual analog scale (p < .001), blood pressure (p < .001), heart rate (p < .001), and agitation-related sequelae (p < .001) end points. The MAAS (kappa = 0.83 [95% confidence interval, 0.72 to 0.94]) was found to be more reliable than subjective assessment using the visual analog scale (intraclass correlation coefficient = 0.32 [95% confidence interval, 0.05 to 0.55]). CONCLUSIONS The MAAS is a valid and reliable sedation scale for use with mechanically ventilated patients in the SICU. Further studies are warranted regarding the effect of MAAS implementation in our SICU on patient outcomes, such as quality of sedation and length of mechanical ventilation, as well as the use of the MAAS in other patient populations (e.g., medical).

Sex differences in depression: a role for preexisting anxiety

The role of anxiety disorders in the development of sex differences in major depression is analyzed. Data come from a longitudinal epidemiologic study of young adults in the Detroit, Michigan area. The Diagnostic Interview Schedule, revised according to DSM-III-R, was used at baseline to measure lifetime psychiatric disorders and at follow-up to measure psychiatric disorders during the 3.5-year interval since baseline assessment. Consistent with previous reports, the lifetime prevalence of major depression was nearly two-fold higher in females than in males. The sex difference was primarily in major depression comorbid with anxiety disorders. Results from Cox-proportional hazards models, with time-dependent covariates, showed that prior anxiety disorder increased the risk for subsequent major depression in both sexes, with no evidence of an interaction. History of anxiety disorder, including number of prior anxiety disorders, accounted for a considerable part of the observed sex difference in major depression. Controlling for prior anxiety reduced by more than 50% the coefficient that estimates the association between gender and major depression. The results suggest that the higher occurrence of anxiety disorders in females than males beginning early in life might explain in large part the higher female risk for major depression. They emphasize the need for further research on sex differences in anxiety disorders.

Smoking and Parkinson's disease: a dose-response relationship.

Objective: To determine whether an inverse dose–response relationship exists between cigarette smoking and PD among ever-smokers and ex-smokers. Methods: Smoking and alcohol consumption were analyzed in 144 PD patients and 464 control subjects, who were frequency matched for sex, race, and age (±5 years), in a population-based case-control study of men and women ≥50 years old in the Henry Ford Health System. Results: With never-smokers as the reference category, there was an inverse association between current light smokers (>0 to 30 pack-years) and PD patients (odds ratio [OR], 0.59; 95% CI, 0.23 to 1.53), and a stronger inverse association of PD with current heavy smokers (>30 pack-years; OR, 0.08; 95% CI, 0.01 to 0.62). When former >30–pack-year smokers were stratified by the interval since quitting, there was an inverse association between those who stopped >20 years ago and PD (OR, 0.86; 95% CI, 0.42 to 1.75), and a greater inverse relationship with those who stopped 1 to 20 years ago (OR, 0.37; 95% CI, 0.19 to 0.72). Alcohol consumption had no independent, significant association with PD, but heavy drinking (>10 drink-years) had a greater effect than light–moderate drinking in reducing but not eliminating the inverse association between smoking and PD. Conclusions: The inverse dose–response relationship between PD and smoking and its cessation is unlikely to be due to bias or confounding, as discussed, providing indirect evidence that smoking is biologically protective.

A Randomized Trial of Sodium Fluoride as a Treatment for Postmenopausal Osteoporosis

The anti-fracture efficacy of sodium fluoride (NaF) was evaluated in 84 postmenopausal white women with spinal osteoporosis. The dose of NaF used was 75 mg/day and all patients in this prospective, randomized, double-blind, placebo-controlled clinical trial received calcium supplements (carbonate salt) 1500 mg/day in addition to participating in a structured physical therapy program. For each of the outcome measures (change in stature, change in cortical bone mass in the forearm and development of new vertebral fractures determined by change in vertebral morphometry and by scintigraphy) there was no significant difference between the fluoride or placebo treated groups. Side effects, predominantly gastrointestinal symptoms and the development of the painful lower extremity syndrome, occurred significantly more frequently in the fluoride group (P<0.05). Peripheral fractures were not more frequent in the fluoride group. We conclude that, in the dose and manner used in this study, NaF is no more effective than placebo in retarding the progression of spinal osteoporosis. There is no role for NaF in the treatment of osteoporosis outside the confines of clinical research.

Multiple risk factors for Parkinson's disease

OBJECTIVE To determine the relative contribution of various risk factors to the development of Parkinsons disease (PD). METHODS Ten variables that were independently associated with PD in a health system population-based case-control study of epidemiological risk factors for the disease were jointly assessed. Stepwise logistic regression, adjusted for sex, race and age was used to develop a multiple variate model that best predicted the presence of PD. The population attributable risk was estimated for each variable in the final model, as well as for all factors together. RESULTS The 10 initial variables included >20 years occupational exposure to manganese or to copper, individually; >20 years joint occupational exposure to either lead and copper, copper and iron, or lead and iron; a positive family history of PD in first- or second-degree relatives; occupational exposure to insecticides or herbicides; occupational exposure to farming; and smoking. Logistic regression resulted in a final model that included >20 years joint occupational exposure to lead and copper (p=0.009; population attributable risk [PAR]=3.9%), occupational exposure to insecticides (p=0.002; PAR=8.1%), a positive family history of PD in first- and second-degree relatives (p=0.001; PAR=12.4%), and smoking </=30 pack-years or not smoking (p=0.005; PAR=41.4%). All four variables combined had a PAR=54.1%. CONCLUSIONS Our final model of PD risk suggests that occupational, environmental lifestyle and, likely, genetic factors, individually and collectively, play a significant role in the etiology of the disease. Clearly, additional risk factors remain to be determined through future research.

Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence.

BACKGROUND Asthma is an inflammatory condition often punctuated by episodic symptomatic worsening, and accordingly, patients with asthma might have waxing and waning adherence to controller therapy. OBJECTIVE We sought to measure changes in inhaled corticosteroid (ICS) adherence over time and to estimate the effect of this changing pattern of use on asthma exacerbations. METHODS ICS adherence was estimated from electronic prescription and fill information for 298 participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity. For each patient, we calculated a moving average of ICS adherence for each day of follow-up. Asthma exacerbations were defined as the need for oral corticosteroids, an asthma-related emergency department visit, or an asthma-related hospitalization. Proportional hazard models were used to assess the relationship between ICS medication adherence and asthma exacerbations. RESULTS Adherence to ICS medications began to increase before the first asthma exacerbation and continued afterward. Adherence was associated with a reduction in exacerbations but was only statistically significant among patients whose adherence was greater than 75% of the prescribed dose (hazard ratio, 0.61; 95% CI, 0.41-0.90) when compared with patients whose adherence was 25% or less. This pattern was largely confined to patients whose asthma was not well controlled initially. An estimated 24% of asthma exacerbations were attributable to ICS medication nonadherence. CONCLUSIONS ICS adherence varies in the time period leading up to and after an asthma exacerbation, and nonadherence likely contributes to a large number of these exacerbations. High levels of adherence are likely required to prevent these events.