Mathematical estimation of the potential effect of vascular remodelling/dilatation on B-mode ultrasound intima-medial thickness.

BACKGROUND: Arterial diameter changes are known to impact wall thickness, but the clinical relevance of the changes is unclear. AIM: To use known mathematical relationships to estimate anticipated changes in arterial wall thicknesses occurring with enlargement of atherosclerotic regions. DESIGN: Mathematical relationships between a cylinder's diameter and its wall thickness were used to calculate the theoretical effect of diameter enlargement on the thickness of an atherosclerotic wall. METHODS: Equating the wall areas of two cylinders, one of smaller diameter than the other, allowed estimation of the degree of thickening that would be needed to maintain intima-medial thickness (IMT) after arterial remodelling. The difference in cylinder diameters was based on arterial diameter enlargement reported with atherosclerosis progression. Thus, the calculated wall changes estimate arterial changes which could go undetected if only IMT is measured by ultrasound. RESULTS: The expected IMT change for diameter enlargement is not a linear function of the diameter change, but varies depending upon initial size (diameter and IMT). Thus a 0.6 mm arterial diameter enlargement would be expected to cause a 0.039-0.235 mm change in IMT, depending on artery size. The estimated IMT change is similar to that associated with major atherosclerotic risk factors. DISCUSSION: The level of vascular remodelling reported with atherosclerosis could have a measurable impact on IMT, suggesting that indicators incorporating both diameter and IMT may be better disease indicators than IMT alone. Arterial diameters, as well as IMT, should be obtained in ultrasound studies of atherosclerosis.

Alcohol consumption with age: a cross-sectional and longitudinal study of the Atherosclerosis Risk in Communities (ARIC) study, 1987-1995.

Previous cross-sectional and longitudinal studies assessing the association between age and drinking are inconsistent. Evaluating 15,425 Black and White men and women from four communities, this study sought to determine whether there was a consistent relation between age and drinking in cross-sectional and longitudinal analyses and to determine change in drinking status and level of consumption (occasional, light to moderate, and heavier drinkers) at follow-up. Cross-sectional analyses of drinking were performed for Atherosclerosis Risk in Communities examinations 1 (1987-1989) and 3 (1993-1995). The changes in drinking status and level were determined for the 12,565 persons with information at both examinations. Prevalence of drinking was generally inversely associated with age in the cross-sectional analyses for all ethnic/gender groups, and drinking prevalence decreased over the 6 years of follow-up for all except Black women. Only among Black drinkers was younger age associated with a higher level of alcohol consumption in both cross-sectional and prospective analyses. Thus, whether drinking prevalence declines, the amount consumed by drinkers is decreased, or whether both factors contribute to the decrease appears to vary with ethnicity and gender. The change in drinking level was substantial with more than 40% of baseline drinkers reporting drinking cessation or a different level of consumption at follow-up.

Orthostatic hypotension as a risk factor for stroke: the atherosclerosis risk in communities (ARIC) study, 1987-1996.

BACKGROUND AND PURPOSE: The association between orthostatic hypotension (OH) and stroke has rarely been investigated in longitudinal studies. The purpose of the present study was to determine whether OH predicts ischemic stroke in a middle-aged, biethnic population after adjustment for known stroke risk factors. Diastolic, systolic, and consensus OH were evaluated for baseline associations and for the ability to predict stroke. METHODS: In 11 707 persons from the Atherosclerosis Risk in Communities (ARIC) cohort who were free of stroke and overt heart disease at baseline, Cox proportional hazards analyses modeled the association between OH at baseline and incident ischemic stroke over 7.9 years of follow-up. OH was defined as a systolic blood pressure drop >/=20 mm Hg (systolic OH), a diastolic blood pressure drop >/=10 mm Hg (diastolic OH), or a drop in either (consensus OH) when a person changed from a supine to standing position. RESULTS: OH was predictive of ischemic stroke, even after adjustment for numerous stroke risk factors (consensus OH: hazard ratio, 2.0; 95% CI, 1.2 to 3.2). While the baseline characteristics associated with OH varied depending on the type of OH, all types of OH had a similar risk of stroke. CONCLUSIONS: OH is an easily obtained measurement that may help to identify middle-aged persons at risk for stroke.

Health-associated changes in drinking: a period prevalence study of the Atherosclerosis Risk In Communities (ARIC) cohort (1987-1995).

BACKGROUND: Several investigators have suggested that drinking cessation occurs because of poor health which may bias studies on the benefit or risk of alcohol consumption. METHODS: Drinking status, level of alcohol consumption, and two measures of health (perceived health and physician diagnosed chronic disease status) were determined from exams 1 (1987-1989) and 3 (1993-1995) on 12,562 African- and European-American participants, who were aged 45-64 years at exam 1 in the ARIC Study. For those in good health at exam 1, logistic regression analyses were used to model the association between health decline and drinking change at exam 3. RESULTS: Among the total population, drinking cessation was significantly more common among those who reported poor health at exam 3, and nondrinkers were unlikely to begin drinking regardless of exam 3 health. Using different measures of health status resulted in associations whose strength and significance varied with ethnicity and, in some cases, by gender. CONCLUSION: While the current data do not prove that the health decline occurred prior to drinking cessation, our findings support the hypothesis that poor health results in drinking changes which could potentially bias studies of alcohol's benefit and risk even when lifetime abstainers are used as the reference group.

Anger proneness predicts coronary heart disease risk: prospective analysis from the atherosclerosis risk in communities (ARIC) study.

BACKGROUND: Increased research attention is being paid to the negative impact of anger on coronary heart disease (CHD). METHODS AND RESULTS: This study examined prospectively the association between trait anger and the risk of combined CHD (acute myocardial infarction [MI]/fatal CHD, silent MI, or cardiac revascularization procedures) and of "hard" events (acute MI/fatal CHD). Participants were 12 986 black and white men and women enrolled in the Atherosclerosis Risk In Communities study. In the entire cohort, individuals with high trait anger, compared with their low anger counterparts, were at increased risk of CHD in both event categories. The multivariate-adjusted hazard ratio (HR) (95% CI) was 1.54 (95% CI 1.10 to 2.16) for combined CHD and 1.75 (95% CI 1.17 to 2.64) for "hard" events. Heterogeneity of effect was observed by hypertensive status. Among normotensive individuals, the risk of combined CHD and of "hard" events increased monotonically with increasing levels of trait anger. The multivariate-adjusted HR of CHD for high versus low anger was 2.20 (95% CI 1.36 to 3.55) and for moderate versus low anger was 1.32 (95% CI 0.94 to 1.84). For "hard" events, the multivariate-adjusted HRs were 2.69 (95% CI 1.48 to 4.90) and 1.35 (95% CI 0.87 to 2.10), respectively. No statistically significant association between trait anger and incident CHD risk was observed among hypertensive individuals. CONCLUSIONS: Proneness to anger places normotensive middle-aged men and women at significant risk for CHD morbidity and death independent of the established biological risk factors.

Lower pulmonary function and cerebral subclinical abnormalities detected by MRI: the Atherosclerosis Risk in Communities study.

STUDY OBJECTIVES: To investigate the association between pulmonary function and (1) cerebral infarction and (2) white matter lesions (WMLs), identified by MRI and believed to represent subclinical lesions of arteriosclerosis, generalized hypoperfusion, or ischemia of the brain. DESIGN: Population-based, cross-sectional study. SETTING: Two communities in the United States. PARTICIPANTS: A sample of 1,917 African-American and white men and women 55 to 72 years old who were selected from the second follow-up examination of the Atherosclerosis Risk in Communities Study cohort. INTERVENTIONS: Observational study. MEASUREMENTS AND RESULTS: The lung function indexes, FEV1 and FVC, were assessed according to American Thoracic Society criteria. Subclinical cerebral infarction and WMLs were assessed by MRI. After adjusting for age, ethnicity, gender, height, and height squared, a 1-SD decrease of FEV1 in nonsmokers was associated with odds ratios (95% confidence interval [CI], 1.31 to 2.03) of 1.63 for infarction and 1.35 (95% CI, 1.08 to 1.69) for WMLs. Of those in the lowest quartile of FEV1, 15% had infarction and WMLs, in contrast to 6% of the individuals in the uppermost quartile of FEV1. Consistent associations were also observed by using FVC as an index of pulmonary function. Similar patterns of association were found among current smokers. The associations were not altered by additional adjustment of conventional risk factors of cardiovascular disease, comorbidity, or cognitive function. CONCLUSION: The results from this population-based study suggest that lower pulmonary function is associated with subclinical cerebral abnormalities.

Geographic variations in utilization rates in Veterans Affairs hospitals and clinics.

BACKGROUND: In the United States, geographic variation in hospital use is common. It is uncertain whether there are similar geographic variations in the health care system of the Department of Veterans Affairs (VA), which differs from the private sector because it predominantly serves men with annual incomes below $20,000, has a central system of administration, and uses salaried physicians. Thus, it might be less likely to have geographic variations. METHODS: We used VA data bases to obtain information on patients treated for eight diseases (chronic obstructive pulmonary disease, pneumonia, congestive heart failure, angina, diabetes, chronic renal failure, bipolar disorder, and major depression). We analyzed their use of hospital and outpatient services by assessing the risk-adjusted numbers of hospital days (the average number of days a patient spent in the hospital per 12 months of follow-up, regardless of the number of hospital stays), hospital-discharge rates, and clinic-visit rates from 1991 through 1995 for the entire system and within the 22 geographically based health care networks. RESULTS: We found substantial geographic variation in hospital use for all eight cohorts of patients and all the years studied. Variations in the numbers of hospital days per person-year among the networks were greatest among patients with chronic obstructive pulmonary disease (ranging from a factor of 2.7 to a factor of 3.1) during a given year and smallest among patients with angina (ranging from a factor of 1.5 to a factor of 2.1). Levels of hospital use were highest in the Northeast and lowest in the West. The variation in the rates of clinic visits for principal medical care among the networks ranged from a factor of approximately 1.6 to a factor of 4.0; variations in the rates were greatest among patients with chronic renal failure and smallest among patients with chronic obstructive pulmonary disease. There was no clear geographic pattern in the rates of outpatient-clinic use. CONCLUSIONS: There are significant geographic variations in the use of hospital and outpatient services in the VA health care system. Because VA physicians are unable to increase their income by changing their patterns of practice, our findings suggest that their practice styles are similar to those of other physicians in their geographic regions.

Plasma fibrinogen and incident hypertension in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Several cross-sectional studies have reported a positive association between plasma fibrinogen levels and prevalent hypertension. Other studies have reported a positive association between hypertension and whole-blood or plasma viscosity, to which fibrinogen contributes. To our knowledge, there has been no prospective study of fibrinogen and incident hypertension. SUBJECTS AND METHODS: We measured plasma fibrinogen levels in a population-based cohort study of middle-aged adults and related it to the occurrence of incident hypertension (systolic blood pressure > or = 140 mmHg or diastolic blood pressure > or = 90 mmHg or use of antihypertensive medication) over 6 years. RESULTS: There was a moderately strong positive association between fibrinogen levels and prevalent hypertension in both men and women, with the odds of hypertension elevated by 50% for the highest fibrinogen quartile versus the lowest. Among 7884 participants at risk, 1609 developed hypertension over 6 years. Adjusted for age, race, field center and baseline systolic blood pressure, the odds ratio of incident hypertension in relation to fibrinogen quartiles was 1.0, 1.07, 1.21 and 1.43 in men (P= 0.003 for trend) and 1.0, 0.92, 0.99 and 0.99 in women (P= 0.89 for trend). After adjustment for other risk factors, the odds ratios were 1.0, 1.03, 1.15 and 1.29 (P= 0.045 for trend) in men and remained nonsignificant in women. CONCLUSIONS: Despite a moderately strong positive association between fibrinogen levels and prevalent hypertension in both sexes, there was only a weak positive association between fibrinogen levels and incident hypertension in men and no association in women. Whether an elevated fibrinogen level is a risk factor for, or a consequence of, hypertension remains unclear.

Heterozygous alpha 1-antitrypsin phenotypes in patients with end stage liver disease.

OBJECTIVE: The objective of the study was to determine the prevalence and associations of abnormal alpha1-antitrypsin phenotypes in Caucasian adults with end stage liver disease with particular emphasis on heterozygous phenotypes and disease from hepatitis C virus. METHODS: All patients (788) with end stage liver disease considered for liver transplantation from July 1990 to June 1996 in a referral-based university hospital transplant center (University of Nebraska Medical Center, Omaha, NE) comprised the study population. Data for the study population was determined by retrospective review of the transplantation database at the transplant center. Hepatitis C virus infection was determined by a second generation ELISA method, and alpha1-antitrypsin phenotyping was performed on agarose gel with serum quantitation using a Behring Nephelometer. RESULTS: Among 683 Caucasian patients with severe liver disease, the prevalences of Pi ZZ, Pi MZ, and Pi MS were 0.4, 7.3, and 8.2%, respectively, compared with 0, 2.8, and 4.2% in the control population. The odds of having a heterozygous Z phenotype were significantly increased in Caucasian patients with hepatitis C virus (odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.1-9.0), alcoholic liver disease (OR = 5.0, 95% CI = 2.6-9.6), primary hepatic malignancy (OR = 7.4, 95% CI = 2.9-19.0), and cryptogenic cirrhosis (OR = 2.6, 95% CI = 1.1-6.3) compared with the control population. Caucasian patients with hepatitis C or B virus were 3.6 times more likely to have a heterozygous Z phenotype than a normal phenotype compared with patients with diseases of autoimmune etiology. CONCLUSION: This study provides evidence of an association of heterozygous Z alpha1-antitrypsin phenotype with end stage liver disease of several etiologies, not hepatitis C virus alone.

Cellular blebbing in superficial colonic epithelial cells occurring with murine graft-versus-host disease.

Subnuclear blebbing of the superficial colonic epithelium, a rarely described light and electron microscopic change in graft-versus-host disease (GVHD), was studied in a murine model of GVHD. Severity of changes induced by transfer of various donor T cell subsets to irradiated, allogeneic recipients, and association with more severe alterations such as erosions and ulceration were evaluated. By light microscopy the basal region of the superficial enterocytes was greatly expanded by eosinophilic to amphophilic, flocculent, sometimes vacuolated material. By electron microscopy these changes were found to be organelle-poor, cytoplasm-filled protrusions from the basal surface of the epithelium. In this model, helper T cells (CD(4+)-enriched, CD(8+)-depleted T cells) transplanted after high dose irradiation were capable of causing the change suggesting cytokine responses may be involved in mediating the cellular injury seen histologically. Close association of blebbing and erosions suggest the blebbing may be the precursor to epithelial erosion or denudation seen in severe intestinal GVHD.

Apoptosis and necrosis. Basic types and mechanisms of cell death.

Apoptosis and necrosis are two fundamental types of cell death. Current knowledge indicates that the key mechanism of apoptosis is endonuclease activation leading to internucleosomal double-stranded chromatin (DNA) breaks, whereas the key mechanism of necrosis is cell membrane damage. The initial alterations of cellular metabolism and electrolyte homeostasis induced by an injurious agent may activate at least four major pathways leading to loss of membrane integrity: membrane phospholipid degradation, production of amphipathic lipids, damage to the cytoskeleton, and generation of toxic oxygen species and free radicals. These insights point the way for further research to establish definitive causes of specific types of cell injury and cell death, and they provide important clues for the design of improved diagnostic approaches and therapeutic interventions.

Barium sulfate crystals in a fine needle aspiration biopsy specimen from a neck mass in a patient with squamous cell carcinoma. A case report.

A fine needle aspirate of a neck mass in a 79-year-old man with a previous laryngectomy for squamous cell carcinoma was submitted for examination. In addition to cytologic findings of squamous cell carcinoma, there were numerous birefringent crystals of varying shapes and sizes. Energy dispersive x-ray analysis confirmed that these crystals were barium sulfate. Recognition of barium sulfate crystals in a fine needle aspiration or other cytologic specimens is important since barium granulomas may mimic neoplasms clinically. Barium sulfate may also indicate rupture of an organ or the presence of a fistula.

Histologic similarity of murine colonic graft-versus-host disease (GVHD) to human colonic GVHD and inflammatory bowel disease.

In a study designed to determine which T-cell subsets are involved in the development of murine graft-versus-host disease (GVHD), a prospective histologic analysis of gastrointestinal involvement was performed. In C57BL/6JXDBA/2F1 (B6D2F1) recipients of DBA/2 donor spleen and bone marrow cells, the colonic histologic findings were found to be similar in many respects to the histologic findings reported in human colonic GVHD and were much more severe and diffuse than were the abnormalities of the small intestine. Host irradiation before transplantation was found to play an additive or synergistic role in the development of GVHD. Furthermore the histologic features noted in DBA/2----B6D2F1 murine colonic GVHD suggest that bone marrow and spleen cell transplantation in this strain combination may be a useful model for studying the immunologic mechanisms involved in human inflammatory bowel disease. Thus severe colonic disease noted during the course of DBA/2----B6D2F1 murine GVHD was found to have significant histopathologic similarities to both human GVHD enteropathy and other inflammatory diseases of the human colon.

Intestinal graft-versus-host disease is initiated by donor T cells distinct from classic cytotoxic T lymphocytes.

In these studies, the role of T helper and T cytotoxic cells in generating intestinal graft-vs.-host disease (GVHD) was examined. Treatment of C57BL/6J (B6) splenocytes with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) selectively removes natural killer cells, cytotoxic T lymphocyte (CTL) precursors, and the capacity to cause lethal GVHD in irradiated B6xDBA/2 F1 (B6D2F1) mice while preserving T helper cell function. Neither control nor Leu-Leu-OMe-treated DBA/2 donor spleen and bone marrow cells were found to induce lethal GVHD in B6D2F1 recipients. However, extensive colonic GVHD developed in B6D2F1 recipients of DBA/2 bone marrow and spleen cells. Enteropathic GVHD in DBA/2----B6D2F1 mice was reduced in severity after anti-L3T4 + C treatment of donor cells, and was eliminated by anti-Thy1.2 + C or the combination of anti-L3T4 and anti-Lyt2 + C treatment of the donor cell inoculum. However, neither anti-Lyt2 + C, Leu-Leu-OMe, nor anti-Lyt2 + C and Leu-Leu-OMe treatment of donor cells significantly decreased severity of gut GVHD. Leu-Leu-OMe treatment of DBA/2 or B6 SpC was comparably effective in preventing in vitro or in vivo generation of B6D2F1-specific CTL. These findings, therefore, demonstrate that histologically severe enteropathic GVHD does not require participation of CTL and is not always associated with high mortality rates.

Anti-growth action on mouse mammary and prostate glands of a monoclonal antibody to prolactin receptor.

Monoclonal antibody (PrR-7A) against purified PRL receptor was used in the following studies. When PRL receptor was chromatographed on affinity columns containing PrR-7A antibody or monoclonal antibody against hemocyanin, which served as a control, PRL receptor was bound to the column containing PrR-7A antibody, but not to the column containing control antibody. When solubilized PRL receptor was incubated with PrR-7A antibody, the specific binding of the receptor was reduced 52%. Female mice were treated with the carcinogen, 7,12-dimethylbenz[a]anthracene, and during the succeeding 48 weeks were treated weekly with PrR-7A antibody or control antibody. In the control group 13% developed mammary carcinomas, and 16% developed moderate-to-severe intraductal hyperplasia. No mammary carcinomas were found in the mice treated with PrR-7A antibody, and only 8% of the mice had moderate-to-severe intraductal hyperplasia. Male mice made hyperprolactinemic by implanted pituitary glands were treated weekly with PrR-7A or control antibody. After 7 weeks of treatment, the mean weight of the prostates of mice treated with PrR-7A antibody was 8 +/- 1.1 mg (mean +/- SE), and that of mice treated with control antibody was 27 +/- 3.6 mg. Similar differences were seen in the protein and DNA content of the prostates. These results indicate that PrR-7A antibody is directed against PRL receptor and that immunization with this antibody reduces the incidence of PRL-dependent mammary tumors and preneoplastic ductal hyperplasia and prevents PRL-induced hyperplasia of the prostate.

Fine needle aspiration cytology of a rhabdomyoma of the pharynx.

The fine needle aspiration (FNA) cytology of an extracardiac adult rhabdomyoma of the pharynx is documented. The smear of the aspirate contained large cells with peripherally located, uniform, round nuclei and abundant granular eosinophilic cytoplasm. In addition to these features, peripheral vacuoles were seen in sections of a cell block prepared from the aspirate. Special stains of the cell block sections and of the surgical specimen showed cross striations in some cells while electron microscopy showed the typical features of adult rhabdomyoma. The findings in this case suggest that FNA can diagnose this rare, benign neoplasm when it presents as a solitary mass in the head and neck region. Its differential diagnosis from other neoplasms that occur in that area is discussed.