Spirometry reference values for American Indian adults: results from the Strong Heart Study.

STUDY OBJECTIVE: To derive spirometry normative values from a large population of American Indian adults and compare them to reference values for white adults. DESIGN: Pulmonary function was assessed using spirometry in participants of the Strong Heart Study, a multicenter, community-based, prospective study of cardiovascular risk factors and disease in American Indians, utilizing American Thoracic Society guidelines and a vigorous quality assurance program. SETTING: Central Arizona, southwestern Oklahoma, central South Dakota, and northeastern North Dakota. PARTICIPANTS: Acceptable spirometry results were obtained from 1,619 women and 1,005 men aged 45 to 74 years. RESULTS: Internal reference values and normal ranges for FEV(1), FVC, and the FEV(1)/FVC ratio were derived from a healthy subgroup of 253 women and 190 men, identified by excluding participants with factors associated with a lower FEV(1). Ten percent of the entire cohort (269 of 2,624 subjects) had airways obstruction, as defined by an FEV(1)/FVC below the lower limit of the normal (LLN) using the internal reference equations. After allowing for measurement "noise," 31 participants were below the LLN using reference equations for white adults from the large National Health and Nutrition Examination Study (NHANES) III study but were normal using the internal reference equations (1.3% false-positive), while 27 participants were classified as normal using NHANES III equations but had airways obstruction using the internal reference equations (1.2% false-negative). Similarly low misclassification rates were seen for a low FVC (prevalence, 17.6%). CONCLUSION: For clinical purposes, NHANES III spirometry reference equations for white adults may be used when testing American Indian women and men aged 45 to 74 years.

A population-based assessment of left ventricular systolic dysfunction in middle-aged and older adults: the Strong Heart Study.

BACKGROUND: Although clinical congestive heart failure (CHF) is increasingly common, few data document the prevalence and correlates of underlying left ventricular (LV) systolic dysfunction (D) in population-based samples. METHODS: Echocardiography was used in the second Strong Heart Study (SHS) examination to identify mild and severe LVD (LV ejection fraction [EF] 40%-54% and <40%, respectively) in 3184 American Indians. RESULTS: Mild and severe LVD were more common in men than women (17.4% vs 7.2% and 4.7% vs 1.8%) and in diabetic than nondiabetic participants (12.7% vs 9.1% and 3.5% vs 1.6%). Stepwise increases were observed from participants with normal EF to those with mild and severe LVD in age (mean 60 vs 61 and 63 years, P <.001), prevalence of overt CHF (2% vs 6% and 28%) and definite coronary heart disease (3% vs 11% and 32%), systolic pressure (129 vs 135 and 136 mm Hg), serum creatinine level (0.98 vs 1.34 and 2.16 mg/dL), and log urinary albumin/creatinine level (3.2 vs 3.7 and 4.7); a negative relation was seen with body mass index (31.1 vs 31.0 and 28.4 kg/m(2)) (all P <.001). In multivariate analyses lower LVEFs were independently associated with clinical CHF and coronary heart disease, lower myocardial contractility, male sex, hypertension, overweight, arterial stiffening (higher pulse pressure/stroke volume) and renal dysfunction (higher serum creatinine level), higher LV mass, and lower relative wall thickness. CONCLUSIONS: LVD, present in approximately 14% of middle-aged to elderly adults, is independently associated with overt heart failure and coronary heart disease, male sex, hypertension, overweight, arterial stiffening, and renal target organ damage and, less consistently, with older age and diabetes.

How to establish a lasting relationship with your host: lessons learned from Mycobacterium spp.

Mycobacterium spp. enjoy an intracellular lifestyle that is fatal to most microorganisms. Bacilli persist and multiply within mononuclear phagocytes in the face of defences ranging from toxic oxygen and nitrogen radicals, acidic proteases and bactericidal peptides. Uptake of Mycobacterium by phagocytes results in the de novo formation of a phagosome, which is manipulated by the pathogen to accommodate its needs for intracellular survival and replication. The present review describes the intracellular compartment occupied by Mycobacterium spp. and presents current ideas on how mycobacteria may establish this niche, placing special emphasis on the involvement of mycobacterial cell wall lipids.

Differences in echocardiographic findings and systemic hemodynamics among non-diabetic American Indians in different regions: The Strong Heart Study.

PURPOSE: This study was undertaken to determine whether differences in left ventricular (LV) and systemic hemodynamic findings exist between American Indians in different regions that might contribute to known differences in cardiovascular morbidity rates among American Indians. METHODS: We compared echocardiography results in 290 non-diabetic Strong Heart Study (SHS) participants in Arizona, 595 in Oklahoma and 572 in North/South Dakota (ND/SD). RESULTS: Participants in the 3 regions were similar in age and gender but those in Arizona had the highest body mass indices and lowest heart rates while those in ND/SD had the lowest diastolic blood pressures (BP). In analyses that adjusted for significant covariates, ND/SD participants had larger aortic (Ao) anular, Ao root, and LV chamber size as well as higher cardiac output and lower peripheral resistance, whereas Arizona participants had increased LV wall thickness and mass and reduced LV myocardial contractility. These findings may contribute to the known high rates of cardiovascular events in ND/SD Indians and to the proportionately higher rate of cardiovascular death than of non-fatal cardiovascular events that has been recently documented in Arizona Indians. CONCLUSIONS: Application of echocardiography to non-diabetic SHS participants reveals that LV chamber and arterial size are larger in ND/SD Indians and that LV wall thicknesses and mass are higher and LV myocardial contractility lower in Arizona Indians, possibly contributing to the higher than expected rates of cardiovascular morbidity and mortality among Indians in Arizona.

Impact of diabetes on cardiac structure and function: the strong heart study.

BACKGROUND: Whether diabetes mellitus (DM) adversely affects left ventricular (LV) structure and function independently of increases in body mass index (BMI) and blood pressure is controversial. METHODS AND RESULTS: Echocardiography was used in the Strong Heart Study, a study of cardiovascular disease in American Indians, to compare LV measurements between 1810 participants with DM and 944 with normal glucose tolerance. Participants with DM were older (mean age, 60 versus 59 years), had higher BMI (32.4 versus 28.9 kg/m(2)) and systolic blood pressure (133 versus 124 mm Hg), and were more likely to be female, to be on antihypertensive treatment, and to live in Arizona (all P<0.001). In analyses adjusted for covariates, women and men with DM had higher LV mass and wall thicknesses and lower LV fractional shortening, midwall shortening, and stress-corrected midwall shortening (all P<0.002). Pulse pressure/stroke volume, a measure of arterial stiffness, was higher in participants with DM (P<0.001 independent of confounders). CONCLUSIONS: Non-insulin-dependent DM has independent adverse cardiac effects, including increased LV mass and wall thicknesses, reduced LV systolic chamber and myocardial function, and increased arterial stiffness. These findings identify adverse cardiovascular effects of DM, independent of associated increases in BMI and arterial pressure, that may contribute to cardiovascular events in diabetic individuals.

Effective preexposure tuberculosis vaccines fail to protect when they are given in an immunotherapeutic mode.

Two vaccine formulations previously shown to induce protective immunity in mice and prevention of long-term necrosis in guinea pigs were tested as potential immunotherapeutic vaccines in mice earlier infected by aerosol with Mycobacterium tuberculosis. Neither vaccine had any effect on the course of the infection in the lungs, but both reduced the bacterial load in the spleen. Similarly, inoculation with Mycobacterium bovis BCG had no effect whatsoever and, if given more than once, appeared to induce an increasingly severe pyogranulomatous response in the lungs of these mice.

Trafficking and release of mycobacterial lipids from infected macrophages.

Analysis of infected macrophages revealed that lipid-containing moieties of the mycobacterial cell wall are actively trafficked out of the mycobacterial vacuole. To facilitate the analysis of vesicular trafficking from mycobacteria-containing phagosomes, surface-exposed carbohydrates were labeled with hydrazide-tagged markers. The distribution of labeled carbohydrate/lipid moieties and subsequent interaction with cellular compartments were analyzed by immunoelectron microscopy and by fluorescence microscopy of live cells. The released mycobacterial constituents were associated with several intracellular organelles and were enriched strikingly in tubular endocytic compartments. Subcellular fractionation of infected macrophages by density gradient electrophoresis showed temporal movement of labeled bacterial constituents through early and late endosomes. Thin layer chromatography analysis of these subcellular fractions confirmed their lipid nature and revealed five dominant bacteria-derived species. These mycobacterial lipids were also found in extracellular vesicles isolated from the medium and could be observed in un-infected 'bystander' cells. Their transfer to bystander cells could expand the bacteria's sphere of influence beyond the immediate confines of the host cell.

Rising tide of cardiovascular disease in American Indians. The Strong Heart Study.

BACKGROUND: Although cardiovascular disease (CVD) used to be rare among American Indians, Indian Health Service data suggest that CVD mortality rates vary greatly among American Indian communities and appear to be increasing. The Strong Heart Study was initiated to investigate CVD and its risk factors in American Indians in 13 communities in Arizona, Oklahoma, and South/North Dakota. METHODS AND RESULTS: A total of 4549 participants (1846 men and 2703 women 45 to 74 years old) who were seen at the baseline (1989 to 1991) examination were subjected to surveillance (average 4.2 years, 1991 to 1995), and 88% of those remaining alive underwent a second examination (1993 to 1995). The medical records of all participants were exhaustively reviewed to ascertain nonfatal cardiovascular events that occurred since the baseline examination or to definitively determine cause of death. CVD morbidity and mortality rates were higher in men than in women and were similar in the 3 geographic areas. Coronary heart disease (CHD) incidence rates among American Indian men and women were almost 2-fold higher than those in the Atherosclerosis Risk in Communities Study. Significant independent predictors of CVD in women were diabetes, age, obesity (inverse), LDL cholesterol, albuminuria, triglycerides, and hypertension. In men, diabetes, age, LDL cholesterol, albuminuria, and hypertension were independent predictors of CVD. CONCLUSIONS: At present, CHD rates in American Indians exceed rates in other US populations and may more often be fatal. Unlike other ethnic groups, American Indians appear to have an increasing incidence of CHD, possibly related to the high prevalence of diabetes. In the general US population, the rising prevalence of obesity and diabetes may reverse the decline in CVD death rates. Therefore, aggressive programs to control diabetes and its risk factors are needed.

All-cause mortality and cardiovascular disease mortality in three American Indian populations, aged 45-74 years, 1984-1988. The Strong Heart Study.

Community mortality surveillance for 1984-1988 was conducted by researchers of the Strong Heart Study, which examined the incidence, prevalence, and risk factors of cardiovascular disease in three American Indian populations, aged 45-74 years, in Arizona, Oklahoma, and South/North Dakota. All-cause and cardiovascular disease mortality rates were determined through the use of death certificate data. Cardiovascular disease deaths were confirmed by independent systematic review of medical records. In all three populations, men had higher all-cause and cardiovascular disease mortality rates than did women. Oklahoma exhibited slightly lower 5-year, age-adjusted, all-cause mortality (96/1,000) than did Arizona (107/1,000) and South/North Dakota (114/1,000). The leading cause of death among both sexes in Oklahoma and in South/North Dakota was cardiovascular disease. Diabetes mellitus led among Arizona women. The other major causes of death were cancer, liver disease including cirrhosis, and injury. When compared with the rates in each state, average annual all-cause mortality rates were higher for the American Indian populations in almost every age group. The all-cause annual mortality rates in the three Indian populations were close to rates in the US black population and higher than the rates of the entire US population and of US whites. This trend was amplified in the 45- to 64-year age group. Only in the 65- to 74-year age group did mortality rates in the Indian population approach those of the US population. Cardiovascular disease mortality rates were close to the US averages in Arizona and Oklahoma, but they were more than two times higher in South/North Dakota among those between 45 and 64 years of age. Thus, American Indians in Arizona, Oklahoma, and South/North Dakota exhibit high all-cause mortality rates. In particular, the South/North Dakota population cardiovascular disease death rate appears to present a potential target for community-based programs to intervene on known risk factors to promote healthy lifestyles.

Disruption of the cellular inflammatory response to Listeria monocytogenes infection in mice with disruptions in targeted genes.

The results of this study to dissect the nature of the acquired immune response to infection with Listeria monocytogenes in mice with targetted gene disruptions show that successful resolution of disease requires the essential presence of alphabeta T cells and the capacity to elaborate gamma interferon. In the absence of either of these entities, mice experience increasingly severe hepatitis and tissue necrosis and die within a few days. The data from this study support the hypothesis that the protective process is the efficient replacement of neutrophils in lesions by longer-lived mononuclear phagocytes; alphabeta-T-cell-knockout mice died from progressive infection before neutrophil replacement could occur, whereas in gammadelta-T-cell-knockout mice this replacement process in the liver has previously been shown to be much slower. In the present study we attribute this delay to reduced production of the macrophage-attracting chemokine MCP-1 in the gammadelta-T-cell-knockout animals. These data further support the hypothesis that gammadelta T cells are important in controlling the inflammatory process rather than being essential to the expression of protection.

The changing requirements for health manpower and the University of Oklahoma College of Medicine.

Sweeping national changes in health care financing and delivery are forcing major modifications in the numbers, types, and distribution of physician manpower thought to be appropriate for the new paradigms. Not surprisingly, these changes are exerting great pressure on medical education institutions to also adapt to the changing requirements. In Oklahoma, these financial and policy changes are accompanied by demands upon the colleges of medicine to increase the numbers of physicians who locate their practices in rural locations. The maintenance of a comprehensive and well balanced basic and advanced medical education effort within these complex and shifting requirements continues to tax the abilities of all faculties, including the Oklahoma University College of Medicine (OUCOM).

Similar responses by macrophages from young and old mice infected with Mycobacterium tuberculosis.

The growth of four isolates of Mycobacterium tuberculosis was compared in cultures of bone marrow-derived macrophages generated from young (3 months) and old (24 months) female C57BL/6 mice. In all four cases, no differences were seen in the course of the in vitro infection over a 10-day culture period. Macrophages from both young and old mice secreted similar levels of nitric oxide if treated with interferon gamma (IFN) 24 h prior to infection. Expression of mRNA encoding an array of early response genes in the two sets of cultures was also generally similar. These data indicate that the capacity of macrophages to respond to infection with a virulent intracellular bacterial infection does not seem to be influenced by the increasing age of the host.

Susceptibility of a panel of virulent strains of Mycobacterium tuberculosis to reactive nitrogen intermediates.

Murine bone marrow-derived macrophages were infected with a panel of virulent isolates of Mycobacterium tuberculosis including laboratory strains Erdman and H37Rv and various clinical isolates in order to determine the sensitivity of each of these strains to the antimycobacterial activities of macrophage-generated reactive nitrogen intermediates (RNI). All of the M. tuberculosis strains grew in murine bone marrow-derived macrophages; however, gamma interferon-primed macrophages limited the initial growth of intracellular bacilli. Some of the mycobacterial strains, including Erdman, were killed over the first 4 days of infection, as evidenced by significant decreases in the number of viable intracellular bacilli determined by a CFU assay. Other mycobacterial strains were not killed during this same period, and some isolates, including CSU 24 and CSU 31, grew steadily in activated macrophages. The accumulation of nitrite on infected monolayers was measured, and it was found that inhibitory levels of RNI did not vary among infections with the different strains. Nitrite tolerance was determined in a cell-free system for each of the strains in order to compare susceptibilities of the strains to RNI. All of the strains tested were killed by levels of RNI generated by the acidification of 10 mM NaNO2 to pH 6.5 or 5.5, and the strains exhibited a range of tolerance to lower concentrations of RNI. No correlations were observed between such cell-free RNI tolerances and the capacity of bacilli to resist macrophage RNI-mediated killing. These results indicate that under stringent conditions, RNI can kill M. tuberculosis, but that under less harsh, more physiological conditions, the effects of RNI range from partial to negligible inhibition.

Progression of chronic pulmonary tuberculosis in mice aerogenically infected with virulent Mycobacterium tuberculosis.

There are several critical differences in the pulmonary granulomatous response to Mycobacterium tuberculosis between the mouse and other animal models such as the guinea pig or rabbit. One key difference is a conspicuous lack of central caseating necrosis in pulmonary lesions of immunologically intact mice. To determine whether normal mice could develop such pathology in response to highly virulent clinical isolates of M. tuberculosis, C57BL/6 mice were infected aerogenically with varying doses of three different strains, and the development of a granulomatous response was followed for as long as a year. Whereas such conditions failed to induce caseating necrosis in the lungs of these mice, all of the infections induced a granulomatous response which progressed similarly. We present here a descriptive report of the gross pathological progression of tuberculosis in the lungs of the mice. In each case, the disease progressed in five discrete stages, which were delineated on the basis of several criteria including the extent of granulomatous involvement, the cell types present, the degree of lymphocyte organization, and the presence of destructive sequelae such as airway epithelium erosion and airway debris. Quicker progression of disease along these five stages was induced by increasing the size of the inoculum or by the more virulent mycobacterial strains. The infections with the virulent strains were not resolved, and the later stages of the granulomatous response coincided with an increasing bacillary load and a loss of organized lymphocytes in the infected lungs which ultimately resulted in the death of the host. These results indicate that although C57BL/6 mice do not manifest a caseating form of pulmonary tuberculosis, they manifest an equally pathogenic granulomatous response which appears as a chronic interstitial fibrosing response that fails to contain the infection at a time that organized lymphocyte involvement wanes in the lung.

Health care of Oklahoma Indians.

The many unique aspects of Indian life extend into the health care arena, of special interest in Oklahoma, the "home of the red man." The long historical relationship of certain Indian tribes with the federal government has resulted in one of the most complicated social, administrative, and governmental arrangements anywhere. A consequence of this relationship was, in effect, a business transaction resulting in the ceding of virtually all Indian lands of the U.S. and an assumption by the latter to provide certain services, including health care, to affected tribes. With the 33 different tribes in Oklahoma; the dual entitlement possessed by Indian people; the contributions of the Indian Health Service to the economy of Oklahoma; and the growing revolution in health care, knowledge of the special circumstances of Indian life and health care is important even for practitioners who do not regularly encounter Indian people in their own practices.

Rheumatoid arthritis in a United States Public Health Service Hospital in Oklahoma: serologic manifestations in rheumatoid arthritis vary among tribal groups.

OBJECTIVE: To study the serologic manifestations of rheumatoid arthritis (RA) at a United States Public Health Service Hospital that serves numerous tribes in Oklahoma. METHODS: Forty-five patients with RA were identified, and serologic studies for antinuclear antibody (ANA), rheumatoid factor, and antibodies to extractable nuclear antigens were performed. Extraarticular manifestations of RA were also evaluated. RESULTS: Twelve of the 45 patients with RA were Kiowa. These patients were significantly more likely to have a positive ANA (75%) than the other patients with RA (28%). In addition, anti-Ro was significantly more common among Kiowa (33%) than among members of other tribes (3%). There was no difference in the extraarticular manifestations of the Kiowa compared with the other Native American tribes. CONCLUSION: RA can be distinctly characterized by serology among groups of American Indians living in the same geographic area.

American Indians and Alaska Natives--overview of the population.

THE ESTIMATED TWO MILLION American Indians and Alaska Natives, while sharing certain genetic traits, belong to groups with distinct social, cultural, political, and biomedical attributes. They share with certain other ethnic minorities high poverty rates, low educational attainment, increased susceptibility to certain diseases, and elevated mortality rates. Hypertension has been reported less frequently among American Indians compared to other U.S. groups, but is increasing in frequency, is strongly associated with obesity and diabetes, and is synergistically associated with diabetes in the etiology of end-stage renal disease. The first priority for dealing with hypertension among American Indians is to maximize efforts toward control. The Indian Health Service (IHS) provides such an opportunity, which is not as readily available to other minorities. In addition to controlling hypertension, areas of fruitful investigation include studies relating hypertension to acculturation, physiology of peripheral adrenergic vasoreceptors, salt and water metabolism, and prevention or amelioration of end-stage renal disease. Understanding some of these basic processes will prove valuable for American Indians and Alaska Natives as well as the entire population.

The University of Oklahoma College of Medicine Rural Health Educational Program.

Training of physicians to meet the health care needs of rural residents has long been a priority of the University of Oklahoma College of Medicine. With establishment of the much imitated Rural Preceptorship Program in 1948, the college launched an ongoing series of efforts all directed toward increasing the number of graduates choosing to practice in rural locations. In addition to the required senior Preceptorship Program, a series of educational programs is available in each year of medical school, actually beginning prior to freshman enrollment. As a result, the college now offers a comprehensive series of educational experiences involving not only four years of medical school, but graduate training in the primary care specialties as well. This report summarizes the various activities of the college that now make up the rural emphasis program, all of which are designed to help ensure an adequate supply of physicians for rural Oklahoma.

Chemokine response in mice infected with Mycobacterium tuberculosis.

We show here that infection of murine macrophages with various strains of Mycobacterium tuberculosis induces the rapid in vitro expression of genes encoding chemokines macrophage inflammatory protein 1 alpha and macrophage inflammatory protein 2, which recruit neutrophils to sites of infection, and macrophage-recruiting chemokines 10-kDa, interferon-inducible protein (IP-10) and macrophage chemotactic protein 1. Three strains of M. tuberculosis, Erdman and the clinical isolates CSU 22 and CSU 46, induced similar levels of secretion of macrophage chemotactic protein 1 from infected macrophage monolayers; however, the Erdman strain failed to induce levels of secretion of tumor necrosis factor alpha similar to those induced by either CSU 22 or CSU 46. Using a low-dose aerosol infection model, we also found that while the Erdman strain induced negligible increases in chemokine mRNA levels in the lungs, infection with either CSU 22 or CSU 46 resulted in greater levels of mRNA production for all four chemokines tested. The growth of these strains in the lungs was, however, equally well contained by acquired host immunity. These data allow us to hypothesize that the chemokine response in the lungs probably does not control the protective granulomatous response and that perhaps other T-cell- or macrophage-associated cytokines such as tumor necrosis factor alpha or interleukin 12 may be involved in this process.