Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension.

The angiotensin converting enzyme (ACE) is a key component of the renin angiotensin system that contributes to the regulation of blood pressure (BP). Recent demonstration of linkage between the ACE locus and elevated BP in a rat model of hypertension has further emphasized ACE as a candidate gene in human hypertension. We report the localization of the ACE gene on the genetic map of chromosome 17, and identify an extremely polymorphic marker at the human growth hormone (hGH) locus which shows no recombination with ACE. We have found no evidence to support linkage between the ACE locus and hypertension, which suggests that mutations at the ACE locus do not commonly contribute to the pathogenesis of hypertension in our test population.

Neonatal thymectomy prevents spontaneous diabetes mellitus in the BB/W rat.

Complete neonatal thymectomy reduced the frequency of spontaneous diabetes mellitus in BioBreeding/Worcester rats from 27 to 3 percent. Incomplete thymectomy also significantly reduced the frequency of diabetes (to 9 percent). These findings strengthen the hypothesis that thymus-dependent, cell-mediated autoimmune destruction of pancreatic B cells is responsible for the pathogenesis of diabetes in this experimental animal.

Inference of a molecular defect of apolipoprotein B in hypobetalipoproteinemia by linkage analysis in a large kindred.

Heterozygous hypobetalipoproteinemia is characterized by reduced plasma concentrations of LDL cholesterol, total triglycerides, and apo B to less than 50% of normal values. The molecular basis of this disorder remains unknown. The phenotype cosegregates with a DNA haplotype of the apo B gene in an Idaho pedigree, with a maximum decimal logarithm of the ratio (LOD) score of 7.56 at a recombination rate of zero. Individuals carrying this haplotype had total cholesterol levels of 96 mg/dl, LDL cholesterol levels of 37 mg/dl, triglycerides levels of 51 mg/dl, and apo B levels of 38 mg/dl. This study strongly suggests that apo B mutations underlie hypobetalipoproteinemia, and demonstrates the power of the candidate gene approach in linkage analysis for unraveling genetic determinants in metabolic disorders of undefined etiology.

Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation.

Familial lipoprotein lipase (LPL) deficiency is a rare genetic disorder accompanied by well-characterized manifestations. The phenotypic expression of heterozygous LPL deficiency has not been so clearly defined. We studied the pedigree of a proband known to be homozygous for a mutation resulting in nonfunctional LPL. Hybridization of DNA from 126 members with allele-specific probes detected 29 carriers of the mutant allele. Adipose tissue LPL activity, measured previously, was reduced by 50% in carriers, but did not reliably distinguish them from noncarriers. Carriers were prone to the expression of a form of familial hypertriglyceridemia characterized by increased plasma triglyceride, VLDL cholesterol and apolipoprotein B, and decreased LDL and HDL cholesterol concentrations. These manifestations were age modulated, with conspicuous differences between carriers and noncarriers observed only after age 40. Several noncarriers exhibited similar lipid abnormalities, but without the inverse relationship between VLDL cholesterol and LDL cholesterol noted among carriers. In addition to age and carrier status, the potentially reversible conditions, obesity, hyperinsulinemia and lipid-raising drug use were contributory. Thus heterozygous lipoprotein lipase deficiency, together with age-related influences, may account for a form of familial hypertriglyceridemia.

Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: interview study from the Third National Cancer Survey.

From personal interviews obtained for 7,518 incident cases of invasive cancer from the population-based Third National Cancer Survey, the quantitative lifetime use of cigarettes, cigars, pipes, unsmoked tobacco, wine, beer, hard liquor, and combined alcohol were recorded, as well as education and family income level. In an initial screening analysis of these data, Mantel-Haenszel 2 X 2 contingency tabulations and multiple regression analyses were used to compare each specific cancer site with controls from other sites to test for associations with the "exposure variables." Significant positive associations with cigarette smoking were found for cancers of the lung, larynx, oral cavity, esophagus, stomach, pancreas, bladder, kidney, and uterine cervix. Other forms of tobacco were associated with cancers of the oral cavity, larynx, lung, and cervix. Consumption of wine, beer, hard liquor, and all combined showed positive associations with neoplasms of the oral cavity larynx, esophagus, colon, rectum, breast, and thyroid gland. College educaton and high income both showed positive associations with cancers of the breast, thyroid gland, uterine corpus, and melanomas in males. These same indicators of high socioeconomic status showed inverse associations with invasive neoplasms of the uterine cervix, lung, lip-tongue, and colon in females. College attendance (but not income) showed an inverse association with stomach cancer and positive association with pancreatic cancer in males. Still other tumor sties showed "suggestive" associations with each of these exposure variables. In the analyses producing these results, age, race, sex, smoking, drinking, education, income, parity, foreign birth, marital status, and geographic location were used as stratification variables separately or in combination when appropriate to assess and control for their potentially confounding affects and to examine results in different strata to assess interaction.

Associations of cancer site and type with occupation and industry from the Third National Cancer Survey Interview.

From the Third National Cancer Survey (TNCS) Interview Study of 7,518 incident cases, lifetime histories of occupations and industries were studied for associations with specific cancer sites and types while controlling for age, sex, race, education, use of cigarettes or alcohol, and geographic location. Lung cancer patients were found more often than expected among several categories including trucking, air transportation, wholesaling, painting, building construction, building maintenance, and manufacturing (furniture, transportation equipment, and food products). Controlling for cigarette smoking did not change these associations. Leukemia and multiple myeloma were associated with sales personnel of both sexes, whereas lymphomas and Hodgkin's disease were excessive among women working in the medical industry. Other associations included rectal cancer with several retail industries; prostate cancer with ministers, farmers, plumbers, and coal miners; malignant melanoma with school teachers; and invasive cervical cancer with women working in hotels and restaurants. Breast cancer patients were more common among women who were teachers or other professionals and who worked in business and finance (even after controlling for education). Many other findings are presented in detailed tables. Results are reported mainly as a research resource for use by other investigators doing work in this field. Suggestions are given for future studies.

Case-control study of antihypertensive and diuretic use by women with malignant and benign breast lesions detected in a mammography screening program.

A significant but low-level association (relative odds, 2.0; P less than 0.05) was observed between the occurrence of breast cancer and the use of rauwolfia derivatives for 5 or more years in the study of 481 breast cancer cases and 1,268 controls from a joint national mammography screening project of the National Cancer Institute and the American Cancer Society. This association was confined to women over age 50 years who were also heavier than average. No confounding effects could be held responsible for this association after adjustment was made for variables such as presence of hypertension, weight, age at first pregnancy, and other breast cancer risk factors. Other antihypertensive and diuretic drugs as well as multiple drug use also exhibited some suggestive associations with breast cancer. Another group of 421 women with benign lesions at breast biopsy were also compared to the 1,268 controls. They showed a significant association between benign lesions and use of thiazides for 5 or more years (relative odds, 2.4; P less than 0.001) whether employed to treat edema or hypertension. Other antihypertensive and diuretic agents also seemed to show this association, but most of them were being used together with thiazides.

Breast cancer risk factors among screening program participants.

PIP: Data were obtained by mailed questionnaire from 405 breast cancer patients identified during the first 2 years of operation of the Breast Cancer detection Demonstration Project in the U.S. and from a sample of 1156 normal screenees (response rate = 88%) in an attempt to examine whetHer the usual risk indicators for breast cancer apply to individuals participating in screening programs. No substantial differences were found between the respondents and the nonrespondents for the variables on which information had been obtained at the time of the initial screening. Nearly all of t(e recognized risk factors were seen in this population. The relative risk (FF) of breast cancer was 3.9 among women whose mothers were also affected; this finding was statistically significant. Relative risk was increased for women reporting early menarche, late menopause, nulliparity, late age when 1st child was born, and excessive weight. The relative risk was not elevated in women with a prior breast biopsy but was excessive for those with more than 1 biopsy. No association with thyroid medications or menopausal hormones was found. Among women having undergone a natural menopause, a nonstatistically significant elevation in the relative risk was noted for long term oral contraceptive users; this excess relative risk was restricted to those using OCs in the presence of breast cancer risk indicators. The results indicate the need for further study of women with extended periods of OC use, particularly when accompanied by other known risk indicators.^ieng

Breast cancer and reproductive history from genealogical data.

With the use of data from the Utah State Cancer Registry and Utah genealogical data, an analysis of 236 breast cancer patients and 937 controls matched on year of birth showed that a late age at the birth of the first child was most strongly associated with incidence of breast cancer (relative odds = 2.0; P less than 0.001). A strong interaction was found between age at first delivery (AFD) and age at last delivery (ALD). The association of AFD with breast cancer incidence was strongest for women with an ALD before 35 years of age even after adjustment for partly (relative odds = 4.1; P less than 0.001). Decreased parity was not significantly associated with breast cancer.

Tumor-associated antigen levels (carcinoembryonic antigen, human chorionic gonadotropin, and alpha-fetoprotein) antedating the diagnosis of cancer in the Framingham study.

Determinations of carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), and alpha-fetoprotein (AFP) were done by use of frozen serum samples antedating the diagnosis of cancer for 9 pancreatic and 8 gastric carcinoma patients from the Framingham Heart Study. The longest intervals for elevated antigens before cancer diagnosis were 10 months for CEA and 26 months for HCG. (The single elevated AFP was found in a sample 10 days before clinical diagnosis.) Samples from 31 controls matched with the cancer subjects by age, sex, vital capacity, and smoking status showed over 20% "false" positive CEA elevations (all smokers with low vital capacities) and over 20% borderline false positive HCG elevations in postmenopausal females. Although 10-26 months' lead time could infer some potential for use of these tumor-associated antigens to help detect malignant neoplasms at an earlier stage, a serious problem of frequent false positives prevents CEA and HCG levels from being useful as cancer-screening tests at this time.

Growth rates of normal and abnormal human mammary epithelia in cell culture.

The in vitro growth rates of different classifications of human mammary epithelium were compared. Samples included 4 established breast cell lines and excised tissue or breast fluid cells originating WOMEN FOR 40 DIFFERENT AND comprising 3 classifications: normal, nonmalignant atypical, and malignant. Growth was quantitated in situ and expressed as population-doubling time. Principal findings were: (a) malignant cells divided at a slower mean rate than normal cells; (b) population-doubling time values of malignant cells were more heterogenous than those of normal cells; (c) cultures from nonmalignant atypias showed population-doubling time means and standard deviations between those of normal and malignant cells; and (d) long-term mammary tumor cell lines divided more slowly than did normal cells. Discussion includes implications of data for the preneoplastic state and cell culture of mammary epithelium.

Human Nasal Myiasis Caused by Oestrus ovis in the Highlands of Cusco, Peru: Report of a Case and Review of the Literature.

Myiasis is the infestation by dipterous larvae. The larvae can infect intact or decaying tissue including the skin or epithelial surfaces of the orbits, nose, and genitourinary and gastrointestinal tracts. We report a case of primary obligatory nasal myiasis by Oestrus ovis in a 56-year-old man from Cusco in Peru. He presented with nasal pruritus, congestion, and sneezing white "cottony" material. The material was identified as O. ovis larvae. A literature review of publications reporting nasal myiasis caused by O. ovis is presented.

Structural analysis of the C-terminal region of chicken gizzard desmin.

The C-terminal sequence of chicken gizzard desmin has been examined by computer programs based on Chou-Fasman prediction of secondary structure, auto-correlation and Fourier analysis of hydrophobic residue distribution, and cross-correlation analysis of acidic and basic residues. These analyses indicate that, although parts of the desmin sequence are alpha-helical, the helical regions may not be as extensive as predicted previously. Detailed analysis of the distribution of the charged residues in the desmin sequence strongly suggests that it cannot form a tropomyosin-like coiled-coil double-helix because of the almost complete absence of stabilizing salt-bridge interactions between proximal pairs of acidic and basic residues. Although the desmin sequence does contain the tropomyosin-like hydrophobic residue distribution, differences exist in the overall distributions of hydrophobes, with clusters of these residues being found in certain regions of the desmin sequence. Analyses of the sequences of porcine desmin and vimentin reveal very similar structural characteristics for these molecules, although vimentin is predicted to have a different structure at its C-terminus.

Major gene effect for insulin levels in familial NIDDM pedigrees.

Insulin resistance and hyperinsulinemia are familial traits that may precede and predict the onset of non-insulin-dependent diabetes mellitus (NIDDM). In some populations, the distribution of fasting insulin levels and measures of in vivo insulin action suggest the effects of a single major gene. We previously noted hyperinsulinemia among unaffected members of 16 large white pedigrees ascertained through two or more NIDDM siblings. To examine the hypothesis that insulin levels are determined by a single major genetic locus, we used segregation analysis to examine fasting insulin levels in 206 family members and 65 spouses who had normal glucose tolerance tests by World Health Organization criteria. Segregation analysis supported a major locus determining fasting insulin levels and segregating as an autosomal recessive allele with a frequency of 0.25. Thus, homozygotes represented 6.25% of the population, and homozygosity for the hyperinsulinemia allele elevated the mean fasting insulin level from 70.3 to 211.1 pM (11.7-35.2 microU/ml). The analysis apportioned the variance in fasting insulin as 33.1% due to the major autosomal locus, 11.4% due to polygenic inheritance, and 55.5% due to unmeasured effects. Homozygotes for the recessive allele had higher 1-h insulin levels than all others (911.7 vs. 427.2 pM [152.0 vs. 71.2 microU/ml]). We also found evidence for a major locus determining 1-h-stimulated insulin levels, with codominant inheritance as the most likely pattern in inheritance. The causal relationship between these findings and NIDDM has not been determined, and segregation of direct measures of insulin action remains to be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost containment of the second-generation cephalosporins by prospective monitoring at a community teaching hospital.

All patients receiving cefoxitin and cefamandole were prospectively reviewed for appropriate and inappropriate utilization. There were two eight-week survey periods. In period 1, 81 (70%) of 115 patients received cefoxitin appropriately and six (40%) of 15 patients received cefamandole appropriately. In patients receiving antibiotics inappropriately, 12 (35%) of the 34 receiving cefoxitin and eight (89%) of the nine receiving cefamandole had infections that could have been treated with less expensive, equally efficacious antibiotics. Changes in antibiotic therapy were made in 79% of patients based on our recommendations. The estimated annual cost saving for these antibiotics was $40,290. During period 2, 73 (91%) of 80 patients were given cefoxitin appropriately and 14 (61%) of 23 patients received cefamandole appropriately. Forty-three percent of those receiving cefoxitin and 33% of those receiving cefamandole inappropriately could have been treated with a less expensive, equally efficacious antibiotic. In 88% of patients, the attending physicians followed our recommendations.

Population-based frequency of dyslipidemia syndromes in coronary-prone families in Utah.

The frequency of familial dyslipidemia syndromes was determined from blood tests in 33 objectively ascertained families with early coronary heart disease (CHD) (two or more siblings with CHD by the age of 55 years). Three fourths of persons with early CHD in these families had 90th percentile lipid abnormalities (cholesterol level at or above the 90th percentile, triglyceride level at or above the 90th percentile, and/or high-density lipoprotein cholesterol (HDL-C) level at or less than the 10th percentile). The HDL-C and triglyceride abnormalities were twice as common as low-density lipoprotein-cholesterol abnormalities. The most common syndromes found were familial combined hyperlipidemia (36% to 48% of families with CHD), familial dyslipidemic hypertension (21% to 54% of families with CHD), and isolated low levels of HDL-C (15%), with overlapping familial dyslipidemic hypertension with familial combined hyperlipidemia and low-level HDL-C. Well-defined monogenic syndromes were uncommon: familial hypercholesterolemia being 3% and familial type III hyperlipidemia, 3%. Another 15% of families with CHD had no lipid abnormalities at the 90th percentile. Physicians should learn to recognize and treat these common familial syndromes before the onset of CHD by evaluating family history and all three standard blood lipid determinations. Failure to recognize and treat them leaves affected family members at high risk of premature CHD.

Dyslipidemias among normoglycemic members of familial NIDDM pedigrees.

OBJECTIVE: To examine the hypothesis that hyperinsulinemia among relatives of NIDDM probands will increase the prevalence of DLPs, we measured insulin levels and examined the frequency of DLPs among NIDDM pedigree members. RESEARCH DESIGN AND METHODS: We performed 2-h 75-g OGTTs and measured lipid and insulin levels of 287 family members and 86 spouses from 16 large Utah pedigrees ascertained for greater than or equal to 2 siblings with NIDDM. RESULTS: One-hour insulin levels were higher among 206 family members with NGT than among 65 NGT spouses (483.3 vs. 361.7 pM, P = 0.05). Among the NGT family members, 32% had cholesterol levels at or above the age- and sex-specific 90th percentile level defined by the LRC studies, 33% had HDL levels less than or equal to 10th percentile, and 20% had triglyceride levels greater than or equal to 90th percentile. DLP (any of the three abnormalities) was found among 58% of NGT family members, which was significantly higher than the expected 27% (P less than 0.00001) and the prevalence among spouses of 45% (P less than 0.05). By NCEP criteria for hyperlipidemia, 40% of family members met criteria for diet and/or pharmacological therapy. CONCLUSIONS: Normoglycemic members of NIDDM pedigrees have a high prevalence of DLPs, which approaches the prevalence in patients with NIDDM. Our data suggest that members of NIDDM pedigrees should be screened carefully for lipid abnormalities.

Innovative blood pressure measurements yield information not reflected by sitting measurements.

A study of 873 healthy adults and children from Utah kindreds was performed to identify redundant and unique information contained in multiple diverse blood pressure determinations. Systolic blood pressure, fourth-phase and fifth-phase diastolic blood pressures, and simultaneous heart rates were measured in subjects sitting, standing, supine, and tilting, during half-maximal handgrip exercise, and just before blood drawing. A correlation matrix of 57 blood pressure and pulse variables in 618 healthy adults was analyzed. Factor analysis of the correlation matrix showed that all systolic blood pressures loaded as a single factor, accounting for 44% of the total variance of the observed variables. All heart rates also loaded together as a single factor. Diastolic blood pressures showed much more heterogeneity of information distributed among five separate factors. The same basic factors were found in young adults (age, 18-35 years) and older adults (age, 36 + years). Children under 12 years of age showed very different factor patterns, and youths 12 to 17 years of age showed patterns intermediate between those of adults and children. In light of recent clinical trials, better definitions are being sought for hypertension. Information from blood pressures other than sitting determinations may improve the definition of hypertension or better predict which patients have the highest risk of hypertension and its cardiovascular complications.

Factor analysis suggesting contrasting determinants for different blood pressure measurements.

A multiple regression analysis was performed on statistically independent factors derived from blood pressure measurements and possible predictive variables in 618 Utah adults. Nine blood pressure factors obtained in a previous study composed the dependent variables; 35 anthropometric, questionnaire, and biochemical variables were reduced by factor analysis to 10 factors and used as independent variables. Body size and obesity had significant independent effects on different types of blood pressure: body size correlated most highly with systolic blood pressure, while obesity correlated most highly with sitting diastolic blood pressure measurements. Smoking did not correlate with sitting blood pressure but did show a significant positive correlation (after controlling for obesity) with tilt and supine diastolic pressure. Alcohol consumption correlated positively with sitting diastolic pressure when the effects of body size and obesity were controlled. No correlations were found between urinary potassium or sodium excretion and any blood pressure factors, but a significant positive correlation was seen between plasma sodium concentration and several different types of diastolic blood pressure measurements. Psychological stress showed a significant independent positive correlation with systolic blood pressure measurements that was strongest in adults over 35 years of age. The multiple correlation values for the multiple regression equations ranged from 0.19 to 0.52.

A gene-environment interaction between inferred kallikrein genotype and potassium.

Urinary kallikrein excretion has been shown statistically to be partially determined by a major gene in large Utah pedigrees with the use of segregation analysis. A previous twin analysis of environmental factors influencing urinary kallikrein level showed that urinary potassium twin differences were strongly related to differences in urinary kallikrein. The present study uses 769 individuals in 58 Utah pedigrees to analyze the association of urinary potassium with urinary kallikrein within statistically inferred kallikrein genotypes. Fitting genotype-specific curves relating urinary kallikrein level to 12-hour urinary potassium amount within a major gene, polygene, and common environment model, we showed a significant statistical urinary potassium interaction with the inferred major gene for kallikrein (P = .0002). The heterozygotes (with a frequency of 50%) had a significant association between urinary kallikrein and potassium (slope, 0.51 +/- 0.04 SD), whereas there was no association with potassium in the low homozygotes, suggesting a genetic defect involving the kallikrein response to potassium. The model predicted that an increase in urinary potassium excretion of 0.8 SD above the mean in these pedigrees would be associated with high kallikrein levels in the heterozygotes similar to the high homozygotes. A decrease of 1.3 SD in urinary potassium excretion in heterozygous individuals was associated with kallikrein levels similar to the homozygous individuals with low kallikrein. Because in the steady state urinary potassium represents dietary potassium intake, this study suggests that an increase in dietary potassium intake in 50% of these pedigree members, estimated to be heterozygous at the kallikrein locus, would be associated with an increase in an underlying genetically determined low kallikrein level.(ABSTRACT TRUNCATED AT 250 WORDS)