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Biomedical subjects

P V Tishler

Publications and source records attributed to P V Tishler.

At least 19 recordsLinked to original sources
PubMed2005

Linkage of serum leptin levels in families with sleep apnea.

OBJECTIVE: To identify regions on the genome linked to plasma leptin levels. DESIGN: Full genome scan with 402 microsatellite markers, spaced approximately 10 cM apart. Data were analyzed using the Haseman-Elston regression linkage analysis. SUBJECTS: A total of 160 sibling pairs from 59 predominantly African American, obese families recruited to participate in a genetic-epidemiological study of obstructive sleep apnea. MEASUREMENTS: Serum leptin levels adjusted for age, sex, race and body mass index (BMI). RESULTS: Suggestive linkage peaks were observed on chromosomes 2 (P=0.00170; marker D2S1384), 3 (P=0.00007; marker D3S3034), 4 (P=0.00020; marker D4S1652) and 21 (P=0.00053; marker D21s1411). CONCLUSION: The peak on chromosome 3 is near the gene for glycogensynthase kinase 2 beta, an important factor in glucose homeostasis. Linkage was generally stronger after BMI adjustment, suggesting the potential influence of a number of metabolic pathways on leptin levels other than those that directly determine obesity levels. The evidence of linkage for leptin levels is consistent with prior linkage analyses for cholesterol, hypertension and other metabolic phenotypes.

Adult↗
PubMed2001

The relationship between craniofacial morphology and obstructive sleep apnea in whites and in African-Americans.

Previous studies of craniofacial risk factors for obstructive sleep apnea (OSA) have been based predominantly on cephalometry. However, differences in head form (measured by the cranial index [CI]) and facial form (measured by the facial index [FI]) are considered by anthropologists to provide a basis for structural variation in craniofacial anatomy. We assessed the association of head and facial form with the apnea hypopnea index (AHI) in 364 white individuals and 165 African-Americans. Data collected included cranial and facial dimensions (using anthropometric calipers), body mass index (BMI), neck circumference, and the AHI. CI and FI differed for whites with OSA (AHI > or = 15) versus those without OSA (AHI < 5) (increased CI and decreased FI in subjects with OSA, p = 0.005 and p = 0.006, respectively). CI and FI did not differ in OSA versus non-OSA groups of African-Americans. In subjects with OSA, the CI in whites was again greater and the FI smaller than those in African-Americans (p = 0.007 and p = 0.004, for CI and FI.) We conclude that brachycephaly is associated with an increased AHI in whites but not in African-Americans. The CI may useful in phenotyping and identifying population subsets with OSA.

Adult↗
PubMed1999

The effect of therapeutic drugs and other pharmacologic agents on activity of porphobilinogen deaminase, the enzyme that is deficient in intermittent acute porphyria.

Drugs and toxins precipitate life-threatening acute attacks in patients with intermittent acute porphyria. These materials may act by directly inhibiting enzyme activity, thus further reducing porphobilinogen (PBG) deaminase activity below the ca. 50% level that results from the gene defect. To test this, we studied the effects of drugs that precipitate acute attacks (lead, phenobarbital, griseofulvin, phenytoin, sulfanilamide, sulfisoxazole, 17alpha-ethinyl estradiol, 5beta-pregnan-3alpha-ol-20-one), drugs that are safe (lithium, magnesium, chlorpromazine, promethazine), and those with uncertain effects (ethyl alcohol, imipramine, diazepam, haloperidol) on activity of PBG deaminase in vitro and in vivo. In the in vitro studies, of PBG deaminase from human erythrocytes from normals and individuals with IAP, only lead (> or = .01 mM) inhibited enzyme activity. Chlorpromazine (> or = .01 mM), promethazine (> or = .01 mM) and imipramine (1 mM) seemed to increase enzyme activity. In most in vivo experiments, male rats were injected intraperitoneally with test material twice daily for 3 days and once on day four; and erythrocyte and hepatic PBG deaminase activity was assayed thereafter. Effects on enzyme activity were observed only with 17alpha-ethinyl estradiol (0.05 microg/kg/day; reduction of 11% in erythrocyte enzyme [NS], and of 20% in liver enzyme [P=.02]), and imipramine (12.5 mg/kg/day; reduction in erythrocyte enzyme activity of 13% [P<.001]). Rats given lead acetate in their drinking water (10 mg/ml) for the first 60 days of life, resulting in high blood and liver lead levels, had increased erythrocyte PBG deaminase (167% of control; P=.004). Thus, enzyme inhibition by lead in vitro was not reflected in a similar in vivo inhibition. The only inhibitory effects in vivo, with ethinyl estradiol and imipramine, appear to be mild and biologically inconsequential. We conclude that inhibition of PBG deaminase activity by materials that precipitate acute attacks is an unlikely mechanism by which these materials exert their harmful effects in patients with IAP.

Animals↗
PubMed1999

Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems.

This study examined risk factors for sleep-disordered breathing (SDB) in children and adolescents; specifically, quantifying risk associated with obesity, race, and upper and lower respiratory problems. Subjects were participants in a genetic-epidemiologic study of SDB and included 399 children and adolescents 2 to 18 yr of age, recruited as members of families with a member (a proband) with known sleep apnea (31 index families) or as members of neighborhood control families (30 families). SDB was assessed with home overnight multichannel monitoring and SDB was defined based on an apneahypopnea index >/= 10 (moderately affected) or < 5 (unaffected). SDB of moderate level was significantly associated with obesity (odds ratio, 4.59; 95% confidence interval [CI], 1.58 to 13.33) and African-American race (odds ratio, 3.49; 95% CI, 1.56 to 8.32) but not with sex or age. After adjusting for obesity, proband sampling, race and familial clustering, sinus problems and persistent wheeze each independently (of the other) predicted SDB. These data suggest the importance of upper and lower respiratory problems and obesity as risk factors for SDB in children and adolescents. Increased risk in African Americans appears to be independent of the effects of obesity or respiratory problems.

Adolescent↗
PubMed1998

Fetal alcohol effects in alcoholic veteran patients.

Fetal alcohol syndrome is often associated with severe physical and neuropsychiatric maldevelopment. On the other hand, some offspring of women who drank during pregnancy appear to be affected in minimal ways and function relatively well within society. We questioned whether this effect of prenatal alcohol in the adult is generally minimal. To bear on this, we determined whether we could distinguish alcohol-exposed from nonexposed individuals in a population of male veterans, selected because of both their accepted level of function within society (e.g., honorable discharge from the military) and their admission to an alcohol treatment unit (thus, a greater likelihood of parental alcoholism, because of its familial aggregation). Consecutively admitted alcoholics (cases; n = 77) with likely maternal alcohol ingestion during their pregnancy or the first 10 years of life were matched with alcoholics with no maternal alcohol exposure during these periods (controls; n = 161). Each subject completed questionnaires regarding personal birthweight, alcohol, drug, educational and work histories, and family (including parental) alcohol and drug histories. We measured height, weight, and head circumference; checked for facial and hand anomalies; and took a frontal facial photograph, from which measurements of features were made. Data were analyzed by univariate statistics and stepwise logistic regression. No case had bona fide fetal alcohol syndrome. With univariate statistical analyses, the cases differed from the controls in 10 variables, including duration of drinking, width of alae nasae, being hyperactive or having a short attention span, and being small at birth. By stepwise logistic regression, the variables marital status, small size at birth, duration of drinking, and the presence of a smooth philtrum were marginally (the first two) or definitely (the last two) significant predictors of case status. Analysis of only the 37 cases in whom maternal prenatal drinking was the most likely yielded a marginal association for small size at birth (odds ratio = 3.1, p = 0.08) and a significant association for the presence of a smooth philtrum (odds ratio = 11.9, p = 0.005). Predictability was poor in all regression models. Based on the presence of this single physical finding (smooth philtrum), we estimate that the prevalence of manifestations of fetal alcohol exposure (fetal alcohol effects) is 6 to 13% in adult male veteran children (not necessarily nonveteran offspring) of women who drank alcohol during pregnancy. Thus, in our study of adult veterans, most individuals who were born to women who drank during pregnancy could not be differentiated from normal individuals, and those who were affected were distinguished by a single, nonspecific physical finding.

Adult↗
PubMed1997

Racial differences in sleep-disordered breathing in African-Americans and Caucasians.

In this case-control family study of sleep-disordered breathing (SDB), we describe the distributions of SDB and SDB risk factors in African-Americans and Caucasians. A total of 225 African-Americans and 622 Caucasians, ages 2 to 86 yr, recruited as members of families with an individual with known sleep apnea (85 index families) or as members of neighborhood control families (63 families) were studied with an overnight home sleep-study, questionnaires, and physical measurements. A subsample underwent cephalometry. Outcome measures were the respiratory disturbance index (RDI) and a binary variable indicating the presence of increased apneic activity (IAA). In both races, a strong relationship was demonstrated between the (log transformed) RDI and age and age2. African-Americans with SDB were younger than Caucasians with SDB (37.2 +/- 19.5 versus 45.6 +/- 18.7 yr, p < 0.01). In subjects < or = 25 yr, RDI level and IAA prevalence were higher in African-Americans (odds ratio, adjusted for obesity, sex, proband sampling, and familial clustering, 1.88, 1.03 to 3.52, 95% CI). In this age group, racial differences also were observed in the relationship between RDI and age (p < 0.001 for the RDI-age interaction). This suggests that young African-Americans may be at increased risk for sleep apnea.

Adolescent↗
PubMed1997

Ventilatory-control abnormalities in familial sleep apnea.

The role of ventilatory-control abnormalities in predisposing to familial sleep-disordered breathing (SDB) was assessed in 31 subjects 28 +/- 10 yr of age (mean +/- SD). Subjects with (n = 10) and without SDB (n = 12) were recruited from 13 families having two or more members with SDB. Nine age- and gender-matched controls were recruited from families having no member with SDB. Respiratory responses to eucapnic hypoxia, and ventilatory and occlusion pressure responses to hyperoxic hypercapnia with and without added resistive loads (6.5 cm H2O/L/s), were assessed through rebreathing. Age, FEV1, and FVC did not differ among the groups. Hypoxic responses (delta VE/delta SaO2) were significantly lower among the first-degree relatives of SDB families than among controls (-0.76 +/- 0.47 L/min/% SaO2, and -1.32 +/- 0.92 L/min/% SaO2, respectively, p < 0.05). Respiratory responses to hypercapnia during unloaded conditions were similar among the groups. With resistive loading, inspiratory impedance, as measured through the relationship of mouth occlusion pressure (P100) to inspiratory flow (VT/TI), increased with increasing hypercapnia to a greater extent in members of SDB families than in controls (0.169 +/- 0.054 cm H2O/L/min versus 0.122 +/- 0.051, respectively, p < 0.05). These data suggest that familial SDB may be based partly on a familial abnormality in ventilatory control associated with blunting of the hypoxic ventilatory response. The greater increase in impedance during inspiratory loading in members of affected families also suggests a propensity for dynamic airway narrowing.

Adult↗
PubMed1996

A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians.

OBJECTIVE: To assess prospectively the risk of myocardial infarction (MI) associated with decreased plasma levels of folate and pyridoxal phosphate (PLP, a form of vitamin B6) in relation to elevated levels of total homocysteine (tHcy). DESIGN: Nested case-control study using prospectively collected blood samples. SETTING: Participants in the Physicians' Health Study. SUBJECTS: 14,916 male physicians, aged 40-84 years, with no prior MI or stroke provided plasma samples at baseline and were followed for 7.5 years. Samples from 333 men who subsequently developed MI, and their paired controls matched by age and smoking, were analyzed for folate and PLP levels. MEASURES OF OUTCOME: Acute MI or death due to coronary disease. RESULTS: In a model controlling for diabetes, angina, hypertension, Quetelet's index, and total/high-density lipoprotein cholesterol, men with the lowest 20% of folate levels (< 2.0 ng/mL) had a relative risk of 1.4 (95% confidence interval 0.9-2.3) compared with those in the top 80%. For the lowest 20% of vitamin B6 values, the relative risk was 1.5 (95% CI: 1.0-2.2). When we included both folate and B6 in a model with cardiovascular risk factors, the relative risk of MI for low as compared to high levels of folate was 1.3 (95% CI: 0.8-2.1) and for PLP, 1.3 (95% CI: 0.9-2.1). Adding tHcy to this model did not add significant predictive value (chi sq = 2.0, p > 0.05), except in the first half of the follow-up interval when men with the top 5% of tHcy values had an almost three-fold increase in risk of MI. CONCLUSIONS: Although not statistically significant, these prospective data are compatible with the hypothesis that low dietary intake of folate and/or vitamin B6 contribute to risk of MI.

Adult↗
PubMed1996

The association of sudden unexpected infant death with obstructive sleep apnea.

We studied the relationship of sudden unexpected infant death/apparent life-threatening events (ALTE) to obstructive sleep apnea (OSA) in 74 index probands who had either sleep-laboratory-confirmed OSA or a clinical diagnosis of OSA requiring treatment, 62 matched control probands, and their spouses and first- and second-degree relatives. Sleep was monitored in the home overnight, and OSA was defined by respiratory disturbance indices (number of apneas/hypopneas per hour of sleep) corrected for normal increases with age. Information on sudden unexpected infant death/ALTE was obtained by questionnaire and was corroborated. For living relatives, data were obtained by questionnaire, examination, or study (cephalometric radiographs, ventilatory responsiveness to hypercapnia and hypoxia). Eight index families had 10 infants with sudden unexpected infant death/ALTE; two control families had three infants with sudden death (p = 0.11). All told, 91 of the 136 families (index plus control) included members with OSA, and all 10 infant death/ALTE families were among these (versus zero of 45 families with no OSA; p = 0.03). The sudden infant death/ALTE families had a greater frequency of two or more members with OSA (p = 0.06), reported more respiratory disease or allergy, were more frequently brachycephalic (p = 0.05), and had a smaller mean posterior nasal spine-basion distance (p = 0.0001) and ratio of anterior mandibular/anterior maxillary dental height (p < 0.05). Ventilatory responses to hypoxia were reduced in members of families with OSA (p = 0.008), with a trend toward the greatest blunting in subjects from families with OSA plus sudden unexpected infant death/ALTE. Thus, OSA in adults and sudden unexpected infant death/ALTE in their biologic relatives appear to be related. Familial factors influencing this association may include the degree of the predilection for OSA, liability for respiratory illness or allergy, dimensions of the oral-pharyngeal airway, and ventilatory response to hypoxia.

Case-Control Studies↗
PubMed1995

Genetic, environmental, and phenotypic links between body mass index and blood pressure among women.

Greater relative weight is associated with higher blood pressure, but the reasons are unknown. The inability of current technology to induce sustained weight loss among overweight persons precludes experimental tests of whether this association is causal. We evaluated the degree to which the covariation between body mass index (BMI; kg/m2) and blood pressure (BP) among women is due to pleiotropic genetic factors, environmental factors, or phenotypic causation. The sample included 75 monozygotic (MZ) and 39 dizygotic (DZ) pairs of adult female twins. "BP" was calculated as the unit-weighted mean of systolic and diastolic. Data were analyzed through structural equation modeling. A model was specified stipulating that additive genetic effects (A) and unique environmental effects (E) each contributed to the covariance between BMI and BP, thus allowing for both pleiotropic and unique environmental influences on the covariance between BMI and BP. Dropping the pleiotropic influences significantly worsened the model (chi 2 = 4.62, df = 1, P = .032), suggesting significant pleiotropic effects. Dropping the environmental influences on the cross-phenotype covariance did not significantly worsen the model (chi 2 = 1.42, df = 1, P = .233). This indicates no significant effect of the environment on the covariance between BMI and BP. Finally, a model of phenotypic causation in which BMI directly influenced BP was fitted. This model provided the best single parameter explanation of the BP-BMI covariation. These data suggest that, among women, regardless of the source of variation, changes in BMI should lead to long-standing changes in BP.

Adult↗
PubMed1995

The familial aggregation of obstructive sleep apnea.

An inherited basis for sleep-disordered breathing (SDB) has been suggested by reports of families with multiple affected members and by a previous study of the familial aggregation of symptoms of SDB. In this study, we quantify and characterize the aggregation of SDB and assess the degree to which familial similarities may be independent of obesity. This was a genetic-epidemiologic study that assessed the distribution of SDB in families identified through a proband with diagnosed sleep apnea and among families in the same community with no relative with known sleep apnea. SDB was assessed with overnight in-home monitoring of airflow, oxygen saturation, chest wall impedance, heart rate, and body movement. Standardized questionnaires were used to assess symptoms, and weight, height, and neck circumference were measured directly. Intergenerational and intragenerational correlation coefficients and pairwise odds ratios (ORs) were calculated with adjustment for proband sampling. In toto, 561 members of 91 families were studied: (1) 47 subjects with laboratory-confirmed SDB (index probands), (2) 44 community control subjects, and (3) the spouses and relatives of 1 and 2. Of all 91 families, 32 (35%) had two or more members with SDB, 30 (33%) had one affected member, and 29 had no affected members. SDB was more prevalent in the relatives of index probands (21%) than among neighborhood control subjects (12%) (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Gender differences in sleep disordered breathing in a community-based sample.

Gender differences in the relative frequency of sleep-disordered breathing (SDB) have been observed in surveys of patient groups referred for clinical evaluation compared with population surveys. In this study, we assessed the associations of gender, SDB, and symptoms of SDB in 389 participants (16 to 84 yr of age) in an ongoing genetic-epidemiologic study of sleep apnea. Subjects included index probands with laboratory-confirmed obstructive sleep apnea syndrome (laboratory sample, n = 36) and their family members and neighbors (the community sample). SDB was assessed with overnight in-home monitoring of airflow, oximetry, heart rate, and chest wall impedance, and symptoms were assessed with standardized questionnaires. In the entire sample, SDB, defined as a respiratory disturbance index [RDI] > or = 15, was more prevalent among males (38%) than among females (15%) (p < 0.05). Males predominated by a ratio of 8:1 in the laboratory sample (31 males, five females). In contrast, the proportion of males to females with SDB was only 2:1 in the community sample, in which an RDI > or = 15 was observed among 26% of males and 13% of females. In the laboratory sample, females tended to be younger and were significantly heavier than males. However, in the community sample, females with SDB were older than male apneic subjects (63.4 +/- 13.9 versus 47.2 +/- 15.6 years, mean +/- SD; p < 0.01), and included a majority of postmenopausal women (75%). No differences in body mass index were noted between males and females with SDB recruited from the community.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Assessment of the validity and utility of a sleep-symptom questionnaire.

Although questionnaires have been developed to assess symptoms of obstructive sleep apnea (OSA), their overall reliability and utility have not been established. We have evaluated the ability of a questionnaire to identify increased apnea activity (IAA) in 465 participants in an epidemiologic study of OSA. Subjects and their roommates each completed a questionnaire and underwent in-home sleep studies. Responses to 56 questions about sleep habits, sleepiness, and daytime performance were analyzed with factor analysis, logistic regression, and receiver-operator curves (ROCs). Factor analysis demonstrated that 16 questions, grouped into five factors (functional impact of sleepiness, self-reported breathing disturbances, roommate-observed breathing disturbances, driving impairment, and insomnia) explained 67% of the variance in the questionnaire data. Symptom questions demonstrated internal consistency (Cronbach correlations: 0.91 to 0.98). Moderate levels of agreement were observed between self- and roommate-reported responses for nine of ten questions asked of both the subject and his/her partner (kappa statistics: 0.34 to 0.57). Logistic regression analysis demonstrated that IAA could be best predicted by three questions about intensity of snoring, roommate-observed choking, and having fallen asleep while driving (ROC area: 0.78). Use of symptoms with data on gender and body mass index (BMI) improved predictive ability by 10% (ROC area: 0.87). Thus, questionnaire data provide a valid means of characterizing symptom distributions in population surveys of OSA. Predictive ability is not significantly improved with multiple questions or a separate roommate questionnaire, but is improved with consideration of data on BMI and gender.

Adult↗
PubMed1992

A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.

OBJECTIVE: To assess prospectively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine. DESIGN: Nested case-control study using prospectively collected blood samples. SETTING: Participants in the Physicians' Health Study. PARTICIPANTS: A total of 14,916 male physicians, aged 40 to 84 years, with no prior myocardial infarction (MI) or stroke provided plasma samples at baseline and were followed up for 5 years. Samples from 271 men who subsequently developed MI were analyzed for homocyst(e)ine levels together with paired controls, matched by age and smoking. MAIN OUTCOME MEASURE: Acute MI or death due to coronary disease. RESULTS: Levels of homocyst(e)ine were higher in cases than in controls (11.1 +/- 4.0 [SD] vs 10.5 +/- 2.8 nmol/mL; P = .03). The difference was attributable to an excess of high values among men who later had MIs. The relative risk for the highest 5% vs the bottom 90% of homocyst(e)ine levels was 3.1 (95% confidence interval, 1.4 to 6.9; P = .005). After additional adjustment for diabetes, hypertension, aspirin assignment, Quetelet's Index, and total/high-density lipoprotein cholesterol, this relative risk was 3.4 (95% confidence interval, 1.3 to 8.8) (P = .01). Thirteen controls and 31 cases (11%) had values above the 95th percentile of the controls. CONCLUSIONS: Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of MI independent of other coronary risk factors. Because high levels can often be easily treated with vitamin supplements, homocyst(e)ine may be an independent, modifiable risk factor.

Adult↗
PubMed1992

Studies in the genetics of obstructive sleep apnea. Familial aggregation of symptoms associated with sleep-related breathing disturbances.

Previous studies of single families have suggested that familial factors may be important in the pathogenesis of obstructive sleep apnea. In this report, the role of inheritance in obstructive sleep apnea was assessed by quantitating the degree of familial clustering of symptoms associated with sleep-related breathing disorders. In total, 272 subjects from 29 families identified through an index case with obstructive sleep apnea and 21 control families with no relative known to have sleep apnea were studied with questionnaires that ascertained health status and symptoms. The unadjusted odds ratios of habitual or disruptive snoring, breathing pauses, and excessive day-time sleepiness in subjects with a single relative with the same symptom were 1.40 to 1.53 (p less than 0.05). Odds ratios increased progressively for subjects with increasing numbers of symptomatic relatives). Adjustment for body mass index, age, and gender modestly reduced these odds ratios to 1.33 to 1.42. These data suggest a significant familial aggregation of symptoms associated with sleep-disordered breathing that appears independent of familial similarities in weight.

Adult↗