Use and misuse of population attributable fractions.
Explore the source record for details and available documents.
Epidemiologic Methods↗
Biomedical subjects
B Newman
Publications and source records attributed to B Newman.
Perspective on BRCA1.
In a very real sense, the search for a breast cancer susceptibility gene reflects the rapid evolution of molecular genetics as a field and the power of molecular technology to accelerate the pace of discovery. This search began with the study of blood proteins through biochemical analysis; the number of loci accessible was limited, and very few consistent results were obtained (1). Then came recombinant DNA technology. The number of available markers, and the information they provide, has grown rapidly over the years. The same is true for the development of new, high-throughput genotyping methods and associated informatics systems and statistical methods, making gene mapping more feasible. For BRCA1, it took five years and 183 markers to identify the chromosomal location as 17q21 (2). It took an additional four years before BRCA1 was cloned (3). In contrast, BRCA2 was localized to chromosome 13q12-13 two months before the cloning of BRCA1 was reported; less than two years later, BRCA2 was cloned (4,5). Characterization of these two genes is still underway, in part, because of unanticipated complexity. This complexity plays out at multiple levels, including the relationship between phenotype and genotype within and between the populations studied, biological function(s), and social consequences. The reviews presented in this issue reflect the breadth of impact that the discovery of the BRCA genes has had on science, medicine, and law. As with most great discoveries, the identification of BRCA1 has forced us to question the fundamentals of our belief systems: what is a mutation, what is a tumor suppressor, what is righteous, and what is ethical?
Journal Article↗
p53 mutations in malignant gliomas.
A population-based series of incident cases of malignant glioma were analyzed for mutations in the tumor suppressor gene p53. Exons 4-8 were screened using PCR-single-strand conformation analysis and confirmed through direct sequencing. Of 62 tumors analyzed, 12 (19%) contained mutations in p53: one 18-bp duplication in exon 5, five point mutations in exon 4, three point mutations in exon 7, two point mutations in exon 8, and a splice-site mutation at the exon 6/intron 7 boundary. In contrast to previous studies of malignant glioma, the prevalence of transversion mutations (56%) was higher than transition mutations (33%). A large proportion of transversion mutations occurred in exon 4, a region that is not routinely screened in gliomas. We present here an improved method for screening exon 4 (and other GC-rich regions) of p53 using PCR-single-strand conformation analysis. The high frequency of transversion mutations suggests a role for exogenous carcinogens in the etiology of malignant glioma.
Adolescent↗
Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk.
To examine the effects of smoking and N-acetylation genetics on breast cancer risk, we analyzed data from an ongoing, population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 498 cases and 473 controls, with approximately equal numbers of African-American and white women, and women under the age of 50 and age 50 years or older. Among premenopausal women, there was no association between current smoking [odds ratio (OR), 0.9; 95% confidence interval (CI), 0.5-1.5] or past smoking (OR, 1.0; 95% CI, 0.6-1.6) and breast cancer risk. Among postmenopausal women, there was also no association with current smoking (OR, 1.2; 95% CI, 0.7-2.0); however, a small increase in risk was observed for past smoking (OR, 1.5; 95% CI, 1.0-2.4). For postmenopausal women who smoked in the past, ORs and 95% CIs were 3.4 (1.4-8.1) for smoking within the past 3 years, 3.0 (1.3-6.7) for smoking 4-9 years ago, and 0.6 (0.3-1.4) for smoking 10-19 years ago. Neither N-acetyltransferase 1 (NAT1) nor N-acetyltransferase 2 (NAT2) genotype alone was associated with increased breast cancer risk. There was little evidence for modification of smoking effects according to genotype, except among postmenopausal women. Among postmenopausal women, ORs for smoking within the past 3 years were greater for women with the NAT1*10 genotype (OR, 9.0; 95% CI, 1.9-41.8) than NAT1-non*10 (OR, 2.5; 95% CI, 0.9-7.2) and greater for NAT2-rapid genotype (OR, 7.4; 95% CI, 1.6-32.6) than NAT2-slow (OR, 2.8; 95% CI, 0.4-8.0). Future studies of NAT genotypes and breast cancer should investigate the effects of environmental tobacco smoke, diet, and other exposures.
Acetyltransferases↗
Association between high-density lipoprotein cholesterol and breast cancer varies by menopausal status.
A nested case-control study was conducted to investigate the hypothesis that women with high levels of high-density lipoprotein cholesterol (HDL-C) are at an increased risk of breast cancer. The source population was a cohort of 95,000 women enrolled in the Kaiser Permanente Medical Care Program who underwent a routine multiphasic health examination between 1964 and 1971. From the more than 2,000 breast cancer cases diagnosed in this cohort, 200 cases were randomly selected for this study. For each case, one control who matched on age and date of examination was chosen. Lipid and lipoprotein levels were measured in archived serum samples collected at the time of the women's examinations. Breast cancer risk factor information was obtained from questionnaires completed by the women when their blood was drawn and was supplemented with information from medical records. HDL-C levels were not significantly different between the cases and controls overall; however, a statistically significant interaction between the HDL-C level and menopausal status at diagnosis was detected. Premenopausal cases had mean HDL-C levels 3.48 mg/dl lower than matched controls [95% confidence interval (CI), -7.05, 0.09], whereas postmenopausal cases had levels 2.05 mg/dl higher than controls (95% CI, -0.94, 5.03). In multivariate conditional logistic regression analyses, the odds ratio associated with each 1 mg/dl increase in HDL-C was 0.96 (95% Cl, 0.93-1.0) for premenopausal women and 1.02 (95% CI, 0.99-1.05) for postmenopausal women. Although many breast cancer risk factors are associated with high HDL-C, the relationship between breast cancer and HDL-C was independent of other factors evaluated.
Adult↗
Familial and personal medical history of cancer and nervous system conditions among adults with glioma and controls.
The causes of glioma, the most common type of primary malignant brain tumor, are poorly understood. This study compared the personal and first-degree familial medical histories of 462 adults newly diagnosed with glioma in the San Francisco Bay Area between August 1, 1991, and March 31, 1994, with those of 443 controls who were frequency-matched on age, sex, and ethnicity. Cases and controls had equivalent personal histories of cancers other than brain cancer and most nervous system conditions, but they differed significantly regarding histories of epilepsy, seizures, or convulsions 3 or more years prior to diagnosis (odds ratio = 3.3, 95% confidence interval (CI) 1.4-7.9), chickenpox (odds ratio = 0.4, 95% CI 0.3-0.6), and shingles (odds ratio = 0.5, 95% CI 0.3-0.8). Four cases (less than 1%) and no controls had known genetic disorders (three had neurofibromatosis and one had tuberous sclerosis). Cases and controls had similar family histories of cancer and seizures. However, the odds ratio for a validated family history of primary brain tumor was 2.3 (95% CI 1.0-5.8). These results suggest that although family history of any cancer probably is not an important risk factor for adult glioma, a family history of brain tumors may play a role. Variation in exposure to or biologic response to common viral infections might play a greater role in the etiology of adult glioma than family history.
Adult↗
Magnetic resonance imaging of the pediatric airway.
OBJECTIVE: To determine the role of magnetic resonance imaging (MRI) and how it relates to endoscopy as well as to other imaging modalities in the evaluation of pediatric airway disorders. DESIGN: A review study of children with various distal airway disorders over a 3-year period. Surgical procedures as well as all diagnostic imaging modalities were reviewed and analyzed with respect to clinical outcome. SETTING: Academic tertiary care children's hospitals. PATIENTS: Forty-nine children between the ages of 1 week and 14 years with the signs and symptoms of distal airway disorders. INTERVENTIONS: Forty-five of 49 children underwent airway endoscopy. Fourteen children also underwent fluoroscopy and 4 underwent echocardiography. When indicated, open surgical repair was performed and used to verify findings in 32 cases. RESULTS: Magnetic resonance imaging was the most accurate modality in defining extrinsic airway abnormalities. The findings of echocardiography were incorrect in 2 of 4 cases, and fluoroscopy, although accurate for tracheal narrowing and tracheomalacia, often could not elucidate that exact cause or missed left mainstem bronchial compression. Furthermore, tracheal narrowing to 50% or greater on MRI correlated 100% with the need for surgical intervention. CONCLUSIONS: Magnetic resonance imaging is a useful modality that has allowed us to accurately diagnose extrinsic pediatric tracheal abnormalities. In certain cases, MRI scans can be obtained prior to endoscopy. In those cases, definitive endoscopy and open repair are performed at the same procedure instead of at 2 separate procedures (ie, one for diagnostic endoscopy and the other for definitive repair).
Adolescent↗
Heritability of factors of the insulin resistance syndrome in women twins.
The insulin resistance syndrome (IRS) is characterized by a combination of interrelated coronary heart disease (CHD) risk factors, including low high-density lipoprotein cholesterol (HDL-C) levels, obesity and increases in triglyceride (TG), blood pressure, small low-density lipoprotein particles (LDL), and both fasting and postload plasma insulin and glucose. Using factor analysis, we previously identified 3 uncorrelated factors that explained 66% of the variance among these variables, based on data from women participating in examination 2 of the Kaiser Permanente Women Twins Study in Oakland, CA during 1989-1990. The factors were interpreted as: 1) body mass/fat distribution, 2) insulin/glucose, and 3) lipids: TG, HDL-C, LDL peak particle diameter. In this analysis, heritability of each of the factors was estimated based on data from 140 monozygotic and 96 dizygotic pairs of non-diabetic women twins. Heritability estimates were calculated using the classical approach, the analysis of variance (ANOVA) approach, and the maximum likelihood approach. For the body mass/fat distribution factor heritability estimates suggest moderate genetic influences; 0.61 (P < 0.001), 0.14 (P > 0.05), and 0.71 (P < 0.001), respectively. The insulin/glucose factor appeared to be highly heritable, with estimates of 0.87, 0.92, and 0.57 (all P < 0.001), respectively. The heritability estimates for the lipid factor were moderate and consistent across methods: 0.25 (P < 0.10), 0.32 (P < 0.05), and 0.30 (P < 0.05), respectively. These results are consistent with genetic influences on each of the 3 "factors," and suggest that both genetic and environmental effects are involved in the clustering of IRS risk factors.
Adolescent↗
Identifying genetic markers to assess the presence of gene-environment interactions.
We analyzed a randomly chosen replicate with the goals of locating the closest markers to the genes involved in the discrete trait and utilizing these as surrogates for the genes in assessing the presence of gene-environment interactions. We screened the markers with an association test prior to using the transmission-disequilibrium test. We performed a segregation analysis, with regressive models and including the selected markers, to understand the underlying genetic mechanism and the role of the environmental factor. We were unsuccessful in locating the relevant markers due to the absence of linkage disequilibrium. Nevertheless, some insights were gained from the methods used.
Chromosome Mapping↗
Genetic influences on changes in body mass index: a longitudinal analysis of women twins.
Numerous studies have demonstrated genetic influences on body fat, but there also may be genetic effects on its intraindividual variation over time. This study examined changes in body mass index (BMI) using longitudinal data from two examinations of the Kaiser Permanente Women Twins Study, performed a decade apart. The analysis included 630 women, 185 monozygotic and 130 dizygotic twin pairs, with average ages of 41 years and 51 years at the two examinations, respectively. Age-adjusted heritability estimates for the change in BMI over the decade ranged from 0.57 to 0.86 (all p < or = 0.001) using three different statistical analysis approaches, indicating that at least half and possibly as much as 85%+, of the variance in the change in BMI is attributable to genetic influences under a polygenic model. These estimates remained statistically significant after adjusting for environmental factors (ranging from 0.57 to 0.78) and with additional adjustment for BMI at baseline (ranging from 0.41 to 0.79), although dizygotic intraclass correlations were low after these adjustments. Thus, in addition to known environmental and behavioral influences, these results provide evidence for genetic influences on changes in BMI over a decade in women.
Adolescent↗
Internal hernia and volvulus of the small bowel following liver transplantation.
Internal herniation with volvulus of the small intestine is an uncommon, but potentially fatal, complication after liver transplantation. We present here four cases in which the herniation occurred around the Roux-en-Y loop used for the biliary reconstruction. One patient died due to intestinal and liver allograft necrosis; another lost almost the entire small intestine and has since undergone successful intestinal transplantation. Two patients survived following surgery that involved reduction of the hernia and closure of the mesenteric defect. Clinical diagnostic implications emphasize early diagnosis and appropriate operative intervention.
Adolescent↗
Esophageal atresia/tracheoesophageal fistula and associated congenital esophageal stenosis.
BACKGROUND: The association of congenital stenosis of the distal esophagus (CES) in children with esophageal atresia/tracheoesophageal fistula complex (TEF) has been described but is thought to be rare. Most reports have been of individual or small numbers of cases. OBJECTIVE: The objective of the study was to evaluate the incidence, clinical and radiographic features of CES associated with TEF, and to compare the clinical and radiographic features of CES with acquired anastomotic strictures in TEF patients. MATERIALS AND METHODS: A retrospective review was undertaken of the records and radiographs of 225 infants with primary TEF repair over a 26-year period. RESULTS: A total of 18 of 225 (8 %) cases of CES associated with TEF and 43 of 225 (19 %) cases of anastomotic strictures were identified. CES was typically a relatively long, smooth circumferential narrowing at the junction of the mid-esophagus and distal esophagus, with normal-caliber esophagus above and below; anastomotic strictures, in contrast, were focal. Diagnosis of CES was delayed in 10 cases and missed on one or more fluoroscopic studies in 14 children. Symptoms, including feeding and respiratory problems and foreign body impaction, were common in both CES and anastomotic strictures; repeated esophageal dilatations were usually necessary. Esophageal perforation complicated dilatation in 6 (33 %) young children with CES, but none of the children with anastomotic strictures (P < 0.001). CONCLUSION: CES in combination with TEF is not rare and usually produces clinical symptoms. The diagnosis may be missed or delayed unless specifically evaluated surgically and radiologically. Esophageal dilatation in CES is potentially hazardous with a high risk of perforation, especially in young children.
Dilatation↗
Computed tomography grade of splenic injury is predictive of the time required for radiographic healing.
It is largely unknown when a child who has suffered a splenic laceration can return to full unrestricted activity. The purpose of this prospective study is to establish whether the grade of splenic injury is predictive of the length of time required for radiographic healing, and to determine whether there are any adverse long-term sequelae after resumption of unlimited activity. Sixty-nine patients underwent successful nonoperative management (NOM) of computed tomography (CT)-documented splenic injury over a 4-year period. Fifty-eight patients completed follow-up. Mean age was 9.8 years (range, 1 to 17) and mean injury severity score (ISS) was 14.4 (range, 4 to 38). Mechanisms of injury were motor vehicle accident (n = 11), motor vehicle pedestrian (n = 5), falls (n = 13), bike crashes (n = 12), sports (n = 8), all-terrain vehicle (n = 4), and horse (n = 5). The CT-documented injury was identified by discharge ultrasound scan (US) in all cases. There were no long-term complications. Mean time to US healing in grade I (n = 9), II (n = 26), III (n = 19), IV (n = 4) injuries was 3.1, 8.2, 12.1, and 20.7 weeks, respectively. P values were significant (P < .01) in all cases when compared with the next lower injury grade. The time to radiographic healing is directly proportional to the severity of the splenic injury. There was excellent correlation between the initial CT scan and identification of the injury on the discharge US. No long-term complications leg, delayed splenic rupture, splenic pseudocyst) were seen in this study. Pediatric patients who have suffered splenic injury can safely return to full unrestricted activity when the US documents healing.
Adolescent↗
Employment status and high blood pressure in women: variations by time and by sociodemographic characteristics.
PURPOSE: The association between employment status and high blood pressure in women was examined at two time periods to determine if associations between employment status and high blood pressure varied by time period or by age, race, education, marital status, or parental status. METHODS: Women participants from the National Health Examination Survey (1960) and the Second National Health and Nutrition Survey (1976-1980) between the ages of 25 and 64 and currently employed or keeping house were included. Logistic regression analysis was used to examine the cross-sectional association between employment status and high blood pressure in each survey, taking into account potential effect modifiers and covariates. RESULTS: In 1960 employment was associated with a slight, but not statistically significant, elevation in odds of high blood pressure. In 1976-1980, it was associated with a modest but significant reduction in odds of high blood pressure. Variations in associations occurred by marital status (protective associations were limited to unmarried women) and race (associations were of stronger magnitude among African-American women). CONCLUSIONS: The employment status-high blood pressure relationship shifted across surveys. Changes in the composition of the employed and nonemployed groups account for at least part of the varying relationships.
Adult↗
Teaching deception skills in a game-play context to three adolescents with autism.
Baron-Cohen (1992) found that students with autism are impaired in their ability to deceive. A multiple-baseline across-subjects design was conceptualized to test the hypothesis that such students could be taught to deceive. Two conditions were presented in baseline and treatment phases. In Condition 1, the student guessed in which hand a small object was hidden when the experimenter presented two closed fists. In Condition 2, the student hid the object and presented two closed fists to the experimenter for a guess. Reinforcement was delivered contingently upon independent guessing during Condition 1 in both baseline and treatment phases. Under Condition 2, reinforcement was delivered noncontingently during the baseline phase and contingently upon successive approximations to the target behavior of deception during the treatment phase. All students displayed the acquisition of at least three of the responses included in the deception response during the baseline phase, and two students showed an erratic acquisition of the total skill during the baseline phase. Results indicate that students with autism can learn to deceive, even without formal intensive training.
Adolescent↗
Identification and characterization of two novel SH2 domain-containing proteins from a yeast two hybrid screen with the ABL tyrosine kinase.
To further our understanding of the molecular mechanism of Bcr-Abl mediated transformation, a yeast two hybrid screen was used to identify proteins binding to the Abl tyrosine kinase. Two partial cDNAs encoding novel SH2 domain-containing proteins were cloned and designated Shd and She. Both have homology to Shb, a previously reported SH2 domain-containing protein. Northern blot analysis showed that She is expressed in heart, lung, brain, and skeletal muscle, while expression of Shd is restricted to the brain. The deduced amino acid sequence of the full length mouse Shd cDNA contains an amino-terminal proline-rich region, and a carboxyterminal SH2 domain. A bacterially expressed Shd domain bound multiple tyrosine-phosphorylated proteins with relative molecular weights of 200, 170, 130, 100, 90, 78, 72 and 32 kDa from K562 cell lysates. Shd contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases. Shd was tyrosine phosphorylated in COS-7 cells co-transfected with Shd and c-Abl or Bcr-Abl. These results suggest that Shd may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system.
Adaptor Proteins, Signal Transducing↗
Very anemic donors may pass copper sulfate screening tests.
Explore the source record for details and available documents.
Adult↗
Increased prevalence of infectious diseases and other adverse outcomes in human T lymphotropic virus types I- and II-infected blood donors. Retrovirus Epidemiology Donor Study (REDS) Study Group.
Disease associations of human T lymphotropic virus types I and II (HTLV-I and -II) infection were studied in 154 HTLV-I-infected, 387 HTLV-II-infected, and 799 uninfected blood donors. Adjusted odds ratios (ORs) and 99% confidence intervals (CIs) were derived from logistic regression models controlling for demographics and relevant confounders. All subjects were human immunodeficiency virus type 1-seronegative. HTLV-II was significantly associated with a history of pneumonia (OR, 2.6; 99% CI, 1.2-5.3), minor fungal infection (OR, 2.9; 99% CI, 1.2-7.1), and bladder or kidney infection (OR, 1.6; 99% CI, 1.0-2.5) within the past 5 years and with a lifetime history of tuberculosis (OR, 3.9; 99% CI, 1.3-11.6) and arthritis (OR, 1.8; 99% CI, 1.2-2.9). Lymphadenopathy (> or =1 cm) was associated with both HTLV-I (OR, 6.6; 99% CI, 2.2-19.2) and HTLV-II (OR, 2.8; 99% CI, 1.1-7.1) infection, although no case of adult T cell leukemia/lymphoma was diagnosed. Urinary urgency and gait disturbance were associated with both viruses. This new finding of increased prevalence of a variety of infections in HTLV-II-positive donors suggests immunologic impairment.
Adolescent↗