Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease.

Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease. We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10(-4)). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease (P< 2 x 10(-7)) and contains the cytokine gene cluster. This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence-each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.

HostSeq: a Canadian whole genome sequencing and clinical data resource.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.

Using cancer registry data: agreement in cause-of-death data between the Ontario Cancer Registry and a longitudinal study of breast cancer patients.

Data from the Ontario Cancer Registry (OCR) were compared with data from a multi-centred prospective cohort of 1655 node-negative breast cancer patients with intensive clinical follow-up. Agreement in cause of death was evaluated using kappa statistics. The accuracy of OCR classification was evaluated against the Mount Sinai Hospital (MSH) study oncologist's interpretation of intensely followed, cohort-collected data as the reference standard. The two sources showed a high level of agreement (kappa statistic [kappa] = 0.88; 95% confidence interval [CI]: 0.86, 0.90) in vital status and cause of death. Among those cases where both sources reported a death, the OCR had a sensitivity of 95% (95% CI: 90.5, 98.8) and a specificity of 88% (95% CI: 79.6, 92.4). The OCR is a valuable tool for epidemiologic studies of breast cancer to acquire adequate and easily attainable cause-of-death information.

MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Increased expression of the multidrug resistance gene (MDR1) has been implicated in osteosarcoma prognosis. This study represents the first prospective assessment of the prognostic value of MDR1 mRNA expression in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: A series of patients with high-grade, nonmetastatic extremity osteosarcoma were enrolled from six tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 30 months). All patients were treated with (neo)adjuvant chemotherapy and surgery. Tumors from 123 patients were analyzed for MDR1 mRNA expression. The association of the level of MDR1 expression with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Using the highest MDR1 value for each patient, a dose-response relationship was not identified between the level of MDR1 expression and systemic relapse (relative risk, 1.15; P =.44). Analyses based on biopsy or resection values alone gave similar results (P =.11 and.41, respectively, log rank test). In multivariate analysis, large tumor size (> 9 cm) was the only significant independent predictor of systemic outcome (relative risk, 2.8; P =.002). CONCLUSION: We did not identify any correlation between MDR1 mRNA expression and disease progression in patients with osteosarcoma. It is likely that alterations in other genes are involved in resistance to chemotherapy in osteosarcoma and that they play a more critical role than MDR1 in this disease.

neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group.

PURPOSE: It remains a challenge to predict which women with axillary node-negative (ANN) breast cancer at greatest risk of relapse may benefit most from adjuvant therapy. Increases in neu/erbB-2 have been implicated in breast cancer prognosis. Although overexpression has been investigated extensively, this study represents the first prospective assessment of the prognostic value of neu/erbB-2 DNA amplification in a cohort of women with newly diagnosed ANN. METHODS: A consecutive series of women was monitored for recurrence (median follow-up duration, 36 months) and tumors from 580 individuals were analyzed for amplification. The association of amplification with risk of recurrence was examined in survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Neu/erbB-2 was amplified in 20% of cases. We found an increased risk of disease recurrence when neu/erbB-2 was amplified > or = twofold that persisted with adjustment for other prognostic factors (relative risk, 2.36; P = .002). We found some evidence that amplification was more important in patients who received chemotherapy compared with untreated patients. CONCLUSION: neu/erbB-2 amplification is an independent prognostic factor for risk of recurrence in ANN breast cancer. Women with tumors without neu/erbB-2 amplification have a good prognosis; aggressive therapy in this group is therefore difficult to justify. On the other hand, even with adjuvant chemotherapeutic treatment, women whose tumors exhibit neu/erbB-2 amplification have an increased risk of recurrence. We encourage a randomized trial to compare more aggressive adjuvant chemotherapy versus standard chemotherapy for ANN women whose tumors exhibit neu/erbB-2 amplification.

Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers.

p53 alterations are the most common genetic lesions observed in lung cancers. Because of the limited size of individual studies, the distributions of p53 alterations by clinicopathological features have not been well characterized. Here, we present meta-analyses describing the occurrence of p53 alterations by patient/tumor characteristics in resected lung cancer. The association between p53 alterations (gene and/or protein) and a variety of variables were evaluated by calculating pooled odds ratios (ORs) and confidence intervals (CIs). p53 alterations were detected in 46.8% of 4684 non-small cell lung cancers. p53 alterations occurred more frequently in the more strongly smoking-associated histotypes: squamous cell (51.2%) and large cell (53.7%) carcinomas versus adenocarcinomas [38.8%; OR (squamous versus adenocarcinoma) = 1.81, 95% CI = 1.55-2.11]. p53 alterations were found to be associated with T1-4, N0-3, stage I-III, differentiation, and sex: OR (T3 versus T1) = 1.62 (95% CI = 0.99-2.65), OR (N1-3 versus N0) = 1.65 (95% CI = 1.27-2.15), OR (stage III versus stage I) = 1.98 (95% CI = 1.35-2.89), OR (poorly and moderately versus well-differentiated) = 3.04 (95% CI = 1.56-5.94), and OR (male versus female) = 1.39 (95% CI = 1.10-1.75). No strong associations between p53 and ras or aneuploidy were observed. Lung cancer studies of p53 and smoking need to consider the effect of histotype, and prognostic studies of p53 should adjust for the effects of T and N or stage and histotype. The apparent association between p53 and sex may be confounded by histotype and must be evaluated by multivariate studies.

Hyperbaric oxygen therapy in chronic stable multiple sclerosis: double-blind study.

We carried out a randomized, double-blind, placebo-controlled trial of hyperbaric oxygen therapy (HBO) in patients with chronic stable MS. Eighty-two patients were treated in a multiplace hyperbaric chamber with gas supplied by mask. Forty-one patients received 20 consecutive daily treatments of 100% O2 followed by 7 "booster" treatments in the next 6 months; 41 control patients received "air" (12.5% O2 at 1.75 atmospheres absolute). There was no significant difference in treatment and control groups in the Extended Kurtzke Disability scores, Kurtzke Functional scores, magnetic resonance imaging, or evoked potentials after the initial 20 treatments or after the boosters. HBO is not effective in treating chronic stable MS.

Hypertension aggregates in families of kidney stone patients with high urinary excretion of uric acid.

OBJECTIVE: To determine whether kidney stone disease (KSD) and hypertension (HTN) share a common familial component that is determined by a specific urinary biochemical abnormality. DESIGN: Familial aggregation study. PATIENTS: Two hundred and twelve KSD patients, aged 18-50 years, collected a 24-h urine sample to measure the urinary excretion of uric acid, calcium, oxalate, magnesium and citrate, and were interviewed about the occurrence of HTN among first-degree relatives. OUTCOME: Positive family history (FHx) of HTN defined as two or more relatives with HTN, and HTN occurring in the fathers, mothers and siblings. RESULTS: Positive FHx of HTN was significantly associated with increasing urinary excretion of uric acid (P = 0.03) but not with the excretion of the other substances. When the patients were divided into those with and without hyperuricosuria, the adjusted odds ratio (OR) for positive FHx of HTN in a hyperuricosuric KSD patient was 3.8 (95% CI, 1.22-11.66). Separate analysis on the occurrence of HTN in the fathers, mothers and siblings of the probands indicated that hyperuricosuria is positively related to HTN occurring in the siblings of the patients (P < 0.001) but not in the fathers or in the mothers. The adjusted OR for HTN occurring in siblings of hyperuricosuric patients compared with siblings of non-hyperuricosuric patients was 3.8 (2.12-6.67). CONCLUSION: Siblings of KSD patients with hyperuricosuria had a significantly increased prevalence of HTN that could not be accounted for by age, family size, body-mass index and personal history of HTN of the probands. Additional studies need to be undertaken to determine whether this familial clustering has a genetic or environmental origin.

A study of smoking, p53 tumor suppressor gene alterations and non-small cell lung cancer.

PURPOSE: The purpose of this study was to investigate the relationship between smoking and p53 tumor suppressor gene alterations, and their association with clinicopathologic features and prognosis in non-small cell lung cancer (NSCLC). METHODS: For 111 of 119 stage I-III NSCLC patients that had been followed prospectively, tumor p53 protein accumulation was measured immunohistochemically (IHC). Staining was evaluated as a score (p53IHCS) combining intensity and percent distribution. RESULTS: Forty-eight of 111 (43%) tumors had p53IHCS > 1. p53 IHC was associated with increasing tumor size (T) (p = 0.035), nodal status (N) (p = 0.091), stage (p = 0.054), and histology: squamous cell carcinoma (70%) and adenocarcinoma (27%) (p = 0.0002). In logistic regression analysis, p53 IHC was associated with squamous cell histology versus other histotypes [adjusted odds ratio (OR)5.90, 95% confidence interval (CI) 2.34-14.90]. p53 IHC was not associated with smoking variables. In multivariate proportional hazards analysis, p53IHCS and pack-years smoked (PY), both as continuous variables, were negative prognostic factors. The adjusted hazard ratios (HR) for the survival outcome recurrence for p53IHCS and PY were 1.20 (95% CI 1.02-1.40) and 1.03 (95% CI 1.01-1.04), and for death due to recurrent disease (DRD) were 1.35 (95% CI 1.11-1.64) and 1.03 (95% CI 1.01-1.04), respectively. Comparing the 75th percentile to the baseline 0, the adjusted HR for p53IHCS (5 vs. 0) was 4.5 and for PY (55 vs. 0) was 5.1 for the outcome DRD. Both variables demonstrated a dose-response relationship with survival. CONCLUSIONS: PY and p53IHCS are significant, independent and important predictors of recurrence and DRD in stage I-III NSCLC.

A population survey in Ontario regarding restrictive measures on smoking: relationship of smoking status to knowledge, attitudes and predicted behaviour.

A population survey of Ontario residents regarding knowledge of the health effects of smoking, attitudes towards restrictive measures, and predicted behaviour was carried out. Telephone responses of 490 current, 290 former, and 581 never smokers were compared. For both active and passive smoking, never smokers were most knowledgeable about health effects, former smokers being less knowledgeable, and current smokers least so. While a majority of each smoking status group supported some restriction on smoking in all 13 settings examined, there were consistent differences among the groups as to degree. Never and former smokers were in close agreement and were more restrictive in their attitudes than current smokers. Prohibition was more strongly favoured by all groups for health and day care facilities, schools, stores, and local transit systems than for other settings. While a majority of smokers thought there would be compliance with restrictions, non-smokers were less optimistic. Smokers were less likely than non-smokers to see a role for governments in enactment; municipal involvement was favoured over other levels by all groups. No group indicated much support for enforcement by police. These findings remained when multivariate analyses controlling for inter-group differences in sociodemographic characteristics were carried out.

Molecular and epidemiologic study of multiresistant Serratia marcescens Infections in a spinal cord injury rehabilitation unit.

Between March 1984 and February 1986, ten patients admitted to a spinal cord injury/stroke rehabilitation unit became bacteriuric with a strain of Serratia marcescens resistant to ampicillin, cephalothin, cefoxitin, ticarcillin, cotrimoxazole, gentamicin, and tobramycin. All the patients were catheterized, and in most, bacteriuria was asymptomatic. The organism was also recovered from their hospital environment (sinks, toilets, urine-collecting basins). Analysis of total plasmid content of multiresistant isolates revealed the presence of two plasmids (7 kilobase, 25.5 kilobase), not found in aminoglycoside susceptible strains of Serratia marcescens. Restriction endonuclease analysis and Southern hybridization (DNA probe: 25.5 kilobase plasmid) verified that these plasmids were identical. The 25.5 kilobase plasmid was purified, introduced by transformation into an Escherichia coli strain C recipient, and was found to mediate resistance to gentamicin and tobramycin. The emergence of multiresistant Serratia marcescens coincided with an increase in antibiotic usage on the ward. The reservoir seemed to be the urinary tracts of asymptomatic catheterized patients and their contaminated hospital environment.

Acute hypoxemia does not affect the umbilical artery flow velocity waveform in fetal sheep.

The present study in sheep was undertaken to test whether acute fetal hypoxemia causes abnormalities in the umbilical artery velocity waveform. A 1-hour period of hypoxemia was induced in six chronically catheterized fetal sheep by reducing the inspired oxygen content of the ewe. During hypoxemia, the ratio of the systolic to diastolic velocity did not change significantly compared with controls. From this experimental evidence, we conclude that normal Doppler waveforms in the umbilical artery do not necessarily imply fetal normoxemia in sheep and that, because a direct cause-effect relationship has not been established, fetuses that have abnormal waveforms are not necessarily hypoxemic. Whether this is also true in humans remains to be shown.

Support among smokers and nonsmokers for restrictions on smoking.

The responses of 387 smokers and 988 nonsmokers obtained in a population-based survey in Ontario, Canada, were compared with regard to knowledge, attitudes, and predicted behavior concerning restrictions on smoking. Responses were tabulated as percentages and weighted according to the sample design. Nonoverlapping 95% confidence intervals provided evidence to reject the null hypothesis. Although smokers were found to be less knowledgable about the health effects of smoking and environmental tobacco smoke, more than 90% of both smokers and nonsmokers agreed with restrictions on smoking in 14 specific settings; for some settings, they disagreed on the extent of restrictions. The groups differed concerning specific bans on cigarette sales, but support was uniformly strong for bans in hospitals, controls on vending machines, and enforcement of the law prohibiting sales to minors. Clear majorities of both groups agreed that local government should enact and enforce restrictions. Smokers were more likely than nonsmokers to predict that smokers would comply with more restrictions, and most smokers indicated that they, themselves, would comply. We conclude that general health education should be bolstered by strategies specifically targeted at smokers. There is a strong basis across the population for restrictions to reduce exposure to environmental tobacco smoke; support for the role of local government in this regard is clear. Noncompliance with more restrictions is unlikely to present enforcement problems. Measures limiting the physical access of youths to tobacco will be widely supported, but strategies to increase support for tax measures are needed.

A population survey on legislative measures to restrict smoking in Ontario: 4. Variables related to knowledge of active and passive smoking health effects and to predicted behavior of smokers and nonsmokers.

Results from the further analysis of a population survey on legislative measures to restrict smoking revealed that identification of subgroups of smokers is more reliable than identification of subgroups of nonsmokers when a variety of attitudes were the measures of interest. A similar pattern emerged when analyses were carried out on knowledge of active and passive smoking health effects and on predicted personal and general compliance. Because distinct sets of variables were found to be related to distinct outcomes, program planning for changes in knowledge and behavior might, of necessity, have to be different. Media messages might be useful for changes in knowledge, while actual experience might be more important for attitude and behavior change.

A population survey on legislative measures to restrict smoking in Ontario: 3. Variables related to attitudes of smokers and nonsmokers.

A telephone survey of 1,383 residents of Ontario was conducted to assess attitudes toward antismoking legislation and knowledge of active and passive smoking health effects. After estimation of population parameters, analyses were carried out separately in smokers and nonsmokers to determine which characteristics, if any, were related to positive and negative attitudes, higher or lower knowledge scores, and predicted compliance or noncompliance with restrictive measures. Both bivariate and multivariate analyses were carried out. This paper reports the results for several measures of attitudes including restrictions on smoking locations and sales, differential insurance rates, control of advertising, and increase in taxes on cigarettes. Identification of smokers who hold negative attitudes is more reliable than identification of nonsmokers who hold positive views. Because different sets of variables were found to be related for the different attitude measures, it may be necessary to design different kinds of programs to prepare individuals for changes in legislation. The companion paper on p. 323 reports on the results for knowledge of active and passive smoking health effects and predicted compliance.

A population survey on legislative measures to restrict smoking in Ontario: 2. Knowledge, attitudes, and predicted behavior.

From the results of a population survey (n = 1,383) in the province of Ontario on legislative measures to restrict cigarette smoking we conclude that more is known about the adverse effects of active smoking than about those of passive smoking. Most people supported some degree of restriction in 13 specified locations. A majority supported total bans on smoking in day care and health-related facilities. Most respondents thought municipal governments should be responsible for legislating such bans and owner/managers responsible for enforcing them. However, there were a variety of opinions on the effectiveness of legislation in helping people to quit smoking. Responses differed slightly according to the geographic locations of the respondents, with residents of urban areas with bylaws being more restrictive. We suggest that such opinions and attitudes be studied further before legislative measures are enacted, so that all segments of the population are satisfied and unnecessary conflicts can be avoided.

A population survey on legislative measures to restrict smoking in Ontario: 1. Design, methodology, and sample representativeness.

Legislative measures restricting cigarette smoking have the potential to influence whether a person begins or continues to smoke and to affect the impact of passive smoking. We surveyed a representative sample of the adult population in Ontario on their knowledge of existing legislation and of the adverse effects of primary and secondary smoking on health. We also assessed their attitudes toward a range of restrictions and changes in legislation as well as their views on the enactment and enforcement of such legislation. This paper reports on the sample design, methods, response rates, and representativeness of the respondents. We used a three-stage stratified cluster design, covering both urban areas (with or without existing smoking bylaws) and rural areas and incorporating telephone interviews using random-digit dialing. The total number of respondents was 1,383, for an overall response rate of 67.5 percent. Despite attempts to ensure anonymity and to convey the importance of participation, we did not achieve total representativeness in sex ratio, age distribution, and certain educational and occupational categories. A companion paper reports on the population estimates of the variables under study.

Restrictions on smoking: growth in population support between 1983 and 1991 in Ontario, Canada.

While much progress in curtailing exposure to environmental tobacco smoke has occurred in Ontario, many jurisdictions still do not have any restrictions on smoking. To assess support in Ontario for restrictions, and recent changes in knowledge, attitudes, and behavior, we compared the findings of a population-based telephone survey conducted in 1991 (n = 1421) to those of a similar survey conducted in 1983 (n = 1383). Increases were found in the population's reported knowledge of specific health effects. Marked changes occurred in attitudes to restrictions on smoking. In 1991, the population consistently favoured more restrictions on smoking and their enactment by all levels of government. A role for local health departments in enforcement was clearly recognized. Most smokers indicated that they would comply with more restrictions. We also found that the self-reported prevalence of smoking had decreased 8 percentage points between 1983 and 1991. Population-based evidence of strong and increasing support for restrictions, accompanied by predictions of a high level of compliance, especially by smokers themselves, should facilitate legislation aimed at further curtailing smoking.

Use of Laplace transform analysis to describe the effect of placental embolisation on umbilical arterial Doppler waveforms in fetal sheep.

This is the first study to investigate changes in umbilical arterial Doppler shift waveforms caused by placental embolisation in fetal lambs described by a Laplace transform analysis method. The complete maximum velocity envelope of the waveform was quantified mathematically by the coefficients of the Laplace transform. The changes in the dominant coefficient were significantly correlated with changes in umbilico-placental vascular resistance. The Doppler shift waveforms reproduced those seen clinically in some growth-retarded pregnancies and were acquired in a clinically realistic manner. Increasing vascular resistance two fold in this experiment appeared to produce more consistent changes in the dominant coefficient of the Laplace transform than in the pulsatility index. Both analysis techniques correlated with umbilico-placental vascular resistance and these correlations were not significantly different from each other.

Experimentally induced changes in heart rate alter umbilicoplacental hemodynamics in fetal sheep.

In the anesthetized sheep fetus, we have accelerated heart rate by atrial pacing (n = 6) or caused decelerations by stimulating the vagus nerve (n = 7). Alterations in heart rate were linearly related to changes in the ratio of the diastolic minimum (D) to systolic maximum (S) of flow and velocity, and to changes in the flow pulsatility index in the umbilical artery. Decelerations slightly increased vascular resistance, and decreased blood flow and mean arterial pressure, but accelerations had no significant effect. The index of impedance was unaltered by either intervention. The major factor mediating the influence of heart rate on blood flow pulsatility in the umbilical artery was the aortic blood pressure pulsatility. An equation was derived to adjust flow D/S to a standardized heart rate. Results showed that heart rate correction can affect the interpretation of experimental data.