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Biomedical subjects

M Corey

Publications and source records attributed to M Corey.

At least 55 records · Page 3Linked to original sources
PubMed1995

The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group.

BACKGROUND: Anecdotal reports suggest an increased frequency of certain cancers in patients with cystic fibrosis, the commonest genetic disorder of whites. One third of patients with cystic fibrosis now reach adulthood, when cancer is more frequent, implying that cancer rates in these patients will increase over time. We investigated the relation between cystic fibrosis and cancer in North American and European patients with cystic fibrosis. Methods. We performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from population-based data on the incidence of cancer. We also analyzed proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. RESULTS: Thirty-seven cancers were observed in the North American cohort during 164,764 person-years of follow-up, as compared with an expected number of 45.6, yielding a ratio of observed to expected cancers of 0.8 (95 percent confidence interval, 0.6 to 1.1). Thirteen digestive tract tumors were observed, as compared with an expected number of two, for a ratio of observed to expected cancers of 6.5 (95 percent confidence interval, 3.5 to 11.1). In Europe, 11 of 39 cancers originated in the digestive tract, yielding a positive association between digestive tract tumors and cystic fibrosis (odds ratio, 6.4; 95 percent confidence interval, 2.9 to 14.0). CONCLUSIONS: Although the overall risk of cancer in patients with cystic fibrosis is similar to that of the general population, there is an increased risk of digestive tract cancers. Persistent or unexplained gastrointestinal symptoms in these patients should be carefully investigated.

Adolescent↗
PubMed1995

The HIV information project for transfusion recipients a decade after transfusion.

OBJECTIVE: To gather information on which to base decisions about a general notification program for pediatric patients a decade after their receiving transfusions. DESIGN: The physicians of a cohort of 1793 patients who underwent cardiac surgery were sent letters asking them to contact and counsel patients identified from cardiovascular surgery and blood bank databases about their risk for human immunodeficiency virus (HIV) infection. Questionnaires were used to collect data about physicians' HIV practices; telephone interviews were conducted to collect information about patients' and parents' knowledge and attitudes about HIV and transfusions. Because of unexpected media interest, questionnaires and interviews were modified to include questions about the source of information. The HIV-testing status of patients reported by physicians was anonymously cross-referenced with specimens received by the Laboratory Services Branch, Ontario Ministry of Health, Toronto. SETTING: A large Canadian pediatric tertiary care hospital in Toronto. PARTICIPANTS: Seven hundred ninety-three patients undergoing cardiopulmonary bypass between 1980 and 1985. RESULTS: The HIV Information Project successfully reached most (approximately 75%) of this cohort and, with the help of the media, many other at-risk transfusion recipients. The information was new for many; almost all informed wanted to undergo testing. The seroprevalence of this group that received multiple transfusions was, at minimum, 8.5 patients in 1000. Six previously unsuspected HIV-seropositive cases were diagnosed. CONCLUSIONS: Although we had assumed that most patients receiving transfusions would be aware of their risk for HIV infection, our results indicate that, even a decade after the transfusion, many recipients were not aware of the risk and wanted to undergo testing. Testing identified asymptomatic infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Six new mutations have been identified in the CFTR gene. These mutations, representing three different categories--missense (R31L, W1098R), nonsense (E1104X), and frameshift (441delA, 681delC, 1461ins4)--are located in exons 2, 4, 5, 9, and 17b of the gene and presumed to cause cystic fibrosis (CF) in patients. All these mutations are probably rare in the population, as no additional examples were found for any of them in a cohort of 545 CF patients. Our study also revealed a benign sequence variation (3499 + 45T-->C) in intron 17b.

Adult↗
PubMed1995

Longitudinal evaluation of serum trypsinogen measurement in pancreatic-insufficient and pancreatic-sufficient patients with cystic fibrosis.

We studied serial measurements of serum cationic trypsinogen in patients with cystic fibrosis to assess the predictability of changes in individuals and the value of longitudinal measurement in defining pancreatic status. Three hundred twenty-nine patients with cystic fibrosis, aged 3 days to 40 years, had serum levels of trypsinogen measured on 2 to 12 occasions for periods ranging from 1 week to 7 years. Patients were classified into three groups on the basis of 72-hour fecal fat studies performed at the time of diagnosis. Two hundred thirty-three patients had pancreatic insufficiency (PI), 78 had pancreatic sufficiency (PS), and 18 had PS at diagnosis but acquired PI during follow-up (PS-->PI). Infants with PI had greatly elevated serum trypsinogen levels that fell sharply in the first years of life, so that by age 7 years more than 95% had subnormal values; individual patient values followed a predictable course similar to previously reported cross-sectional age-related values. In patients with PS, serum trypsinogen levels generally remained within or above the normal range and, after age 10 years, were well above the upper limit for PI patients. Within-patient variance was significantly greater (p < 0.0001) in patients with PS than in those with PI who were older than 7 years of age. Changes in patients within PS-->PI generally followed the pattern seen in patients with PI, but values in older patients tended to be in the higher range. We concluded that serial measurement of serum trypsinogen is a valuable tool for monitoring the pancreatic status of patients with cystic fibrosis and PS.

Adolescent↗
PubMed1995

Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations.

OBJECTIVE: To compare differences in epithelial chloride conductance according to class of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: We evaluated the relationship between the functional classes of CFTR mutations and chloride conductance using the first diagnostic sweat chloride concentration in a large cystic fibrosis (CF) population. RESULTS: There was no difference in sweat chloride value value between classes of CFTR mutations that produce no protein (class I), fail to reach the apical membrane because of defective processing (class II), or produce protein that fails to respond to cyclic adenosine monophosphate (class III). Those mutations that produce a cyclic adenosine monophosphate-responsive channel with reduced conductance (class IV) were associated with a significantly lower, intermediate sweat chloride value. However, patients with the mutations that cause reduced synthesis or partially defective processing of normal CFTR (class V) had sweat chloride concentrations similar to those in classes I to III. CONCLUSION: Studies of differences in chloride conductance between functional classes of CFTR mutations provide insight into phenotypic expression of the disease.

Child↗
PubMed1995

Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis.

The clinical presentation and outcome of 32 children with primary sclerosing cholangitis (PSC) are reviewed, the largest North American series. The majority of patients were diagnosed in their second decade (median age: 13 years). Four children presented before the age of 2 years, but none in the neonatal period. Seventeen patients had inflammatory bowel disease (IBD), all with colitis, 14 ulcerative colitis, and 3 Crohn's disease. Eight patients presented with chronic liver disease before clinical onset of IBD. Only 8 of 32 patients were jaundiced at presentation. Fifteen of 32 had a normal serum alkaline phosphatase (ALP) level at presentation. Nine children presented with features similar to those of autoimmune hepatitis. Cholangiography was performed in all cases and classified by a scoring system specifically developed for pediatric patients. Intrahepatic disease predominated; in only three cases a common bile duct stricture was identified requiring stenting. Findings on the initial liver biopsy were classified according to Ludwig's criteria for staging PSC: there were 15 biopsies in stages 1 to 2 and 17 biopsies stages 3 to 4. HLA class I and II antigens were determined in 27 patients. An increased incidence of HLA B8 and DR2(15) but not DRw52a (DRB3*0101) was found. Anti-neutrophil cytoplasmic antibody (ANCA) was positive in 10 of 24 patients tested. Survival analysis indicated that a later age at presentation, splenomegaly, and prolonged prothrombin time (PT) at presentation were significant contributors to the prediction of poor outcome (i.e., death or listing for transplantation). Liver transplantation was successfully performed in seven children. Physicians must maintain a high index of suspicion of PSC in any child or young adult presenting with chronic liver disease, especially in the presence of IBD, even with a normal serum alkaline phosphatase level.

Adolescent↗
PubMed1993

Passive smoking and lung function in cystic fibrosis.

The relationship between passive exposure to cigarette smoking and objective measures of health was examined in 340 patients with cystic fibrosis attending a large hospital-based clinic. Patients who came from households with smokers did not differ from those living in smoke-free households in terms of nutritional status, clinical scores, spirometry, or colonization with Pseudomonas. The number of cigarettes smoked in the household was not significantly related to nutritional status, clinical score, spirometry, or hospitalization. Similar results were found when children 6 to 11 yr of age were analyzed separately, except that height percentile was negatively related to the number of cigarettes smoked in the household. The effects of household exposure to cigarette smoke were further evaluated by analyzing changes in nutritional status, clinical score, and spirometry over a 15-yr period among patients whose families never, always, stopped, or started smoking during this time. Height percentile increased slightly during this interval among those whose households never smoked, whereas no change occurred among patients whose households always smoked, and a decline was seen among patients whose households quit. These differences were statistically significant. Patients whose households never smoked had consistently higher pulmonary function measurements than did patients whose families always smoked, although the differences were not statistically significant. The rates of decline were similar in these two groups. Patients whose households stopped smoking had significantly lower pulmonary functions at the end of the study than did subjects whose households never smoked.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Prediction of mortality in patients with cystic fibrosis.

BACKGROUND: The majority of patients with cystic fibrosis die in early adulthood of lung disease. Lung transplantation is a treatment option for patients with advanced pulmonary disease, although the waiting period for organs may be as long as two years. Our purpose was to determine whether the risk of death due to respiratory failure could be predicted one or two years in advance on the basis of pulmonary function, blood gas levels, and nutritional status. METHODS: The study cohort consisted of 673 patients followed between 1977 and 1989. In each patient, pulmonary function, blood gas levels, nutritional status, and vital status were assessed between 1977 and 1987. Cox proportional-hazards regression analysis was used to compute the relative risk of death within one or two years after particular measurements. The effects of age and sex on mortality were also included in the analysis. RESULTS: One hundred ninety patients (28 percent) died during the study period. Overall, patients with a forced expiratory volume in one second (FEV1) less than 30 percent of the predicted value, a partial pressure of arterial oxygen below 55 mm Hg, or a partial pressure of arterial carbon dioxide above 50 mm Hg had two-year mortality rates above 50 percent. Among the laboratory measurements, the FEV1 was the most significant predictor of mortality, but age and sex were also significant in predicting risk. After adjustment for age and sex, the relative risk of death within two years was 2.0 (95 percent confidence interval, 1.9 to 2.2) for each decrement in the FEV1 of 10 percent below the predicted value. Among patients with the same FEV1, the relative risk of death was 2.0 (95 percent confidence interval, 1.5 to 2.6) in patients 10 years younger than other patients, and 2.2 (1.6 to 3.1) in female patients as compared with male patients. CONCLUSIONS: Patients with cystic fibrosis should be considered candidates for lung transplantation when the FEV1 falls below 30 percent of the predicted value. Female patients and younger patients may need to be considered for transplantation at an earlier stage.

Adolescent↗
PubMed1992

Binding of Pseudomonas cepacia to normal human intestinal mucin and respiratory mucin from patients with cystic fibrosis.

Although not as prevalent as Pseudomonas aeruginosa, Pseudomonas cepacia is another opportunistic pathogen which colonizes the lungs of at least some patients with cystic fibrosis. A subgroup of these patients exhibits the "cepacia syndrome", i.e., a rapid clinical deterioration and death within one year. To investigate potential early sites of bacterial attachment, we have measured the specific binding of P. cepacia isolates from cystic fibrosis (CF) sputa to both CF and non-CF mucins purified from respiratory and intestinal secretions, respectively. As shown in microtiter binding assays, clinical isolates from 19/22 patients were found to bind to both mucins, with the highest specific binding exhibited by isolates from eight patients, seven of whom later died with the cepacia syndrome. No differences were observed in the binding capacity of the two (CF versus non-CF) mucins. Binding was specific, saturable, and not influenced by tetramethylurea, a disruptor of hydrophobic associations. Individual sugars were ineffective as hapten inhibitors, as were several lectins. Mucins treated by reduction/alkylation or chloroform/methanol extraction showed enhanced bacterial binding, findings which were attributed to exposure of underlying binding sites. Deglycosylation procedures indicated that mucin receptors for P. cepacia include N-acetylglucosamine and N-acetylgalactosamine, probably linked together as part of core oligosaccharide structures. P. cepacia isolates also bound to buccal epithelial cells, and mucin partially inhibited the binding of those isolates of P. cepacia that also had the ability to bind to mucin. We speculate that specific binding of P. cepacia to secreted mucins may be an early step in the pathogenesis of the cepacia syndrome.

Bacterial Adhesion↗
PubMed1992

Decline of exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency.

Patients with cystic fibrosis and pancreatic sufficiency were investigated for evidence of progressive pancreatic disease. From a cohort of 630 patients, 20 pancreatic-sufficient patients became pancreatic insufficient after an average duration of 5.6 y (range 0.6-20.6 y) from diagnosis. Among 54 patients documented to be pancreatic sufficient by direct pancreatic stimulation test, 47 remained pancreatic sufficient and seven developed pancreatic insufficiency. The patients who ultimately developed pancreatic insufficiency were younger and had greatly reduced outputs of enzyme, fluid, and electrolytes. Those who remained pancreatic sufficient showed enzyme secretion close to or within the non-cystic fibrosis control range. Twenty of these patients underwent a second pancreatic stimulation test after an average interval of 4 y (range 1.3-6.2 y). No significant alteration in enzyme, fluid, or electrolyte output was seen in the patients who remained pancreatic sufficient, but there was further reduction in enzyme and fluid output in the patients who developed pancreatic failure. In conclusion, the majority of pancreatic-sufficient patients with pancreatic enzyme secretion within the control range showed no deterioration of function over an extended time period. However, a small number of pancreatic-sufficient patients with reduced enzyme and fluid secretion are at risk of pancreatic failure.

Adolescent↗
PubMed1992

Genetic determination of exocrine pancreatic function in cystic fibrosis.

We showed elsewhere that the pancreatic function status of cystic fibrosis (CF) patients could be correlated to mutations in the CF transmembrane conductance regulator (CFTR) gene. Although the majority of CF mutations--including the most common, delta F508--strongly correlated with pancreatic insufficiency (PI), approximately 10% of the mutant alleles may confer pancreatic sufficiency (PS). To extend this observation, genomic DNA of 538 CF patients with well-documented pancreatic function status were analyzed for a series of known mutations in their CFTR genes. Only 20 of the 25 mutations tested were found in this population. They accounted for 84% of the CF chromosomes, with delta F508 being the most frequent (71%), and the other mutations accounted for less than 5% each. A total of 30 different, complete genotypes could be determined in 394 (73%) of the patients. The data showed that each genotype was associated only with PI or only with PS, but not with both. This result is thus consistent with the hypothesis that PI and PS in CF are predisposed by the genotype at the CFTR locus; the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----T, 1717-1G----A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T.

Alleles↗
PubMed1992

Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus.

The glycine-to-aspartic acid missense mutation at codon 551 (G551D), which is within the first nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator (CFTR), is the third most common cystic fibrosis (CF) mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta F508, the most common CF mutation, we studied 79 compound heterozygotes for G551D/delta F508, from nine centers in Europe and North America. Each subject was matched, by age and sex, with a delta F508 homozygote from the same center. A retrospective cohort analysis was performed on the following outcome parameters: age at diagnosis, sweat chloride, meconium ileus at birth, height, weight, weight for height, FVC, FEV1, chest X-ray score, pseudomonas colonization, pancreatic sufficiency, and Shwachman clinical score. There was less meconium ileus among the G551D/delta F508 compound heterozygotes (relative risk 0.33; 95% confidence interval .13-.86), as well as a trend toward later age at diagnosis of pancreatic insufficiency. No statistically significant difference was found between the groups for any other parameter. These results suggest that the CF genotype can be a predictor of pancreatic and intestinal phenotype. Prenatal counseling for the two genotype groups should differ only with respect to probability of meconium ileus. Clinical outcome (after survival of meconium ileus) for G551D/delta F508 compound heterozygotes and delta F508 homozygotes is indistinguishable; therefore, prognostic counseling should not differ.

Adolescent↗
PubMed1992

Wheezing in infants with cystic fibrosis: clinical course, pulmonary function, and survival analysis.

Wheezing is a common finding in infants with cystic fibrosis (CF). This study was undertaken to determine the prevalence of wheezing in infants with CF and to compare the clinical outcome of those who wheezed in infancy with that of those who did not. The study cohort included 229 CF patients born between 1965 and 1979 with CF diagnosed before 2 years of age. Fifty-seven (25%) had physician-documented wheezing during the first 2 years of life. Wheezing had resolved by the age of 2 years in 50% of the patients and by the age of 4 years in 75%. Although wheezing seemed to be linked to a family history of allergy and asthma, the frequency of the delta F508 mutation was similar to that of the non-wheezers. There was no significant difference in survival at the age of 13 years between the two groups. At the age of 7 years, patients who had wheezed had significantly lower forced expiratory flow rate at mid-expiratory phase (85 +/- 34% predicted) compared with those with no wheezing history (101 +/- 34% predicted). At the age of 13 years, forced expiratory volume in 1 second values was lower in the wheezing group (69 +/- 24% predicted vs 78 +/- 21% predicted), as was forced expiratory flow rate at mid-expiratory phase (56 +/- 33% predicted vs 69 +/- 30% predicted). In conclusion, although wheezing in infants with CF seems to have diminished with age, pulmonary function abnormalities were more evident at 7 and 13 years of age in the group that wheezed than in the group that did not.

Cohort Studies↗
PubMed1991

The cystic fibrosis gene and resting energy expenditure.

To determine whether the increase in resting energy expenditure in cystic fibrosis is associated with the primary genetic defect (delta F508) or with declining pulmonary function, or both, we tested resting every energy expenditure prospectively in 32 male subjects (aged 7 to 39 years) who were normally nourished and had good pulmonary function. They were categorized into three genotype groups on the basis of the presence or absence of delta F508 and pancreatic function. Mean resting energy expenditure was 104% of the predicted value and was not associated with genotype. When 29 subjects with normal nutritional status but variable lung function were added to the group, there was a strong correlation between declining pulmonary function and increased resting energy expenditure. We conclude that increased resting energy expenditure in normally nourished boys and men with cystic fibrosis appears to be more closely associated with declining pulmonary function than with genotype.

Adolescent↗
PubMed1991

Use of the Pediatric Risk of Mortality score to predict nosocomial infection in a pediatric intensive care unit.

OBJECTIVE: To define infection rates in patients with Pediatric Risk of Mortality (PRISM) scores greater than and less than 10 on admission to the pediatric ICU (PICU). DESIGN: Descriptive. SETTING: An 18-bed PICU admitting patients of all ages except nonsurgical neonates; within a 585-bed tertiary care pediatric hospital. PATIENTS: Patients admitted to the PICU from July 1987 to February 1988 inclusive. Of 685 admitted, 480 were followed for greater than or equal to 72 hr. METHODS: The baseline state of the patients on admission was determined by a designated intensivist using the PRISM score. Other variables included age, length of stay, and hospital day of onset of infection. Infections were identified by a designated intensivist who undertook prospective daily bedside observation, chart, radiographic, and laboratory review. MEASUREMENTS AND MAIN RESULTS: Equal portions of patients had PRISM scores less than and greater than 10. Significantly more infections occurred in the high PRISM population (10.8% vs. 3.4%, p less than .001). This association held through age, service, and length of stay. Sensitivity, specificity, positive and negative predictive values of a PRISM score greater than 10 were 75%, 53%, 11%, and 97%, respectively. Bacteremias accounted for 36% of infections, skin/eye/drain site 22%, respiratory 16%, wound 15%, and urine 9%. The most prevalent organisms were coagulase-negative staphylococci (32%), Pseudomonas aeruginosa (23%), Candida sp. (20%), and S. aureus (9%). CONCLUSIONS: A PRISM score greater than 10 on PICU admission characterizes a population within the PICU at increased risk of infection. However, 93% of patients did not develop infection and thus, a negative predictive value of 97% yields little additional information.

Adolescent↗