The glutathione S-transferase mu polymorphism as a marker for susceptibility to lung carcinoma.

Glutathione S-transferase (GST) enzymes detoxify carcinogens in tobacco smoke. Interindividual variation in GST function may be related to differences in risk for smoking-related cancer. Leukocytes from 50% of Caucasians lack GST activity toward trans-stilbene oxide (TSO), due to a deletion of the gene for the GST-mu enzyme. Presence of GST-TSO activity in leukocytes has been associated with low risk for lung cancer among cigarette smokers. We sought to determine whether GST activity in lung tissue is determined by the same gene polymorphism and whether it is associated with risk for lung cancer. Subjects were cigarette smokers, identified at the time of lung resection or autopsy in Seattle hospitals. Uninvolved lung tissue was obtained from 35 patients with lung carcinoma and 43 control patients and assayed for GST-mu activity with TSO, for the presence of the GST-mu gene product with an immunological assay, and for the GST-mu gene with Southern blotting. Mailed questionnaires were used to collect information on subjects' smoking histories and exposures which might alter enzyme activity. Interindividual results from the three assays correlated well. Smokers with high GST-TSO enzyme activity present in their lung tissue had a lower risk for lung carcinoma than did smokers with no or low activity (relative risk = 0.30; 95% confidence interval, 0.11-0.79), as did smokers with GST-mu antigen identified in lung tissue versus those with no antigen (relative risk = 0.30; 95% confidence interval, 0.11-0.79). Smokers with both maternal and paternal copies of GST-mu DNA (n = 7) had a lower cancer risk than smokers lacking GST-mu DNA (n = 30; relative risk = 0.35; 95% confidence interval, 0.06-2.10). High GST-mu activity appeared to be associated with a greater decrease in lung cancer risk among 38 heavy cigarette smokers (relative risk = 0.15; 95% confidence interval, 0.03-0.64) than among 38 light smokers (relative risk = 0.61; 95% confidence interval, 0.14-2.60). Presence or absence and number of copies of the GST-mu gene appear to determine activity of the GST-mu enzyme in lung. Smokers with the GST-mu enzyme have approximately one-third of the risk for lung carcinoma of smokers without the enzyme.

Association of Chlamydia pneumoniae immunoglobulin A seropositivity and risk of lung cancer.

Chlamydia pneumoniae is a common respiratory pathogen that has also been associated with risk for chronic diseases, including atherosclerotic cardiovascular disease. Two recent studies have reported an association between serological evidence of past infection with the organism and lung cancer. To further evaluate this association, we conducted a case-control study among a subgroup of white male smokers identified for a population-based case-control study of lung cancer in western Washington between 1993 and 1995. Serum specimens obtained at study enrollment from 143 cases and 147 controls were tested for C. pneumoniae IgG, IgM, and IgA antibodies. In multivariate analysis controlling for smoking variables and educational status, IgA antibody titer 216 was independently associated with risk of lung cancer among subjects <60 years of age [odds ratio (OR), 2.67; 95% confidence interval (CI), 1.21-5.89] but not among older subjects (OR, 0.69; 95% CI, 0.34-1.43). Among subjects <60 years of age, there was suggestive evidence of a stronger association among current smokers (OR 4.31; 95% CI, 1.36-13.68) than former smokers (OR 1.50; 95% CI, 0.48-4.75; P for interaction term, 0.26). Additional studies, including prospective serological evaluations, are needed to further assess the possible significance of this association.

Glutathione S-transferase M1 and susceptibility to nasopharyngeal carcinoma.

Genetic polymorphisms for enzymes that metabolize tobacco smoke have been reported to determine susceptibility to several smoking-related cancers, including cancers of the lung, bladder, and head and neck. Glutathione S-transferase M1 (GSTM1) detoxifies benzo(a)pyrene and other carcinogens in tobacco smoke. Approximately 50% of Caucasians lack the GSTM1 gene. Because the most common type of nasopharyngeal cancer (NPC), squamous cell carcinoma, is related to smoking, we sought to determine whether GSTM1 is associated with risk for NPC. Cases (n = 83) were from a population-based study conducted from 1987 to 1993 at five cancer registries in the United States. Random-digit dialing controls (n = 114) were matched to the cases for age, sex, and registry. Subjects participated in a phone interview and blood draw. Absence of GSTM1 was associated with increased risk for NPC (odds ratio = 1.9, 95% confidence interval = 1.0-3.3 for all cases; and odds ratio = 1.7, 95% confidence interval = 0.8-3.5 for squamous cell cases). This relationship was not modified by smoking history, but stronger relationships between glutathione S-transferase and NPC were suggested among subjects who used alcohol more frequently than others, older subjects (50 or more years of age), and women relative to men. These data indicate that absence of GSTM1 moderately increases risk for NPC and add to growing evidence that GSTM1 is a determinant of risk for several smoking-related cancers.

Metabolic gene polymorphism frequencies in control populations.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

Biochemical discrimination of pathologic pregnancy from early, normal intrauterine gestation in symptomatic patients.

The authors have examined the utility of using the rate of change of the human chorionic gonadotropin (hCG) level and progesterone concentration to distinguish ectopic from normal intrauterine pregnancies. Patients suspicious for ectopic pregnancy had three outcomes: normal intrauterine gestation (NIUG), ectopic pregnancy (ECT), and inevitable abortion (IAB). The rate of change of the hCG level and the progesterone concentration distinguish NIUG from ECT with good sensitivity and specificity at optimal cut-offs of 0.14 (rate of change of the logarithm of hCG) and 8 ng/mL (progesterone). As the biochemical parameters of the ECT and IAB groups overlap, stating that NIUG can be biochemically distinguished from ECT is misleading. Thus, the authors have grouped them together as pathologic pregnancies (PATH). The rate of change of the hCG level and the progesterone concentration distinguish NIUG from PATH with good sensitivity and specificity with the same optimal cut-offs of 0.14 (rate of change of the logarithm of hCG) and 8 ng/mL (progesterone).

Recurrent intussusception. Risks and features.

OBJECTIVE: To determine the risk factors associated with recurrent intussusception (RI) and to characterize the timing, features, and complications of RI. DESIGN: Retrospective chart review. SETTING: Children's Hospital and Medical Center, Seattle, Wash. PARTICIPANTS: All patients with a diagnosis of intussusception who underwent barium enema as treatment for reduction between October 1, 1979 and December 31, 1990. Children with RI (N = 23, seven with two or more recurrent episodes) were classified as the case group; children with a single intussusception (N = 234), controls. RESULTS: There were no statistically significant differences in age, sex, race, symptoms, duration of symptoms, or results of the physical examination between the case group and controls. Reduction of the initial intussusception by a barium enema occurred in 96% of patients in the case group vs 62% of the controls (odds ratio, 13.50; 95% confidence intervals, 2.10 to 563.4; P = .003). Only one of 33 episodes of RI followed an operative reduction. In comparing the first recurrent episode with the initial episode, there was a significant reduction in the proportion of patients presenting with lethargy (0% vs 30%; Fisher Exact Test, P = .009) or blood in the stool (5% vs 52%; P < .002) and a drop in the median duration of symptoms from 20 to 6 hours. CONCLUSIONS: Recurrent intussusception cannot be predicted by presenting features or symptoms; operative reduction due to a failed reduction by a barium enema reduces the risk of RI; and patients with RI have fewer symptoms with a shorter duration.

Results of a directly observed intermittent isoniazid preventive therapy program in a shelter for homeless men.

We offered directly supervised isoniazid preventive therapy to middle-aged and elderly men who were exposed to tuberculosis during an outbreak of cases at a homeless shelter. Isoniazid, 900 mg, was administered twice weekly to men at the shelter and at the downtown Public Health Clinic. We report on compliance and adverse reactions associated with this preventive regimen. Isoniazid preventive therapy was offered to 64 men. Forty-seven men (73%) began therapy, and 23 of them (49%) completed the 6- to 12-month regimen. Men who failed to complete isoniazid therapy received a median of 11 biweekly doses (range, 1 to 41 doses) over a median of 9 wk (range, 3 to 37 wk). The most common reason for incomplete treatment was that the men no longer frequented the shelter. One hepatotoxic reaction occurred, for a 2.1% cumulative incidence among all men who started therapy and a 3.7% cumulative incidence among the 27 known alcoholic men who began therapy. In addition, we sought to identify personal characteristics of the men that might be associated with noncompliance. Out-of-state location of personal contacts in case of emergency was strongly associated with poor compliance. These data provide some assurance that directly supervised isoniazid preventive therapy may be offered safely to sheltered elderly men with a high prevalence of alcoholism. Further improvements in compliance with isoniazid preventive therapy in homeless populations may depend on the development of a therapeutic regimen of only 2 to 3 months duration.

Acute conjunctivitis in childhood.

We obtained specimens for culture from the lids and conjunctivae of 95 patients with acute conjunctivitis and 91 control children of similar age and, in addition, stained the conjunctival scrapings with Giemsa and Gram stains. The conjunctivitis was attributed to bacterial infection in 76 patients, viral infection in 12 children, and allergy in 2 patients; no cause was identified in the remaining 5 patients. In most cases the etiologic diagnosis was based on the results of laboratory studies. By separately culturing microorganisms in specimens from the lids and conjunctivae of patients and control subjects, we could distinguish normal flora from pathogens, and blepharitis from conjunctivitis. Staphylococci, corynebacteria, and alpha-hemolytic streptococci were the predominant organisms recovered from the lids of control subjects. In contrast, Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis were the major pathogens cultured from the conjunctival specimens from patients with bacterial conjunctivitis. Gram stains of conjunctival scrapings provided a rapid means of predicting the pathogen in 51 of 55 cases of bacterial conjunctivitis. Giemsa stains of conjunctival scrapings provided etiologic information in 81 of 84 cases, showing neutrophilia in bacterial infections, lymphocytosis in viral infections, and eosinophilia in allergic disease. These results indicate that most cases of acute conjunctivitis in children can be diagnosed on the basis of differential cultures of microorganisms from the lid and conjunctiva, together with Giemsa stains of conjunctival scrapings.

Relationships between cerebrovascular events, APOE polymorphism and Alzheimer's disease in a community sample.

To investigate whether the APOE*4 allele modified the relationship between cerebrovascular events and Alzheimer's disease (AD), we collected evidence of previous stroke or transient ischemic attack (TIA) and determined APOE genotype among 102 subjects with AD and 375 nondemented subjects in a community-based study of dementia. Subjects with a history of stroke or TIA were twice as likely to have AD as subjects without such a history. However, APOE*4 carriers with a history of stroke/TIA were 5 times more likely than APOE*4 carriers without such a history to have AD (odds ratio = 5.3, 95% confidence interval = 1.4-20.9). History of stroke/TIA had little effect on the likelihood of having AD in subjects without an APOE*4 allele.

Eosinophilic fasciitis in children frequently progresses to scleroderma-like cutaneous fibrosis.

We evaluated longterm outcome in 21 pediatric patients with biopsy proven eosinophilic fasciitis (EF), 4 followed in our rheumatology clinic and 17 reported in the literature. Two-thirds of these patients developed residual cutaneous fibrosis, while one-third enjoyed complete resolution of disease. Children under age 7 years were twice as likely as those over age 7 years to experience disease progression to cutaneous fibrosis [relative risk = 2.0 (95% confidence intervals 1.2, 3.4)]. Fourteen of 17 patients with extensive disease at diagnosis (involvement of 3-4 extremities +/- trunk) progressed to cutaneous fibrosis whereas all 4 patients with minimal disease (involvement of 1-2 extremities) at onset resolved completely. We detected no association between progression to cutaneous fibrosis and sex of patient, duration of symptoms prior to therapy, type of therapy, history of prior physical stress, or laboratory variables at diagnosis.

MR imaging of bone marrow in children with osteosarcoma: effect of granulocyte colony-stimulating factor.

OBJECTIVE: Granulocyte colony-stimulating factor (GCSF) is used to stimulate myeloid cell production and function in children undergoing chemotherapy for osteosarcoma. We hypothesize that GCSF can cause reconversion of marrow from fatty to hematopoietic and that this change can be detected by MR imaging at sites away from the primary tumor. This benign effect of treatment should not be confused with tumor spread. MATERIALS AND METHODS: MR images of marrow of the affected and contralateral limbs were retrospectively reviewed for 16 patients with osteosarcoma of the femur or tibia; nine of these patients had received GCSF. A grade was assigned to marrow signal intensity at sites away from the tumor, and findings before and after treatment were compared. The validity of MR image interpretation was assessed by comparing the signal intensity of marrow with the histologic appearance of marrow at 19 resection margins. RESULTS: Changes consistent with reconversion were seen on MR images in seven of nine patients who had received GCSF in addition to chemotherapy and in none of seven patients who had received chemotherapy alone. The difference in proportions was statistically significant (p = .006; Fisher's exact test, two tailed). The histologic appearance of marrow at the resection margins agreed with the interpretation of the short-Tl inversion recovery sequence in all cases (100%). CONCLUSION: The findings suggest that GCSF causes changes in the MR imaging appearance of marrow. Histologic correlation supports the hypothesis that these changes are attributable to reconversion from fatty to hematopoietic marrow. Awareness of this finding is important to avoid false-positive diagnosis of marrow metastases.

Association of elevated umbilical cord blood creatine kinase and myoglobin levels with the presence of cocaine metabolites in maternal urine.

STUDY OBJECTIVE: To determine whether an association exists between antenatal cocaine exposure and elevated levels of creatine kinase (CK) and myoglobin in umbilical cord blood collected upon delivery. STUDY POPULATION: 105 anonymous maternal urines with corresponding infant umbilical cords bloods. METHODS: Maternal urines were screened for cocaine metabolites by the Syva EMIT assay, with positive specimens confirmed by gas chromatography/mass spectrometry. For all 8 positives, plus the first 47 of the negatives collected, matched infant cord blood specimens were analyzed for myoglobin by radioimmunoassay and CK by kinetic enzyme activity assay. Cord bloods matched to the remaining 50 cocaine-negative urines were not analyzed. A two-tailed Mann-Whitney test was used to evaluate the significance of differences in CK and myoglobin levels between the two groups. RESULTS: CK levels were evaluated twofold in the cocaine-positive group as compared to the cocaine negative group (mean 383 +/- 260 vs. 189 +/- 68 IU/L, p = 0.005). Myoglobin levels were twofold higher in the cocaine-positive group compared to the cocaine negative group (mean 55.9 +/- 37.1 vs. 33.3 +/- 26.8 ng/mL, p = 0.077). CONCLUSION: Antenatal cocaine exposure is associated with elevated cord blood CK, and possibly with elevated cord blood myoglobin. Additional studies, using larger study populations and more sensitive methods of detecting antenatal cocaine exposure, along with detailed follow-up examination of infants, are indicated.

Nontraumatic pediatric musculoskeletal MR imaging: comparison of conventional and fast-spin-echo short inversion time inversion-recovery technique.

PURPOSE: To compare conventional short inversion time inversion-recovery (STIR) with fast spin-echo (FSE) STIR techniques to evaluate suspected nontraumatic musculoskeletal abnormalities. MATERIALS AND METHODS: Thirty STIR and FSE-STIR examinations in 26 pediatric patients with suspected nontraumatic musculoskeletal abnormalities were prospectively evaluated. Qualitative (subjective) and quantitative (five-point rank score) analyses of the images were performed. RESULTS: FSE-STIR was faster than STIR (mean, 2 minutes 25 seconds and 6 minutes 35 seconds, respectively). Fat suppression was slightly better with STIR. Image degradation due to motion was judged similar. Lesion contrast to muscle was slightly better with STIR than FSE-STIR, and lesion contrast to fat was equivalent. Qualitatively, lesion conspicuity was similar: All lesions were seen with both techniques. CONCLUSION: FSE-STIR can replace STIR when an inversion-recovery fat-suppression sequence is desired. Considerable imaging time is saved.

Escherichia coli O 157:H7-associated hemolytic-uremic syndrome after ingestion of contaminated hamburgers.

We conducted a retrospective analysis of 37 children with Escherichia coli O157:H7-associated hemolytic-uremic syndrome. The infection was traced to contaminated hamburgers at a fast-food restaurant chain. Within 5 days of the first confirmed case, the Washington State Department of Health identified the source and interrupted transmission of infection. Ninety-five percent of the children initially had severe hemorrhagic colitis. Nineteen patients (51%) had significant extrarenal abnormalities, including pancreatitis, colonic necrosis, glucose intolerance, coma, stroke, seizures, myocardial dysfunction, pericardial effusions, adult respiratory disease syndrome, and pleural effusions. Three deaths occurred, each in children with severe multisystem disease. At follow-up two children have significant impairment of renal function (glomerular filtration rate < 80 ml/min/per 1.73 Hm2); both of these children have a normal serum creatinine concentration. Hemolytic-uremic syndrome is the most common cause of acute renal failure in children, and this experience emphasizes the systemic nature of this disease. Clinicians should anticipate that multisystem involvement may occur in these patients, necessitating acute intervention or chronic follow-up. This outbreak of Hemolytic-uremic syndrome also highlights the microbiologic hazards of inadequately prepared food and emphasizes the importance of public health intervention in controlling Hemolytic-uremic syndrome.