Accuracy and interrater reliability for the diagnosis of Barrett's neoplasia among users of a novel, portable high-resolution microendoscope.

The high-resolution microendoscope (HRME) is a novel imaging modality that may be useful in the surveillance of Barrett's esophagus in low-resource or community-based settings. In order to assess accuracy and interrater reliability of microendoscopists in identifying Barrett's-associated neoplasia using HRME images, we recruited 20 gastroenterologists with no microendoscopic experience and three expert microendoscopists in a large academic hospital in New York City to interpret HRME images. They prospectively reviewed 40 HRME images from 28 consecutive patients undergoing surveillance for metaplasia and low-grade dysplasia and/or evaluation for high-grade dysplasia or cancer. Images were reviewed in a blinded fashion, after a 4-minute training with 11 representative images. All imaged sites were biopsied and interpreted by an expert pathologist. Sensitivity of all endoscopists for identification of high-grade dysplasia or cancer was 0.90 (95% confidence interval [CI]: 0.88-0.92) and specificity was 0.82 (95% CI: 0.79-0.85). Positive and negative predictive values were 0.72 (95% CI: 0.68-0.77) and 0.94 (95% CI: 0.92-0.96), respectively. No significant differences in accuracy were observed between experts and novices (0.90 vs. 0.84). The kappa statistic for all raters was 0.56 (95% CI: 0.54-0.58), and the difference between groups was not significant (0.64 vs. 0.55). These data suggest that gastroenterologists can diagnose Barrett's-related neoplasia on HRME images with high sensitivity and specificity, without the aid of prior microendoscopy experience.

High resolution microendoscopy for classification of colorectal polyps.

BACKGROUND AND STUDY AIMS: It can be difficult to distinguish adenomas from benign polyps during routine colonoscopy. High resolution microendoscopy (HRME) is a novel method for imaging colorectal mucosa with subcellular detail. HRME criteria for the classification of colorectal neoplasia have not been previously described. Study goals were to develop criteria to characterize HRME images of colorectal mucosa (normal, hyperplastic polyps, adenomas, cancer) and to determine the accuracy and interobserver variability for the discrimination of neoplastic from non-neoplastic polyps when these criteria were applied by novice and expert microendoscopists. METHODS: Two expert pathologists created consensus HRME image criteria using images from 68 patients with polyps who had undergone colonoscopy plus HRME. Using these criteria, HRME expert and novice microendoscopists were shown a set of training images and then tested to determine accuracy and interobserver variability. RESULTS: Expert microendoscopists identified neoplasia with sensitivity, specificity, and accuracy of 67 % (95 % confidence interval [CI] 58 % - 75 %), 97 % (94 % - 100 %), and 87 %, respectively. Nonexperts achieved sensitivity, specificity, and accuracy of 73 % (66 % - 80 %), 91 % (80 % - 100 %), and 85 %, respectively. Overall, neoplasia were identified with sensitivity 70 % (65 % - 76 %), specificity 94 % (87 % - 100 %), and accuracy 85 %. Kappa values were: experts 0.86; nonexperts 0.72; and overall 0.78. CONCLUSIONS: Using the new criteria, observers achieved high specificity and substantial interobserver agreement for distinguishing benign polyps from neoplasia. Increased expertise in HRME imaging improves accuracy. This low-cost microendoscopic platform may be an alternative to confocal microendoscopy in lower-resource or community-based settings.

Measurement of colonic polyps by radiologists and endoscopists: who is most accurate?

The purpose was to determine the accuracy of polyp measurement by endoscopy and CT. A colonic phantom was constructed containing 12 simulated polyps of known diameter. Polyp diameter was estimated during endoscopy by two observers independently. The phantom was then scanned using a 64-detector-row machine and diameter estimated by a further two observers independently, using 2D and 3D visualisation methods. All measurements were obtained twice. Bland-Altman statistics were used to assess agreement between observers' estimates and the reference diameter. The mean difference between observers' measurements and the reference diameter was smallest for estimates made using 3D CT (-0.09 mm and -0.03 mm) and greatest for endoscopy (-1.10 mm and -1.19 mm), with 2D CT intermediate. However, 95% limits of agreement were largest for 3D CT estimates (-4.38 mm to 4.20 mm). Estimates by 2D CT consistently overestimated polyp diameter, whereas endoscopy consistently underestimated diameter. In contrast, measurements by 3D CT were a combination of over- and under-estimates, with a tendency for disagreement to increase with the size of the polyp. The effect of observer experience was small and repeatability was best for 2D CT. Measurement error was encountered with all three modalities tested. Estimates made by 2D CT were believed to offer the best compromise overall.

Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study.

BACKGROUND: The histopathology of AIDS-associated myelopathy (AM) closely resembles that of myelopathies due to cobalamin or folate deficiency, with white matter vacuolization in the spinal cord. The pathogenesis of AM appears unrelated to direct HIV infection of the spinal cord. There is abnormal trans-methylation metabolism in AM, with decreased availability of the methyl group donor S-adenosyl-methionine (SAM). The authors hypothesized that treatment with l-methionine, the direct metabolic precursor of SAM, might improve AM. OBJECTIVE: To determine the safety and efficacy of l-methionine treatment in AM. METHODS: Fifty-six patients with clinical diagnosis of AM were randomized to a Phase II, double-blind, placebo-controlled study comparing the effect of l-methionine 6 g/day in two divided doses with that of placebo. Study duration was 12 weeks. All patients had somatosensory evoked potentials with prolonged central conduction time (CCT) at entry. Change in CCT was the primary endpoint of the study. Frequency of adverse events (AEs) was used to assess safety. Secondary endpoints were strength, spasticity, and urinary function. Biochemical measurements included serum methionine and homocysteine and CSF SAM. RESULTS: There were no significant differences in AEs between the two groups. Serum homocysteine increased in l-methionine-treated patients from 7.2 (+/-5.2 SD) to 12.6 (+/-6.15 SD) micromol/L. The mean CCT at baseline was 25.9 milliseconds (+/-7.3 SD) for the treatment group and 24.1 milliseconds (+/-7.0 SD) for the placebo group. At completion, it was 3.0 milliseconds (+/-6.1 SD) for the treatment group and 23.6 milliseconds (+/-5.5 SD) for the placebo group (p = 0.17). In a subset of 15 patients with CSF studies, SAM levels increased in the l-methionine but not in the placebo group (p = 0.07). There was no significant effect of treatment on strength, spasticity, or urinary function. CONCLUSIONS: l-methionine was safe and well tolerated although in some patients induced an increase of serum homocysteine. There was a nonsignificant improvement in CCT in treated patients but no benefit in any of the clinical measures.

Abnormal cobalamin-dependent transmethylation in AIDS-associated myelopathy.

BACKGROUND: White matter vacuolization of the spinal cord is common in patients with AIDS and may lead to clinical manifestations of myelopathy. The pathogenesis of AIDS-associated myelopathy (AM) is unknown and may be related to metabolic abnormalities rather than to direct HIV infection. The striking pathologic similarity between AM and the vacuolar myelopathy associated with vitamin B(12) deficiency suggests that abnormal metabolism of the B(12)-dependent transmethylation pathway may be important in the pathogenesis of AM. METHODS: The authors compared S-adenosyl-methionine (SAM), methionine, homocysteine, and glutathione in serum and CSF of 15 patients with AM vs. 13 HIV-infected controls without myelopathy (HWM). They also compared the results with a non-HIV--infected reference population (NC). All patients had normal B(12), folate, and methylmalonic acid levels. RESULTS: There was a decrease in CSF SAM in the AM group compared with the HWM group (p < 0.0001) and the NC group (p < 0.0001). CSF SAM in the HWM group was also lower than that in the NC group (p = 0.015). Serum methionine was also reduced in serum of the myelopathic group compared with the NC group (p = 0.006). CONCLUSIONS: AM is associated with an abnormality of the vitamin B(12)-dependent transmethylation pathway.

AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid.

The pathogenesis of AIDS-associated myelopathy is unknown. Elevated HIV-1 viral load in CSF has been associated with cognitive impairment. The authors investigated if a similar association exists in patients with myelopathy. The authors evaluated levels of HIV-1 RNA in the CSF of 16 individuals with AIDS myelopathy and in 16 nonmyelopathic HIV-infected control subjects. There was no correlation between levels of HIV-1 RNA and the presence or severity of myelopathy.

Antiphosphatidyl serine antibodies are independently associated with ischemic stroke.

OBJECTIVE: To determine whether elevated titers of antiphosphatidyl serine antibodies (aPS) are associated with an increased risk of ischemic stroke in a general stroke population. BACKGROUND: aPS are members of the family of antiphospholipid antibodies that has been associated with increased stroke risk. Although aPS have been demonstrated to occur in 18% of a group of young patients with cerebrovascular symptoms, their prevalence in the general stroke population is unknown, and no controlled study to assess the strength of their association with ischemic stroke has been undertaken previously. METHODS: A case-control study comparing 267 acute ischemic stroke patients and 653 community controls. Sera were obtained immediately after acute stroke in patients. Titers of IgG aPS >16 IgG phospholipid units or IgM aPS >22 IgM phospholipid units were considered positive. Odds ratios (ORs) were obtained by logistic regression, adjusting for age, gender, race/ethnicity, history of hypertension, diabetes mellitus, cardiovascular disease, and cigarette smoking. RESULTS: The adjusted OR was 5.6 (95% confidence interval [CI] 1.8, 18.0) for IgG aPS and 2.9 (95% CI 1.6, 5.3) for IgM aPS. The adjusted OR for either an elevated IgG or IgM aPS was 3.2 (95% CI 1.8, 5.5). CONCLUSIONS: This study demonstrates that elevated IgG and IgM antiphosphatidyl serine antibodies titers are associated with increased risk of ischemic stroke. The prevalence of these antibodies is lower, but the associated stroke risk is comparable with that of anticardiolipin antibodies.

Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity.

BACKGROUND AND PURPOSE: Previous studies have produced conflicting results regarding the putative association between anticardiolipin antibodies (aCL) and infarction in the general stroke population. These inconsistencies may be a function of sample size and methodological differences among the studies. The purpose of the present study, the largest case-control study of this issue to date, was to assess aCL status as an independent risk factor for ischemic stroke in a multiethnic, urban population. METHODS: We obtained aCL titers in 524 hospitalized acute stroke patients and 1020 community controls enrolled in the Minorities Risk Factors and Stroke Study. The results were interpreted as negative (30.0 GPL or 15.0 MPL units). Odds ratios (ORs) were adjusted for age, sex, race/ethnicity, history of diabetes, hypertension, atrial fibrillation, coronary artery disease, and current cigarette smoking. RESULTS: A positive aCL titer was present in 11% (111/1020) of controls and 34% (180/524) of cases. The adjusted OR for any positive aCL titer was 4.0 (95% CI, 3.0 to 5.5). For any positive IgG aCL titer this value was 3.9 (95% CI, 2.8 to 5.5), and for any positive IgM aCL titer it was 3.4 (95% CI, 2.1 to 5.5). There were no significant differences in ORs associated with high- or low-positive IgG or IgM aCL titers. CONCLUSIONS: In the largest study of its kind to date, aCL antibodies were demonstrated to be independent stroke risk factors across the 3 ethnic groups studied, conferring a 4-fold increased risk of ischemic stroke. IgG and for the first time IgM aCL were each shown to be associated with increased stroke risk. The prevalence of these antibodies and the stroke risk associated appear greater than previously reported.

Pesticides and inner-city children: exposures, risks, and prevention.

Six million children live in poverty in America's inner cities. These children are at high risk of exposure to pesticides that are used extensively in urban schools, homes, and day-care centers for control of roaches, rats, and other vermin. The organophosphate insecticide chlorpyrifos and certain pyrethroids are the registered pesticides most heavily applied in cities. Illegal street pesticides are also in use, including tres pasitos (a carbamate), tiza china, and methyl parathion. In New York State in 1997, the heaviest use of pesticides in all counties statewide was in the urban boroughs of Manhattan and Brooklyn. Children are highly vulnerable to pesticides. Because of their play close to the ground, their hand-to-mouth behavior, and their unique dietary patterns, children absorb more pesticides from their environment than adults. The long persistence of semivolatile pesticides such as chlorpyrifos on rugs, furniture, stuffed toys, and other absorbent surfaces within closed apartments further enhances urban children's exposures. Compounding these risks of heavy exposures are children's decreased ability to detoxify and excrete pesticides and the rapid growth, development, and differentiation of their vital organ systems. These developmental immaturities create early windows of great vulnerability. Recent experimental data suggest, for example, that chlorpyrifos may be a developmental neurotoxicant and that exposure in utero may cause biochemical and functional aberrations in fetal neurons as well as deficits in the number of neurons. Certain pyrethroids exert hormonal activity that may alter early neurologic and reproductive development. Assays currently used for assessment of the toxicity of pesticides are insensitive and cannot accurately predict effects to children exposed in utero or in early postnatal life. Protection of American children, and particularly of inner-city children, against the developmental hazards of pesticides requires a comprehensive strategy that monitors patterns of pesticide use on a continuing basis, assesses children's actual exposures to pesticides, uses state-of-the-art developmental toxicity testing, and establishes societal targets for reduction of pesticide use.

Polymorphisms of H-ras-1 and p53 in breast cancer and lung cancer: a meta-analysis.

Certain polymorphic variants of H-ras-1 and p53 have been investigated for an association between inheritance and cancer risk. The results of a metaanalysis, which reviews studies of H-ras-1 rare alleles and p53 codon 72 allelic variants in breast and lung cancer, are presented. The data constituted evidence for elevated risk of both breast and lung cancer with inheritance of rare H-ras-1 alleles. Calculated population attributable risks are 0.092 and 0.037 for breast and lung cancer, respectively. The frequency of the rare H-ras-1 alleles was observed to be greater in African Americans than in Caucasians, and a specific allele (A3.5) that is common in African Americans was found only at low frequency in Caucasians. For p53 a consensus has yet to be reached. Lung cancer studies conducted in Caucasian and African-American populations have found no evidence of risk associated with the proline variant of codon 72. Two similar studies conducted in Japanese populations suggested an association between p53 genotype distribution and lung cancer risk. However, one implicates the proline allele but the other implicates the arginine allele. The frequency of the proline variant is significantly dependent on race. Frequencies have been reported for control populations of Japanese (0.347 and 0.401), Caucasian (0.295, 0.284, and 0.214), African American (0.628 and 0.527), and Mexican American (0.263).

Chrysotile asbestos fibers mediate homologous recombination in Rat2 lambda fibroblasts: implications for carcinogenesis.

Asbestos fibers are widespread environmental carcinogens whose mutagenicity is now established. Nonetheless, the molecular nature of these mutations and the mechanisms by which they accelerate carcinogenesis remain poorly understood. We have assessed the ability of asbestos fibers to promote homologous recombination, a potent mechanism for generating intrachromosomal rearrangements, such as deletions, and mitotic recombination. For this, we have developed a new assay which determines the extent to which a marker gene present in DNA introduced by asbestos can recombine with homologous genes residing in a transfected cell. We have demonstrated that Calidria chrysotile fibers are mutagenic and are able to mediate transfection of molecularly marked mutant lacI genes in a manner that results in their preferential recombination with homologous wild-type genes in the transfected cell. Asbestos induced recombination events may play a significant role in asbestos mutagenesis and carcinogenesis, and promotion of recombination may underlie the well-recognized synergy of asbestos with other carcinogens.

Relation of spirometric function to radiographic interstitial fibrosis in two large workforces exposed to asbestos: an evaluation of the ILO profusion score.

OBJECTIVES: To analyse quantitatively the relations of spirometric lung function (forced vital capacity (FVC)) to radiographic interstitial pulmonary fibrosis (assessed by the International Labour Organisation (ILO) profusion score of small irregular opacities) in two large workforces exposed to different intensities of asbestos. These analyses consider the question whether a similar profusion score n differently exposed workers is associated with a similar effect on lung function. METHODS: Surveys of two workforces, insulators (n = 2611) and sheet metal workers (n = 1245), by the same investigators allowed comparison of the effects of the two levels of exposure to asbestos. The two groups were of similar age and had similar percentages of non-smokers and smokers. All radiographs were read by the same expert reader. RESULTS: Consistent with their less continuous and less intense exposure to asbestos, metal workers had: (a) far less frequent radiographic asbestosis (profusion score > or = 1/0, 17.5% v 59.6% for insulators): (b) less severe radiographic asbestosis (only 1.1% had scores > or = 2/1 v 13.3% of insulators); (c) a similar slope to that seen in insulators for the relation between FVC and profusion score when pleural thickening was absent; (d) less frequent pleural fibrosis (36% v 75%); and (e) less frequent restrictive impairment (23% v 33%). In both insulators and metal workers, lung function was below normal even when lung fields were normal, FVG fell with increasing profusion, it was lower in smokers and in those with pleural thickening at comparable profusion scores, and these was no difference in FVC between scores 0/1 and 1/0. CONCLUSION: The decrease in FVC with increasing profusion score in both workforces as well as the similar slopes for the relation between FVG and profusion score and the similar FVG at similar scores in the absence of pleural thickening confirm the ILO profusion score as an acceptable assessment of pulmonary fibrosis.

Spirometric impairments in long-term insulators. Relationships to duration of exposure, smoking, and radiographic abnormalities.

A study of 2,611 long-term asbestos insulators was well suited to provide information on (1) the prevalence of spirometric impairments in a large, well-defined population and (2) the effects of cigarette smoking, radiographic abnormalities, and duration from onset of exposure on pulmonary function. Prevalences are reported by a mutually exclusive classification of impairments (normal, restrictive, obstructive, small airways, and combined) as well as by abnormality of specific spirometric tests (FVC, FEV1/FVC, and midexpiratory time). Only 3 percent of nonsmokers (NS) had obstruction and 6 percent a decreased FEV1/FVC. Frequency of restriction did not vary by smoking history; it was 31 percent in NS and current smokers (CS) and 34 percent in ex-smokers (XS). Obstruction (present in 17 percent) and combined impairment (in 18 percent) were most common in CS. The FEV1/FVC was decreased in 35 percent of CS and 18 percent of XS. The FVC was decreased in 49 percent of CS, 44 percent of XS, and 33 percent of NS. Normal spirometry was most common when the radiograph was normal (almost half the workers with normal radiographs had normal spirometry). Nevertheless, FVC was reduced in 27 percent of those with normal radiographs and a normal radiograph was seen in 11 percent of workers with restriction. Restrictive and combined impairments were most frequent when both parenchyma and pleura were abnormal. Restriction was more frequent in isolated pleural disease (seen in 34 percent such subjects) than in isolated parenchymal disease (22 percent). The contribution of pleural fibrosis to reduced FVC and of asbestos exposure and smoking both to reduced FVC and to reduced FEV1/FVC was confirmed by regression analysis. That reduced FVC and reduced FEV1/FVC are both more frequent in insulators who have smoked (compared with NS insulators or smokers in the general population) suggests an interaction between asbestos and smoking in producing both these physiologic abnormalities.

Myopathies associated with human immunodeficiency virus and zidovudine: can their effects be distinguished?

Myopathy may occur as a complication of human immunodeficiency virus type 1 (HIV) infection or from its treatment, zidovudine (ZDV). We reviewed our experience with HIV-infected subjects referred for neuromuscular evaluation and compared features of myopathy in ZDV-treated (+ZDV) and untreated (-ZDV) patients. Fifty patients had myopathy, 25 diagnosed by pathologic criteria and 25 by clinical and other laboratory support. Twenty patients with myopathy had weight loss sufficient for the diagnosis of HIV wasting syndrome. Thirty-one subjects were +ZDV and 19 were -ZDV. Patients in each group presented with proximal weakness, although myalgia was more common in +ZDV patients. Both groups had elevated serum CK to a similar degree (medians: +ZDV, 485; -ZDV, 471). Muscle biopsies revealed myofiber degeneration, variable inflammatory infiltrates, inclusion bodies, and mitochondrial abnormalities in both groups. We followed response to ZDV withdrawal in 15 patients. Four had increased strength, three noted less myalgia, and eight had no clinical improvement. Twelve of 13 patients improved with prednisone. Although it is difficult to distinguish the myopathies of HIV and ZDV by clinical or pathologic criteria, in the majority of our patients, myopathy is due to HIV rather than ZDV.

Comparative quantitative evaluation of pleural fibrosis and its effects on pulmonary function in two large asbestos-exposed occupational groups--insulators and sheet metal workers.

Two large (N = 1584 and N = 1330) population groups of workers exposed to asbestos as insulators (I) or sheet metal workers (SM) were compared. Prevalence rates of radiographic changes including pleural fibrosis (circumscribed and diffuse) were found to be much higher in I than SM. An integrative index of pleural fibrosis (INDEX) showed similar distribution patterns in the two groups; the effect of INDEX on FVC% predicted was more marked in insulators. Factors that could contribute to this difference are thought to be the higher prevalence of interstitial pulmonary fibrosis (probably including that which is not yet radiologically detectable) in I than in SM, the possibility of more extensive pleural fibrosis in areas not accessible to the standard chest X ray (and thus not affecting INDEX) and a higher proportion of diffuse pleural fibrosis in the I group.

Childhood asthma and passive smoking. Urinary cotinine as a biomarker of exposure.

To assess the relationship between passive smoking and asthma, we investigated (1) whether passive smoking was more prevalent among asthmatic than control children and (2) whether exposure to tobacco smoke was higher in acute asthma than in nonacute asthma. Three groups were recruited into a case-control study: 72 acute asthmatic children from the emergency room (ER), 35 nonacute asthmatic children from the asthma clinic, and 121 control children from the ER. Both questionnaire and urinary cotinine/creatinine ratio (CCR) were used to assess passive smoking. Levels of CCR greater than or equal to 30 ng/mg were used to identify children exposed at home. Mean CCR was also computed. Acute and nonacute asthmatic children had similar prevalences of passive smoking at home. Acute cases showed a higher mean CCR than nonacute cases, but this was not significant. In comparing all asthmatic to control children, smoking by the maternal caregiver was more prevalent among asthmatic children (odds ratio OR = 2.0, 95% CI 1.1, 3.4). This was confirmed by CCR greater than or equal to 30 ng/mg (OR = 1.9, 95% CI 1.04, 3.35) and by the difference in mean CCR (43.6 versus 25.8 ng/mg, p = 0.06). We conclude that smoking by the maternal caregiver is associated with clinically significant asthma in children. We could not show that it is a trigger of acute asthma attacks.

Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer.

The etiology of human breast cancer is unknown; accepted risk factors, e.g., menstrual, reproductive, and family histories, are implicated in less than half of all cases. Various halogenated hydrocarbons--acting as either co-carcinogens or promoting agents--which are derived from the environment and are concentrated in human fatty stores, may also play a role in breast cancer risk. A pilot study was undertaken to measure and compare levels of chemical residues in mammary adipose tissue from women with malignant and nonmalignant breast disease. Elevated levels of polychlorinated biphenyls, bis (4-chlorophenyl)-1,1 dichloroethene, and bis(4-chlorophenyl)-1,1,1 trichloroethane were found in fat samples from women with cancer, compared with those who had benign breast disease. These results, although preliminary, suggest a role for environmentally derived suspect carcinogens in the genesis of mammary carcinoma.

Relationship of pulmonary function to radiographic interstitial fibrosis in 2,611 long-term asbestos insulators. An assessment of the International Labour Office profusion score.

Radiographic evidence of interstitial fibrosis (IF) secondary to asbestos inhalation (using the International Labour Office [ILO] profusion of small irregular opacities) was compared with FVC as an independent indicator of IF. In addition, spirometric indices of airflow (FEV1/FVC and FET25-75%) were correlated with the radiographic profusion score. A study of 2,611 long-term insulators was well designed for these analyses since all subjects were from the same trade, there were sufficient (n = 515) nonsmokers to assess the effects of asbestos exposure in the absence of smoking, most (60%, n = 1,557) of the workers had parenchymal abnormalities (scores greater than or equal to 1/0), and there was a greater prevalence of high scores than in other published series (347 workers or 13.3% had scores greater than or equal to 2/1). Looking at all subjects, the FVC decreased as profusion score increased. The FVC was abnormal (88.0% of predicted) even when the profusion score was clearly normal (0/0). The FVC was lower at any score in smokers and in workers with pleural thickening (more so with diffuse thickening). There was, however, no difference in FVC between intermediate scores 0/1 versus 1/0 and 1/2 versus 2/1. Airflow increased with greater profusion, tending to overcome a decrease seen at lesser profusion scores. These results provide a greater understanding of the relationships among profusion scores, smoking, pleural diseases, and pulmonary function.