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.

Neoplastic and life-span effects of chronic exposure to tritium. II. Rats exposed in utero.

A study was conducted to determine the effects on neoplasia incidence and life-span of exposure in utero to a major environmental radionuclide. Sprague-Dawley rats were continuously exposed to tritiated water (HTO) from conception through birth in doses of 0, 1, 10, 50, and 100 muCi HTO/ml body water. HTO administration was terminated at birth. Calculated cumulative doses during gestation were approximately 0, 6.6, 66, 330, and 660 rads of total body irradiation. Under these exposure conditions, the two highest doses resulted in sterile offspring. Animals surviving through 30 days postnatally were defined as the study population and observed until their deaths. Intrauterine exposures to doses up to 66 rads had no significant effects on either sex with respect to life-span, overall neoplasia incidence, incidence rate, or onset of mammary fibroadenomas. Females exposed to 330 or 660 rads were sterile and had lower incidence rates of mammary fibroadenomass than did controls; at 660 rads females had a lower incidence of overall neoplasia and reduced mean life-spans. Sterile male offspring had reduced mean longevity after irradiation at 660 rads. Regardless of dose group, females had significantly higher incidences of neoplasia and longer life-spans than males.

Neoplastic and life-span effects of chronic exposure to tritium. I. Effects on adult rats exposed during pregnancy.

Female Sprague-Dawley rats were continuously exposed to equilibrium levels of tritiated water (HTO) during pregnancy. The tritium activities were 1, 10, 50, and 100 muCi HTO/ml body water which provided cumulative, whole-body radiation doses of approximately 6.6, 66, 330, and 660 rads. Administration of the radioisotope was terminated at parturition. Throughout their life-spans and at autopsy, the dams showed an increased incidence of mammary fibroadenomas at exposure to 330 and 660 rads. Although the data for the incidence of malignant mammary neoplasms were consistent with a linear dose response, the small numbers of tumors preclude specific definition of the dose-response curve. Postexposure life-spans for dams chronically exposed to 66, 330, and 660 rads during pregnancy were reduced by 14, 24, and 22%, respectively. Accelerated aging was also demonstrated in these rats: The mean age for mammary fibroadenoma onset decreased with an increasing dose of radiation.

Leukemia following treatment of germ cell tumors in men.

We investigated the incidence of leukemia occurring subsequent to the treatment of germ cell tumors in men at our institution over a 30-year interval and found four patients with acute nonlymphocytic leukemia (ANLL) and one patient with chronic myelomonocytic leukemia. The relative risk (observed/expected cases) estimates for the development of leukemia ranged from 13.7 (P = .0005) in the total population to 50.1 (P = .0001) in the group treated with cytotoxic agents alone. All three patients with ANLL treated with contemporary antileukemic therapy had complete responses, with survivals of 7, 29, and 133 + months. In a review of the literature, 14 additional cases of germ cell tumors were found in which the men subsequently developed leukemia. It is concluded that leukemia following germ cell tumors is increased in incidence and is likely to be treatment induced. Complete responses and long-term survival are possible in secondary leukemia and aggressive antileukemic therapy should be given.

ECG abnormalities in polymyositis.

Electrocardiographic abnormalities were found in 25 (32.5%) of 77 patients with polymyositis. Left anterior hemiblock (13.0%) and right bundle-branch block (9.1%) were the most common abnormalities. No association could be found between these defects and clinical activity of polymyositis, severity of duration of disease, or degree of creatine kinase level elevation. Similarly, there was no association with age or the presence of certain clinical conditions such as rash or arthritis. In only two patients, both children, did an ECG abnormality improve with corticosteroid therapy. Three patients with heart block died suddenly. This study points up the need for continual close observation of patients with inflammatory muscle disease, even after apparent remission.

Seasonal distribution of antiphospholipid antibodies.

BACKGROUND AND PURPOSE: The purpose of this study was to determine if there was a seasonal variation in antiphospholipid antibody (aPL) titers and whether this variation differed between stroke cases and control subjects. METHODS: IgG and IgM anticardiolipin and antiphosphatidyl serine antibody titers were obtained on serum samples from 884 stroke patients and 1024 control subjects over a 7-year period. Temporal distributions by month of blood draw were evaluated. RESULTS: Marked seasonal differences in the proportion of positive titers were found for control subjects, but no seasonal variability among patients was noted. In control subjects, positive titers occurred less frequently in the summer months, mirroring the seasonal trends seen in respiratory track infections and rheumatic fever. CONCLUSIONS: Our data suggest some aPL antibodies arise from different origins in patients and control subjects. The seasonality observed in the apparently normal population may be related to antibodies of infectious origin and is consistent with the reported lack of association with thrombosis of infection-related antibodies.

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.

Progression to AIDS in patients with lymphadenopathy or AIDS-related complex: reappraisal of risk and predictive factors.

PURPOSE: In 1985, we reported that acquired immunodeficiency syndrome (AIDS) developed in 14 of 81 (17%) men with generalized lymphadenopathy followed prospectively for an average of 13 months. The presence of oral thrush or constitutional symptoms, or both, or severely impaired T4+ cell responses to specific antigen (interferon-gamma production) accurately identified patients at immediate risk for AIDS. The purpose of the current report is to describe the progress of these 81 patients during the three and a half years since enrollment and to include new data on initial serum levels of beta 2 microglobulin and human immunodeficiency virus (HIV) p24 antigen. PATIENTS AND METHODS: The mean age of the 81 patients was 35.4 years; 79 were homosexuals and two were drug abusers. Immunologic testing was performed once at the time of enrollment in all patients. Seventy-seven of the 81 patients were seropositive for HIV antibody. Frozen samples of serum, also obtained at initial study, were assayed in 1988 for beta 2 microglobulin and HIV p24 antigen. The clinical status of patients was determined six, 14, and 36 months after enrollment was closed (June 1984) by either interview and examination or telephone contact with private physicians. RESULTS: After three and a half years of follow-up, 42 patients have developed AIDS, including (1) 77% who had had thrush or symptoms, or both, (2) 80% to 88% of those who originally demonstrated marked immunologic abnormalities (skin test anergy, less than 200 T4+ cells/mm3, T4/T8 cell ratio of less than 0.5, severely impaired interferon-gamma production [less than 25 U/mL], or elevated serum beta 2 microglobulin level [greater than 3.0 mg/L], and (3) 95% of patients with HIV p24 antigenemia. However, AIDS also developed in 51% of patients who had had more apparently benign initial manifestations (lymphadenopathy alone, herpes zoster), in 41% to 54% despite normal initial results for either T4+ cell number, interferon-gamma secretion, beta 2 microglobulin, or skin testing, and in 44% of those whose sera did not contain HIV antigen. CONCLUSION: These updated results demonstrate the remarkably poor prognosis of patients with generalized lymphadenopathy or AIDS-related complex irrespective of initial clinical, immunologic, and serologic findings, and suggest that essentially all such persons may be candidates for antiviral therapy.

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).

Unraveling the chronic toxicity of lead: an essential priority for environmental health.

Although population exposure to lead has declined, chronic lead toxicity remains a major public health problem in the United States affecting millions of children and adults. Important gaps exist in knowledge of the pathophysiology of chronic lead intoxication. These gaps have impeded development of control strategies. To close current gaps in knowledge of chronic lead toxicity, we propose an integrated, multidisciplinary, marker-based research program. This program combines a) direct measurement of individual lead burden by 109Cd X-ray fluorescence analysis of lead in bone, b) determination of ALA-D phenotype, an index of individual susceptibility to lead, and c) assessments of subclinical injury produced by lead in the kidneys, nervous system and, reproductive organs. Data from this research will provide answers to questions of great public health importance: a) Are current environmental and occupational standards adequate to prevent chronic lead intoxication? b) is lead mobilized from the skeleton during pregnancy or lactation to cause fetal toxicity? c) Is lead mobilized from bone during menopause to cause neurotoxicity? d) What is the significance of genetic variation in determining susceptibility to lead? e) What is the contribution of lead to hypertension, renal disease, chronic neurodegenerative disease or declining sperm counts? f) Is chelation therapy effective in reducing body lead burden in persons with chronic overexposure to lead?

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.

Mortality from pulmonary embolism in the United States: 1962 to 1984.

To examine the effect of advances in the prevention of and therapy for PE, we reviewed mortality for PE in the United States from 1962 to 1984. Age-adjusted PE mortality increased by 67 to 100 percent between 1962 and 1974 for white and non-white men and women. From 1975 to 1984, these rates declined by 20 to 28 percent. Non-white PE mortality was greater than white PE mortality; men had a greater risk of PE death than women. Age-specific patterns (more than 40 years of age) of PE mortality followed those of the age-adjusted death rates, with increases noted in all groups between 1962 and 1974 and declines during the 1975-1984 period. These patterns might reflect improved ascertainment of cases and better prevention of disease. The magnitude of the rates suggests that the list of indications for prophylactic anticoagulation should be re-examined for possible expansion.

The association of blunted nocturnal blood pressure dip and stroke in a multiethnic population.

Nondipping has been defined as a reduction in the mean systolic and diastolic blood pressure (BP) of <10% from awake to sleep. We hypothesized that nondipping might be associated with stroke in minority populations. We monitored BP over a 24 h period with an ambulatory device in 166 cases from a multiethnic population of stroke survivors (63 blacks, 61 non-Hispanic whites, and 42 Caribbean Hispanics, aged 69.5 +/- 11 years) and 217 community control subjects (73 blacks, 107 non-Hispanic whites, and 67 Caribbean Hispanics, aged 69 +/- 9 years). Prevalence of nondipping was significantly greater among cases than among control subjects (64% v. 37%, P < .001). In a multiple logistic regression model adjusted for traditional risk factors for stroke, nondipping conferred an increased risk for stroke. Probability of stroke associated with nondipping (odds ratio (OR) 2.5, confidence interval (CI) 1.6 to 4.0) was equal to that of traditional risk factors. Nondipping increased the chance of having a stroke in both non-Hispanic whites (OR 4.2, P < .001) and blacks/Caribbean Hispanics (OR 1.9, P = .03). The strength of the contribution of nondipping to stroke risk was similar in all ethnic groups. Nondipping was associated with stroke in both men and women. Given the previous reports that nondipping contributes to stroke risk in European and Asian populations, these data suggest that nondipping may be universally associated with risk for stroke.

No association between serum cholesterol and growth in preadolescent American children.

To determine the relation between serum cholesterol level (SCL) and growth in preadolescent children (2-12 years of age) in the United States, we examined the association of SCL and three measures of growth in a national sample of American children from 1971 to 1974. We investigated three parameters: sitting height, standing height, and weight and undertook separate analyses for sex and race. We found no consistent statistically significant associations with any of these three measures of growth. This result did not change when we adjusted the data for age alone or for age, poverty index, serum protein level, and hematocrit. We conclude that growth in this population group is not dependent on SCL.

Relationship of isokinetic torque to isometric torque.

Isokinetic muscle testing has become an increasingly popular method for measuring muscle performance. However, the relationship of isokinetic strength measurements to static strength measurements remains unclear. The relationship between maximal isokinetic and maximal isometric torque was investigated at angular velocities of 24, 48, 96, and 192 degrees/s for both flexion and extension of the elbow joint. Twenty-four subjects were tested bilaterally, and discrete torque values at the positions of 60 and 90 degrees of flexion were obtained from the continuous isokinetic records for comparison with isometric torques recorded at the same two positions. Data were analyzed using an analysis of covariance with isokinetic torque, the dependent variable, expressed as a function of isometric torque and as a function of the design variables side and position. The results demonstrated significant effects of side and position and also demonstrated the dependence of isokinetic strength on velocity. Confidence intervals were determined for the prediction of isokinetic torque from observed isometric torque for normal individuals, providing a potentially useful tool to aid in the diagnosis of muscular disorders.

Patella lead x-ray fluorescence measurements are independent of sample orientation.

In vivo x-ray fluorescence bone lead measurements assess long-term lead exposure. Tibia, calcaneus, and patella are the most commonly sampled bones. Patella measurements also include lead signals from the distal femur, proximal tibia, and synovium. It is therefore important to know whether the orientation of the patella relative to the measurement system substantially affects the measured patella lead concentrations and their measurement uncertainties. This study examined whether these parameters exhibited a dependence on the orientation of the patella with respect to the measurement system, a dependence that could arise from varying nonpatella contributions. There was no effect of orientation on measured patella lead concentration, but there was a highly significant effect of orientation on the measurement uncertainty. These data do not conclusively show that there are no nonpatella contributions to a patella lead measurement; rather, that any such contributions are not a function of measurement orientation over the range of orientations considered. Further study is required if the contribution of nonpatella tissues to a patella lead XRF-measured concentration is to be fully addressed. This study also filled a gap in the literature by quantifying the within-patella (29%) and between-patella (71%) variability of measured patella lead concentrations from replicate measures of nine patellae.

The effect of measurement location on tibia lead XRF measurement results and uncertainty.

The aims of this study were to determine whether the location on the tibia measured by 109Cd-based K-shell x-ray fluorescence (XRF) affected the measurement result and its uncertainty, and whether higher tibia lead levels at the extremities of the tibia and/or inhomogeneity in the distribution of lead in the tibia could be inferred therefrom. Replicate XRF measurements were performed at multiple locations on ten adult cadaver intact legs and on nine bare tibiae dissected from them. Mean lead levels in the bare tibiae ranged from 16 to 48 microg Pb per g of bone mineral. Bare tibia measurements showed that both the XRF result and its uncertainty increased towards the proximal and distal ends of the tibia. The XRF result decreased away from the medial-lateral mid-point of the tibia, but XRF uncertainty was not significantly affected. Intact leg measurements showed no effect of proximal distal location on XRF result but did show an effect on XRF uncertainty. We conclude that the XRF method used can determine the differences in bone lead level resulting from the more trabecular composition at the ends of the tibia, and we present limited evidence for localized regions of low tibia lead level.

Variability in XRF-measured tibia lead levels.

A few studies have examined the variability in 109Cd-based K-shell x-ray fluorescence (KXRF) bone lead measurements from replicate measurements made either at the same time or over a period of time, and one of these studies has shown that the uncertainty in an individual measurement is an underestimate of the standard deviation of replicate measurements. Variability in KXRF tibia lead measurements was assessed from ten cadaver intact legs, from the bare tibiae dissected from nine of these legs, and from four in vivo volunteers. Cadaver legs underwent replicate measurements on multiple occasions. In vivo volunteers underwent single measurements of the left tibia monthly for one year. Average tibia lead levels in the cadaver legs and in vivo volunteers ranged from 6 to 50 and from 6 to 13 microg Pb per g of bone mineral respectively. The factors influencing the standard deviation of replicate measurements were investigated. Both cadaver and in vivo measurements confirmed that the uncertainty in an individual measurement is an underestimate of the standard deviation of replicate measurements, suggesting a methodological deficiency probably shared by most current 109Cd-based K-shell XRF lead measurement systems.

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.

Detection of adducts of deoxyribonucleic acid in white blood cells of roofers by 32P-postlabeling. Relationship of adduct levels to measures of exposure to polycyclic aromatic hydrocarbons.

To assess the utility of adducts of deoxyribonucleic acid (DNA) as biomarkers of exposure to carcinogens in an industrial population, a pilot study of roofers occupationally exposed to polycyclic aromatic hydrocarbons was conducted. DNA isolated from white blood cells of roofers and nonoccupationally exposed comparison subjects matched for age, sex, and smoking status was analyzed for DNA adducts with the use of 32P-postlabeling methods. Occupational exposures to polycyclic aromatic hydrocarbons were assessed by personal air sampling and skin wipes. Ten of the 12 roofers, but only 2 of the 12 comparison subjects, had detectable levels of aromatic DNA adducts in the 32P-postlabeling assay. Among the roofers, the post-shift levels of polycyclic aromatic hydrocarbons in the skin wipes were correlated with the DNA adduct levels. These results suggest that 32P-postlabeling assay may be useful for monitoring internal exposures to complex mixtures of aromatic hydrocarbons in industrial populations.