The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.

Information dissemination and use: critical components in occupational safety and health.

BACKGROUND: Information dissemination is a mandated, but understudied, requirement of occupational and environmental health laws and voluntary initiatives. Research is needed on the factors that enhance and limit the development, transfer, and use of occupational safety and health information (OSH). Contemporary changes in the workforce, workplaces, and the nature of work will require new emphasis on the dissemination of information to foster prevention. METHODS: Legislative and regulatory requirements and voluntary initiatives for dissemination of OSH information were identified and assessed. Literature on information dissemination was reviewed to identify important issues and useful approaches. RESULTS: More than 20 sections of laws and regulations were identified that mandated dissemination of occupational and environmental safety and health information. A four-stage approach for tracking dissemination and considering the flow of information was delineated. Special areas of dissemination were identified: the information needs of the changing workforce, new and young workers; small businesses; and workers with difficulty in understanding or reading English. CONCLUSIONS: We offer a framework for dissemination of OSH information and underscore the need to focus on the extent to which decision-makers and others receive and use such information. More solid data are also needed on current investments in disseminating, diffusing and applying OSH information and on the utility of that information. Am. J. Ind. Med. 44:515-531, 2003. Published 2003 Wiley-Liss, Inc.

Identifying high-risk small business industries for occupational safety and health interventions.

BACKGROUND: Approximately one-third (32%) of U.S. workers are employed in small business industries (those with 80% of workers in establishments with fewer than 100 employees), and approximately 53 million persons in private industry work in small business establishments. This study was performed to identify small business industries at high risk for occupational injuries, illnesses, and fatalities. METHODS: Small business industries were identified from among all three- and four-digit Standard Industrial Classification (SIC) codes and ranked using Bureau of Labor Statistics (BLS) data by rates and numbers of occupational injuries, illnesses, and fatalities. Both incidence rates and number of injury, illness, and fatality cases were evaluated. RESULTS: The 253 small business industries identified accounted for 1,568 work-related fatalities (34% of all private industry). Transportation incidents and violent acts were the leading causes of these fatalities. Detailed injury and illness data were available for 105 small business industries, that accounted for 1,476,400 work-related injuries, and 55,850 occupational illnesses. Many of the small business industries had morbidity and mortality rates exceeding the average rates for all private industry. The highest risk small business industries, based on a combined morbidity and mortality index, included logging, cut stone and stone products, truck terminals, and roofing, siding, and sheet metal work. CONCLUSIONS: Identification of high-risk small business industries indicates priorities for those interested in developing targeted prevention programs.

Plug flow cytometry extends analytical capabilities in cell adhesion and receptor pharmacology.

BACKGROUND: Plug flow cytometry is a recently developed system for the automated delivery of multiple small boluses or "plugs" of cells or particles to the flow cytometer for analysis. Important system features are that sample plugs are of precisely defined volume and that the sample vessel need not be pressurized. We describe how these features enable direct cell concentration determinations and novel ways to integrate flow cytometers with other analytical instruments. METHODS: Adhesion assays employed human polymorphonuclear neutrophils (PMNs) loaded with Fura Red and Chinese hamster ovary (CHO) cells cotransfected with genes for green fluorescent protein (GFP) and human P-selectin. U937 cells expressing the human 7-transmembrane formyl peptide receptor were loaded with the fluorescent probe indo-1 for intracellular ionized calcium determinations. A computer-controlled syringe or peristaltic pump loaded the sample into a sample loop of the plug flow coupler, a reciprocating eight-port valve. When the valve position was switched, the plug of sample in the sample loop was transported to the flow cytometer by a pressure-driven fluid line. RESULTS: In stirred mixtures of PMNs and CHO cells, we used plug flow cytometry to directly quantify changes in concentrations of nonadherent singlet PMNs. This approach enabled accurate quantification of adherent PMNs in multicell aggregates. We constructed a novel plug flow interface between the flow cytometer and a cone-plate viscometer to enable real-time flow cytometric analysis of cell-cell adhesion under conditions of uniform shear. The High Throughput Pharmacology System (HTPS) is an instrument used for automated programming of complex pharmacological cell treatment protocols. It was interfaced via the plug flow coupling device to enable rapid (< 5 min) flow cytometric characterization of the intracellular calcium dose-response profile of U937 cells to formyl peptide. CONCLUSIONS: By facilitating the coupling of flow cytometers to other fluidics-based analytical instruments, plug flow cytometry has extended analytical capabilities in cell adhesion and pharmacological characterization of receptor-ligand interactions.

Upstairs downstairs: vertical integration of a pediatric service.

BACKGROUND: The combined effects of recent changes in health care financing and training priorities have compelled academic medical centers to develop innovative structures to maintain service commitments yet conform to health care marketplace demands. In 1992, a municipal hospital in the Bronx, New York, affiliated with a major academic medical center reorganized its pediatric service into a vertically integrated system of four interdependent practice teams that provided comprehensive care in the ambulatory as well as inpatient settings. One of the goals of the new system was to conserve inpatient resources. OBJECTIVE: To describe the development of a new vertically integrated pediatric service at an inner-city municipal hospital and to test whether its adoption was associated with the use of fewer inpatient resources. DESIGN: A descriptive analysis of the rationale, goals, implementation strategies, and structure of the vertically integrated pediatric service combined with a before-and-after comparison of in-hospital resource consumption. METHODS: A before-and-after comparison was conducted for two periods: the period before vertical integration, from January 1989 to December 1991, and the period after the adoption of vertical integration, from July 1992 to December 1994. Four measures of inpatient resource use were compared after adjustment for case mix index: mean certified length of stay per case, mean number of radiologic tests per case, mean number of ancillary tests per case, and mean number of laboratory tests per case. Difference-in-differences-in-differences estimators were used to control for institution-wide trends throughout the time period and regional trends in inpatient pediatric practice occurring across institutions. Results. In 1992, the Department of Pediatrics at the Albert Einstein College of Medicine reorganized the pediatric service at Jacobi Medical Center, one of its principal municipal hospital affiliates, into a vertically integrated pediatric service that combines ambulatory and inpatient activities into four interdependent practice teams composed of attending pediatricians, allied health professionals, house officers, and social workers. The new vertically integrated service was designed to improve continuity of care for patients, provide a model of practice for professional trainees, conserve scarce resources, and create a clinical research infrastructure. The vertically integrated pediatric service augmented the role of attending pediatricians, extended the use of allied health professionals from the ambulatory to the inpatient sites, established interdisciplinary practice teams that unified the care of pediatric patients and their families, and used less inpatient resources. Controlling for trends within the study institution and trends in the practice of pediatrics across institutions throughout the time period, the vertical integration was associated with a decline in 0.6 days per case, the use of 0.62 fewer radiologic tests per case, 0.21 fewer ancillary tests per case, and 2.68 fewer laboratory tests per case. CONCLUSIONS: We conclude that vertical integration of a pediatric service at an inner-city municipal hospital is achievable; conveys advantages of improved continuity of care, enhanced opportunities for primary care training, and increased participation of senior clinicians; and has the potential to conserve significant amounts of inpatient resources.

Social problem-solving skills of children with traumatic brain injury.

Studies of specific social skill deficits in adults with traumatic brain injury (TBI) have begun to appear [1,2], but there are few empirical studies of children with TBI. This study examined social problem-solving skills in boys and girls with TBI and a matched group of non-injured peers, ages 7-13. The TBI group generated fewer total solutions on a social problem-solving measure, largely reflecting situation-specific differences in generated solutions. The TBI group also generated fewer positive assertive, and more indirect responses to peer group entry situations than the comparison group. Implications are discussed for a model of social information processing in paediatric brain injury.

Content validity of the Psychiatric Symptom Index, CES-depression Scale, and State-Trait Anxiety Inventory from the perspective of DSM-IV.

We compared the item content of three commonly used scales of psychiatric symptoms [the broad-band Psychiatric Symptom Index (Ilfeld) and two narrow-band scales, the Center for Epidemiologic Studies-Depression Scale (Radloff) and the State-Trait Anxiety Inventory (Spielberger)], with diagnostic criteria and criterion-based symptoms for Major Depressive Episode and Generalized Anxiety Disorder as they appeared in DSM-IV. The Psychiatric Symptom Index and the Center for Epidemiologic Studies-Depression Scale each measured 7 of 9 criterion-based symptoms of Major Depressive Episode. The Psychiatric Symptom Index and State-Trait Anxiety Inventory each measured 5 of 8 domains for Generalized Anxiety Disorder. The Psychiatric Symptom Index had comparable content validity to the narrow-band measures. All met a majority of DSM-IV criteria for depression and anxiety, supporting their applicability for current research.

Depression and maltreatment as predictors of social competence and social problem-solving skills in school-age children.

Childhood depression and child maltreatment have been shown to be important predictors of childhood adjustment problems, including difficulties in the spheres of home, school, and peer relationships. In this study, depression and maltreatment were used to predict social competence and social problem-solving skills, as rated by self, parent, and teacher. The total sample contained 68 children (35 girls, 33 boys), most of whom were at high-risk either due to poverty, physical abuse and neglect (as determined by substantiated Protective Services reports), or exposure to negative life events. Hierarchical multivariate regression analyses were used to identify the contribution of depression and maltreatment to social competence and social problem-solving skills. Depression predicted parents' and teachers' ratings of social competence and parents' ratings of peer rejection. Additionally, depression predicted children's ratings of social competence and both measures of social problem-solving skills. Maltreatment predicted parents' and teachers' ratings of social competence. Gender predicted teachers' ratings of peer rejection and social competence. An additive effect of depression and maltreatment was found such that children who are depressed and maltreated have the lowest social competence as rated by parents and teachers. These children are, therefore, doubly at risk for problems in future relationships.

Follow-up study of chrysotile asbestos textile workers: cohort mortality and case-control analyses.

Previous studies of mortality among white males employed in a Charleston, South Carolina asbestos textile plant using chrysotile demonstrated significant excess mortality due to asbestos-related disease and a steep exposure-response relationship for lung cancer. This cohort was further studied by adding 15 years of follow-up and including mortality among white female and black male workers. Nested case-control analyses were undertaken to further explore possible differences in lung cancer risk by textile operation as well as possible confounding by mineral oil exposures. Preliminary data for white males have been previously published. White males experienced statistically significant excess mortality due to lung cancer (standardized mortality ratio [SMR] = 2.30; confidence interval [CI] = 1.88-2.79), all causes (SMR = 1.48; CI = 1.38-158), all cancers (SMR = 1.50; CI = 1.29-1.72), diabetes mellitus (SMR = 2.05; CI = 1.18-3.33), heart disease (SMR = 1.41; CI = 1.26-1.58), cerebrovascular disease (SMR = 1.50; CI = 1.08-2.02), pneumoconiosis and other respiratory diseases (SMR = 4.10; CI = 3.10-5.31), and accidents (SMR = 1.49; CI = 1.15-1.91). Among white females, statistically significant excesses occurred for lung cancer (SMR = 2.75; CI = 2.06-3.61), all causes (SMR = 1.21; CI = 1.11-1.32), pneumoconiosis and other respiratory diseases (SMR = 2.40; CI = 1.53-3.60), and other respiratory cancers (SMR = 14.98; CI = 4.08-38.7). Among the total cohort of black males, the only statistically significant excess observed was for pneumoconiosis (SMR = 2.19; CI = 1.23-3.62). Based on historical exposure measurements at the plant, there was a positive exposure-response relationship for both lung cancer and pneumoconiosis. Data for the entire cohort demonstrate an increase in the lung cancer relative risk of 2-3% for each fiber/cc-year of cumulative chrysotile exposure. This relationship was more consistent for the white male workers. The excess risk for lung cancer among white males and females appeared to occur at cumulative exposures lower than those for black males. Possible reasons for the lesser lung cancer risk among black males include less smoking and differences in airborne fiber characteristics experienced by black males as a result of plant job placement patterns. The case-control analysis found employment in preparation and carding operations (where most of the black males worked) to be associated with a slightly reduced lung cancer risk, although not statistically significant, whereas spinning and twisting employment was associated with a statistically significant increased lung cancer risk compared to other plant operations.(ABSTRACT TRUNCATED AT 400 WORDS)

Mortality patterns among female and male chrysotile asbestos textile workers.

This study updates a retrospective cohort mortality analysis of workers from a South Carolina textile plant where chrysotile asbestos was the primary exposure. The update adds 15 years of observation to the original study, adds analyses of white women and black men, and allows comparison of mortality risks between race/gender groups. The total cohort includes 3,022 workers: 1,229 white women (363 deaths), 1,247 white men (607 deaths), and 546 black men (289 deaths). Statistically significant risks for lung cancer were observed among white women (standardized mortality ratio [SMR] = 2.07; 90% confidence interval [CI] = 1.55-2.71) and white men (SMR = 2.24; 90% CI = 1.83-2.72); both of these groups exhibited positive exposure-response trends. Although the lung cancer risk among black men was lower than expected (SMR = 0.70; 90% CI = 0.42-1.08), a statistically significant increase was observed at high levels of exposure. Statistically significant excess risk for pneumoconiosis and other respiratory diseases were observed for all race/gender groups. Despite the relatively high percentage of white women lost to follow-up and missing death certificates, both of which allow underestimation of the true relative risk, statistically significant excess risks were observed for lung cancer and pneumoconiosis among this group.

Mortality of workers employed in shoe manufacturing.

A retrospective cohort mortality study was conducted among 7814 white shoe manufacturing workers followed from 1940 through 1982. The workers were potentially exposed to solvents (including toluene) and solvent-based adhesives. Benzene may have been present as an impurity of toluene. Mortality due to leukemia and aleukemia was not statistically significantly elevated. Statistically significant excess mortality due to cancer of the trachea, bronchus and lung was observed in the total cohort [standardized mortality ratio (SMR) 147, 95% confidence interval (95% CI) 120-180] and showed a statistically significant trend in standardized relative risk with increasing potential latency, but not with increasing duration of employment. Chronic nonmalignant respiratory disease was significantly elevated among the men (SMR 158, 95% CI 114-217) but was less than expected among the women (SMR 79), a finding suggesting a possible contribution of smoking to the mortality from respiratory cancer. However, adjustment for the potential effects of smoking did not completely eliminate the increased risk for lung cancer.

A mortality study of workers at seven beryllium processing plants.

The International Agency for Research on Cancer (IARC) has found that the evidence for the carcinogenicity of beryllium is sufficient based on animal data but "limited" based on human data. This analysis reports on a retrospective cohort mortality study among 9,225 male workers employed at seven beryllium processing facilities for at least 2 days between January 1, 1940, and December 31, 1969. Vital status was ascertained through December 31, 1988. The standardized mortality ratio (SMR) for lung cancer in the total cohort was 1.26 (95% confidence interval [CI] = 1.12-1.42); significant SMRs for lung cancer were observed for two of the oldest plants located in Lorain, Ohio (SMR = 1.69; 95% CI = 1.28-2.19) and Reading, Pennsylvania (SMR = 1.24; 95% CI = 1.03-1.48). For the overall cohort, significantly elevated SMRs were found for "all deaths" (SMR = 1.05; 95% CI = 1.01-1.08), "ischemic heart disease" (SMR = 1.08; 95% CI = 1.01-1.14), "pneumoconiosis and other respiratory diseases" (SMR = 1.48; 95% CI = 1.21-1.80), and "chronic and unspecified nephritis, renal failure, and other renal sclerosis" (SMR = 1.49; 95% CI = 1.00-2.12). Lung cancer SMRs did not increase with longer duration of employment, but did increase with longer latency (time since first exposure). Lung cancer was particularly elevated (SMR = 3.33; 95% CI = 1.66-5.95) among workers at the Lorain plant with a history of (primarily) acute beryllium disease, which is associated with very high beryllium exposure. The lung cancer excess was not restricted to plants operating in the 1940s, when beryllium exposures were known to be extraordinarily high. Elevated lung cancer SMRs were also observed for four of the five plants operating in the 1950s for workers hired during that decade. Neither smoking nor geographic location fully explains the increased lung cancer risk. Occupational exposure to beryllium compounds is the most plausible explanation for the increased risk of lung cancer observed in this study. Continued mortality follow-up of this cohort will provide a more definitive assessment of lung cancer risk at the newer plants and among cohort members hired in the 1950s or later at the older plants. Further clarification of the potential for specific beryllium compounds to induce lung cancer in humans, and the possible contribution of other exposures in specific processes at these plants, would require a nested case-control study. We are currently assessing whether available industrial hygiene data would support such an analysis.

Enhancing the quality of epidemiologic studies.

Three principles can improve epidemiologic studies (1) Conduct open scientific review of research protocols and final reports, (2) Disseminate study results to all appropriate parties, and (3) Incorporate new scientific methods into the research and utilize expertise from other disciplines. The procedures we describe are used within the Industrywide Studies Branch of the National Institute for Occupational Safety and Health to implement these principles.

New developments in the Life Table Analysis System of the National Institute for Occupational Safety and Health.

In the 1970s, the National Institute for Occupational Safety and Health developed a Life Table Analysis System to analyze occupational cohort studies. We have updated the original system by adding two new features: direct standardization with a test for linear trend, and analyses by lagged exposure (either duration of exposure or cumulative exposure). We have also updated US reference rates through 1989. The updated systems and documentation (version F) are available upon request. In collaboration with the National Cancer Institute, we have also developed multiple cause-of-death rate files, which consider contributory as well as underlying cause. These files (also available upon request) will enable investigators to derive the expected prevalence of diseases at death, which can then be compared with the observed prevalence in an exposed cohort. Work is currently underway to produce a personal computer version of the Life Table Analysis System.

Benzene and leukemia. An epidemiologic risk assessment.

To assess quantitatively the association between benzene exposure and leukemia, we examined the mortality rate of a cohort with occupational exposure to benzene. Cumulative exposure for each cohort member was estimated from historical air-sampling data and, when no sampling data existed, from interpolation on the basis of existing data. The overall standardized mortality ratio (a measure of relative risk multiplied by 100) for leukemia was 337 (95 percent confidence interval, 154 to 641), and that for multiple myeloma was 409 (95 percent confidence interval, 110 to 1047). With stratification according to levels of cumulative exposure, the standardized mortality ratios for leukemia increased from 109 to 322, 1186, and 6637 with increases in cumulative benzene exposure from less than 40 parts per million-years (ppm-years), to 40 to 199, 200 to 399, and 400 or more, respectively. A cumulative benzene exposure of 400 ppm-years is equivalent to a mean annual exposure of 10 ppm over a 40-year working lifetime; 10 ppm is the currently enforceable standard in the United States for occupational exposure to benzene. To examine the shape of the exposure-response relation, we performed a conditional logistic-regression analysis, in which 10 controls were matched to each cohort member with leukemia. From this model, it can be calculated that protection from benzene-induced leukemia would increase exponentially with any reduction in the permissible exposure limit.

Mortality patterns among styrene-exposed boatbuilders.

In order to test the hypothesis that leukemia and lymphoma may be associated with exposure to styrene, cause-of-death patterns were studied at two reinforced plastic boatbuilding facilities. There were 5,021 workers who met the criterion of having worked at the two plants between 1959 and 1978. Based on industrial hygiene surveys conducted at the two plants, 2,060 individuals were determined to have worked in departments classified as having high exposure to styrene. There were 176 deaths observed among the total cohort, in comparison to 195.3 deaths expected (standardized mortality ratio [SMR] = 90). Among the high styrene exposure group, 47 deaths were observed in comparison to 41.5 deaths expected (SMR = 113). No leukemia or lymphoma deaths were observed in either the high exposure group or the total cohort. An excess of accidental deaths among the high exposure group (18 observed vs 12.4 expected) did not appear to be due to styrene's acute central nervous system effects, since none of the individuals were employed at the facilities at the time of their death. However, the possibility of a chronic effect could not be dismissed. While leukemia and lymphoma did not appear to be related to styrene exposure, the study had little statistical power to detect excesses of these diseases, due to the short length of observation and the young age of most cohort members. It was concluded that the cohort should provide increasingly useful information on chronic styrene toxicity as the population ages and the observation period increases.

The influence of naturally and artificially elevated levels of sodium in drinking water on blood pressure in school children.

Building on prior work on sodium (Na) in drinking water and its effects on blood pressure (BP), two variations of the initial University of Massachusetts studies were carried out in other locations using the same methodology as the original investigations. A Texas/Oklahoma study compared the BP of 7th graders in two economically similar communities whose drinking water Na levels were 25 mg/L and 275 mg/L, a difference 2 1/2 times that in the original University of Massachusetts studies. A second study in Ohio, within only one community, compared the BP's of the 7th graders with a home water softener to their peers drinking the same water unsoftened (400 ppm total hardness). Although both studies have some complicating factors, the preliminary results indicate some effect of elevated Na in drinking water upon blood pressure in normotensive children.