A MORTALITY STUDY OF BUTYL-CHLOROBUTYL RUBBER WORKERS

Worker populations are potentially exposed to multiple chemical substances simultaneously during the performance of routine tasks. The acute health effects from exposure to toxic concentrations of these substances are usually well-described. However, very little is known about the long-term health effects of chronic low dose exposure to all except a few chemical substances. A mortality study was performed on a population of workers employed at a butyl rubber manufacturing plant in Baton Rouge, Louisiana for the period 1943-1978, with special emphasis on potential exposure to methyl chloride.^ The study population was enumerated using company records. The mortality experience among the population was evaluated by comparing the number of observed deaths (total and cause-specific) to the expected number of deaths, based on the U.S. general age, race, sex specific rates. An internal comparison population was assembled to address the issue of lack of comparability when the U.S. rates are used to calculate expected deaths in an employed population.^ There were 18% fewer total observed deaths compared to the expected when the U.S. death rates were used to obtain the expected. Deaths from specific causes were also less than expected except when numbers of observed and expected deaths were small. Similar results were obtained when the population was characterized by intensity and duration of potential exposure to methyl chloride. When the internal comparison population was utilized to evaluate overall mortality of the study population, the relative risk was about 1.2.^ The study results were discussed and conclusions drawn in light of certain limitations of the methodology and study population size. ^

An assessment of the relative influence of a vapor recovery system in reducing occupational exposure to volatile organic compounds in high performance liquid chromatography

Occupational exposures to organic solvents, specifically acetonitrile and methanol, have the potential to cause serious long-term health effects. In the laboratory, these solvents are used extensively in protocols involving the use of high performance liquid chromatography (HPLC). Operators of HPLC equipment may be potentially exposed to these organic solvents when local exhaust ventilation is not employed properly or is not available, which can be the case in many settings. The objective of this research was to characterize the various sites of vapor release in the HPLC process and then to determine the relative influence of a novel vapor recovery system on the overall exposure to laboratory personnel. The effectiveness of steps to reduce environmental solvent vapor concentrations was assessed by measuring exposure levels of acetonitrile and methanol before and after installation of the vapor recovery system. With respect to acetonitrile, the concentration was not statistically significant with p=0.938; moreover, exposure after the intervention was actually higher than prior to intervention. With respect to methanol, the concentration was not statistically significant with p=0.278. This indicates that the exposure to methanol after the intervention was not statistically significantly higher or lower than prior to intervention. Thus, installation of the vapor recovery device did not result in statistically significant reduction in exposures in the settings encountered, and acetonitrile actually increased significantly.^

COSTS AND EFFECTS OF ARKANSAS' LONG-TERM CARE DEMONSTRATION PROJECT (MEDICAID, CHANELLING, COMMUNITY ASSESSMENT)

The purpose of this study was to assess the impact of the Arkansas Long-Term Care Demonstration Project upon Arkansas' Medicaid expenditures and upon the clients it serves. A Retrospective Medicaid expenditure study component used analyses of variance techniques to test for the Project's effects upon aggregated expenditures for 28 demonstration and control counties representing 25 percent of the State's population over four years, 1979-1982.^ A second approach to the study question utilized a 1982 prospective sample of 458 demonstration and control clients from the same 28 counties. The disability level or need for care of each patient was established a priori. The extent to which an individual's variation in Medicaid utilization and costs was explained by patient need, presence or absence of the channeling project's placement decision or some other patient characteristic was examined by multiple regression analysis. Long-term and acute care Medicaid, Medicare, third party, self-pay and the grand total of all Medicaid claims were analyzed for project effects and explanatory relationships.^ The main project effect was to increase personal care costs without reducing nursing home or acute care costs (Prospective Study). Expansion of clients appeared to occur in personal care (Prospective Study) and minimum care nursing home (Retrospective Study) for the project areas. Cost-shifting between Medicaid and Medicare in the project areas and two different patterns of utilization in the North and South projects tended to offset each other such that no differences in total costs between the project areas and demonstration areas occurred. The project was significant ((beta) = .22, p < .001) only for personal care costs. The explanatory power of this personal care regression model (R('2) = .36) was comparable to other reported health services utilization models. Other variables (Medicare buy-in, level of disability, Social Security Supplemental Income (SSI), net monthly income, North/South areas and age) explained more variation in the other twelve cost regression models. ^

THE SHORT- AND LONG-TERM EFFECTS OF A HANDBOOK ON THE ANTIMICROBIAL PRESCRIBING PATTERNS OF HOSPITAL PHYSICIANS

This study evaluates the effect of a specially designed, physician-oriented handbook of antimicrobial use on the prescribing patterns of a group of fifty doctors at a university hospital. Data were evaluated over a peroid of one-and-one-half years, before and after the distribution of the handbook. For the purposes of this study, antimicrobial therapy was classified: (1) inappropriate if it violated one of a number of recognized principles of antimicrobial therapy, (2) appropriate if it agreed with specific recommendations or alternatives given in the distributed reference handbook, and (3) acceptable if it was neither inappropriate nor appropriate as defined by the handbook. An initial survey of antimicrobial prescribing patterns was made. Five months later the handbook was distributed and a two-week orientation program, consisting of the distribution and promotion of the problem-oriented, pocket-size handbook of appropriate antimicrobial therapy, was conducted. The handbook, which was developed by the authors and reviewed and approved by a panel of infectious disease specialists, presented guidelines for appropriate and efficacious usage of antimicrobial agents as most currently accepted in common clinical infections. Subsequent surveys were then conducted two weeks, three months, and six months after distribution of the handbook. A statistically significant difference (p < 0.01) in antimicrobial prescribing patterns was noted between the survey conducted two weeks after the introduction of the handbook and the other surveys. In this survey, while therapy classified inappropriate decreased from 44% to 28%, therapy appropriate as recommended increased from 31% to 53%. The findings of this study demonstrate that the introduction and promotion of the handbook decreases abuse and increases proper use of antimicrobial therapy, although the effect is sustainable for only a short duration--no longer than three months. These results indicate the need for a vigorous, updated program to achieve and maintain current appropriate antibotic therapy in clinical medicine. ^

Effects of a dog walking program with older adults in long-term care

The purpose of this study was to determine if walking a dog would increase motivation to adhere to a walking program and result in an increase in walking endurance and mobility among institutionalized elderly. An experimental pre and post test two group randomly assigned study design was utilized. Thirty subjects, 20 females and 10 males with an average age of 72, were enrolled from three long-term care facilities. The walking program was 3 times a week for 6 weeks. The experimental group walked with a certified therapy dog and the handler. The control group walked with only the handler. The Outcome Expectations for Exercise Scale (OEES) was used to measure the perceived benefits of exercise. The 2-minute walk test and the 30 second chair stand test were administered before and after the walking program. The OEES scores did not significantly predict adherence to the program. The pre- and post-chair stand test and the 2-minute walk test did not show statistical significant differences between groups. All of the participants did show an increase (7 minutes) in walking time during the 6 week period (p=0.048). The mean pre and post walk test scores for participants with stroke/arthritis were significantly less than those without stroke/arthritis (p=0.013). The experimental group had 12 subjects with stroke/arthritis compared with 6 in the control group. The walk test means in feet walked were 362.44 ± 130.36 (control) vs. 201.27 ± 106.25 (experimental), p=0.001. The results indicate walking practice has the potential to increase walking time and endurance. Because residents of long-term care facilities were not allowed outside the facilities without accompaniment, the presence of the dog handler was key to their walking. Analysis of conversations during the walks indicated that for participants who walked with dogs, the dogs did serve as motivation for continuing in the program. ^

In-utero exposure to chemotherapy: What are the long term effects?

There is not a large body of evidence on in-utero exposure to chemotherapy for pregnancy-associated cancers to help determine the long term effects on offspring. This study is a systematic review of long term follow-up to find evidence for adverse outcomes in exposed offspring. In order for studies to be eligible for this systematic review, they had to have a median follow up of at least 24 months with the resulting child. PubMed, Medline, and Scopus were the databases used, and we included all eligible articles, regardless of the date of publication. The search resulted in six articles meeting the eligibility requirements. The review of findings of these studies suggested that there is not enough evidence to make a determination of the risk of chemotherapy for the offspring. Exposed children in the sample of reviewed papers did have some medical conditions, but the rate and type did not differ from the non-exposed population. However, a limitation of this literature review is the very small sample size of publications on this important topic. This finding of few studies on this topic is an important result of this systematic review. More research and long term follow-up studies must be conducted to address this issue.^

Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory.

A number of studies have established a role for vascular endothelial growth factor (VEGF) in angiogenesis. Recent reports have shown that VEGF overexpression in the hippocampus improves learning and memory and is associated with enhanced neurogenesis. PTK787/ZK222584 (PTK/ZK) is a reported inhibitor of VEGFR signaling that is currently being tested for its effects on lung and colon cancer. However, the influence of this drug on cognition has not been examined. In the present study, we questioned if post-training administration of PTK/ZK influences hippocampus-dependent memory. When administered to rats immediately following massed training in the Morris water maze, PTK/ZK impaired spatial memory retention tested 48 h later. This impairment was evidenced by increased latency to the hidden platform and fewer platform crossings. However, this impairment was not associated with a change in neurogenesis during this time frame. PTK/ZK infusion did not reduce VEGFR or AKT phosphorylation, but increased the phosphorylation of ERK. These studies suggest that VEGFR inhibitors such as PTK/ZK may negatively influence cognition.

Long-term gastrointestinal complications of Clostridium difficile associated diarrhea (CDAD)

Background. The incidence of Clostridium difficile -associated diarrhea (CDAD) is increasing worldwide likely because of increased use of broad spectrum antibiotics and the introduction of a clonal hyper-virulent strain called the BI strain. Short-term complications of CDAD include recurrent disease, requirement for colectomy, and persistent disease. However, data on the long-term consequences of CDAD are scarce. Among other infectious diseases (Shigella, Salmonella, and Campylobacter), long-term consequences such as irritable bowel syndrome (IBS), chronic dyspepsia/diarrhea, and other GI effects have been noted. Since the mechanism of action of these agents is similar to C.difficile, we hypothesized that patients with CDAD have greater likelihood of developing IBS and other functional gastrointestinal disorders (FGIDs) in the long-term as compared to a general sample of recently hospitalized patients. ^ Objective. To evaluate the long-term gastrointestinal complications of CDAD, (IBS, functional diarrhea, functional abdominal bloating, functional constipation and functional abdominal pain syndrome). ^ Methods. The current study was a secondary analysis of a previously completed observational case-control outcome study. Adult CDAD patients at St. Luke's Episcopal Hospital, Houston (SLEH) were followed up and interviewed by telephone six months after the initial diagnosis thereafter evaluated for the development of IBS and other FGIDs. A total of 46 patients with CDAD infection were recruited at SLEH between May-November 2007. The comparators were patients hospitalized in SLEH within one month before or after the admission of the reference case, hospital length of stay within one week longer or shorter than reference case, and age within 10 years more or less than the reference case. Cases and comparators were compared using Fisher's exact test. A p<0.05 was considered significant. ^ Results. Thirty CDAD patients responded to the questionnaires and were compared to 40 comparators. No comparator developed a FGID, while 3 (10%) CDAD patients developed new onset IBS (p=0.07), 4 (13.3%) developed new onset Functional Diarrhea (p=0.03), and 3 (10%) developed new onset Functional Constipation (p=0.07). No patient developed Functional Abdominal Bloating and Functional Abdominal Pain Syndrome. ^ Conclusion. In this study, new onset functional diarrhea was significantly more common in patients CDAD within six months after initial infection compared to matched controls.^

Syndromic surveillance at a long term shelter for persons displaced by hurricanes Katrina and Rita conducted by the San Antonio Metropolitan Health District

Background. Beginning September 2, 2005, San Antonio area shelters received approximately 12,700 evacuees from Hurricane Katrina. Two weeks later, another 12,000 evacuees from Hurricane Rita arrived. By mid-October, 2005, the in-shelter population was 1,000 people. There was concern regarding the potential for spread of infectious diseases in the shelter. San Antonio Metropolitan Health District (SAMHD) established a syndromic surveillance system with Comprehensive Health Services (CHS) who provided on-site health care. CHS was in daily contact with SAMHD to report symptoms of concern until the shelter closed December 23, 2005. ^ Study type. The objective of this study was to assess the methods used and describe the practical considerations involved in establishing and managing a syndromic surveillance system, as established by the SAMHD in the long-term shelter clinic maintained by CHS for the hurricane evacuees. ^ Methods. Information and descriptive data used in this study was collected from multiple sources, primarily from the San Antonio Metropolitan Health District’s 2006 Report on Syndromic Surveillance of a Long-Term Shelter by Hausler & Rohr-Allegrini. SAMHD and CHS staff ensured that each clinic visit was recorded by date, demographic information, chief complaint and medical disposition. Logs were obtained daily and subsequently entered into a Microsoft Access database and analyzed in Excel. ^ Results. During a nine week period, 4,913 clinic visits were recorded, reviewed and later analyzed. Repeat visits comprised 93.0% of encounters. Chronic illnesses contributed to 21.7% of the visits. Approximately 54.0% were acute care encounters. Of all encounters, 17.3% had infectious disease potential as primarily gastrointestinal and respiratory syndromes. Evacuees accounted for 86% and staff 14% of all visits to the shelter clinic. There were 782 unduplicated individuals who sought services at the clinic, comprised of 63% (496) evacuees and 36% (278) staff members. Staff were more likely to frequent the clinic but for fewer visits each. ^ Conclusion. The presence of health care services and syndromic surveillance provided the opportunity to recognize, document and intervene in any disease outbreak at this long-term shelter. Constant vigilance allowed SAMHD to inform and reassure concerned people living and working in the shelter and living outside the shelter.^

Long-term impact of a weight management summer camp on obese children

Background: interventions that focus on improving eating habits, increasing physical activity, and reducing sedentary behaviors on weight status and body mass index percentile and z-scores in youths have not been well documented. This study aimed to determine the short and long term effects of a 2-week residential weight management summer camp program for youths on weight, BMI, BMI percentile, and BMI z-score. ^ Methods: A sample of 73 obese multiethnic 10-14 years old youths (11.9 ± 1.4) attended a weight management camp called Kamp K'aana for two weeks and completed a 12-month follow-up on height and weight. As part of Kamp K'aana, participants received a series of nutrition, physical activity and behavioral lessons and were on an 1800 kcal per day meal plan. Anthropometric measurements of height and weight were taken to calculate participants' BMI percentiles and z-scores. Paired t-tests, chi square test and ANCOVA, adjusting for age, gender, and ethnicity were used to assess changes in body weight, BMI, BMI percentiles and BMI z-scores pre to two-weeks post-camp and 12 months post-camp. ^ Results: Significant reductions in body weight of 3.6 ± 1.4 (P = 0.0000), BMI of 1.4 ± 0.54 (P = 0.0000), BMI percentile of 0.45 ± 0.06 (P = 0.0000), and BMI z-score of 0.1 ± 0.06 (P = 0.0000) were observed at the end of the camp. Significant reductions in BMI z-scores (P < 0.001) and BMI percentile (P < 0.001) were observed at the 12-month reunion when compared to pre- and two-weeks post camp data. There was a significant increase in weight and BMI (P = 0.0000) at the 12-month reunion when compared to pre and post camp measurements. ^ Conclusion: Kamp K'aana has consistently shown short-term reductions in weight, BMI, BMI percentile, and BMI z-score. Results from analysis of long-term data suggest that this intervention had beneficial effects on body composition in an ethnically diverse population of obese children. Further research which includes a control group, larger sample size, and cost-analysis should be conducted.^

Post-translational regulation of an Aplysia glutamate transporter during long-term facilitation.

Regulation of glutamate transporters accompanies plasticity of some glutamatergic synapses. The regulation of glutamate uptake at the Aplysia sensorimotor synapse during long-term facilitation (LTF) was investigated. Previously, increases in levels of ApGT1 (Aplysia glutamate transporter 1) in synaptic membranes were found to be related to long-term increases in glutamate uptake. In this study, we found that regulation of ApGT1 during LTF appears to occur post-translationally. Serotonin (5-HT) a transmitter that induces LTF did not increase synthesis of ApGT1. A pool of ApGT1 appears to exist in sensory neuron somata, which is transported to the terminals by axonal transport. Blocking the rough endoplasmic reticulum-Golgi-trans-Golgi network (TGN) pathway with Brefeldin A prevented the 5-HT-induced increase of ApGT1 in terminals. Also, 5-HT produced changes in post-translational modifications of ApGT1 as well as changes in the levels of an ApGT1-co-precipitating protein. These results suggest that regulation of trafficking of ApGT1 from the vesicular trafficking system (rough endoplasmic reticulum-Golgi-TGN) in the sensory neuron somata to the terminals by post-translational modifications and protein interactions appears to be the mechanism underlying the increase in ApGT1, and thus, glutamate uptake during memory formation.

The ubiquitin-proteasome system is necessary for long-term synaptic depression in Aplysia.

The neuropeptide Phe-Met-Arg-Phe-NH(2) (FMRFa) can induce transcription-dependent long-term synaptic depression (LTD) in Aplysia sensorimotor synapses. We investigated the role of the ubiquitin-proteasome system and the regulation of one of its components, ubiquitin C-terminal hydrolase (ap-uch), in LTD. LTD was sensitive to presynaptic inhibition of the proteasome and was associated with upregulation of ap-uch mRNA and protein. This upregulation appeared to be mediated by CREB2, which is generally regarded as a transcription repressor. Binding of CREB2 to the promoter region of ap-uch was accompanied by histone hyperacetylation, suggesting that CREB2 cannot only inhibit but also promote gene expression. CREB2 was phosphorylated after FMRFa, and blocking phospho-CREB2 blocked LTD. In addition to changes in the expression of ap-uch, the synaptic vesicle-associated protein synapsin was downregulated in LTD in a proteasome-dependent manner. These results suggest that proteasome-mediated protein degradation is engaged in LTD and that CREB2 may act as a transcription activator under certain conditions.

TGF-beta1 in Aplysia: role in long-term changes in the excitability of sensory neurons and distribution of TbetaR-II-like immunoreactivity.

Exogenous recombinant human transforming growth factor beta-1 (TGF-beta1) induced long-term facilitation of Aplysia sensory-motor synapses. In addition, 5-HT-induced facilitation was blocked by application of a soluble fragment of the extracellular portion of the TGF-beta1 type II receptor (TbetaR-II), which presumably acted by scavenging an endogenous TGF-beta1-like molecule. Because TbetaR-II is essential for transmembrane signaling by TGF-beta, we sought to determine whether Aplysia tissues contained TbetaR-II and specifically, whether neurons expressed the receptor. Western blot analysis of Aplysia tissue extracts demonstrated the presence of a TbetaR-II-immunoreactive protein in several tissue types. The expression and distribution of TbetaR-II-immunoreactive proteins in the central nervous system was examined by immunohistochemistry to elucidate sites that may be responsive to TGF-beta1 and thus may play a role in synaptic plasticity. Sensory neurons in the ventral-caudal cluster of the pleural ganglion were immunoreactive for TbetaR-II, as well as many neurons in the pedal, abdominal, buccal, and cerebral ganglia. Sensory neurons cultured in isolation and cocultured sensory and motor neurons were also immunoreactive. TGF-beta1 affected the biophysical properties of cultured sensory neurons, inducing an increase of excitability that persisted for at least 48 hr. Furthermore, exposure to TGF-beta1 resulted in a reduction in the firing threshold of sensory neurons. These results provide further support for the hypothesis that TGF-beta1 plays a role in long-term synaptic plasticity in Aplysia.

Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

A model of the roles of essential kinases in the induction and expression of late long-term potentiation.

The induction of late long-term potentiation (L-LTP) involves complex interactions among second-messenger cascades. To gain insights into these interactions, a mathematical model was developed for L-LTP induction in the CA1 region of the hippocampus. The differential equation-based model represents actions of protein kinase A (PKA), MAP kinase (MAPK), and CaM kinase II (CAMKII) in the vicinity of the synapse, and activation of transcription by CaM kinase IV (CAMKIV) and MAPK. L-LTP is represented by increases in a synaptic weight. Simulations suggest that steep, supralinear stimulus-response relationships between stimuli (e.g., elevations in [Ca(2+)]) and kinase activation are essential for translating brief stimuli into long-lasting gene activation and synaptic weight increases. Convergence of multiple kinase activities to induce L-LTP helps to generate a threshold whereby the amount of L-LTP varies steeply with the number of brief (tetanic) electrical stimuli. The model simulates tetanic, -burst, pairing-induced, and chemical L-LTP, as well as L-LTP due to synaptic tagging. The model also simulates inhibition of L-LTP by inhibition of MAPK, CAMKII, PKA, or CAMKIV. The model predicts results of experiments to delineate mechanisms underlying L-LTP induction and expression. For example, the cAMP antagonist RpcAMPs, which inhibits L-LTP induction, is predicted to inhibit ERK activation. The model also appears useful to clarify similarities and differences between hippocampal L-LTP and long-term synaptic strengthening in other systems.