TB research at UT-Houston--a review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis.

Tuberculosis remains a major threat as drug resistance continues to increase. Pulmonary tuberculosis in adults is responsible for 80% of clinical cases and nearly 100% of transmission of infection. Unfortunately, since we have no animal models of adult type pulmonary tuberculosis, the most important type of disease remains largely out of reach of modern science and many fundamental questions remain unanswered. This paper reviews research dating back to the 1950's providing compelling evidence that cord factor (trehalose 6,6 dimycolate [TDM]) is essential for understanding tuberculosis. However, the original papers by Bloch and Noll were too far ahead of their time to have immediate impact. We can now recognize that the physical and biologic properties of cord factor are unprecedented in science, especially its ability to switch between two sets of biologic activities with changes in conformation. While TDM remains on organisms, it protects them from killing within macrophages, reduces antibiotic effectiveness and inhibits the stimulation of protective immune responses. If it comes off organisms and associates with lipid, TDM becomes a driver of tissue damage and necrosis. Studies emanating from cord factor research have produced (1) a rationale for improving vaccines, (2) an approach to new drugs that overcome natural resistance to antibiotics, (3) models of caseating granulomas that reproduce multiple manifestations of human tuberculosis. (4) evidence that TDM is a key T cell antigen in destructive lesions of tuberculosis, and (5) a new understanding of the pathology and pathogenesis of postprimary tuberculosis that can guide more informative studies of long standing mysteries of tuberculosis.

Studies on the {\it in vivo} function of a phosphatidylinositol transfer protein from {\it Saccharomyces cerevisiae}

Phosphatidylinositol transfer proteins (PI-TP's) catalyze the transfer of phosphatidylinositol and phosphatidylcholine between membranes in vitro. However the in vivo function of these proteins is unknown. In this thesis we have used a combined biochemical and genetic approach to determine the importance of PI-TP in vivo. An oligonucleotide based on the amino terminal sequence of the PI-TP from Saccharomyces cerevisiae, was used to screen a yeast genomic library for the gene encoding PI-TP (PIT1 gene). Yeast strains transformed with the positive clones showed overproduction of transfer activities and transfer protein in the 100,000 x g supernatants. The 5$\sp\prime$ terminus of the PIT1 gene correlates with the predicted codons for residues 3-30 of the determined protein sequence. Tetrad analysis of a heterozygous diploid (PIT1/pit1::LEU2) revealed that the PIT1 gene is essential for cell growth. Non-viable spores could be rescued by transformation of the above diploid prior to sporulation, with a plasmid borne copy of the wild type gene. Sequencing of the entire PIT1 gene has revealed that the PIT1 gene is identical to the SEC14 gene. The sec14 ts mutant which exhibits conditional defects at the Golgi stage of protein secretion, is also temperature sensitive for PI-TP activity in vitro. These findings represent the first instance in which a physiological function has been assigned to any phospholipid transfer protein. ^

Energy expenditure, body-part discomfort and mental work load among nurses

The purpose of this prospective observational field study was to present a model for measuring energy expenditure among nurses and to determine if there was a difference between the energy expenditure of nurses providing direct care to adult patients on general medical-surgical units in two major metropolitan hospitals and a recommended energy expenditure of 3.0 kcal/minute over 8 hours. One-third of the predicted cycle ergometer VO2max for the study population was used to calculate the recommended energy expenditure.^ Two methods were used to measure energy expenditure among participants during an 8 hour day shift. First, the Energy Expenditure Prediction Program (EEPP) developed by the University of Michigan Center for Ergonomics was used to calculate energy expenditure using activity recordings from observation (OEE; n = 39). The second method used ambulatory electrocardiography and the heart rate-oxygen consumption relationship (HREE; n = 20) to measure energy expenditure. It was concluded that energy expenditure among nurses can be estimated using the EEPP. Using classification systems from previous research, work load among the study population was categorized as "moderate" but was significantly less than (p = 0.021) 3.0 kcal/minute over 8 hours or 1/3 of the predicted VO2max.^ In addition, the relationships between OEE, body-part discomfort (BPCDS) and mental work load (MWI) were evaluated. The relationships between OEE/BPCDS and OEE/MWI were not significant (p = 0.062 and 0.091, respectively). Among the study population, body-part discomfort significantly increased for upper arms, mid-back, lower-back, legs and feet by mid-shift and by the end of the shift, the increase was also significant for neck and thighs.^ The study also provided documentation of a comprehensive list of nursing activities. Among the most important findings were the facts that the study population spent 23% of the workday in a bent posture, walked an average of 3.14 miles, and spent two-thirds of the shift doing activities other than direct patient care, such as paperwork and communicating with other departments. A discussion is provided regarding the ergonomic implications of these findings. ^

Structure and function study of prostaglandin H synthase

Prostaglandin H synthase (PGHS) is a key enzyme in biosynthesis of prostaglandins, thromboxane, and prostacyclin. It has two activities, cyclooxygenase and peroxidase. "PGHS" means PGHS-1. A current hypothesis considers the cyclooxygenase reaction to be a free radical chain reaction, initiated by interaction of the synthase peroxidase with hydroperoxides leading to the production of a tyrosyl free radical. According to this hypothesis, tyrosyl residue(s) may play a key role in the cyclooxygenase reaction. Tetranitromethane (TNM) can relatively selectively nitrate tyrosines at pH 8.0. The effect of TNM on both cyclooxygenase activity and peroxidase activity has been examined: reaction of the synthase holoenzyme with TNM at pH 8.0 led to inactivation of both activities, with the cyclooxygenase activity being lost rapidly and completely, while the peroxidase activity was lost more slowly. Indomethacin, a non-steroidal anti-inflammatory agent, can protect the synthase from the inactivation of TNM. Amino acid analyses indicated that a loss of tyrosine and formation of nitrotyrosine residues occurred during reaction with TNM, and that TNM-reacted holoenzyme with $<$10% residual cyclooxygenase activity had about 2.0 nitrotyrosine/subunit.^ PGH synthase is known to be an endoplasmic reticulum membrane-associated protein. Antibodies directed at particular PGHS peptide segments and indirect immunofluorescence have been used to characterize the membrane topology of crucial portions of PGHS. PGHS was expressed in COS-1 cells transfected with the appropriate cDNA. Stably-transfected human endothelial cells were also used for the topology study. The cells were treated with streptolysin-O, which selectively permeabilizes the plasma membrane, or with saponin to achieve general membrane disruption, before incubation with the antipeptide antibodies. Bound antipeptide antibody was stained by FITC-labelled secondary antibody and visualized by fluorescence microscopy. With the antipeptide antibodies against residues 51-66, 156-170 or 377-390, there was a significant reticular and perinuclear pattern of staining in cells permeabilized with saponin but not in cells permeabilized with SLO alone. Antibodies directed against the endogenous C-terminal peptide or against residues 271-284 produced staining in cells permeabilized with saponin, and also in a lower, but significant fraction of cells permeabilized with SLO. Similar results were obtained when COS-1 cells expressing recombinant PGHS with a viral reporter peptide inserted at the C-terminus were stained with antibody against the reporter epitope.^ The PGHS C-terminal sequence is similar to that of the consensus KDEL ER retention signal. The potential function of the PGHS C-terminus segment in ER retention was examined by mutating this segment and analyzing the subcellular distribution of the mutants expressed in COS-1 cells. None of the mutants had an altered subcellular distribution, although some had greatly diminished the enzyme activities. (Abstract shortened by UMI.) ^

Establishing occupational and environmental health design requirements for Lunar and Mars settlements

In a study of Lunar and Mars settlement concepts, an analysis was made of fundamental design assumptions in five technical areas against a model list of occupational and environmental health concerns. The technical areas included the proposed science projects to be supported, habitat and construction issues, closed ecosystem issues, the "MMM" issues--mining, material-processing, and manufacturing, and the human elements of physiology, behavior and mission approach. Four major lessons were learned. First it is possible to relate public health concerns to complex technological development in a proactive design mode, which has the potential for long-term cost savings. Second, it became very apparent that prior to committing any nation or international group to spending the billions to start and complete a lunar settlement, over the next century, that a significantly different approach must be taken from those previously proposed, to solve the closed ecosystem and "MMM" problems. Third, it also appears that the health concerns and technology issues to be addressed for human exploration into space are fundamentally those to be solved for human habitation of the earth (as a closed ecosystem) in the 21st century. Finally, it is proposed that ecosystem design modeling must develop new tools, based on probabilistic models as a step up from closed circuit models. ^

Evaluating the relative status of health and safety programs for minority academic and research institutions

A variety of occupational hazards are indigenous to academic and research institutions, ranging from traditional life safety concerns, such as fire safety and fall protection, to specialized occupational hygiene issues such as exposure to carcinogenic chemicals, radiation sources, and infectious microorganisms. Institutional health and safety programs are constantly challenged to establish and maintain adequate protective measures for this wide array of hazards. A unique subset of academic and research institutions are classified as historically Black universities which provide educational opportunities primarily to minority populations. State funded minority schools receive less resources than their non-minority counterparts, resulting in a reduced ability to provide certain programs and services. Comprehensive health and safety services for these institutions may be one of the services compromised, resulting in uncontrolled exposures to various workplace hazards. Such a result would also be contrary to the national health status objectives to improve preventive health care measures for minority populations.^ To determine if differences exist, a cross-sectional survey was performed to evaluate the relative status of health and safety programs present within minority and non-minority state-funded academic and research institutions. Data were obtained from direct mail questionnaires, supplemented by data from publicly available sources. Parameters for comparison included reported numbers of full and part-time health and safety staff, reported OSHA 200 log (or equivalent) values, and reported workers compensation experience modifiers. The relative impact of institutional minority status, institution size, and OSHA regulatory environment, was also assessed. Additional health and safety program descriptors were solicited in an attempt to develop a preliminary profile of the hazards present in this unique work setting.^ Survey forms were distributed to 24 minority and 51 non-minority institutions. A total of 72% of the questionnaires were returned, with 58% of the minority and 78% of the non-minority institutions participating. The mean number of reported full-time health and safety staff for the responding minority institutions was determined to be 1.14, compared to 3.12 for the responding non-minority institutions. Data distribution variances were stabilized using log-normal transformations, and although subsequent analysis indicated statistically significant differences, the differences were found to be predicted by institution size only, and not by minority status or OSHA regulatory environment. Similar results were noted for estimated full-time equivalent health and safety staffing levels. Significant differences were not noted between reported OSHA 200 log (or equivalent) data, and a lack of information provided on workers compensation experience modifiers prevented comparisons on insurance premium expenditures. Other health and safety program descriptive information obtained served to validate the study's presupposition that the inclusion criteria would encompass those organizations with occupational risks from all four major hazard categories. Worker medical surveillance programs appeared to exist at most institutions, but the specific tests completed were not readily identifiable.^ The results of this study serve as a preliminary description of the health and safety programs for a unique set of workplaces have not been previously investigated. Numerous opportunities for further research are noted, including efforts to quantify the relative amount of each hazard present, the further definition of the programs reported to be in place, determination of other means to measure health outcomes on campuses, and comparisons among other culturally diverse workplaces. ^

Man-induced activities modify demographic parameters in a long-lived species: effects of poisoning and health policies

Recent changes in sanitary policies within the European Union (EU) concerning disposal of carcasses of domestic animals and the increase of non-natural mortality factors, such as illegal poisoning, are threatening European vultures. However, the effects of anthropogenic activities on demographic parameters are poorly studied. Using a long-term study (1994–2011) of the threatened Pyrenean Bearded Vulture Gypaetus barbatus population, we assess the variation in the proportion of breeding pairs, egg-laying dates, clutch size, breeding success, and survival following a sharp reduction in food availability in 2005 due to the application of restrictive sanitary policies decreasing livestock carcass availability. We found a delay in laying dates and a regressive trend in clutch size, breeding success, and survival following policy change. The maintenance of specific supplementary feeding stations for Bearded Vultures probably reduced the negative effects of illegal poisoning and food shortages, which mainly affected subadult survival. A drop in food availability may have produced changes in demographic parameters and an increase in mortality due to an increased exposure to contaminated food. As a result, supplementary feeding as a precautionary measure can be a useful tool to reduce illegal poisoning and declines in demographic parameters until previous food availability scenarios are achieved. This study shows how anthropogenic activities through human health regulations that affect habitat quality can suddenly modify demographic parameters in long-lived species, including those, such as survival, with high sensitivity to population growth rate.

Occupational mobility chains and the role of job opportunities for upward, lateral and downward mobility in Switzerland

This paper addresses the rarely studied relationship between job vacancies and inter-firm upward, lateral, and downward status mobility in an occupationally segmented labor market, taking Switzerland as the example. To conceptualize mobility mechanisms in this type of labor market, we introduce the concept of “occupational mobility chains” and test its validity. This concept provides the backdrop for developing time-dependent measures of individual job opportunities based on Swiss Job Monitor data. We link these measures with career data taken from the Swiss Life History Study and employ event history analysis to test different propositions of the ways in which status mobility is contingent on the number and the status of vacant positions. Results support our assumption that in occupationally segmented labor markets vacant positions affect status mobility only to the degree that they are located within workers’ occupational mobility chains.

Passive wireless sensor systems can recognize activites of daily living

The ability to determine what activity of daily living a person performs is of interest in many application domains. It is possible to determine the physical and cognitive capabilities of the elderly by inferring what activities they perform in their houses. Our primary aim was to establish a proof of concept that a wireless sensor system can monitor and record physical activity and these data can be modeled to predict activities of daily living. The secondary aim was to determine the optimal placement of the sensor boxes for detecting activities in a room. A wireless sensor system was set up in a laboratory kitchen. The ten healthy participants were requested to make tea following a defined sequence of tasks. Data were collected from the eight wireless sensor boxes placed in specific places in the test kitchen and analyzed to detect the sequences of tasks performed by the participants. These sequence of tasks were trained and tested using the Markov Model. Data analysis focused on the reliability of the system and the integrity of the collected data. The sequence of tasks were successfully recognized for all subjects and the averaged data pattern of tasks sequences between the subjects had a high correlation. Analysis of the data collected indicates that sensors placed in different locations are capable of recognizing activities, with the movement detection sensor contributing the most to detection of tasks. The central top of the room with no obstruction of view was considered to be the best location to record data for activity detection. Wireless sensor systems show much promise as easily deployable to monitor and recognize activities of daily living.

Feasibility study of a single-blind randomised controlled trial of an occupational therapy intervention.

BACKGROUND Several factors facilitate or hinder efficacy research in occupational therapy. Strategies are needed, therefore, to support the successful implementation of trials. AIM To assess the feasibility of conducting a randomised controlled trial (RCT). The main feasibility objectives of this study were to assess the process, resources, management, and scientific basis of a trial RCT. MATERIAL AND METHODS A total of 10 occupational therapists, between the ages of 30 and 55 (M 43.4; SD 8.3) with seven to 26 years' (M 14.3; SD 6.1) experience, participated in this study. Qualitative data collected included minutes of meetings, reports, and field notes. The data were analysed based on the principles of content analysis, using feasibility objectives as the main categories. RESULTS Data analysis revealed strengths in relation to retention and inclusion criteria of participants, the study protocol, study organisation, and the competence of researchers. Weaknesses were found related to recruitment, randomisation, data collection, time for training and communication, commitment, and design. CONCLUSION The findings indicated that there are several factors which had a considerable impact on the implementation of an RCT in practice. However, it was useful to assess methods and procedures of the trial RCT as a basis to refine research plans.

Texas dental hygiene/dietitian occupational health study

Occupational asthma is the most common form of reported occupational respiratory disease in many industrialized countries. Recent studies show that environmental exposures account for up to 40% of the cases of asthma and that 2% to 15% of all cases of asthma are attributable to occupational exposures. In the dental workplace, dental hygienists are exposed to hazardous substances. Among these hazards are respiratory sensitizers, irritants and infectious agents. A cross-sectional study of Texas dental hygienists was conducted to assess the prevalence of occupational asthma. Registered dietitians were surveyed as a comparison group, because this group is similar in demographic makeup to dental hygienists, but conducts no clinical treatment with associated hazardous exposures. Neither the questionnaire survey nor the cover letter revealed the focus of this investigation. Three hundred and thirty five dental hygienists licensed to practice in the state of Texas as of January 1, 1999, and 320 dietitians that are also licensed by the state of Texas were randomly selected. (Abstract shortened by UMI.)^

An international assessment of the comprehensibility of material safety data sheets (MSDSs)

Material Safety Data Sheets (MSDSs) are an integral component of occupational hazard communication systems. These documents are used to disseminate hazard information to workers on chemical substances. The primary purpose of this study was to investigate the comprehensibility of MSDSs by workers at an international level. ^ A total of 117 employees of a multi-national petrochemical company participated; thirty-nine (39) each in the United States, Canada and the United Kingdom. Overall participation rate of those approached to participate was 82%. These countries were selected as they each utilize one of the three major existing hazard communication systems for fixed workplaces. The systems are comprised of the Occupational Safety and Health Administration's Hazard Communication Standard in the United States, the Workplace Hazardous Materials Information System (WHMIS) in Canada, and the compilation of several European Union directives addressing classification, labeling of substances and preparations, and MSDSs in Europe. ^ A pretest posttest randomized study design was used, with the posttest being comparable to an open book test. The results of this research indicated that only about two-thirds of the information on the MSDSs was comprehended by the workers with a significant difference identified among study participants based on country comparisons. This data was fairly consistent with the results of previous MSDS comprehensibility studies conducted in the United States. There was no significant difference in the comprehension level among study participants when taking into account the international hazard communication standard that the MSDS complied with. Marginally, age, education level and experience level did not have a significant impact on the comprehension level. ^ Participants did find MSDSs to be satisfactory in providing the information needed to protect them regardless of their views on the readability and formatting of MSDSs. The health-related information was the least comprehended as less than half of it was comprehended on the basis of the responses. The findings from this research suggest that there is much work needed yet to make MSDSs more comprehensible on a global basis, particularly regarding health-related information. ^

Role of the cyclin dependent kinase-4 in normal and neoplastic proliferation

In the last few years, our laboratory has studied the regulatory mechanisms of proliferation and differentiation in epidermal tissues. Our results showed differences in the roles of cyclin dependent-kinases 4 and 6, and the three D-type cyclins, during normal epidermal proliferation and neoplastic development. Thus, to elucidate the role of the different cell cycle regulators, we developed transgenic mice that overexpress CDK4 (K5-CDK4), or their cognate D-type cyclins, in epithelial tissues. The most severe phenotype was observed in K5-CDK4 animals that developed dermal fibrosis, epidermal hyperplasia and hypertrophy. Forced expression of CDK4 in the epidermal basal cell layer increased the malignant conversion of skin papillomas to squamous cell carcinomas (SCC). Contrastingly, lack of CDK4 completely inhibited tumor development, suggesting that CDK4 is required in this process. Biochemical studies demonstrated that p21 Cip1 and p27Kip1 inhibitors are sequestered by CDK4 resulting in indirect activation of Cyclin E/CDK2, implicating the non-catalytic activity of CDK4 in deregulation of the cell cycle progression. ^ It has been proposed that the proliferative and oncogenic role of Myc is linked to its ability to induce the transcription of CDK4, cyclin D1, and cyclin D2 in vitro. Deregulation of Myc oncogene has been found in several human cancers. Also it has been demonstrated that CDK4 has the ability to functionally inactivate the product of the tumor suppressor gene Rb, providing a link between Myc and the CDK4/cyclin D1/pRb/p16 pathway in some malignant tumors. Here, we sought to determine the role of CDK4 as a mediator of Myc activities by developing a Myc overexpressing mouse nullizygous for CDK4. We demonstrated that lack of CDK4 results in reduced keratinocyte proliferation and epidermal thickness in K5-Myc/CDK4-null mice. In addition, complete reversion of tumor development was observed. All together, this work demonstrates that CDK4 acts as an oncogene independent of the D-type cyclin levels and it is an important mediator of the tumorigenesis induced by Myc. In addition, we showed that the sequestering activity of CDK4 is critical for the development of epidermal hyperplasia during normal proliferation, malignant progression from papillomas to squamous cell carcinomas, and tumorigenesis induced by Myc. ^

Occupational respiratory disease in the services industry

Objective. To describe the spectrum and occurrence of occupational exposures of relevance to the respiratory system and their subsequent adverse effects within the service industries and occupations, as outlined by the U.S. Department of Labor Bureau of Labor Statistics Occupational Outlook Handbook, 2007. ^ Design. Systematic review of the literature from an Ovid search including years 1950 to 2008. Initially, occupational respiratory disease categories were searched, and then combined with each of the different occupations for a comprehensive review of the literature. ^ Results. Ten groups within the U.S. Department of Labor Bureau of Labor Statistics Occupational Outlook Handbook, 2007 were identified as having exposures leading to occupational respiratory disease. These include janitors/cleaners, dental personnel, cosmetology professionals, traffic police, veterinary personnel, firefighters, healthcare workers, bakers, and bar/restaurant workers. The most common respiratory disorder affecting this population was occupational asthma caused by many different exposures in each occupation. The biggest limitation was the absence of a uniform reporting method for occupational respiratory diseases. ^ Conclusion. There is evidence that there are risks for occupational respiratory disease in the services industry. ^ Key Words: occupational and respiratory disease and service industries ^

A simplified protocol for the treatment of acute radiation overexposures from sources external to the body

When compared to other types of occupational injuries, radiation overexposure events are somewhat rare, so health care providers may not be familiar with the actual clinical care to be provided when such an event occurs. Radiation overexposure treatment decisions are predicated on the amount of radiation dose received, which is a value many health care providers may not have the knowledge or expertise to either calculate or even estimate. Even the different units of measure for radiation exposure and dose received can be a source of confusion. The prompt treatment of radiation overexposure victims could be enhanced and facilitated through the creation of a single, simple protocol that consists of the various means of dose measurement and estimation, correlated to the corresponding appropriate clinical care measures. This culminating experience will assemble essential information currently maintained in disparate references to create a single, simplified protocol to facilitate the treatment of victims of acute external radiation overexposure. ^