Epidermal biomarkers of the skin barrier in atopic and contact dermatitis.

Dysfunction of the skin barrier plays a critical role in the initiation and progression of inflammatory skin diseases, such as atopic dermatitis and contact dermatitis. Epidermal biomarkers can aid in evaluating the functionality of the skin barrier and understanding the mechanisms that underlay its impairment. This narrative review provides an overview of recent studies on epidermal biomarkers associated with the function and integrity of the skin barrier, and their application in research on atopic dermatitis and contact dermatitis. The reviewed studies encompass a wide spectrum of molecular, morphological and biophysical biomarkers, mainly obtained from stratum corneum tape strips and biopsies. Lipids, natural moisturizing factors, and structural proteins are the most frequently reported molecular biomarkers. Additionally, corneocyte surface topography and elasticity show potential as biomarkers for assessing the physical barrier of the skin. In contact dermatitis studies, biomarkers are commonly employed to evaluate skin irritation and differentiate between irritant and allergic contact dermatitis. In atopic dermatitis, biomarkers are primarily utilized to identify differences between atopic and healthy skin, for predictive purposes, and monitoring response to therapies. While this overview identifies potential biomarkers for the skin barrier, their validation as epidermal biomarkers for atopic dermatitis and contact dermatitis has yet to be established.

A workers' health surveillance online training programme for occupational physicians.

BACKGROUND: To support occupational physicians (OPs) in the implementation of workers' health surveillance (WHS), a training programme was developed. AIMS: (i) To evaluate the effects of a WHS training programme for OPs on knowledge, self-efficacy and skills to implement WHS. (ii) To evaluate to what extent a WHS training programme is acceptable and feasible for implementation in practice. METHODS: A single-blinded randomized controlled trial with waiting-list control group was used. The WHS training programme consisted of an e-learning and a 4.5-h online training session. OPs completed a knowledge test (0-8), self-efficacy questionnaires on knowledge and skills (6-60), and vignette assignments (0-16) to measure skills. OPs completed the questionnaires, either before and after the WHS training programme (intervention group), or before the training programme (control group) while receiving the training programme after the waiting period. All OPs completed questionnaires about the training's acceptability, and feasibility for implementation in practice. ANCOVA and Poisson regression analyses were conducted. RESULTS: The self-efficacy score (M = 44.1 versus M = 37.2) (P < 0.001) and skills score (M = 9.6 versus M = 8.3) (P < 0.05) of OPs in the training group (N = 16) were higher than the control group (N = 23). No effect was found on knowledge. Evaluation of acceptability and feasibility showed that 21 (58%) OPs were very satisfied with the training part on initiating WHS, and 29 (85%) would recommend the WHS training programme to colleagues. CONCLUSIONS: This WHS training programme has a positive effect on self-efficacy and skills of OPs to implement WHS, and may be acceptable and feasible to implement in practice.

Do overweight/obesity and low levels of leisure-time vigorous physical activity moderate the effect of occupational physical activity on self-rated health of construction workers?

PURPOSE: To investigate the combined effects of occupational physical activity (OPA) and either overweight/obesity or low levels of leisure-time vigorous physical activity (LTVPA) on self-rated health. METHODS: A longitudinal study was performed among 29,987 construction workers with complete data on 2 Workers' Health Surveillance Programs during 2010-2018. Self-reported OPA involved strenuous work postures and manual material handling. Low level of LTVPA was defined as self-reported vigorous activity for less than three times per week lasting at least 20 min per session. Overweight and obesity were based on Body Mass Index (BMI) (25.0 ≤ BMI < 30.0 kg/m2 and BMI ≥ 30.0 kg/m2, respectively) using measured body height and weight. Self-rated health was measured using a single item question. Logistic regression analysis was used to investigate the associations between the separate risk factors at baseline and self-rated health at follow-up. The combined effects of demanding OPA and either overweight/obesity or low level of LTVPA on self-rated health were analyzed using the relative excess risk due to interaction (RERI). RESULTS: Mean follow-up duration was 31.7 (SD = 14.9) months. Construction workers with strenuous work postures (OR 1.35 95% CI 1.25-1.46), manual material handling (OR 1.29 95% CI 1.19-1.40), obesity (OR 1.31 95% CI 1.17-1.47) and low LTVPA (OR 1.13 95% CI 1.01-1.25) were more likely to report poor self-rated health at follow-up. No statistically significant interaction effects were found for OPA and obesity or low LTVPA. CONCLUSIONS: OPA, obesity and low level of LTVPA were separate risk factors for poor self-rated health, but did not appear to have a synergistic effect.

Workers' health surveillance targeting mental health: evaluation of a training.

BACKGROUND: Mental health complaints occur frequently among healthcare workers. A workers' health surveillance mental health module (WHS-MH) was found to be effective in improving work functioning of nurses, although not implemented regularly. Therefore, training for occupational physicians and nurses to facilitate the implementation of WHS-MH was developed and evaluated. AIMS: This study was aimed to evaluate the effect of training on knowledge, self-efficacy and motivation to implement WHS-MH, and to evaluate participants' satisfaction with the training. METHODS: Three-hour training was held among 49 occupational physicians and nurses in the Netherlands. Effect on knowledge, self-efficacy and motivation was assessed using knowledge tests and questionnaires before and immediately after the training. Satisfaction with the training was measured using questionnaires after the training. RESULTS: A mean knowledge test score of 5.3 (SD = 1.6) was found before training, which did not significantly increase after training (M = 5.6, SD = 1.8). In total, 43% agreed or strongly agreed to have sufficient skills to implement WHS-MH, which significantly increased to 78% after the training. Furthermore, 87% agreed or strongly agreed to be motivated to initiate WHS, which significantly increased to 94% after the training. The majority of participants were satisfied with the training. CONCLUSIONS: Training may enhance the implementation of the WHS-MH through increasing self-efficacy and motivation. However, no effect on level of knowledge to implement WHS-MH was found.

Perceived barriers and facilitators in the assessment of occupational diseases.

BACKGROUND: Information is collected worldwide on the diagnosis and assessment of occupational diseases (ODs) by occupational physicians (OPs). However, information on perceived facilitators and barriers to assessment is scarce. AIMS: To evaluate the perceived barriers and facilitators in the assessment of ODs by OPs. METHODS: We conducted a qualitative study, using interviews and focus groups. We held 12 interviews and two focus groups with Dutch OPs, to identify barriers and facilitators in the assessment of ODs. RESULTS: Case definition, exposure assessment, attribution to work, guidelines and decision tools, external expertise, individual motivation and consequences were identified as themes. Barriers and facilitators were mainly reported regarding assessing work attribution, e.g. how to assess multifactorial causes or the need for training, and individual motivation such as the perceived lack of usefulness or the need for monitoring suspected OD cases. Within the theme of consequences, only barriers to the assessment of ODs were reported, including the liability of employers. CONCLUSIONS: Perceived facilitators in the assessment of ODs were practical assessment tools, multifaceted education, ability to assess work exposures and professional independence. Perceived barriers were lack of usefulness, lack of urgency, complexity of assessment and concerns about liability issues.

Improving the assessment of occupational diseases by occupational physicians.

BACKGROUND: The prevention of occupational diseases is limited by a lack of insight into occupational exposure to risk. We developed a six-step approach to improve the diagnosis and reporting of occupational diseases and the selection of subsequent preventive actions by occupational physicians (OPs). AIMS: To evaluate the effect of the six-step approach on the transparency and quality of assessing occupational diseases and the usability of the six-step approach according to OPs and their satisfaction with it. METHODS: A randomized controlled trial. OPs in the control group used the standard information available. OPs in the intervention group used the six-step approach and accompanying educational materials. The actions and decisions of OPs in both groups were analysed using 17 performance indicators. To address the second issue, OPs used the six-step approach over 6 weeks and rated its usability and their satisfaction in relation to several aspects. RESULTS: The average score of the OPs in the intervention group (n = 110) was statistically significantly higher (11/17 performance indicators, 62% of the maximum score) than that of the OPs in the control group (n = 120, 5/17 performance indicators, 30% of the maximum score, P < 0.001). The usability aspects of the six-step approach had mean scores of 7 and 8. Mean satisfaction with the six-step approach was 8. CONCLUSIONS: The six-step approach resulted in better evidence-based and transparent decision-making about occupational diseases by OPs. Usability and satisfaction were rated as satisfactory by the OPs.

Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet.

BACKGROUND/OBJECTIVES: In the context of obesity, epigenetic mechanisms regulate cell-specific chromatin plasticity, perpetuating gene expression responses to nutrient excess. MacroH2A1, a variant of histone H2A, emerged as a key chromatin regulator sensing small nutrients during cell proliferation and differentiation. Mice genetically ablated for macroH2A1 (knockout (KO)) do not show overt phenotypes under a standard diet. Our objective was to analyse the in vivo role of macroH2A1 in response to nutritional excess. METHODS: Twelve-week-old whole-body macroH2A1 KO male mice were given a high-fat diet (60% energy from lard) for 12 weeks until being killed, and examined for glucose and insulin tolerance, and for body fat composition. Energy expenditure was assessed using metabolic cages and by measuring the expression levels of genes involved in thermogenesis in the brown adipose tissue (BAT) or in adipogenesis in the visceral adipose tissue (VAT). RESULTS: Under a chow diet, macroH2A1 KO mice did not differ from their wild-type (WT) littermates for body weight, and for sensitivity to glucose or insulin. However, KO mice displayed decreased heat production (P<0.05), and enhanced total activity during the night (P<0.01). These activities related to protection against diet-induced obesity in KO mice, which displayed decreased body weight owing to a specific decrease in fat mass (P<0.05), increased tolerance to glucose (P<0.05), and enhanced total activity during the day (P<0.05), compared with WT mice. KO mice displayed increased expression of thermogenic genes (Ucp1, P<0.05; Glut4, P<0.05; Cox4, P<0.01) in BAT and a decreased expression of adipogenic genes (Pparγ, P<0.05; Fabp4, P<0.05; Glut4, P<0.05) in VAT compared with WT mice, indicative of augmented energy expenditure. CONCLUSIONS: Genetic eviction of macroH2A1 confers protection against diet-induced obesity and metabolic derangements in mice. Inhibition of macroH2A1 might be a helpful strategy for epigenetic therapy of obesity.

Online reporting and assessing new occupational health risks in SIGNAAL.

BACKGROUND: Changes in work and working conditions continuously give rise to new work-related health risks. Without sufficient knowledge of these, opportunities for prevention and intervention may be missed. AIMS: To develop, implement and evaluate an online tool called SIGNAAL for reporting and assessment of new work-related health risks by occupational health physicians and experts in the Netherlands and Belgium. METHODS: Development and implementation of SIGNAAL to allow both easy and sufficient detailed reporting by occupational health physicians and structured and transparent assessment by occupational health experts. A new work-related health risk is defined as a work-related disease due to specific exposure in a specific work setting not described in the literature before. RESULTS: The online reporting and assessment tool proved to be a feasible means of reporting possible new combinations of health problems and exposures in the work situation. Eleven of the 15 cases reported until October 2014 were fully assessed: one was an entirely new work-related disease, four were known but uncommon work-related diseases, five were known but new in the reported work situation and one was a well-known work-related disease. CONCLUSIONS: An online reporting system used in an occupational health setting can provide insight into new work-related health risks by creating a structured way to gather, report and assess new combinations of health problems and exposure in the workplace.

The impact of common mental disorders on work ability in mentally and physically demanding construction work.

PURPOSE: To gain insight into (1) the prevalence and incidence of common mental disorders (CMD) and low work ability among bricklayers and construction supervisors; (2) the impact of CMD on current work ability and work ability 1 year later and (3) the added value of job-specific questions about work ability for detecting signs of low work ability. METHODS: We randomly selected 750 bricklayers and 750 supervisors. This sample was surveyed by means of a baseline questionnaire and a follow-up questionnaire 1 year later. Work ability was measured with the first three questions of the Work Ability Index and job-specific questions. Self-reported CMD were measured with instruments designed to detect a high need for recovery after work, distress and depression. We used univariate logistic regression to analyse the presence or absence of CMD as independent variable. RESULTS: The prevalence and incidence of CMD among 199 bricklayers and 224 supervisors was 22 %/10 % and 32 %/15 %, respectively. The prevalence of low general work ability was comparable for both occupations (5 %). CMD were associated with low current work ability and low work ability at follow-up (ORs 4.3-22.4), but not with a reduction in work ability 1 year later. Questions on job-specific work ability resulted in more indications of low work ability among both occupations than did questions on general work ability. CONCLUSIONS: Regardless of occupation, workers who report CMD at baseline have a high likelihood of current low work ability and low work ability 1 year later.

Stress amongst dental students: a systematic review.

The present study was conducted to provide future researchers and dental educators with an overview of stress amongst undergraduate dental students reported in the literature. This overview is needed for the development of a new questionnaire measuring the level of stressors including students, staff and process of dental education. In addition, the review can be used to modify dental curricula to decrease such stress and produce better dentists. Our study consisted of a systematic review of 49 peer-reviewed articles published between 1966 till October 2008 in English, discussing different aspects of stress amongst undergraduate dental students. These aspects are demographic variables of stress, sources of stress, impact of stress, indicators of stress, instruments measuring stress level and management of stress. Major sources of reported stress were related to examinations, clinical requirements and dental supervisors. Studies suggest using signs and symptoms for early detection of stress and proper intervention.

Psychometric properties of burnout measures: a systematic review.

AIMS: Occupational Burnout (OB) is currently measured through several Patient-Reported Outcome Measures (PROMs) and some of them have become widely used in occupational health research and practice. We, therefore, aimed to review and grade the psychometric validity of the five OB PROMs considered as valid for OB measure in mental health professionals (the Maslach Burnout Inventory (MBI), the Pines' Burnout Measure (BM), the Psychologist Burnout Inventory (PBI), the OLdenburg Burnout Inventory (OLBI) and the Copenhagen Burnout Inventory (CBI)). METHODS: We conducted systematic literature searches in MEDLINE, PsycINFO and EMBASE databases. We reviewed studies published between January 1980 and September 2018 following a methodological framework, in which each step of PROM validation, the reference method, analytical technics and result interpretation criteria were assessed. Using the COnsensus-based Standards for the selection of health Measurement Instruments we evaluated the risk of bias in studies assessing content and criterion validity, structural validity, internal consistency, reliability, measurement error, hypotheses testing and responsiveness of each PROM. Finally, we assessed the level of evidence for the validity of each PROM using the GRADE approach. RESULTS: We identified 6541 studies, 19 of which were included for review. Fifteen studies dealt with MBI whereas BM, PBI, OLBI and CBI were each examined in only one study. OLBI had the most complete validation, followed by CBI, MBI, BM and PBI, respectively. When examining the result interpretation correctness, the strongest disagreement was observed for MBI (27% of results), BM (25%) and CBI (17%). There was no disagreement regarding PBI and OLBI. For OLBI and CBI, the quality of evidence for sufficient content validity, the crucial psychometric property, was moderate; for MBI, BM and PBI, it was very low. CONCLUSION: To be validly and reliably used in medical research and practice, PROM should exhibit robust psychometric properties. Among the five PROMs reviewed, CBI and, to a lesser extent, OLBI meet this prerequisite. The cross-cultural validity of these PROMs was beyond the scope of our work and should be addressed in the future. Moreover, the development of a diagnostic standard for OB would be helpful to assess the sensitivity and specificity of the PROMs and further reexamine their validity.The study protocol was registered in PROSPERO (CRD 42019124621).

Determinants of effective clinical learning: a student and teacher perspective in Saudi Arabia.

CONTEXT: Graduating clinically competent medical students is probably the principal objective of all medical curricula. Training for clinical competence is rather a complex process and to be effective requires involving all stakeholders, including students, in the processes of planning and implanting the curriculum. This study explores the perceptions of students of the College of Medicine at King Abdul-Aziz Bin Saud University for Health Sciences (KASU-HS), Riyadh, Saudi Arabia of the features of effective clinical rotations by inviting them to answer the question: "Which experiences or activities in your opinion have contributed to the development of your clinical competence? This college was established in 2004 and adopted a problem-based learning curriculum. METHODS: This question was posed to 24 medical students divided into three focus groups. A fourth focus group interview was conducted with five teachers. Transcriptions of the tape-recorded focus group interviews were qualitatively analyzed using a framework analysis approach. FINDINGS: Students identified five main themes of factors perceived to affect their clinical learning: (1) the provision of authentic clinical learning experiences, (2) good organization of the clinical sessions, (3) issues related to clinical cases, (4) good supervision and (5) students' own learning skills. These themes were further subdivided into 18 sub-themes. Teachers identified three principal themes: (1) organizational issues, (2) appropriate supervision and (3) providing authentic experiences. CONCLUSION: Consideration of these themes in the process of planning and development of medical curricula could contribute to medical students' effective clinical learning and skills competency.

Work-relatedness of inguinal hernia: a systematic review including meta-analysis and GRADE.

PURPOSE: Clinicians need to know whether inguinal hernia (IH) can be attributed to work to answer questions regarding prevention and medical causation. This review describes whether work-related risk factors are associated with IH. METHODS: A systematic review was performed in Medline via PubMed until February 3rd, 2020. Inclusion criteria were that IH was diagnosed by a clinician, and workers exposed to work-related risk factors were compared to workers less exposed or not at all. A quality assessment and a meta-analysis using Cochrane's RevMan 5.3 were performed, including GRADE for quality of evidence. RESULTS: The search resulted in 540 references. Fourteen studies fulfilled the inclusion criteria, of which three were included in a meta-analysis, all three being of high quality, including 621 workers diagnosed with IH. The meta-analysis revealed significant associations with physically demanding work (OR 2.30, 95% CI 1.56-3.40). Two prospective studies, including 382 and 22,926 cases revealed associations that this was true for male workers with a lateral IH that reported standing or walking for more than six hours per workday (OR 1.45, 95% CI 1.12-1.88) or lifting cumulative loads of more than 4000 kg per workday (OR 1.32, 95% CI 1.27-1.38). The level of certainty for the latter two work-related risk factors was moderate and high according to GRADE. CONCLUSION: Lateral IH among males is associated with work-related risk factors depending on the level of exposure to the time standing/walking per workday, or the amount of load lifted per workday.

Working height, block mass and one- vs. two-handed block handling: the contribution to low back and shoulder loading during masonry work.

The goal of this study was to compare the effects of the task variables block mass, working height and one- vs. two-handed block handling on low back and shoulder loading during masonry work. In a mock-up of a masonry work site, nine masonry workers performed one- and two-handed block-lifting and block-placing tasks at varying heights (ranging from floor to shoulder level) with blocks of varying mass (ranging from 6 to 16 kg). Kinematics and ground reaction forces were measured and used in a 3-D linked segment model to calculate low back and shoulder loading. Increasing lifting height appeared to be the most effective way to reduce low back loading. However, working at shoulder level resulted in relatively high shoulder loading. Therefore, it was recommended to organise masonry work in such a way that blocks are handled with the hands at about iliac crest height as much as possible.

Criteria for a good referral system for psychiatric patients: the view from Saudi Arabia.

The development and implementation of quality referral systems reflects sound national health planning. This review appraised the data on referral systems, in particular psychiatric referrals, with special reference to Saudi Arabia. A computer search was made of relevant literature in the past 2 decades. The rate and process of referring patients through referral letters varies globally across practice settings and is initiated by an array of factors linked with health consumers, health providers and delivery systems. Referral systems, including consultation-liaison services, are an essential component of any health care organization for offering a complete range of good quality, specialized health services.

Writing a Cochrane systematic review on preventive interventions to improve safety: the case of the construction industry.

OBJECTIVES: The objective of this paper is to describe the main steps and to conduct a systematic literature review on preventive interventions concerning work-related injuries and to illustrate the process. METHODS: Based on the Cochrane handbook, a structured framework of six steps was outlined for the development of a systematic review. This framework was used to describe a Cochrane systematic review (CSR) on the effectiveness of interventions to prevent work related injuries in the construction industry. RESULTS: The 6 main steps to write a CSR were: formulating the problem and objectives; locating and selecting studies; assessing study quality; collecting data; analysing data and presenting results; and interpreting results. The CSR on preventing injuries in the construction industry yielded five eligible intervention studies. Re-analysis of original injury data of the studies on regulatory interventions, through correcting for pre-intervention injury trends led to different conclusions about the effectiveness of interventions than those reported in the original studies. CONCLUSIONS: The Cochrane handbook for systematic reviews of interventions provides a practical and feasible six-step framework for developing and reporting a systematic review for preventive interventions.

Association between Work and Chronic Obstructive Pulmonary Disease (COPD).

To support occupational physicians in their assessment and notification of occupational diseases, diagnostic registration guidelines are developed with information about associations between work-related risk factors and diseases. The objective of this review of systematic reviews is to examine whether work-related risk factors are associated with chronic pulmonary obstructive disease (COPD). We searched the electronic database of Medline for systematic reviews published between 1 January 2009 and 20 June 2017. Reviews were included when COPD was assessed by data on lung function and when work-related exposures to vapors, dusts, gases, or fumes (VDGF) were described. One author selected studies and extracted data; two authors assessed study quality using A MeaSurement Tool to Assess systematic Reviews (AMSTAR). In all eight systematic reviews included, various exposures to vapors, dusts, gases, and fumes (VGDF) at work are associated with COPD. Two-thirds of the included studies are cross-sectional and show a high heterogeneity in population, setting, and mostly self-reported-exposures. Two high-quality reviews (AMSTAR score ≥ 9) including meta-analyses show associations and excess risk of COPD for work-related general exposure to VDGF with a summary odds ratio of 1.4 (95% confidence interval (CI) 1.19⁻1.73) and to inorganic dust with a mean difference in predicted forced expiratory volume in one second (FEV1) of -5.7% (95% CI: -8.62% to -2.71%). Exposure to VGDF at work is associated with a small but increased risk of COPD. More detailed workplace measurements of specific VGDF are warranted to gain an insight into dose⁻response relationships.

Interventions for preventing injuries in the construction industry.

BACKGROUND: Construction workers are frequently exposed to various types of injury-inducing hazards. A number of injury prevention interventions have been proposed, yet the effectiveness of these is uncertain. OBJECTIVES: To assess the effects of interventions for preventing injuries among workers at construction sites. SEARCH STRATEGY: We searched the Cochrane Injuries Group's specialised register, CENTRAL, MEDLINE, EMBASE, PsycINFO, OSH-ROM (including NIOSHTIC and HSELINE), EI Compendex. The reference lists of relevant papers, reviews and websites were also searched. The searches were not restricted by language or publication status. All databases were searched up to June 2006. SELECTION CRITERIA: Randomized controlled trials, controlled before-after studies and interrupted time series of all types of interventions for preventing fatal and non-fatal injuries among workers at construction sites. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study quality. For interrupted time series, we reanalysed the studies and used an initial effect, measured as the change in injury-rate in the year after the intervention, as well as a sustained effect, measured as the change in time trend before and after the intervention. MAIN RESULTS: Five interrupted time series studies met the inclusion criteria. Three studies evaluated the effect of regulations, one evaluated a safety campaign, and one a drug-free workplace program on fatal or non-fatal injuries compared to no drug-free workplace program. The overall methodological quality was low. The regulatory interventions did not show either an initial or sustained effect on fatal or non-fatal injuries, with effect sizes of 0.69 (95% confidence interval (CI) -1.70 to 3.09) and 0.28 (95% CI 0.05 to 0.51). The safety campaign did have an initial and sustained effect, reducing non-fatal injuries with effect sizes of -1.82 (95% CI -2.90 to -0.75) and -1.30 (95% CI -1.79 to -0.80) respectively. The drug-free workplace program did have an initial and sustained effect, reducing non-fatal injuries compared to no intervention, with effect sizes of -6.74 (95% CI -10.02 to -3.54) and -1.76 (95% CI -3.11 to -0.41) respectively. AUTHORS' CONCLUSIONS: The vast majority of technical, human factors and organisational interventions which are recommended by standard texts of safety, consultants and safety courses, have not been adequately evaluated. There is no evidence that regulations for reducing fatal and non-fatal injuries are effective. There is limited evidence that a multifaceted safety campaign and a multifaceted drug program can reduce non-fatal injuries in the construction industry.

The epithelial glycoprotein 2 (EGP-2) promoter-driven epithelial-specific expression of EGP-2 in transgenic mice: a new model to study carcinoma-directed immunotherapy.

The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), a M(r) 38,000 transmembrane antigen also known as 17-1A or Ep-CAM, is commonly used for targeted immunotherapy of carcinomas because it is strongly expressed by most carcinomas. EGP-2 is, however, also expressed in most normal epithelia. To evaluate anti-EGP-2-directed treatment-associated effects on tumors and on EGP-2-positive normal tissue, we generated EGP-2-expressing transgenic mice. A 55-kb DNA fragment consisting of the 14-kb genomic coding sequence of the human EGP-2 gene with approximately 10-kb-upstream and approximately 31-kb-downstream sequences was isolated and used to direct EGP-2 expression in an epithelium-specific manner. In the EGP-2 transgenic mice, EGP-2 appeared to be specifically expressed in all of those epithelial tissues that also express EGP-2 in humans, whereas all of the other tissues were negative. The specific in vivo localization of the i.v. administered anti-EGP-2 monoclonal antibody MOC31 was studied in EGP-2-positive and -negative tumors induced s.c. in this EGP-2 transgenic mouse model. Immunohistochemical analysis showed specific localization of MOC31 in the EGP-2-positive tumors but not in the EGP-2-negative tumors. No anti-EGP-2 monoclonal antibody localization was observed in any of the EGP-2-positive normal mouse tissues, which indicated a limited in vivo accessibility. In conclusion, an EGP-2 transgenic mouse model has been generated that expresses the EGP-2 antigen as in humans and, therefore, can serve as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities in both tumors and normal tissue.

The role of glucose, pyruvate and lactate in ATP production by rat spermatocytes and spermatids.

The ATP content of pachytene spermatocytes and round spermatids, isolated from rat testes, was not maintained during incubation of the germ cells in the presence of glucose. Glucose was metabolized via glycolysis at a considerable rate, but the rate of oxidation of the resulting endogenous pyruvate in the mitochondria was too low to support fully ATP production. Exogenous pyruvate (0.25 mM) or exogenous L-lactate (3-6 mM), however, were effective energy substrates. The lactate dehydrogenase reaction in isolated germ cells favoured the rapid conversion of pyruvate to lactate, at the expense of reducing equivalents from mitochondrial NADH. Hence, to support ATP production by the germ cells via mitochondrial metabolism of endogenous pyruvate, a relatively high concentration of exogenous lactate may be essential. In the spermatogenic microenvironment in vivo, such high concentrations of lactate could result from the net production of lactate by Sertoli cells. The mitochondria of the isolated germ cells produced ATP probably at a close to maximal rate, and spermatogenesis therefore may be extremely sensitive to compounds which interfere with mitochondrial energy metabolism and respiratory control.