Updated assessment of occupational safety and health hazards of climate change.

Workers, particularly outdoor workers, are among the populations most disproportionately affected by climate-related hazards. However, scientific research and control actions to comprehensively address these hazards are notably absent. To assess this absence, a seven-category framework was developed in 2009 to characterize the scientific literature published from 1988-2008. Using this framework, a second assessment examined the literature published through 2014, and the current one examines literature from 2014-2021. The objectives were to present literature that updates the framework and related topics and increases awareness of the role of climate change in occupational safety and health. In general, there is substantial literature on worker hazards related to ambient temperatures, biological hazards, and extreme weather but less on air pollution, ultraviolet radiation, industrial transitions, and the built environment. There is growing literature on mental health and health equity issues related to climate change, but much more research is needed. The socioeconomic impacts of climate change also require more research. This study illustrates that workers are experiencing increased morbidity and mortality related to climate change. In all areas of climate-related worker risk, including geoengineering, research is needed on the causality and prevalence of hazards, along with surveillance to identify, and interventions for hazard prevention and control.

Weaning onto solid foods: some of the challenges.

Weaning--the transition from milk to solid food--influences life-long health. Dietary challenges during weaning include providing sufficient critical nutrients such as iron with minimal added sugar and fat and no added salt. This study assessed the inclusion of iron-containing red meat in infant diets before age one year, and the Irish commercial baby food environment. Of mothers with an infant under 30 months of age who were surveyed in shopping centres in Ireland (n195), 82% (n159) reported wanting more weaning information. A quarter (n24) of infants over age 12 months (n97) received no iron-containing red meat before age one year. A scan of commercial baby foods in Ireland identified 448 products. While all complied with baby food legislation, 15% (n69) were intrinsically high in sugar and fat, or contained added salt. This study indicates the need for specific guidance on best infant feeding practice in Ireland.

Prevalence of overweight and obesity in Irish school children, using four different definitions.

OBJECTIVE: To determine the prevalence of overweight and obesity in Irish children using four different weight-for-height methods and to examine secular trends from previous national data. DESIGN: A cross-sectional survey. Weight and height were measured according to standard procedures and used to determine the prevalence of overweight and obesity using four weight-for-height methods of assessment, actual relative weight, the Centers for Disease Control and Prevention body mass index (BMI) for age charts for boys and girls, the BMI reference curves for the UK 1990 and the International Obesity Task Force age- and sex-specific BMI cutoffs. SETTING: The survey was carried out between 2003 and 2004 in the Republic of Ireland. SUBJECTS: Random representative sample of 596 children aged 5-12 years. RESULTS: The prevalence of overweight and obesity in Irish children is high, but varies considerably with each method. The prevalence of obesity in boys ranged from 4.1 to 11.2 % and in girls from 9.3 to 16.3%. Between 1990 and 2005, depending on the method used, there was a two-to-fourfold increase in obesity in children aged 8-12 years. CONCLUSION: It is evident given the variation displayed in the prevalence of obesity when using the different methods, that there is a discernible need for a single definition to identify the obese child in Ireland. The findings show a high prevalence of overweight and obesity in Irish school children and the increase in the prevalence of obesity over the last 15 years highlights this growing public health issue.

Reducing obesity and related chronic disease risk in children and youth: a synthesis of evidence with 'best practice' recommendations.

Childhood obesity is a global epidemic and rising trends in overweight and obesity are apparent in both developed and developing countries. Available estimates for the period between the 1980s and 1990s show the prevalence of overweight and obesity in children increased by a magnitude of two to five times in developed countries (e.g. from 11% to over 30% in boys in Canada), and up to almost four times in developing countries (e.g. from 4% to 14% in Brazil). The goal of this synthesis research study was to develop best practice recommendations based on a systematic approach to finding, selecting and critically appraising programmes addressing prevention and treatment of childhood obesity and related risk of chronic diseases. An international panel of experts in areas of relevance to obesity provided guidance for the study. This synthesis research encompassed a comprehensive search of medical/academic and grey literature and the Internet covering the years 1982-2003. The appraisal approach developed to identify best practice was unique, in that it considered not only methodological rigour, but also population health, immigrant health and programme development/evaluation perspectives in the assessment. Scores were generated based on pre-determined criteria with programmes scoring in the top tertile of the scoring range in any one of the four appraisal categories included for further examination. The synthesis process included identification of gaps and an analysis and summary of programme development and programme effectiveness to enable conclusions to be drawn and recommendations to be made. The results from the library database searches (13,158 hits), the Internet search and key informant surveys were reduced to a review of 982 reports of which 500 were selected for critical appraisal. In total 158 articles, representing 147 programmes, were included for further analysis. The majority of reports were included based on high appraisal scores in programme development and evaluation with limited numbers eligible based on scores in other categories of appraisal. While no single programme emerged as a model of best practice, synthesis of included programmes provided rich information on elements that represent innovative rather than best practice under particular circumstances that are dynamic (changing according to population subgroups, age, ethnicity, setting, leadership, etc.). Thus the findings of this synthesis review identifies areas for action, opportunities for programme development and research priorities to inform the development of best practice recommendations that will reduce obesity and chronic disease risk in children and youth. A lack of programming to address the particular needs of subgroups of children and youth emerged in this review. Although immigrants new to developed countries may be more vulnerable to the obesogenic environment, no programmes were identified that specifically targeted their potentially specialized needs (e.g. different food supply in a new country). Children 0-6 years of age and males represented other population subgroups where obesity prevention programmes and evidence of effectiveness were limited. These gaps are of concern because (i) the pre-school years may be a critical period for obesity prevention as indicated by the association of the adiposity rebound and obesity in later years; and (ii) although the growing prevalence of obesity affects males and females equally; males may be more vulnerable to associated health risks such as cardiovascular disease. Other gaps in knowledge identified during synthesis include a limited number of interventions in home and community settings and a lack of upstream population-based interventions. The shortage of programmes in community and home settings limits our understanding of the effectiveness of interventions in these environments, while the lack of upstream investment indicates an opportunity to develop more upstream and population-focused interventions to balance and extend the current emphasis on individual-based programmes. The evidence reviewed indicates that current programmes lead to short-term improvements in outcomes relating to obesity and chronic disease prevention with no adverse effects noted. This supports the continuation and further development of programmes currently directed at children and youth, as further evidence for best practice accumulates. In this synthesis, schools were found to be a critical setting for programming where health status indicators, such as body composition, chronic disease risk factors and fitness, can all be positively impacted. Engagement in physical activity emerged as a critical intervention in obesity prevention and reduction programmes. While many programmes in the review had the potential to integrate chronic disease prevention, few did; therefore efforts could be directed towards better integration of chronic disease prevention programmes to minimize duplication and optimize resources. Programmes require sustained long-term resources to facilitate comprehensive evaluation that will ascertain if long-term impact such as sustained normal weight is maintained. Furthermore, involving stakeholders in programme design, implementation and evaluation could be crucial to the success of interventions, helping to ensure that needs are met. A number of methodological issues related to the assessment of obesity intervention and prevention programmes were identified and offer insight into how research protocols can be enhanced to strengthen evidence for obesity interventions. Further research is required to understand the merits of the various forms in which interventions (singly and in combination) are delivered and in which circumstances they are effective. There is a critical need for the development of consistent indicators to ensure that comparisons of programme outcomes can be made to better inform best practice.

Effect of a high-beef diet on the fecal bacterial flora of humans.

Ten human volunteers completed a 4-month diet series consisting of 1 month each of a control diet, a meatless diet, a high-beef diet, and the same control diet. Fat and fiber contents were essentially the same in all four diets, but protein content was doubled during the high-beef diet. During the 4th week on each diet, three stool specimens collected from each volunteer were analyzed for chemical composition and content of facultative, aerobic, and anaerobic bacteria. The bacteriological data are presented in this paper. High beef protein consumption had little effect on the composition of the intestinal flora. There were no significant differences in total counts of facultative and aerobic or anaerobic organisms in the feces when volunteers were on meatless or high-beef diets. At the species level, when counts during the two control diets were comparable, in only three instances did the change from the meatless to a high-beef diet significantly influence the bacterial numbers. The ratio of mean counts of anaerobic to facultative and aerobic organisms was approximately 15:1 during the meatless diet and 34:1 during the high-meat diet. The data indicate that animal protein consumption has little effect on the fecal bacterial profile in humans.

Electromagnetic guidance for catheter-based transendocardial injection: a platform for intramyocardial angiogenesis therapy. Results in normal and ischemic porcine models.

OBJECTIVES: To test the feasibility of myocardial angiogenic gene expression using a novel catheter-based transendocardial injection system. BACKGROUND: Angiogenesis has been induced by direct injection of growth factors into ischemic myocardium during open-heart surgery. Catheter-based transendocardial injection of angiogenic factors may provide equivalent benefit without need of surgery. METHODS: A new guidance system for intramyocardial therapy utilizes magnetic fields and catheter-tip sensors to locate a position in space and reconstruct three-dimensional left ventricular (LV) electromechanical maps without using fluoroscopy. A retractable 27G needle was coupled with the guidance system for LV transendocardial injection. In 12 pigs, the catheter was used to inject 0.1 ml of methylene-blue (MB) dye and 8 pigs had myocardial injections of adenoviral vector (1 x 10(10) particles per site) containing the LacZ transgene. Ten pigs underwent catheter-based transendocardial injection and six pigs were injected using transepicardial approach with the gene encoding adenovirus vascular endothelial growth factor-121 (Ad.VEGF121; 1 x 10(10) viral particles x 6 sites) and sacrificed at 24 h. Injection sites were identified with ultraviolet light by coinjection of fluorescent beads. RESULTS: Overall, 138 of 152 attempted injection MB tracks (91%) were found after sacrifice. Tissue staining was 7.1+/-2.1 mm in depth and 2.3+/-1.8 mm in width. No animal had pericardial effusion or tamponade. In Ad.LacZ injected animals, gross pathology showed positive staining in injected zones, and histology confirmed positive myocyte staining. Adenovirus vascular endothelial growth factor-121 injected sites showed high levels of VEGF121 production that was of similar magnitude whether injected using the transendocardial (880.4+/-412.2 pg VEGF121/mg protein) or transepicardial (838.3+/-270 pg VEGF121/mg protein) delivery approach (p = 0.62). CONCLUSIONS: Using this magnetic guidance catheter-based navigational system, transgenes can effectively be transfected into designated myocardial sites. Thus, if it is determined that direct intramyocardial injection of angiogenic factors enhances collateral function in patients, this less invasive catheter-based system offers a similar gene delivery efficiency and, thus, may have clear advantages compared with the surgically-based transepicardial injection approach.

Dehydroepiandrosterone replacement in aging humans.

Because so much medical and media attention has been drawn to the alleged benefits of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS), it is important to evaluate the effects of replacement therapy objectively using double blind, cross-over, randomized research methodology. In this 9-month study, healthy older men (n = 39) received replacement dose DHEA. Lean body mass, blood hematology, chemistry and endocrine values, as well as urological and psychological data were measured. Data showed some mild and temporary, but significant, changes during oral use of 100 mg DHEA for 3 months compared with placebo taken for 3 months. Body composition did not change during the 6 months of treatment, nor did any urological parameters. Concomitant with the endocrine changes, some small but, significant, variations in blood values (blood urea nitrogen, creatinine, uric acid, alanine transaminase, cholesterol, high density lipoprotein, and potassium) were found. After cessation of DHEA and placebo, followed by 3 months of no treatment, all values previously found to be altered returned to entry baseline. Well publicized effects of the drug reported by others, such as a sense of well-being or improved sexual function, were not found in this study.

Total body potassium--a guide to nutritional health in patients undergoing continuous ambulatory peritoneal dialysis.

Nutritional status in patients undergoing continuous ambulatory peritoneal dialysis was estimated by serial simultaneous measurements (3 to 6 months) of total body potassium, weight, serum, albumin, total serum globulins and IgG, IgA, IgM, total iron binding capacity, and hematocrit. Correlations were performed between the changes per month in these measurements and with episodes of peritonitis per month. Changes per month in serum albumin and total iron binding capacity correlated with total body potassium. Serum immunoglobulins fell with time on continuous ambulatory peritoneal dialysis but there was no correlation with the other measurements. Changes in total body potassium per month correlated negatively with episodes of peritonitis per month. Of these measured parameters only the change in total body potassium per month reflected long-term clinical consequences of peritonitis. The studies suggest that lower rates of infection, hopefully now possible with solutions in plastic bags, will prevent catabolism.

Effect of dietary egg on serum cholesterol and triglyceride of human males.

One hundred fourteen male volunteers (mean age 44.6 years) consumed one whole egg daily in their customary diets for 3 months. Their final serum cholesterol (SCHOL) and triglycerides (STG) levels were compared with their initial levels on customary free choice diets and also with their levels after a 3-month elimination of dietary whole eggs. All subjects had previously confirmed normal serum lipid levels and no history of heart disease. Four-day food records were kept during both experimental dietary periods. A Latin square design allowed analysis for seasonal effects on lipid levels. No significant change in mean SCHOL on either diet was found; there was a seasonal effect on mean STG. Significant linear associations of fat intake and of energy intake were found. There was no significant association of dietary cholesterol intake with either SCHOL or STG.

Total body potassium in aging humans: a longitudinal study.

Total body potassium (TBK) data calculated from longitudinal measurements over 18 y of 40K by whole-body counting of 564 male and 61 female healthy humans in a 2-pi liquid scintillation counter show little change in females younger than 50 y compared with males of those ages. Males show less TBK from 41 y onward as they age, with most rapid rate of loss between 41 and 60 y. Females have a rapid loss of TBK when they are older than 60 y; the loss is at a greater rate than that of males. Percent total body fat calculated from total body weight and lean body mass (LBM) derived from TBK document greater adiposity in females at all ages except ages 51-60 y when females are similar to males in change in percent fat per year per centimeter.

Effect of dietary egg on human serum cholesterol and triglycerides.

One hundred sixteen male volunteers between the ages of 32 and 62 years (mean age 46) consumed two whole fresh eggs daily in their customary diets for 3 months and also eliminated eggs for 3 months before or after eating eggs. The men had had normal-range serum cholesterol and triglycerides for the past 7 years. Four-day food records kept by them in each experimental period were assessed for nutrient intake. A Latin square design allowed analyses for season and sequential effects on serum lipids. The serum cholesterol and triglyceride levels at the end of 6 months were compared with their initial levels on customary free choice diets as well as their levels after the first 3 months of study. No significant increase in mean serum cholesterol was found nor was there a significant association of dietary cholesterol intake with either serum cholesterol or triglyceride.

Dietary "meats" and serum lipids.

The mean values for serum total cholesterol for 47 males, aged 32 to 62 yr who, over a 10 1/2 month study ate, within a self-selected diet, beef as the only meat for 3 months, poultry and fish for 3 months, and pork for 3 months showed no statistically significant difference, whereas 17 of 29 females of the same age who participated in the same study had borderline statistically significant differences in mean values (p less than 0.055). When data from all subjects were considered together, no statistically significant changes in mean serum total cholesterol or serum triglycerides were noted, but there were significant changes in mean high-density lipoprotein cholesterol values, both upward and downward. The important results of this study are documentary to the lack of influence of "meat" and its fat on effecting a significant change in serum total cholesterol within a self-selected diet.

Serum lipids in humans fed diets containing beef or fish and poultry.

One half of a group of 129 men and women (74 men and 55 women), in a cross-over design at, within a self-selected diet, one egg and at least 5 oz of beef daily for 3 months while the other half at one egg and at least 5 oz of poultry and fish daily. Then they reversed their diets for 3 months. Blood samples were drawn by venipuncture before the study started and at the end of the 3 and 6 months, for analyses of serum total cholesterol, triglycerides, and high density lipoprotein cholesterol. No statistically significant changes were found in serum lipids in men. In women serum triglycerides but not other serum lipids were significantly higher when poultry and fish had been ingested.

Structure-activity relationships of the potent combined endothelin-A/endothelin-B receptor antagonist Ac-DDip16-Leu-Asp-Ile-Ile-Trp21: development of endothelin-B receptor selective antagonists.

The endothelins (ETs) are a family of bicyclic 21-amino acid-containing peptides that are highly potent and prolonged vasoconstrictors. The discovery of potent ET antagonists will facilitate the understanding of the physiological and/or pathophysiological role of ET. Structure-activity studies have revealed the importance of the C-terminal hexapeptide (residues 16-21) of ET (His16-Leu17-Asp18-Ile19-Ile20-Trp21) to the development of potent antagonists at both receptor subtypes (ETA and ETB). In particular, it has been shown that Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (Dip = 3,3-diphenylalanine) has low nanomolar affinity for the two endothelin receptor subtypes and is a functional antagonist of ET activity, both in vitro and in vivo at both receptors. Herein, we will describe the structure-activity relationships of Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893) with a particular emphasis on modifications that lead to enhanced receptor affinity and/or individual receptor subtype selectivity. In particular, we will demonstrate how we utilized PD 142893 to develop ETB receptor selective ligands and the pharmacological differences that exist between species ETB receptors with respect to their affinity for C-terminal hexapeptide antagonists.

Butenolide endothelin antagonists with improved aqueous solubility.

Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome the use of specific iv formulations for preclinical studies on additional drug candidates, analogues with improved aqueous solubility were desired. Several analogues were synthesized with substitution patterns that allowed for the formation of either acid or base addition salts. These derivatives had dramatically improved aqueous solubility. In addition, these analogues retained equivalent or improved ETA receptor selectivity and antagonist potency, versus 1, both in vitro and in vivo. Compound 29, which contains as a substituent the sodium salt of a sulfonic acid, has an ETA IC50 = 0.38 nM, ETA selectivity of 4200-fold, and ETA functional activity of KB = 7.8, all of which are similar or superior to those of 1. Compound 29 also has vastly superior aqueous solubility and solubility duration, compared to 1. Furthermore, 29 after iv infusion displays improved activity to 1 in preventing acute hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 microg/kg/h.

Structure-activity relationships in a series of orally active gamma-hydroxy butenolide endothelin antagonists.

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.

Use of fluorescent microspheres to localize in vivo gene transfer injection sites.

The potential for using gene therapy to treat a variety of disease states is growing rapidly. Many vector types and delivery systems have been developed that allow the optimization of protein production levels and kinetics for a given therapeutic gene product. In cases in which a transient, localized delivery of gene product is desired, any determination of the locale of transfected tissue by non-marker genes is problematic. We describe a technique by which the use of fluorescent microspheres can help in identifying potentially transfected tissue. Adenovirus containing the gene for beta-galactosidase (beta-gal) was mixed with fluorescent microspheres and injected into rat skeletal muscle and porcine myocardium. The injection sites could be visualized under ultraviolet light and correlated with beta-gal enzyme expression. This method is simple, inexpensive and generally useful for in vivo gene transfer experiments.

Facile entry to the tetracyclic 5-7-6-3 tigliane ring system.

[figure: see text] A tandem anionic 5-exo-dig cyclization/Claisen rearrangement sequence was used to effect a facile, "one-pot" conversion of an appropriately substituted 4-alkyn-1-ol to the tetracyclic carbon core structure of phorbol. The synthesis was conducted using readily available nonracemic starting materials to provide the target structure as a single enantiomer in high chemical yield.

Risk factors for recurrence of hemorrhagic endovasculitis of the placenta.

OBJECTIVE: To assess the potential for recurrence of placental hemorrhagic endovasculitis and to identify clinical or pathologic cofactors that might influence recurrence of this lesion or subsequent pregnancy outcome. METHODS: Ninety-seven women with a placenta affected by hemorrhagic endovasculitis, who also had at least one placenta referred to the Michigan Placental Tissue Registry from a subsequent pregnancy, were identified from 10,531 referrals between 1978 and 1988. Histologic slides from 209 placentas and clinical data from 211 infants (two sets of twins) from initial (first) and subsequent referrals were analyzed. Placentas were graded for the presence, extent, and severity of hemorrhagic endovasculitis and chronic villitis of unknown etiology; for placental lesions indicative of hypertensive maternal vessel disease; and for intravascular nucleated erythrocytes and chorionic thrombi. Maternal data included age, gravidity, number of previous losses, and history of toxemia or hypertension. All data were analyzed for significance using chi2 and t tests. Outcome assessment was based on recurrence of hemorrhagic endovasculitis and infant viability with the second referral. RESULTS: With first referrals, 80 of 98 infants (81.6%) were stillborn. Among second referrals, 26 of 98 infants (26.5%) were stillborn. Hemorrhagic endovasculitis recurred in 28 second placentas (28.9%); of these, 18 infants (64.3%) were stillborn. Higher rates of recurrence were found with progressively higher first-referral chronic villitis severity scores (P < .02), higher hypertensive placental lesion scores (P < .001), and first referrals with a history of toxemia or hypertension (P < .02). Recurrence of hemorrhagic endovasculitis was higher in patients with two or more of these factors in first referrals (P < .001). Subsequent stillbirth was more frequent with progressively higher first-referral hypertensive placental lesion scores (P < .01) and in first placentas with two or more risk factors (P = .064). Hemorrhagic endovasculitis severity scores, intravascular nucleated erythrocytes, and chorionic thrombi were associated with stillbirth in index pregnancies only. Maternal age, gravidity, or history of prior losses were not predictive. CONCLUSIONS: Placental hemorrhagic endovasculitis is associated with pregnancy loss and can recur in some patients. Interrelations among placental hemorrhagic endovasculitis, chronic villitis, maternal hypertension, and adverse outcomes in subsequent pregnancies are apparent. This information may be useful in patient counseling.