Social contributors to cardiometabolic diseases in indigenous populations: an international Delphi study.

OBJECTIVE: The objective of this study was to identify priority social factors contributing to indigenous cardiometabolic diseases. STUDY DESIGN: A three-round Delphi process was used to consolidate and compare the opinions of 60 experts in indigenous cardiometabolic health from Australia, New Zealand and the United States. METHODS: Round one: three open-ended questions: (i) historical, (ii) economic and (iii) sociocultural factor contributors to cardiometabolic disease risk. Round two: a structured questionnaire based on the results from the first round; items were ranked according to perceived importance. Final round: the items were reranked after receiving the summary feedback. RESULTS: Several key findings were identified: (i) an important historical factor is marginalisation and disempowerment; (ii) in terms of economic and sociocultural factors, the panellists came to the consensus that the socio-economic status and educational inequalities are important; and (iii) while consensus was not reached, economic and educational factors were also perceived to be historically influential. CONCLUSION: These findings support the need for multilevel health promotion policy. For example, tackling financial barriers that limit the access to health-promoting resources, combined with improving literacy skills to permit understanding of health education.

Covalent protein adducts of hydroquinone in tissues from rats: identification and quantitation of sulfhydryl-bound forms.

The Michael-type addition of sulfhydryl groups to benzoquinone (BQ) or substituted benzoquinones is proposed as the primary mechanism by which these electrophilic intermediates react with either cellular glutathione or protein sulfhydryls. This reaction constitutes a reductive alkylation with a substituted hydroquinone (HQ) derivative resulting from the addition. In the case of HQ, oxidative conversion of the parent material to BQ followed by conjugation with glutathione leads to metabolic activation, producing intermediates which are nephrotoxic as well as having other proposed biological activities. Chemically, BQ may react with more than 1 equiv of glutathione (or other sulfhydryl reagents) to produce HQ derivatives substituted with up to four sulfhydryl groups. Similarly, multiply substituted protein-S adducts of HQ were anticipated to occur in vivo following administration of this material. In the current studies, sulfhydryl-bound HQ protein adducts were detected and quantitated in protein isolated from rats using a modification of the alkaline permethylation procedure of Slaughter and Hanzlik [(1993) Anal. Biochem. 208, 288-295]. In particular, total protein-S adducts to HQ in kidney or blood reached a level of 420 or 80 pmol/mg of protein, respectively, 6 h following a single gavage dose of 100 mg/kg HQ. Measured half-lives of protein-S adducts in kidney and blood were 23.9 and 36.0 h, respectively. The applicability of protein-S adducts as a tissue dosimeter for HQ is discussed.

Covalent protein adducts of hydroquinone in tissues from rats: quantitation of sulfhydryl-bound forms following single gavage or intraperitoneal administration or repetitive gavage administration.

The current studies were conducted to investigate the degree and type of protein binding of hydroquinone (HQ) in the rat following single oral or intraperitoneal (ip) or repeated oral administrations. Male or female F-344 rats or male SD rats received a single dose of HQ at 0, 25, 50, or 100 mg/kg by either gavage or ip injection (SD rats only). In addition, male or female F-344 or male SD rats received HQ by gavage for 6 weeks (5 days/week) at 0, 25, or 50 mg/kg/day. Sulfhydryl-bound HQ was quantitated in protein from blood, kidneys, livers, or spleens 24 h after treatment using an alkaline permethylation procedure. The amount of total protein-S adducts increased with increasing dose in all the tissues that were assayed. Female rats had higher levels of adducts in blood, livers, and kidneys than did male rats when they were treated orally. Male F-344 rats treated orally had elevated levels of adducts in these same tissues compared to SD rats treated orally. For all genders and strains of rats and for all treatment regimens, mono-adducts predominated in livers (>72% of total). In the kidneys, tri- and tetrasubstituted adducts predominated with the summation accounting for >60% of the total. Ip administration of HQ resulted in significantly elevated levels of adducts in all the tissues that were examined, with the greatest increases seen for protein from blood and spleens. Levels of protein-S adducts of HQ in rat kidney following a single gavage administration correlated well with previously published differences in acute HQ nephrotoxicity in rats (female F-344 rat > male F-344 rat > male SD rat). Elevated levels of HQ protein-S adducts following repeated gavage administration did not correlate to measurable clinical signs of nephrotoxicity. Evidence is presented suggesting a possible role for the prostaglandin H synthase complex in the metabolic activation of HQ. In addition, protein arylation alone cannot account for the greater sensitivity of male F-344 rats toward chronic administration of HQ. The sensitivity of male F-344 rats to HQ is likely due to other factors, including the incidence and severity of chronic progressive nephropathy.

In vivo percutaneous absorption of [14C]DEHP from [14C]DEHP-plasticized polyvinyl chloride film in male Fischer 344 rats.

These studies investigated the migration of di(2-ethylhexyl) phthalate (DEHP) contained as a plasticizer in polyvinyl chloride (PVC) from plastic film and its absorption through rat skin in iivo. Sheets of PVC film (15 cm2) plasticized with [14C]DEHP were applied to the shaved backs of eight male rats in two separate experiments. For Study I, the PVC film was removed after 24 hr, the animals were rewrapped to prevent them from ingesting any residual DEHP at the exposure site, and urine and faeces were collected at regular intervals for 7 days. For Study II, the PVC film was removed after 24 hr, and the animals were immediately killed by CO2 inhalation. Urine and faeces were collected at 24 hr, and the exposure site was washed and rinsed to remove residual [14C]DEHP. In both studies, the amounts of radioactivity transferred from the film were extremely small, amounting to 0.0643% (Study I) and 0.126% (Study II) of that applied. The transferred radioactivity was found to be in three separate fractions. Radioactivity readily removed from the skin (mean 75% of the transferred radioactivity), radioactivity remaining at the application site at sacrifice. and absorbed radioactivity, that is, that distributed systemically or eliminated. The mean absorption rates for DEHP, calculated from the sum of the quantities absorbed plus that present in the exposure site, were: Study I, 0.239, and Study II, 0.242 microg/cm2/hr.

Dermal absorption and pharmacokinetics of isopropanol in the male and female F-344 rat.

Isopropanol (IPA), as a 70% aqueous solution, was applied under occluded conditions to the shaved backs of male and female Fischer F-344 rats for a period of 4 hr. Maximum analyzed blood concentrations of IPA were attained at 4 hr and decreased steadily following removal of the test material. Blood concentrations were below the limit of quantification at 8 hr. Acetone (ACE) blood levels rose steadily during the 4-hr exposures and continued to rise following removal of the test material, reaching peak analyzed levels at 4.5 hr (male) and 5 hr (females). ACE blood concentrations were below the limit of quantification at 24 hr. Basic pharmacokinetic parameters were similar for male and female rats with mean, first-order elimination half-lives for IPA and ACE of 0.8 to 0.9 hr and 2.1 to 2.2 hr, respectively. Following iv administration of [14C]IPA, 50-55% of the dose was eliminated as 14CO2 with lesser amounts recovered as expired volatiles or in urine. Total recoveries following iv administration were 83% for both males and females. Following a 4-hr dermal exposure to [14C]IPA (70% aqueous solution), 84-86% of the dose was recovered from the application site. Dermal absorption rates were calculated by two independent methods. The values obtained were 0.78 +/- 0.03 and 0.85 +/- 0.04 mg/cm2/hr for males and 0.77 +/- 0.13 and 0.78 +/- 0.16 mg/cm2/hr for females. Calculated permeability coefficients of 1.37 to 1.50 x 10(-3) cm/hr for males and 1.35 to 1.37 x 10(-3) cm/hr for females indicate that in the rat, IPA is rapidly absorbed dermally when applied under occluded conditions.

Differences in the nephrotoxicity of hydroquinone among Fischer 344 and Sprague-Dawley rats and B6C3F1 mice.

The present studies indicate pronounced species-, sex-, and strain- related differences in the acute nephrotoxicity of hydroquinone (HQ) when administered by gavage to male and female Sprague-Dawley (SD) rats, Fischer 344 (F344) rats, and B6C3F1 mice. Following a single dose of 400 mg/kg, male and female F344 rats displayed pronounced enzymuria and glucosuria. In female F344 rats, urinary alkaline phosphatase and glucose were the most sensitive indicators of renal toxicity, reaching levels of, respectively, 157 times and 137 times control values within 24 h of dosing. HQ treatment of male F344 rats also resulted in significant enzymuria, although it was less marked than that seen in female F344 rats. Significant numbers of epithelial cells were also present in the urine from F344 rats at 200 (female) or 400 mg/kg (male and female). SD rats did not show evidence of elevated levels of urinary enzymes or increased blood urea nitrogen (BUN) after oral administration of HQ at a dose level of 400 mg/kg. Oral administration of HQ to male and female B6C3F1 mice at 350 mg/kg resulted in only slight but significant increases in BUN.

Measurement of cell proliferation in the kidneys of Fischer 344 and Sprague-Dawley rats after gavage administration of hydroquinone.

Oral administration of hydroquinone (HQ) over 2 years to male Fischer 344 (F344) rats results in a dose-related nephropathy and an increase in the incidence of renal tubule adenomas. Female F344 rats, B6C3F1 mice, and Sprague-Dawley (SD) rats are resistant to the chronic renal toxicity of HQ, and nephrotoxicity was not seen in dogs or humans following subchronic exposure. To better characterize the early development of renal toxicity in rats, cell proliferation was quantitated within the proximal (P1, P2, and P3) and distal tubule segments of the kidney in rats given 0, 2.5, 25, or 50 mg/kg HQ by gavage. Male and female F344 rats were treated for 1, 3, or 6 weeks, and male SD rats were treated for 6 weeks. Cell proliferation was quantitated by incorporation of bromodeoxyuridine, detected immunohistochemically, into newly synthesized DNA. At 6 weeks, renal cell proliferation was increased over vehicle-controls in male F344 rats dosed at 50 mg/kg. Significant elevations (p < 0.001) occurred in the P1 segments (87%) and in the P2 segments (50%) but the elevation in the P3 segment (34%) was not statistically significant. Urinalyses revealed increases in the rate of excretion of enzymes indicative of proximal tubular damage. Histopathologic evaluation of the kidneys was consistent with a dose-related tubular degeneration in the male F344 rat. No chemical-related effects were observed in the kidneys of female F344 and male SD rats. These data parallel the findings of sex- and strain-specific kidney adenomas in the 2-year bioassays, and suggest that chemically induced cell proliferation secondary to toxicity may be important in the pathogenesis of benign renal tumors in male F344 rats treated with HQ.

Colonic surgery. The splenic connection.

Colonic resections, particularly those that require mobilization of the splenic flexure, occasionally will lead to injury of the spleen. Under these circumstances, the abdominal surgeon has traditionally considered incidental splenectomy to be the only safe alternative. Currently, a better understanding of splenic physiology and its role in sepsis prevention has reversed this trend. These efforts to preserve splenic function have resulted in various options available to the surgeon, herein reviewed. The results obtained in 36 general surgical patients with splenic injuries suggest that the salvage of the spleen is a safe alternative. In situations where salvage is impossible, the surgeon can resort to omental autotransplantation of the removed spleen, a recently described technique of appealing simplicity. The results obtained with this procedure in 23 other patients are presented.