New PBPK model applied to old occupational exposure to benzene

An intensive program of benzene monitoring using new techniques was undertaken in Western Europe in the late 1960s and early 1970s. Significant exposure was found in the transport of benzene and gasoline, particularly during the loading of barges, and during the loading and operation of sea-going vessels. The ceiling threshold limit value of 25 ppm recommended at that time generated problems in assessing exposure, so alternative criteria were proposed. During that period some shore-based exposures were reported, and their significance was discussed in several articles. The information gained at that time is reexamined by physiologically based pharmacokinetic (PBPK) modeling and is used to help validate an improved PBPK model, which is described and tested on results from experimental exposure in a companion article. The old field data, comprising five specific studies, confirm the relevance of modeling to assessment of occupational exposure, and demonstrate its value for interpretation of field data, which is seldom as complete, systematic, or accurate as that obtained in experimental work. The model suggests that metabolism of benzene in humans may not be restricted to the liver. Sites and processes of metabolism merit further investigation.     

Effect of dietary alpha-linolenic acid on thrombotic risk factors in vegetarian men

BACKGROUND: Vegetarians have lower platelet and plasma concentrations of n-3 polyunsaturated fatty acids (PUFAs) than do omnivores. We recently showed that male vegetarians have higher platelet aggregability than do omnivores. OBJECTIVE: We investigated whether male vegetarians (n = 17) who consumed an increased amount of dietary alpha-linolenic acid (ALA) showed any changes in their tissue profile of PUFAs, plasma thromboxane concentrations, platelet aggregability, or hemostatic factors. DESIGN: During the study, all subjects maintained their habitual vegetarian diets except that a proportion of dietary fat was replaced with vegetable oils and margarines that were provided. Initially, all subjects consumed a low-ALA diet (containing safflower oil and safflower oil-based margarine) for 14 d; they then consumed either a moderate-ALA diet (containing canola oil and canola oil-based margarine) or a high-ALA diet (containing linseed oil and linseed oil-based margarine) for 28 d. Blood samples were collected at day 0 (baseline), day 14, and day 42. RESULTS: Eicosapentaenoic acid, docosapentaenoic acid, total n-3 PUFAs, and the ratio of n-3 to n-6 PUFAs were significantly increased (P < 0.05), whereas the ratio of arachidonic acid to eicosapentaenoic acid was decreased (P < 0.05), in platelet phospholipids, plasma phospholipids, and triacylglycerols after either the moderate-ALA or high-ALA diet compared with the low-ALA diet. No significant differences were observed in thrombotic risk factors. CONCLUSION: ALA from vegetable oils (canola and linseed) has a beneficial effect on n-3 PUFA concentrations of platelet phospholipids and plasma lipids in vegetarian males.     

Incidents in obstetric anaesthesia and analgesia: an analysis of 5000 AIMS reports.

We aimed to explore the first 5000 incidents reported to the Australian Incident Monitoring Study (AIMS) involving anaesthesia for obstetric patients and found 203 such incidents. Analysis and classification identified seven main incident groups; regional anaesthetic techniques (33%), anaesthetic equipment problems (13%), "wrong drug" errors (10%), other drug-related problems (16%), difficult/failed intubation (9%), problems with the endotracheal tube (9%) and other problems (10%). When compared to the incidents in the main database, obstetric cases were found to be over-represented with respect to accidental dural puncture, post dural puncture headache, failed intubation in emergency situations and the incidence of certain types of "wrong drug" error. The implications of these reports regarding safe practice of obstetric anaesthesia are discussed.     

The association of diet and thrombotic risk factors in healthy male vegetarians and meat-eaters.

OBJECTIVE: The aim of this study was to assess thrombosis tendency in subjects who were habitual meat-eaters compared with those who were habitual vegetarians. DESIGN: Cross-sectional comparison of habitual meat-eaters and habitual vegetarians. SETTING: Free living subjects. SUBJECTS: One hundred and thirty-nine healthy male subjects (vegans n = 18, ovolacto vegetarians n = 43, moderate-meat-eaters n = 60 and high-meat-eaters n = 18) aged 20-55 y who were recruited in Melbourne. OUTCOME MEASURES: Dietary intake was assessed using a semi-quantitative Food Frequency Questionnaire. The parameters of thrombosis were measured by standard methods. RESULTS: Saturated fat and cholesterol intakes were significantly higher and polyunsaturated fat (PUFA) was significantly lower in the meat-eaters compared with vegetarians. In the meat-eaters, the platelet phospholipids AA levels were significantly higher than in the vegetarians, but there was no increase in ex vivo platelet aggregation and plasma 11-dehydro thromboxane B2 levels. Vegetarians, especially the vegans, had a significantly increased mean collagen and ADP stimulated ex vivo whole blood platelet aggregation compared with meat-eaters. The vegan group had a significantly higher mean platelet volume than the other three dietary groups. However, meat-eaters had a significantly higher cluster of cardiovascular risk factors compared with vegetarians, including increased body mass index, waist to hip ratio, plasma total cholesterol (TC), triacylglycerol and LDL-C levels, ratio of TC/HDL-C and LDL-C/HDL-C and plasma factor VII activity. CONCLUSIONS: Consumption of meat is not associated with an increased platelet aggregation compared with vegetarian subjects.     

A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma

We examined the relationship between a functional polymorphism (667C-- >T, ala-->val) of the methylenetetrahydrofolate reductase gene (MTHFR) and the risk of colorectal adenomas in the prospective Nurses' Health Study. Among 257 incident polyp cases and 713 controls, the MTHFR val/val polymorphism [relative risk (RR) = 1.35, 95% confidence interval (CI) 0.84-2.17] was not significantly associated with risk of adenomas. This lack of association was observed for both small (RR = 1.36, 95% CI 0.76-2.45) and large (RR = 1.32, 95% CI 0.66-2.66) adenomas. Furthermore, there was no significant interaction between this polymorphism and consumption of either folate, methionine or alcohol. We also examined the relationship of a newly identified polymorphism (asp919gly) of the methionine synthase gene (MS) with the risk of colorectal adenomas in the same population. The MS gly/gly polymorphism was also not significantly associated with risk of colorectal adenomas (RR = 0.66, 95% CI 0.26-1.70). These results, which need to be confirmed in other studies, suggest that the MTHFR val/val polymorphism, which has been previously inversely associated with risk of colorectal cancer, plays a role only in a late stage (adenoma-- >carcinoma) of colorectal tumorigenesis, and/or may protect against malignant transformation in the subset of benign adenomas, which may progress to malignancy.      

Ten years of glaucoma blindness in Fife 1990-99 and the implications for ophthalmology, optometry and rehabilitation services.

The aim of this study was to determine the characteristics of the patients in Fife who were registered as blind with a main diagnosis of glaucoma between 1990 and 1999. The case notes of 87 people were studied. The average age at registration was 78 years (S.D. = 14). By the time of first referral to hospital, more than half were already aware of visual loss. Forty-five per cent of referrals had no optometry input. Compliance with treatment was poor in at least 26% of patients. Only 44% had glaucoma surgery. There were significant findings with regard to mental health, particularly dementia, which was eventually present in 24%. At least one-third of patients had a hearing impairment. One-third of those registered as blind could have been registered earlier. However, staff from the local provider of rehabilitation and social work services for the blind were shown to have provided prompt and helpful support to 95% of those registered. Consideration should be given to the way in which elderly patients with advanced glaucoma are managed, with awareness of mental health and hearing problems and emphasis on early referral to rehabilitation services.     

Randomized trial of diaspirin cross-linked hemoglobin solution as an alternative to blood transfusion after cardiac surgery. The DCLHb Cardiac Surgery Trial Collaborative Group

BACKGROUND: Risks associated with transfusion of allogeneic blood have prompted development of methods to avoid or reduce blood transfusions. New oxygen-carrying compounds such as diaspirin cross-linked hemoglobin (DCLHb) could enable more patients to avoid allogeneic blood transfusion. METHODS: The efficacy, safety, hemodynamic effects, and plasma persistence of DCLHb were investigated in a randomized, active-control, single-blind, multicenter study in post-cardiac bypass surgery patients. Of 1,956 screened patients, 209 were determined to require a blood transfusion and met the inclusion criteria during the 24-h post-cardiac bypass period. These patients were randomized to receive up to three 250-ml infusions of DCLHb (n = 104) or three units of packed erythrocytes (pRBCs; n = 105). Further transfusions of pRBCs or whole blood were permitted, if indicated. Primary efficacy end points were the avoidance of blood transfusion through hospital discharge or 7 days postsurgery, whichever came first, and a reduction in the number of units of pRBCs transfused during this same time period. Various laboratory, physiologic, and hemodynamic parameters were monitored to define the safety and pharmacologic effect of DCLHb in this patient population. RESULTS: During the period from the end of cardiopulmonary bypass surgery through postoperative day 7 or hospital discharge, 20 of 104 (19%) DCLHb recipients did not receive a transfusion of pRBCs compared with 100% of control patients (P < 0.05). The overall number of pRBCs administered during the 7-day postoperative period was not significantly different. Mortality was similar between the DCLHb (6 of 104 patients) and the control (8 of 105 patients) groups. Hypertension, jaundice/hyperbilirubinemia, increased serum glutamic oxalo-acetic transaminase, abnormal urine, and hematuria were reported more frequently in the DCLHb group, and there was one case of renal failure in each group. The hemodynamic effects of DCLHb included a consistent and slightly greater increase in systemic and pulmonary vascular resistance with associated increases in systemic and pulmonary arterial pressures compared with pRBC. Cardiac output values decreased more in the DCLHb group patients after the first administration than the control group patients. At 24 h postinfusion, the plasma hemoglobin level was less than one half the maximal level for any amount of DCLHb infused. CONCLUSIONS: Administration of DCLHb allowed a significant number (19%) of cardiac surgery patients to avoid exposure to erythrocytes postoperatively.