Visual search and urban driving under the influence of marijuana and alcohol

The purpose of the present study was to assess the effects of low doses of marijuana and alcohol, and their combination, on visual search at intersections and on general driving proficiency in the City Driving Test. Sixteen recreational users of alcohol and marijuana (eight males and eight females) were treated with these substances or placebo according to a balanced, 4-way, cross-over, observer- and subject-blind design. On separate evenings, subjects received weight-calibrated doses of THC, alcohol or placebo in each of the following treatment conditions: alcohol placebo + THC placebo, alcohol + THC placebo, THC 100 &mgr;g/kg + alcohol placebo, THC 100 &mgr;g/kg + alcohol. Alcohol doses administered were sufficient for achieving a blood alcohol concentration (BAC) of about 0.05 g/dl. Initial drinking preceded smoking by one hour. The City Driving Test commenced 15 minutes after smoking and lasted 45 minutes. The test was conducted over a fixed route within the city limits of Maastricht. An eye movement recording system was mounted on each subject's head for providing relative frequency measures of appropriate visual search at intersections. General driving quality was rated by a licensed driving instructor on a shortened version of the Royal Dutch Tourist Association's Driving Proficiency Test. After placebo treatment subjects searched for traffic approaching from side streets on the right in 84% of all cases. Visual search frequency in these subjects did not change when they were treated with alcohol or marijuana alone. However, when treated with the combination of alcohol and marijuana, the frequency of visual search dropped by 3%. Performance as rated on the Driving Proficiency Scale did not differ between treatments. It was concluded that the effects of low doses of THC (100 &mgr;g/kg) and alcohol (BAC < 0.05 g/dl) on higher-level driving skills as measured in the present study are minimal. Copyright 2001 John Wiley & Sons, Ltd.     

Overexpression of arginase alters circulating and tissue amino acids and guanidino compounds and affects neuromotor behavior in mice

Arginine is an intermediate of the ornithine cycle and serves as a precursor for the synthesis of nitric oxide, creatine, agmatine and proteins. It is considered to be a conditionally essential amino acid because endogenous synthesis only barely meets daily requirements. In rapidly growing suckling neonates, endogenous arginine biosynthesis is crucial to compensate for the insufficient supply of arginine via the milk. Evidence is accumulating that the intestine rather than the kidney plays a major role in arginine synthesis in this period. Accordingly, ectopic expression of hepatic arginase in murine enterocytes by genetic modification induces a selective arginine deficiency. The ensuing phenotype, whose severity correlates with the level of transgene expression in the enterocytes, could be reversed with arginine supplementation. We analyzed the effect of arginine deficiency on guanidine metabolism and neuromotor behavior. Arginine-deficient transgenic mice continued to suffer from an arginine deficiency after the arginine biosynthetic enzymes had disappeared from the enterocytes. Postweaning catch-up growth in arginine-deficient mice was characterized by increased levels of all measured amino acids except arginine. Furthermore, plasma total amino acid concentration, including arginine, was significantly lower in adult male than in adult female transgenic mice. Decreases in the concentration of plasma and tissue arginine led to significant decreases in most metabolites of arginine. However, the accumulation of the toxic guanidino compounds, guanidinosuccinic acid and methylguanidine, corresponded inversely with circulating arginine concentration, possibly reflecting a higher oxidative stress under hypoargininemic conditions. In addition, hypoargininemia was associated with disturbed neuromotor behavior, although brain levels of toxic guanidino compounds and ammonia were normal.     

Risk sharing as a supplement to imperfect capitation: a tradeoff between selection and efficiency

This paper describes forms of risk sharing between insurers and the regulator in a competitive individual health insurance market with imperfectly risk-adjusted capitation payments. Risk sharing implies a reduction of an insurer's incentives for selection as well as for efficiency. In a theoretical analysis, we show how the optimal extent of risk sharing may depend on the weights the regulator assigns to these effects. Some countries employ outlier or proportional risk sharing as a supplement to demographic capitation payments. Our empirical results strongly suggest that other forms of risk sharing yield better tradeoffs between selection and efficiency.     

An nconventional view of dacryocystorhinostomy

Twenty-one dacryocystorhinostomy operations were assessed by nasendoscopy. In fourteen of the 15 successful operations pre-operative radiography had demonstrated a low obstruction in the lacrimal passages. Postoperatively the nasal ostia in this group showed great morphological diversity. In five of the 6 operations which were not clinically successful a high obstruction in the lacrimal passages had been demonstrated pre-operatively. In all cases in this group the nasal ostia were closed. In these 5 cases with an obstruction in the canaliculus communis, minimal or absent flow of tears through the dacryocystorhinostomy may be assumed. The surgical technique was the same in all 21 cases. The high canalicular problem seems to be responsible for the failure of these 5 operations. A notable feature was that nasendoscopy revealed a closed nasal ostium. This suggests that sufficient tearflow through the dacryocystorhinostomy is necessary to keep this open. To what extent the individual variation in tearflow and patency of the canalicular system is responsible for the morphological variation in the nasal ostium, as observed in the clinically successful group, is not yet clear.     

On the possible role of long chain fatty acylcarnitine accumulation in producing functional and calcium permeability changes in membranes during myocardial ischaemia

A radioisotope procedure was used to determine long chain fatty acylcarnitine concentrations in fractions of porcine myocardium that had been subjected to different periods of ischaemia (0, 1, 2, and 3 h). In myocardial tissue from non-ligated hearts acylcarnitine concentrations were 0.32(0.03) and 1.53(0.04) nmol.mg-1 protein for homogenate and sarcolemma enriched membrane respectively, which indicates a preferential membrane localisation of long chain fatty acylcarnitine. Both the total and membrane acylcarnitine contents were increased about twofold after 2 h of ischaemia. The accumulation of long chain fatty acylcarnitine was not correlated temporally with changes in adenosine triphosphate dependent calcium uptake activity of homogenates (mainly a function of sarcoplasmic reticulum membranes), sodium gradient induced calcium uptake, and calcium permeability of sarcolemma preparations. Homogenate adenosine triphosphate dependent calcium uptake was decreased by 36% after 3 h of ischaemia. Sodium gradient induced calcium uptake was enhanced about twofold after 1 h of ischaemia, and calcium permeability of sarcolemmal vesicles was decreased by 20% after 3 h of ischaemia. After in vitro incubation of isolated sarcolemma membranes with (1-14C)-palmitoylcarnitine radiolabelled molecules that remained associated with the membrane even after repeated washing were incorporated. No changes were observed in the sodium gradient induced calcium uptake when less than 6 nmol (1(-14)C)- palmitoylcarnitine per mg sarcolemma protein were bound or incorporated into the lipid phase. This exceeded the maximal endogenous concentrations of 3.2(0.6) nmol long chain fatty acylcarnitine per mg sarcolemma protein observed during myocardial ischaemia. The results suggest that the intracellular increase in long chain acylcarnitine during almost zero myocardial flow is not critical to sarcolemmal sodium and calcium permeability and sarcoplasmic reticulum calcium pumping activity.     

Reversible gall bladder dysfunction in severe pancreatic insufficiency.

The present study was undertaken to examine the intestinal phase of cholecystokinin (CCK) secretion and gall bladder contraction in patients with severe pancreatic insufficiency. Plasma CCK concentrations, measured by radioimmunoassay, and gall bladder contraction by cholescintigraphy were studied in response to intraduodenal fat with and without addition of pancreatic enzymes. Fasting plasma CCK concentrations were in the same range in six patients with pancreatic insufficiency with (2.6 (0.2) pmol/l) and without (2.6 (0.3) pmol/l) addition of pancreatic enzymes and in six healthy subjects (2.0 (0.4) pmol/l). The integrated plasma CCK secretion in response to intraduodenal fat was significantly (p less than 0.005) reduced in the patients without addition of enzymes (46 (13) pmol/1.90 min) compared with healthy subjects (199 (22) pmol/1.90 min), but increased significantly (p less than 0.01) by the addition of pancreatic enzymes (174 (25) pmol/1.90 min) to values not significantly different from healthy subjects. Similarly, gall bladder emptying in response to intraduodenal fat was significantly (p less than 0.01) reduced in patients with pancreatic insufficiency without addition of enzymes (at 90 min: 35 (11)%) compared with healthy subjects (at 90 min: 66 (7)%) but significantly (p less than 0.01) increased by addition of pancreatic enzymes (at 90 min: 70 (8)%) to values not significantly different from healthy subjects. These results indicate that patients with severe pancreatic insufficiency have impaired gall bladder emptying after intraduodenal fat, which can be normalised by the addition of pancreatic enzymes. This impaired gall bladder emptying appears to be the result of a reduced plasma CCK response. Thus, intra-intestinal pancreatic enzymes play an important role in the intestinal phase of CCK secretion and gall bladder emptying.     

Subcutaneous emphysema of the lower extremity of abdominal origin

Three cases of subcutaneous emphysema of the lower extremity due to abdominal disease are reported. These were due to (a) perforation of the sigmoid, (b) perirectal abscess, and (c) non-traumatic metastatic gas gangrene due to emphysematous cholecystitis. The mechanisms and anatomical pathways are discussed.     

Effects of an antifibrin monoclonal antibody and fragments thereof on some properties of fibrin

Antifibrin monoclonal antibody Y22, of IgG1-subclass, has its epitope in the D-domain of fibrin. In a thrombin time assay, Y22 and its F(ab)2 fragments interfere with clotting of citrated plasma. Transmission and scanning electronmicroscopic studies show that clotting of citrated blood or plasma in the presence of Y22 results in formation of thin, short fibrin fibres. The (smaller) Fab fragments of Y22 did not have an anti-clotting effect. This suggests that the anticoagulant effect of Y22 is due to steric hindrance of the association of fibrin monomers. A control antibody and its F(ab)2 and Fab fragments have no effect on fibrin formation. In a parabolic rate assay, Y22 Fab fragments interfered strongly with the fibrin-induced enhancement of the t-PA-catalyzed plasminogen activation, whereas intact Y22 and a control antibody did not. In contrast with their effects on the fibrin assembly, the effects of Y22, Y22-F(ab)2 and Y22-Fab on the capacity of fibrin to act as a rate-enhancer in the plasminogen activation by t-PA appears to decrease with the size of the immunoreactive entity. As is discussed, this may be due to the differential accessibility of sites involved in stimulation and polymerization which are located in the fibrin D-domain.     

The effect of nifedipine on ischemia-induced changes in the biochemical properties of isolated sarcolemmal vesicles and the ultrastructure of myocardium

To investigate whether slow Ca2+ channel blockers protect against development of changes in properties of the sarcolemma and in the tissue ultrastructure during myocardial ischemia, nifedipine was administered prior to occlusion (up to 3 hours) of the left anterior descending coronary artery in anesthetized pigs. Intravenous doses which reduced arterial blood pressure by 20-25%, had no effect on the time-dependent reduction of Ca2+-calmodulin and cyclic AMP-dependent 32P incorporation into sarcolemmal phospholamban-like protein. Nifedipine blocked the reduction in the activity of sarcolemmal 5'-nucleotidase. Nifedipine had no significant effect on the long-chain fatty acylcarnitine accumulation in sarcolemma. A marked delay in the appearance of ultrastructural indicators of irreversible tissue injury in subepicardial myocardium was observed, when nifedipine was infused. Particularly the reduced appearance of electron-dense bodies in mitochondria suggested a reducing effect of nifedipine on cellular net gain of Ca2+. Apparently, ischemia-induced loss of the ability of the proteinkinases to incorporate phosphate into sarcolemmal phospholamban-like protein is not a process secondary to Ca2+ overload of the myocardium. The involvement of accumulation of long-chain fatty acylcarnitine within the sarcolemma may also be excluded. The membrane defect as indicated by a change in phosphorylation-mediated control of Ca2+ transport may itself be associated with the development of ischemia (-reperfusion)-induced Ca2+ overload.