Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice.

In humans, cerebral malaria is a rare but often lethal complication of infection with Plasmodium parasites, the occurrence of which is influenced by complex genetic factors of the host. We used a mouse model of experimental cerebral malaria (ECM) with Plasmodium berghei ANKA to study genetic factors regulating appearance of neurological symptoms and associated lethality. In a genome-wide screen of N-ethyl-N-nitrosourea-mutagenized mice derived from C57BL/6J (B6) and 129S1/SvImJ (129) mouse strains, we detected a strong interaction between the genetic backgrounds of these strains, which modulates ECM resistance. We have mapped a major gene locus to central chromosome 4 (log of the odds (LOD) 6.7; 79.6-97.3 Mb), which we designate Berr8. [corrected]. B6 alleles at Berr6 are associated with resistance, and are inherited in a co-dominant fashion. In mice heterozygous for Berr6 B6/129 alleles, resistance to ECM is strongly modulated by a second locus, Berr7, that maps to the proximal portion of chromosome 1 (LOD 4.03; 41.4 Mb). 129 alleles at Berr7 are associated with ECM resistance in a dosage-dependent fashion. Results are discussed in view of the possible role of this two-locus system in susceptibility to unrelated inflammatory conditions in mice and humans.

Drug absorption from the small intestine in immediate postoperative patients.

BACKGROUND: The effects of surgery on gastric emptying have been documented for a considerable time, but less is known about the effects in the small intestine. It is thought that there is minimal diminution in the absorptive capacity of the small intestine after operation, although there is no literature on drug absorption in the early period after surgery. This study investigated drug absorption from the small bowel in patients undergoing abdominal surgery. METHODS: A prospective study of patients undergoing major abdominal surgery in which patients acted as their own preoperative controls was carried out. Patients were administered the test substances, acetaminophen and (99m)TcDTPA, before operation and 2 days after operation. Small intestine transit times, plasma concentrations and other pharmacokinetic variables were compared using Student's paired t-test. Two complementary studies were carried out to establish pharmacokinetic parameters. RESULTS: There were no significant differences in the pre- and postoperative values of t(max), area under the curve, and area under the moment curve (AUMC) before and after operation (P>0.05). There were significant differences between the pre- and postoperative values of C(max) [C(max (preop))>C(max (postop)); P<0.05] and the pre- and postoperative values of mean residence time (MRT) [MRT((preop))

Comparative efficacy and pharmacokinetics of racemic bupivacaine and S-bupivacaine in third molar surgery.

PURPOSE: To compare the efficacy and pharmacokinetics of racemic bupivacaine (rac-bupivacaine) with S-bupivacaine as primary local anesthetic agent in bilateral impacted third molar extractions. METHOD: A randomised, double blind, two period cross-over design was employed. Six subjects (2 males, 4 females; age 19-25 years; weight 69.2+/-9.4 kg) received bupivacaine hydrochloride injection (6.6 ml) as rac-bupivacaine (0.5% as salt) or S-bupivacaine (0.5% as base) prior to extraction of impacted third molars on one side and three weeks later on the other side. Anesthesia, blood loss associated with surgery and post-operative pain experience were evaluated. Plasma samples were analysed for bupivacaine enantiomers by chiral HPLC. RESULTS: In 7/12 operations, anesthesia adequate for surgery was delayed (>10 min) or unsatisfactory requiring lidocaine rescue medication. Despite this, there were no significant differences in onset and duration of anesthesia, blood loss or post-operative pain experience between the two arms of the study. Pharmacokinetic parameters were not significantly different and there was no evidence of chiral inversion after dosing with S-bupivacaine. CONCLUSIONS: Both study drugs were inadequate as single anesthetic agent for third molar surgery. Any decision to use S-bupivacaine for oral surgery must rest on evidence that it is less toxic than the racemic drug.

Screening patients with chest pain in the emergency department using electron beam tomography: a follow-up study.

OBJECTIVES: The high sensitivity of electron beam tomography (EBT) in the detection of coronary artery calcium (CAC) and obstructive coronary artery disease prompted us to investigate the association between CAC detection and future cardiac events in patients with acute chest pain syndromes requiring hospitalization. BACKGROUND: Three studies have documented that EBT is a rapid and efficient screening tool for patients admitted to the emergency department (ED) with chest pain, but there is a paucity of long-term follow-up data on these chest pain patients. METHODS: We conducted a prospective observational study of 192 patients admitted to the ED of a large tertiary care hospital for chest pain syndromes. Upon admission, patients underwent EBT scanning in addition to the usual care for chest pain syndromes. During the 17-month enrollment period, 221 patients were scanned (54% men with a mean age of 53 +/- 9 years). Average follow-up was 50 +/- 10 months using chart review. RESULTS: Fifty-eight patients had coronary events confirmed by a blinded medical record review. The presence of CAC (a total calcium score >0) and increasing score quartiles were strongly related to the occurrence of hard cardiac events including myocardial infarction and death (p < 0.001) and all cardiovascular events (p < 0.001). Stratification by age- and gender-matching further increased the prognostic ability of EBT (for scores above vs. below the age- and gender-matched CAC scores; odds ratio: 13.1, 95% confidence intervals: 5.62, 35.9). CONCLUSIONS: These data support previous reports demonstrating that the presence of CAC in a symptomatic cohort is a strong predictor of future cardiac events. This study supports the use of EBT in a symptomatic cohort with prompt discharge of those patients with negative scans. Furthermore, the absence of CAC is associated with a very low risk of future cardiac risk events in this population over the subsequent seven years (annual event rate <1%).

The regenerative deficit of peripheral nerves in experimental diabetes: its extent, timing and possible mechanisms.

Diabetes mellitus is reported to impair peripheral nerve regeneration, but the extent, timing and selectivity of the deficit is unclear. We studied regeneration of motor and sensory fibres in mice with experimental diabetes induced using streptozotocin (STZ). The mouse model featured several advantages over its counterpart in rats given STZ, while exhibiting the expected slowing of motor conduction velocity. Serial studies addressed fibre regrowth for up to 10 weeks after both sciatic nerve crush injury and complete sciatic nerve transection. Following nerve crush, there was a delay in motor fibre reinnervation of tibial innervated interosseous muscles of diabetics, manifest as a slow recovery of the M-wave recorded from these muscles. Despite an apparent recovery in M-waves by 6 weeks, this was not accounted for by restitution of tibial axon numbers in diabetic mice. Histological studies distal to crush or transection identified substantial delays in the regrowth of the numbers and calibre of regenerating myelinated fibres in diabetics for up to 8-10 weeks. Moreover, this delay was observed in both the tibial (largely motor) and sural (non-motor) distal sciatic branches. There was an associated delay in macrophage invasion and their later resorption in the diabetic nerves, indicating that a potential mechanism of impaired regeneration might be abnormal macrophage participation in nerve repair. Our findings indicate that during nerve regeneration, diabetic motor and sensory fibres have substantial and persistent deficits in regrowth associated with abnormalities in macrophage participation.

Cavanagh and Leclerc shape-from-shadow pictures: do line versions fail because of the polarity of the regions or the contour?

Shape-from-shadow perception fails when the contour bordering a shadowed area is reduced to a black line, and the shadow area becomes white. It might be that the polarity of the shadowed and illuminated areas has to be from dark on the shadowed side to light on the illuminated side for successful perception. Or it may be that the line, which has two contours, has one too many for shape-from-shadow processing. Alternatively, the problem might be that one of the contours of the line is incorrectly polarised. To test these explanations, three shape-from-shadow figures were prepared, each depicting the same referent--an elderly person. All three figures had two correctly polarised areas. One figure had a correctly polarised contour at the border between the areas. One had two correctly polarised contours. The other had one correctly polarised contour and one incorrectly polarised contour. The referent of the figure with one incorrectly polarised contour was the one difficult to make out. The result has implications for several theories, including an account of a demonstration by Hering involving penumbra.

Are metaphors elliptical similes?

What is the relation between metaphors and similes? Aristotle's "comparison theory" holds that metaphors are elliptical similes: "Sam is a pig" is simply a short form of "Sam is like a pig." In contrast, it has been suggested that metaphors cannot be elliptical similes because metaphors are "stronger" than similes. We know metaphors are stronger, it is argued, because of examples involving corrections, such as "Peter is not just like a rock, he is a rock." The argument from corrections can be challenged on logical and empirical grounds. The ability to correct a simile with a metaphor does not entail that metaphors are stronger than similes when used on their own, which is likely to be the most frequent case. Although four experiments indicate that when corrections are involved, metaphors are indeed stronger than similes in several respects, alas a further four experiments indicate that these differences are largely eliminated when metaphors and similes are used on their own. We note that this pattern of results is consistent with the comparison theory, and we offer an explanation of the effects of corrections.

Exercise testing and electron beam computed tomography in the evaluation of coronary artery disease.

OBJECTIVES: This study compared coronary artery calcium (CC) as detected by electron beam computed tomography (EBCT) with conventional stress testing in the evaluation of patients with symptoms suggestive of coronary artery disease (CAD). BACKGROUND: Exercise electrocardiogram treadmill stress testing (treadmill-ECG) is limited by its requirement of a normal resting ECG and the ability of the patient to exercise adequately. The addition of myocardial imaging agents such as technetium improves the sensitivity and specificity but substantially increases the cost and prolongs the testing time. The use of EBCT provides a noninvasive and rapid method for identifying the presence and amount of CC, which has been shown to be related to atherosclerosis, and may provide additional information in combination with more traditional noninvasive testing methods. METHODS: A total of 97 patients underwent technetium stress testing (technetium-stress), treadmill-ECG, and EBCT coronary scanning within three months of coronary angiography for the evaluation of chest pain. RESULTS: The relative risk (RR) of obstructive angiographic CAD for an abnormal test was higher for EBCT (4.53) than either treadmill-ECG (1.72) or technetium-stress (1.96). The low specificity of EBCT (47%) was improved by the addition of treadmill-ECG (83%, p < 0.05). CONCLUSIONS: Electron beam computed tomography has a higher diagnostic ability than either treadmill-ECG or technetium-stress for the detection of obstructive angiographic CAD. Electron beam computed tomography is an accurate and noninvasive alternative to traditional stress testing for the detection of obstructive CAD in symptomatic patients.

Polypharmacy in a general surgical unit and consequences of drug withdrawal.

AIMS: To identify drug usage/withdrawal in surgical patients and the relative risk this imposes on postoperative surgical complications. METHODS: A prospective survey of patients' medicines, oral intake (food/fluids/ medicines) and postoperative complications was carried out in the General Surgical Unit, Dunedin Hospital, Dunedin, New Zealand. RESULTS: One thousand and twenty-five general surgical patients aged >/= 16 years, were entered into the study. Half of the patients were taking medicines unrelated to surgery. On average these patients received 9 different drugs (range 1-47) from a selection of 251, of which 21% were released in the last 10 years. The mean number of these drugs taken increased with age, vascular surgery and other major procedures. The majority of patients (53%) were taking drugs for cardiovascular problems. Only 8% of admissions were on the drugs more traditionally recognized to be of importance to the surgery, i.e. steroids and diabetic therapy. With respect to risk, taking a drug unrelated to surgery was associated with an increased relative risk of a postoperative complication by 2.7 (95% C.I. 1.76-4.04) compared with those who were not taking any drug. Cardiovascular drugs contributed significantly to this risk; when they were excluded from analysis, the risk dropped to 1.8 (95% C.I. 1.14-2.93). Death may be more common in those taking ACE inhibitors. Drug withdrawal and complications were analysed and as the time without medicines increased (range 1-42 days) so did the complication rate (chi2 = 14.7, DF = 2, P = 0.007). Of those patients who were taking a cardiovascular medicine and were without their normal medicines for a period of time postoperatively, 12% suffered a cardiac complication. CONCLUSIONS: Many patients admitted to a general surgical ward, are taking medicines unrelated to surgery. Drug therapy unrelated to surgery is a useful predictor for increased postoperative complications and one for which preventive action can be taken. This study provides evidence that withdrawal of regular medicines may add significant risk to the surgery and further complicate outcome. The longer patients were without their regular medicines the more nonsurgical complications they suffered. Reintroduction of patients' regular medicines early in their postoperative course may decrease morbidity and mortality in-patients.

Stereoselective glucuronidation of formoterol by human liver microsomes.

AIMS: Formoterol is a beta2-adrenoceptor agonist marketed as a racemic mixture of the active (R; R)- and inactive (S; S)-enantiomers (rac-formoterol). The drug produces prolonged bronchodilation by inhalation but there is significant interpatient variability in duration of effect. Previous work has shown that in humans formoterol is metabolized by conjugation with glucuronic acid but little is known about the stereoselectivity of this reaction. The aim of the present study was to investigate the glucuronidation of formoterol enantiomers in vitro by human liver microsomes. METHODS: The kinetics of formation of formoterol glucuronides during incubation of racemate and of single formoterol enantiomers with human liver microsomes (n=9) was characterized by chiral h.p.l.c. assay. RESULTS: The kinetics of glucuronidation of the two formoterol enantiomers obeyed the Michaelis-Menten equation. Glucuronidation of formoterol was stereoselective and occurred more than two times faster for (S; S)-formoterol than for (R; R)-formoterol. In incubations with single formoterol enantiomers, the median (n=9) Km values for (R; R)-glucuronide and (S; S)-glucuronide were 827.6 and 840.4 microm, respectively, and the median V max values were 2625 and 4304 pmol min-1 mg-1, respectively. Corresponding values determined in incubations with rac-formoterol were 357.2 and 312.1 microm and 1435 and 2086 pmol min-1 mg-1 for (R; R)- and (S; S)-glucuronide, respectively. Interindividual variation was large with the ratio of V max/Km (S; S/R; R) ranging from 0.57 to 6.90 for incubations with rac-formoterol. CONCLUSIONS: Our study demonstrates that glucuronidation of formoterol by human liver microsomes is stereoselective and subject to high interindividual variability. These findings suggest that clearance of formoterol in humans is subject to variable stereoselectivity which could explain the variation in duration of bronchodilation produced by inhaled formoterol in patients with asthma.

Depictions of motion devised by a blind person.

A blind man (E.A.) was asked to draw pictures suggesting wheels in various kinds of motion. Six pictures were drawn by E.A. The pictures were shown to sighted subjects, who were asked to assign labels to the pictures, in a multiple-choice format. The labels were assigned at a rate above chance. We argue that the pictures are metaphoric and that pictorial metaphor relies on common properties of the static picture and the kinetic referent.

Which way is upright and normal? Haptic perception of letters above head level.

In three experiments, the perception of the apparent orientation of block letters shown in various orientations above the subject's head in the horizontal plane was examined. A block letter F with its front facing down toward the observer has two crossbars on its right side; the top is the part with the long crossbar, and the base has no bar. The experiments involved changing the locations of these parts with respect to the observer. In Experiment 1, the subjects using touch most often identified a letter as having its left and right sides in a normal orientation if the front of the block letter faced upwards away from the observer, with the bar on the right and the top of the letter farther from the subject than the letter's base. In Experiment 2, the subjects judging visual uprightness favored positions in which the bars were on the right, the top of the block letter was near them, and the letter's front faced downwards toward the observer. In Experiment 3, the subjects using touch most often assessed letters as being upright if the top of the letter was the farthest part and the bar was on the right. The results suggest that, when assessing orientation, subjects using touch favored positions that would be reached by a letter moving vertically upwards from table height, but subjects relying on vision favored positions reached by a letter moving in an are centered on the subject's head (on the eyes, in particular).

Aptness predicts preference for metaphors or similes, as well as recall bias.

Why might we sometimes prefer a metaphor such as "genes are blueprints" to a simile such as "genes are like blueprints"? One possibility is that metaphors are preferred when the comparison between a tenor (e.g., genes) and a vehicle (e.g., blueprints) seems especially apt. That is, metaphors might be used when the comparison captures many salient features of the tenor in question. The present experiments examined the relation between the aptness of comparisons and people's preferences for expressing those comparisons as metaphors or as similes. In Experiment 1, it was found that there is consensus on how to express particular comparisons. In Experiment 2, it was found that this preference can be predicted from the aptness of a comparison. It was also found that aptness can predict errors in the recall of comparisons. These findings have implications for theories of metaphor.

Heavy long-term ethanol consumption induces an alpha- to beta-myosin heavy chain isoform transition in rat.

Alcoholic heart muscle disease is characterized by structural changes which include chamber dilation, ventricular hypertrophy, and myocyte damage. These effects often lead to contractile dysfunction and ultimately to heart failure if alcohol consumption is not terminated. In rat models for heart failure in which heart failure is induced by pressure or volume overload, there is a shift in the myosin heavy chain (MHC) isoforms, from alpha to beta. As a result of this MHC transition, there is typically a decrease in myosin ATPase activity. We utilized a rat model of chronic alcohol consumption in order to determine if alcohol causes a similar shift in MHC isoforms and changes in myosin ATPase activity. A liquid diet containing 9% ethanol (46% of daily calories; 11.8 g/kg/day) was administered to adult rats for a period of 60 or 90 days. This heavy consumption of ethanol resulted in an average blood ethanol content of 150 mg %. The relative abundance of beta-MHC isoform protein increased from a control level of 9.7% to 35.1% in hearts of ethanol-fed rats, following 90 days of ethanol consumption. In a separate set of experiments, the levels of alpha-MHC and beta-MHC mRNA were demonstrated to increase by 150% and 230%, respectively. Following a 60 day treatment, there was a significant reduction in the actomyosin Mg2+ -ATPase activity in the myofibrillar preparations from hearts of ethanol-fed rats compared to hearts from control-fed rats. In addition, the myosin Ca2+ -ATPase activity was decreased 17% and 30% after 60 and 90 days of ethanol consumption, respectively. The present study demonstrates that chronic ethanol consumption induces an increase in the proportion of the total MHC content composed of the beta-isoform. This isoform transition is accompanied by an accumulation of beta-MHC mRNA, suggesting that the switch is organized pretranslationally. A functional consequence of this transition in MHC phenotype is demonstrated by significant decreases in the myofibrillar and myosin ATPase activities.

Effects of surgery on the pharmacokinetic parameters of drugs.

As with other forms of stress, surgery is a time of fluctuating haemodynamics, physiological shifts, intense metabolic changes, and protein catabolism and anabolism. At times, these changes can occur within hours. There is a reasonable body of literature concerning the adverse effects of surgery on gastric emptying, but not on the effects of surgery on the distribution, metabolism and excretion of drugs. Gastric emptying is diminished or absent following major procedures, which prevent the delivery of orally administered drugs to their major site of absorption, the small bowel. Changes in the paracellular absorption of drugs may occur postoperatively, although transcellular absorption appears to be unimpaired. Distribution is affected by changes in blood volume, alterations in circulation, increases in the extracellular fluid and changes in the circulating plasma protein levels, such as albumin and alpha 1-acid glycoprotein. Little is known about alterations in drug metabolism following surgery. However, it has been shown that systemic hypoxia alters the function of some of the cytochrome P450 (CYP) system and increased levels of cytokines have an effect on the metabolism of at least 1 drug. In addition, the renal elimination of drugs is affected in patients postoperatively, although the effects of biliary clearance in this period are difficult to determine. Despite the lack of research into pharmacokinetics during the postoperative period, and given the immense and often sudden changes observed in patients post-surgery, it is reasonable to recommend vigilance with respect to drug therapy during this period.

Usefulness of electron beam computed tomography scanning for distinguishing ischemic from nonischemic cardiomyopathy.

OBJECTIVES: This study was undertaken to evaluate the ability of electron beam computed tomography (EBCT) to distinguish ischemic from nonischemic causes of cardiomyopathy by evaluating heart failure patients for coronary calcification (CC). BACKGROUND: The etiology of heart failure, whether coronary-induced or nonischemic, may be difficult to discern clinically. Differentiation of ischemic from nonischemic etiology is clinically important for both therapeutic and prognostic implications. With its ability to noninvasively discern and quantitate coronary artery calcification, EBCT correlates well with angiographic stenosis and thus may be useful in distinguishing ischemic and nonischemic cardiomyopathies. METHODS: One hundred and twenty-five patients with cardiomyopathy (ejection fraction <0.40) and known coronary anatomy underwent EBCT coronary scanning to evaluate for CCs within 3 months of coronary angiography. RESULTS: Of the 72 patients who were found to have ischemic cardiomyopathy, 71 patients had CC by EBCT (sensitivity 99%, p < 0.001), mean score 798+/-899. In comparison, among the 53 patients without significant coronary artery disease (CAD) (nonischemic cardiomyopathy), the mean score was significantly lower (17+/-51; p < 0.0001), and 44 patients had a CC score of 0 (no CC present). The specificity of EBCT to exclude CAD in patients with cardiomyopathy was 83%, using a threshold CC score of 0, and 92% for scores <80 (p < 0.001). Overall accuracy for determining the etiology of cardiomyopathy (differentiating ischemic from nonischemic) was 92% for this technique. CONCLUSIONS: This prospective, blinded study indicates that EBCT detected CC accurately and can noninvasively distinguish between cardiomyopathy because of CAD and nonischemic causes of left ventricular dysfunction.