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.

The expression of myosin heavy chain isoforms in normal and hypertrophied chicken slow muscle.

Hypertrophy was produced in the anterior latissimus dorsi (ALD) muscle of 5-wk-old chickens by application of a load to the humerus. After 4 wk, hypertrophied ALD muscles were greater than 2.5 times heavier than contralateral control ALD muscles. Two isomyosins are distinguishable in normal ALD muscles by their different electrophoretic mobilities. It is shown here that the faster migrating SM-1 isomyosin decreases in abundance with age and that the application of an overload enhances both the rate and extent of this process. Monoclonal antibodies were selected by an immunotransfer technique that were specific for the heavy chains associated with either SM-1 or SM-2, or cross-reacted with both isoforms. The cellular distribution of the SM-1 and SM-2 isomyosins was analyzed by immunofluorescent technique using these antibodies. Anti-SM-1 and anti-SM-2 antibodies reacted with separate populations of cells, whereas the third antibody reacted with all myocytes in the normal ALD muscle. These data suggest that there is an exclusive cellular distribution of myosin heavy chains associated with SM-1 and SM-2 proteins. Immunofluorescent analysis of hypertrophied muscle showed the anti-SM-2-specific antibody reacting with all myocytes, whereas the anti-SM-1-specific antibody reacted with none. This is consistent with the elimination of the SM-1 isoform in hypertrophied muscles.

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%).

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.

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.

Mitochondrial gene expression is impaired by ethanol exposure in cultured chick cardiac myocytes.

OBJECTIVE: A depression in cytochrome c oxidase (COX) activity occurs following chronic embryonic ethanol exposure in vivo. The aim of this study was to examine the effect of chronic ethanol exposure on COX activity in isolated cardiac cells maintained in vitro. Additionally, the mechanism by which ethanol produces an impairment in COX activity was evaluated by examining mitochondrial gene expression. METHODS: Spontaneously beating cardiac myocyte cultures were established from 10-day embryonic chick hearts. Various concentrations of ethanol (0-250 mM) were introduced at the time of plating and cells were harvested over 7 days. COX activity was determined in myocyte homogenates. The levels of nuclear-encoded (COXIV) and mitochondrial-encoded (COXII) subunit proteins were measured by Western blotting. Relative levels of mitochondrial DNA and the mitochondrially-encoded COXIII mRNA were determined by Southern and Northern blotting. RESULTS: A consistent decrease in COX activity in ethanol-exposed cardiac myocytes of approximately 30% was observed with an ethanol concentration of 25 mM. Increasing the ethanol concentration to 250 mM produced only a minor enhancement of this effect, while severely decreasing cellular viability. The content of the mitochondrially-encoded COXII subunit was reduced by ethanol exposure, while that of the nuclear-encoded COXIV subunit was unchanged. The content of the mitochondrially-encoded COXIII mRNA was unchanged by ethanol exposure. However, prolonged ethanol exposure produced an increase in mitochondrial DNA levels in cardiac myocytes. CONCLUSIONS: Ethanol exposure of cardiac myocytes produces deficits in COX activity in the absence of systemic variables, indicating that ethanol has a direct effect on cardiac mitochondria. The ethanol-induced decrease in COX activity is correlated with a specific decrease in at least one mitochondrially-encoded gene product, COXII. No changes were observed in the level of the nuclear-encoded COXIV subunit, indicating that expression of this nuclear-encoded gene is not impaired by ethanol exposure.

Peritoneal access and related complications in continuous ambulatory peritoneal dialysis.

Over a four-year period, 50 patients underwent continuous ambulatory peritoneal dialysis. After 24 months, 48 percent of the patients continued to receive continuous ambulatory peritoneal dialysis treatment (including those who underwent continuous ambulatory peritoneal dialysis with bottled solutions from 1977 to 1978). Using solutions in plastic bags, 63 percent of patients continued to undergo continuous ambulatory peritoneal dialysis after 24 months. The mortality rate at 24 months was 23 percent overall and 15 percent for those using plastic bags. There was an overall average of 2.4 episodes of peritonitis a year per patient and 1.3 episodes a year per patient from 1979 through 1980, when only the technique with plastic bags was used. The number of days a patient was hospitalized averaged 48 per year, and 37 days per year in 1979 and 1980. Fifty-five percent of catheters remained functional at 24 months. Other complications included 15 hernias, 15 skin and tunnel infections, 12 leaks, and five cuff extrusions. Improved catheters and further reductions in the incidence of peritonitis will most likely result in a decreased number of patients who withdraw from continuous ambulatory peritoneal dialysis therapy.

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.

Control of myosin heavy chain expression in cardiac hypertrophy.

The control of myosin expression by thyroid hormone is analyzed as an example of compensatory mechanisms of the heart. Two topics are discussed in detail: polymorphism of cardiac myosin heavy chains in the mammalian heart, and effect of thyroid hormone on myosin heavy chain expression by thyroid hormone. Our current knowledge about the identity of heavy chains and their corresponding isomyosins myosins is summarized and the dynamic nature of the myosin phenotype of the heart is discussed. The data on the thyroid hormone's role include studies in which the synthesis rate of the 2 classes of heavy chains (alpha and beta) was compared with their respective messenger RNA levels. A close correlation was observed and is consistent with pretranslational control. Transcription of myosin heavy chain genes was examined using isolated nuclei in a run-off experiment The rate of gene transcription was found to be the principal determinant of the cytoplasmic level of messenger RNA and of the isomyosin composition of the heart.

Long-term compressive property durability of carbon fibre-reinforced polyetheretherketone composite in physiological saline.

In total hip arthroplasty, concerns such as corrosion and stress shielding associated with stiff metallic femoral components have led to the development of low stiffness advanced fibre-reinforced polymer (FRP) composite femoral components. Carbon fibre-reinforced polyetheretherketone (CF/PEEK) composite material is now one of the primary material systems being considered for composite hip stem development. As a hip stem, a composite material must be able to support a complex state of stress in the in vivo environment without failure. Considering the loading conditions of a hip stem (superimposed compression and bending), and the fact that FRP composites typically possess lower compressive than tensile strength, the compressive behaviour of FRP composites becomes very important for femoral component design. This paper presents an investigation of the long-term durability of 0 degree and 90 degrees compressive strengths of CF/PEEK composite following physiological saline saturation. 0 degree and 90 degrees compressive moduli and Poisson ratio (v12) properties are also reported. Samples were tested following conditioning in physiological saline at 37, 65 and 95 degrees C for time periods from 0 to 5000 h. Dry samples were tested as controls. Results show no significant loss in compressive property values of the saline-saturated or the dry control samples as a function of conditioning time or temperature.

Developmentally regulated expression of cytochrome-c oxidase isoforms in regenerating rat skeletal muscle.

The developmental expression of tissue-specific isoforms of cytochrome-c oxidase (COX) subunit VIII [heart (COX VIII-H) and liver (COX VIII-L)] and the influence of innervation were examined in regenerating fast [extensor digitorum longus (EDL)] and slow (soleus) muscles. In adult muscles, COX VIII-H was the predominant isoform. The COX VIII-L mRNA was expressed 3 days after induction of regeneration, and it progressively decreased after 7, 10, 14, and 30 days of regeneration in both muscles. In contrast, the expression of COX VIII-H mRNA accumulated as myogenesis proceeded to the myotube stage between 7 and 10 days of regeneration and progressively increased to near control levels by 30 days. The influence of innervation on the expression of COX VIII and alpha-actin isoforms was examined in control, innervated, and denervated regenerating muscles at 3 and 10 days. The relative expression of COX VIII-L mRNA in denervated regenerating EDL muscles was significantly greater, while that of COX VIII-H was significantly less than in innervated regenerating EDL muscles after 10 days of regeneration. Similarly, cardiac alpha-actin mRNA levels were elevated in denervated regenerating EDL muscles after 10 days of regeneration. In conclusion, motor innervation influences the transition from the COX VIII-L to COX VIII-H isoform during myogenesis in regenerating muscles.

Skeletal muscle mitochondria from AZT-treated rats have a diminished response to chronic electrical stimulation.

Inhibition of DNA polymerase gamma-function mediated by 3'-azido-3'-deoxythymidine (AZT) has been proposed to cause a myopathy by reducing mitochondrial DNA (mtDNA) replication. Repeated bouts of exercise stimulate an increase in mtDNA replication, mitochondrial content, and mitochondrial volume fraction. Therefore, adaptation of rat skeletal muscle [tibialis anterior (TA)] mitochondria exposed to AZT (1 mg/ml for 35 days) and then to electrical stimulation for 8 h/day (7, 14, 21 days) with continued AZT treatment was examined. Fourteen and 21 days of stimulation increased TA cytochrome oxidase (CO) activity, mtDNA, and CO subunit III and VIc mRNA levels in both groups. The TA CO activity and CO III mRNA increases after 14 and 21 days of stimulation were diminished in AZT-treated rats. TA glyceraldehyde-3-phosphate dehydrogenase was reduced in normal rats after chronic stimulation but was unchanged in AZT-treated rats. Chronic stimulation increased the mitochondrial volume fraction by 80 and 40% in normal and AZT-treated rats, respectively. These results indicate diminution, but not complete inhibition, of mitochondrial adaptation by AZT-treated skeletal muscle in response to stimulation.

Ventricular myosin expression in developing and regenerating muscle, cultured myotubes, and nascent myofibers of overloaded muscle in the chicken.

In embryonic chicken skeletal muscle, the presence of a ventricular myosin heavy chain (MHC) is demonstrated by reactivity with an anti-ventricular MHC antibody. Developmental repression of the ventricular MHC expression occurs earlier in embryonic fast twitch posterior latissimus dorsi (PLD) than in embryonic slow-tonic anterior latissimus dorsi (ALD) muscles. Ventricular MHC expression also occurs in developing myotube cultures and in regenerating ALD muscles. Following the application of a weight overload, a population of nascent myofibers emerges in ALD but not PLD muscles which express a ventricular MHC. Localization of cells reactive with anti-ventricular and anti-fast MHC antibodies suggests that satellite cells participate in nascent myofiber formation. In addition, some mature ALD muscle fibers demonstrate reactivity with these antibodies, suggesting that satellite cell fusion with mature myofibers also occurs in overloaded ALD muscles and results in the reinitiation of the embryonic phenotype in hypertrophying fibers. The presence of cells reacting exclusively with the anti-fast antibody after removal of the overload for 9 wk indicates that nascent myofiber formation results in the establishment of a new myofiber population with an abnormal phenotype in overloaded ALD muscles. These cells form a lattice-like network around normal fascicles.

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.

Symbolic forms can be mnemonics for recall.

Form symbolism using squares and circles can aid recall. In Experiment 1, subjects saw 20 words, each presented in a circle or a square. Words like SOFT and MOTHER were presented in circles in the "congruent" condition, whereas the same words were presented in squares in the "incongruent" condition. Two experiments revealed that words in the congruent condition were more likely to be recalled. A comparison of the conditions with a baseline condition, in which 20 listed words were not closely related to either of the shapes, suggests that the effect was more likely due to facilitation produced by the congruent condition than to inhibition from the incongruent condition.

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.

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.

Specification and initial evaluation of a multiple application teleradiology system.

The digitization and transmission of medical images is becoming increasingly more important and available. The selection of appropriate clinical applications for teleradiology systems is an important factor in determining the success of such ventures. In this paper, the selection of such applications and the evaluation of the teleradiology system is described. The system (LIAISON, CAPTEC Ltd, Malahide, Ireland) is PC based and is capable of digitization and transmission of three categories of medical images: (1) plain film radiographs; (2) CT film data and (3) video sequences such as ultrasound scans. A comprehensive technical evaluation was carried out on the acquisition and display station in which various parameters such as spatial resolution, signal-to-noise ratio (SNR), and distortion were investigated. Results showed that the system performed well within specifications. An exploratory clinical evaluation was performed using a case mix of subtle fractures, chests and dislocations, and CT scans. Here the system performed well with a diagnostic accuracy of 95% for the digital image compared with the analogue image.

Glutaraldehyde-cross-linked meniscal allografts: mechanical properties.

Removal of a severely damaged medial meniscus has been shown to lead to degradation of the articular cartilage and formation of degenerative arthritis. To counter this degenerative effect, meniscal prostheses, including glutaraldehyde-cross-linked allografts, have been evaluated in dogs. The purpose of this research was to quantify the mechanical properties of both fresh and glutaraldehyde-cross-linked canine medial menisci. Mechanical properties quantified were tensile strength, tensile modulus, and compressive stiffness. In addition, water content of compressive test samples was measured. Analysis of variance showed significantly lower tensile strength and tensile modulus and significantly higher compressive stiffness for the glutaraldehyde-cross-linked menisci, as compared to fresh specimens. Measurement of the weight percentage of water in fresh and cross-linked samples revealed no significant differences in water content. When implanted into a joint, the increased compressive stiffness could increase the peripheral tensile load. Due to the decreased tensile strength in this region, the prosthetic meniscus could be susceptible to peripheral tears.