Alterations in Plasmodium falciparum genotypes during sequential infections suggest the presence of strain specific immunity

Many of the asexual stage Plasmodium falciparum proteins that are the targets of host protective responses are markedly polymorphic. The full repertoire of diversity is not defined for any antigen. Most studies have focused on the genes encoding merozoite surface proteins 1 and 2 (MSP1, MSP2). We explored the extent of diversity of some of the less studied merozoite surface antigens and analyzed the degree of complexity of malaria field isolates by deriving nucleotide sequences of several antigens. We have determined the genotype of apical membrane antigen 1 (AMA1) in a group of 30 field samples, collected over 29 months, from individuals living in an area of intense malaria transmission in Irian Jaya, identifying 14 different alleles. AMA1 genotyping was combined with previously determined MSP2 typing. AMA1 had the greatest power in distinguishing between isolates but methodological problems, especially when mixed infections are present, suggest it is not an ideal typing target. MSP1, MSP3, and glutamate-rich protein genotypes were also determined from a smaller group of samples, and all results were combined to derive an extended antigenic haplotype. Within this subset of 10 patients, nine different genotypes could be discerned; however, five patients were all infected with the same strain. This strain was present in individuals from two separate villages and was still present 12 months later. This strain was predominant at the first time point but had disappeared at the fourth time point. This significant change in malaria genotypes could be due to strain-specific immunity developing in this population.

Location of innervation zones of sternocleidomastoid and scalene muscles - a basis for clinical and research electromyography applications

Objectives: Advances in surface electromyography (sEMG) techniques provide a clear indication that refinement of electrode location relative to innervation zones (IZ) is required in order to optimise the accuracy, relevance and repeatability of the sEMG signals. The aim of this study was to identify the IZ for the sternocleidomastoid and anterior scalene muscles to provide guidelines for electrode positioning for future clinical and research applications. Methods: Eleven volunteer subjects participated in this study. Myoelectric signals were detected from the sternal and clavicular heads of the stemocleidomastoid and the anterior scalene muscles bilaterally using a linear array of 8 electrodes during isometric cervical flexion contractions. The signals were reviewed and the IZ(s) were identified, marked on the subjects' skin and measurements were obtained relative to selected anatomical landmarks. Results: The position of the IZ lay consistently around the mid-point or in the superior portion of the muscles studied. Conclusions: Results suggest that electrodes should be positioned over the lower portion of the muscle and not the mid-point, which has been commonly used in previous studies. Recommendations for sensor placement on these muscles should assist investigators and clinicians to ensure improved validity in future sEMG applications. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Responses to a clinical test of mechanical provocation of nerve tissue in whiplash associated disorder

Involvement of nerve tissue may contribute to the persistence of pain following a whiplash injury. This study aimed to investigate responses to the brachial plexus provocation test (BPPT) in 156 subjects with chronic whiplash associated disorder (WAD) with and without associated arm pain and 95 asymptomatic control subjects. The range of elbow extension (ROM) and visual analogue scale (VAS) pain scores were measured. Subjects with chronic WAD demonstrated significantly less ROM and higher VAS scores with the BPPT than the asymptomatic subjects (P

Vascular dysfunction and heart failure: Epiphenomenon or etiologic agent?

Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)-induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response.

Enterohepatic circulation - Physiological, pharmacokinetic and clinical implications

Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism. Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed. In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.

Usefulness of clinical risk markers and ischemic threshold to stratify risk in patients undergoing major noncardiac surgery

The risk of cardiac events in patients undergoing major noncardiac surgery is dependent on their clinical characteristics and the results of stress testing. The purpose of this study was to develop a composite approach to defining levels of risk and to examine whether different approaches to prophylaxis influenced this prediction of outcome. One hundred forty-five consecutive patients (aged 68 +/- 9 years, 79 men) with >1 clinical risk variable were studied with standard dobutamine-atropine stress echo before major noncardiac surgery. Risk levels were stratified according to the presence of ischemia (new or worsening wall motion abnormality), ischemic threshold (heart rate at development of ischemia), and number of clinical risk variables. Patients were followed for perioperative events (during hospital admission) and death or infarction over the subsequent 16 10 months. Ten perioperative events occurred in 105 patients who proceeded to surgery (10%, 95% confidence interval [CI] 5% to 17%), 40 being cancelled because of cardiac or other risk. No ischemia was identified in 56 patients, 1 of whom (1.8%) had a perioperative infarction. Of the 49 patients with ischemia, 22 (45%) had 1 or 2 clinical risk factors; 2 (9%, 95% CI 1% to 29%) had events. Another 15 patients had a high ischemic threshold and 3 or 4 risk factors; 3 (20%, 95% Cl 4% to 48%) had events. Twelve patients had a low ischemic threshold and 3 or 4 risk factors; 4 (33%, 95% CI 10% to 65%) had events. Preoperative myocardial revascularization was performed in only 3 patients, none of whom had events. Perioperative and long-term events occurred despite the use of beta blockers; 7 of 41 eta blocker-treated patients had a perioperative event (17%, 95% CI 7% to 32%); these treated patients were at higher anticipated risk than untreated patients (20 +/- 24% vs 10 +/- 19%, p = 0.02). The total event rate over late follow-up was 13%, and was predicted by dobutamine-atropine stress echo results and heart rate response. (C) 2002 by Excerpta Medica, Inc.

A prospective, randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into the treatment paradigm for patients with knee osteoarthritis (Part 1 of 2): clinical results

Objective: First, to assess the clinical effectiveness of hylan G-F 20 in an appropriate care treatment regimen (as defined by the American College of Rheumatology (ACR) 1995 guidelines) as measured by validated disease-specific outcomes and health-related quality of life endpoints for patients with osteoarthritis (OA) of the knee. Second, to utilize the measures of effectiveness and costs in an economic evaluation (see accompanying manuscript). Design: A total of 255 patients with OA of the knee were enrolled by rheumatologists or orthopedic surgeons into a prospective, randomized, open-label, 1-year, multi-centred trial, conducted in Canada. Patients were randomized to 'Appropriate care with hylan G-F 20' (AC+H) or 'Appropriate care without hylan G-F 20' (AC). Data were collected at clinic visits (baseline, 12 months) and by telephone (1, 2, 4, 6, 8, 10, and 12 months). Results: The AC+H group was superior to the AC group for all primary (% reduction in mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale: 38% vs 13%, P=0.0001) and secondary effectiveness outcome measures. These differences were all statistically significant and exceeded the 20% difference between groups seta priori by the investigators as the minimum clinically important difference. Health-related quality of life improvements in the AC+H group were statistically superior for the WOMAC pain, stiffness and physical function (all P

Clinical evaluation of the WOMAC 3.0 OA Index in numeric rating scale format using a computerized touch screen version

Background: The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index is a previously described self-administered questionnaire covering three domains: pain, stiffness and function. It has been validated in patients with osteoarthritis (OA) of the hip or knee in a paper-based format. Aim: To validate the WOMAC 3.0 using a numerical rating scale in a computerized touch screen format allowing immediate evaluation of the questionnaire. In the computed version cartoons, written and audio instruments were included in order facilitate application. Methods: Fifty patients, demographically balanced, with radiographically proven primary hip or knee OA completed the classical paper and the new computerized WOMAC version. Subjects were randomized either to paper format or computerized format first to balance possible order effects, Results: The intra-class correlation coefficients for pain, stiffness and function values were 0.915, 0.745 and 0.940, respectively. The Spearman correlation coefficients for pain, stiffness and function were 0.88, 0.77 and 0.87, respectively. Conclusion: These data indicate that the computerized WOMAC OA index 3.0 is comparable to the paper WOMAC in all three dimensions. The computerized version would allow physicians to get an immediate result and if present a direct comparison with a previous exam. (C) 2002 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.

Whither our Art? Clinical Wisdom & Evidence-based Medicine

The relationship between evidence-based medicine (EBM) and clinical judgement is the subject of conceptual and practical dispute. For example, EBM and clinical guidelines are seen to increasingly dominate medical decision-making at the expense of other, human elements, and to threaten the art of medicine. Clinical wisdom always remains open to question. We want to know why particular beliefs are held, and the epistemological status of claims based in wisdom or experience. The paper critically appraises a number of claims and distinctions, and attempts to clarify the connections between EBM, clinical experience and judgement, and the objective and evaluative categories of medicine. I conclude that to demystify clinical wisdom is not to devalue it. EBM ought not be conceived as needing to be limited or balanced by clinical wisdom, since if its language is translatable into terms comprehensible and applicable to individuals, it helps constitute clinical wisdom. Failure to appreciate this constitutive relation will help perpetuate medical paternalism and delay the adoption of properly evidence-based practice, which would be both unethical and unwise.

Application of spatial analysis techniques to adjust for fertility trends and identify interplot competition in early stage sugarcane selection trials

Most sugarcane breeding programs in Australia use large unreplicated trials to evaluate clones in the early stages of selection. Commercial varieties that are replicated provide a method of local control of soil fertility. Although such methods may be useful in detecting broad trends in the field, variation often occurs on a much smaller scale. Methods such as spatial analysis adjust a plot for variability by using information from immediate neighbours. These techniques are routinely used to analyse cereal data in Australia and have resulted in increased accuracy and precision in the estimates of variety effects. In this paper, spatial analyses in which the variability is decomposed into local, natural, and extraneous components are applied to early selection trials in sugarcane. Interplot competition in cane yield and trend in sugar content were substantial in many of the trials and there were often large differences in the selections between the spatial and current method used by the Bureau of Sugar Experiment Stations. A joint modelling approach for tonnes sugar per hectare in response to fertility trends and interplot competition is recommended.

Neuro-angiostrongylosis in wild Black and Grey-headed flying foxes (Pteropus spp)

Objective To identify nematodes seen in histological sections of brains of flying foxes (fruit bats) and describe the associated clinical disease and pathology. Proceedures Gross and histological examination of brains from 86 free-living flying foxes with neurological disease was done as part of an ongoing surveillance program for Australian bat lyssavirus. Worms were recovered, or if seen in histological sections, extracted by maceration of half the brain and identified by microscopic examination. Histological archives were also reviewed. Results There was histological evidence of angiostrongylosis in 16 of 86 recently submitted flying foxes with neurological disease and in one archival case from 1992. In 10 flying foxes, worms were definitively identified as Angiostrongylus cantonensis fifth-stage larvae. A worm fragment and third stage larvae were identified as Angiostrongylus sp, presumably A cantonensis, in a further three cases. The clinical picture was dominated by paresis, particularly of the hind-limbs, and depression, with flying foxes surviving up to 22 days in the care of wildlife volunteers. Brains containing fifth-stage larvae showed a moderate to severe eosinophilic and granulomatous meningoencephalitis (n = 14), whereas there was virtually no inflammation of the brains of bats which died when infected with only smaller, third-stage larvae (n = 3). There was no histological evidence of pulmonary involvement. Conclusion This is the first report of the recovery and identification of A cantonensis from free-living Australian wildlife. While anglostrongylosis is a common cause of paresis in flying foxes, the initial clinical course cannot be differentiated from Australian bat lyssavirus infection, and wildlife carers should be urged not to attempt to rehabilitate flying foxes with neurological disease.

The differential role of alcohol expectancies, drinking refusal self-efficacy and coping resources in predicting alcohol consumption in community and clinical samples

This study explored the relationship between coping, alcohol expectancies and drinking refusal self-efficacy in predicting drinking behaviour in both community and clinical samples. These variables were found to have differential effects in their association with frequency and volume of alcohol consumption across the two samples. Generally, drinking refusal self-efficacy was a more salient factor in relation to frequency and volume of community drinking, while coping and expectancies were more strongly associated with frequency of drinking sessions by problem drinkers. The interaction between expectancies and drinking refusal self-efficacy was related to volume of consumption in both groups, while coping and expectancies interacted in their association with frequency in the clinical group. The findings are discussed with regard to the different patterns of cognitive variables governing the decision to drink and the amount consumed in each drinking session, which may differentiate community and problem drinkers.