Cue competition between elementary trained stimuli: US miscuing, interference, and US omission

The present series of experiments was designed to assess whether rule-based accounts of Pavlovian learning can account for cue competition effects observed after elemental training. All experiments involved initial differential conditioning training with A-US and B alone presentations. Miscuing refers to the fact that responding to A is impaired after one B-US presentation whereas interference is the impairment of responding to A after presentation of C-US pairings. Omission refers to the effects on B of A alone presentations. Experiments 1-2a provided clear evidence for miscuing whereas interference was not found after 1, 5 or 10 C-US pairings. Moreover, Experiments 3 and 3a found only weak evidence for interference in an A-US, B I C-US, D I A design used previously to show the effect. Experiments 4 and 5 failed to find any effect of US omission after one or five omission trials. The present results indicate that miscuing is more robust than is the interference effect. Moreover, the asymmetrical effects of US miscuing and US omission are difficult to accommodate within rule-based accounts of Pavlovian conditioning. (C) 2002 Elsevier Science (USA). All rights reserved.

Quantification and stability of everolimus (SDZ RAD) in human blood by high-performance liquid chromatography-electrospray tandem mass spectrometry

We report here a validated method for the quantification of a new immunosuppressant drug, everolimus (SDZ RAD), using HPLC-tandem mass spectrometry. Whole blood samples (500 mul) were prepared by protein precipitation, followed by C-18 solid-phase extraction. Mass spectrometric detection was by selected reaction monitoring with an electrospray interface operating in positive ionization mode. The assay was linear from 0.5 to 100 mug/l (r(2) > 0.996, n = 9). The analytical recovery and inter-day imprecision, determined using whole blood quality control samples (n = 5) at 0.5, 1.2, 20.0, and 75.0 mug/l, was 100.3-105.4% and less than or equal to7.6%, respectively. The assay had a mean relative recovery of 94.8 +/- 3.8%. Extracted samples were stable for up to 24 h. Fortified everolimus blood samples were stable at -80 degreesC for at least 8 months and everolimus was found to be stable in blood when taken through at least three freeze-thaw cycles. The reported method provides accurate, precise and specific measurement of everolimus in blood over a wide analytical range and is currently supporting phase 11 and III clinical trials. (C) 2002 Elsevier Science B.V. All rights reserved.

Dimensionality and clinical importance of pain and disability in hand osteoarthritis: Development of the Australian/Canadian (AUSCAN) Osteoarthritis Hand Index

Objective: To develop a reliable, valid, and responsive self-administered questionnaire to probe pain, stiffness and physical disability in patients with osteoarthritis (OA) of the hand. Design: In order to assess the dimensionality of the symptomatology of hand OA, a self-administered questionnaire was developed to probe various aspects of pain (10 items), stiffness (two items), and physical function (83 items). The question inventory was generated from eight existing health status measures and an interactive process involving four rheumatologists, two physiotherapists, and an orthopaedic surgeon. Results: Face-to-face interviews were conducted with 50 OA hand patients; 39 females and 11 males with mean age 62.8 years and mean disease duration 9.4 years. Items retained were those which fulfilled specified selection criteria: prevalence greater than or equal to60% and mean importance score approximating or exceeding 2.0 Item exclusion criteria included low prevalence, gender-based, ambiguous, duplicates or similarities, alternatives, composite items, and items that were too restrictive. This process resulted in five pain, one stiffness and nine function items which have been proposed for incorporation in the AUSCAN Index. Conclusions: Using a traditional development strategy, we have constructed a self-administered multi-dimensional outcome measure for assessing hand OA. The next stage includes reliability, validity and responsiveness testing of the 15-item questionnaire. (C) 2002 OsteoArthritis Research Society Intenational. Published by Elsevier Science Ltd. All rights reserved.

Combined physiotherapy and education is efficacious for chronic low back pain

Manual therapy, exercise and education target distinct aspects of chronic low back pain and probably have distinct effects, This study aimed to determine the efficacy of a combined physiotherapy treatment that comprised all of these strategies. By concealed randomisation, 57 chronic low back pain patients were allocated to either the four-week physiotherapy program or management as directed by their general practitioners, The dependent variables of interest were pain and disability. Assessors were blind to treatment group. Outcome data from 49 subjects (86%) showed a significant treatment effect. The physiotherapy program reduced pain and disability by a mean of 1.5/10 points on a numerical rating scale (95% CI 0.7 to 2.3) and 3.9 points on the 18-point Roland Morris Disability Questionnaire (95% CI 2 to 5.8), respectively. The number needed to treat in order to gain a clinically meaningful change was 3 (95% CI 3 to 8) for pain, and 2 (95% CI 2 to 5) for disability. A treatment effect was maintained at one-year follow-up. The findings support the efficacy of combined physiotherapy treatment in producing symptomatic and functional change in moderately disabled chronic low back pain patients.

Outcomes after trans-tibial amputation: The relationship between quiet stance ability, strength of the hip abductor muscles and gait

Background and Purpose Previous research regarding the symmetry of trans-tibial amputees has examined weight distribution and various gait parameters between prosthetic and sound limbs. However, to date, no known research has determined if asymmetry is present in the strength of the hip abductor muscles or if correlations exist between these categories of symmetry. The purpose of the present study was, therefore, to document asymmetry present in stance, strength and gait measures, and to determine the relationship between these variables. Method Twenty-three elderly, unilateral trans-tibial amputees stood on two adjacent forceplates whilst the weight distribution and standard deviation (SD) of the anterior-posterior and the medio-lateral centre of pressure excursion (COPE) under each limb was recorded during four 40 s trials: quiet stance (QS), with eyes open and eyes closed; and even stance (ES), with eyes open and eyes closed. Gait measures (velocity, cadence, step and stride lengths, stance:swing ratio and period of double support) over 10 m of fast, yet safe walking and measures of the strength of hip abductor muscles were also obtained by use of a stride analyser and a dynamometer, respectively. Results No significant differences were found between QS and ES measures. However, significantly more weight was taken on the sound limb than on the amputated limb. Notably, more anterior-posterior movement occurred under the sound limb than the amputated limb, with this becoming more apparent with the eyes closed. Movement in the medio-lateral direction was found to be the same between sides. No differences in muscle strength or gait measures between limbs were demonstrated. However. strong hip abductor muscles were correlated with increased weight-bearing on the amputated limb, improved gait parameters and reduced medio-lateral COPE under the amputated limb. Conclusions This research confirms the asymmetrical nature of amputee stance and demonstrates symmetry of strength and gait measures between limbs. The correlations between hip abductor muscle strength, weight distribution and gait measures illustrates the importance of pre- and postoperative training of these muscles. Copyright © 2002 Whurr Publishers Ltd.

Assault-related admissions to hospital in Central Australia

Objective: To determine the number of assault-related admissions to hospital in the Central Australia region of the Northern Territory over a six-year period. Design and setting: Retrospective analysis of all patients admitted to Alice Springs Hospital (ASH) and Tennant Creek Hospital (TCH) from July 1995 to June 2001, where the primary cause of injury was assault. Main outcome measures: Frequency of assault-related admission to hospital; demographic characteristics of the victims. Results: in the six years, there were 2449 assault-related admissions to ASH and 545 to TCH. Adults aged 25-34 years were most frequently hospitalised for assault, in a proportion greater than their proportion in the NT population, Females represented 59.7% of people admitted to ASH and 54.7% to TCH, greater than their proportion in the NT population. Aboriginals comprised 95.2% of ASH and 89.0% of TCH admissions, and were admitted in a significantly greater proportion than their proportion in the NT population (P < 0.001). The age-adjusted hospital admission rate resulting from assault has increased (P = 0.002) at an average rate of 1.6 (SE, 0.2) per 10 000 people per year. The proportion of assault-related admissions associated with alcohol has also increased significantly (P < 0.001). Conclusion: The frequency of assault-related admissions to hospital, especially among the Aboriginal population, suggests that this major public health issue is escalating.

Should we debrief and counsel people who have had psychological shock?

Design: Randomised controlled trial of psychological debriefing. Setting: A British teaching hospital (the Radcliffe Hospital, Oxford). Patients: 66 men and 40 women, aged 17–69 years, admitted to hospital after a motor vehicle accident. Most had been the driver of a car. Median admission duration was four days for the 52 control patients and eight days for the 54 who underwent the intervention. Interventions: A debriefing of about one hour on Day 2 of admission, encouraging patients to describe the accident and express their emotions, followed by a cognitive appraisal which included describing common reactions to traumatic experiences and suggesting a range of people who might be able to assist in the future, including the patient's general practitioner. 91 patients were assessed at four months and 61 were assessed at three years. Control patients had no debriefing or counselling. Main outcome measures: Impact of Event Scale (IES, which focuses on intrusive thoughts and avoidance of similar situations to the event); Brief Symptom Inventory (BSI, a measure of 53 symptoms); and other questions related to physical pain and functional activities. Main results: At four months there was still considerable psychological morbidity among the patients who were followed up. There was a significant difference (P < 0.05) in changes of IES between the 42 who received the intervention, in whom it increased from 15 (standard deviation [SD], 15) to 16 (SD, 15), and the 49 controls, in whom it fell from 15 (SD, 12) to 13 (SD, 14). Similarly, two subscales of the BSI score changed significantly between the intervention group, among whom it deteriorated from 0.5 (SD, 0.5) to 0.6 (SD, 0.8), and the control s, in whom it hardly changed from 0.4 (SD, 0.3) to 0.4 (SD, 0.4). Among the 61 patients followed for three years, the 30 randomised to receive the intervention were significantly worse, by self-report, both psychologically and physically. Their mean IES score deteriorated from a baseline of 15 (SD, 14) to 16 (SD, 18). In comparison, scores for the 31 control patients improved from 16 (SD, 12) to 13 (SD, 17). The difference in change was significant (P < 0.05). Among all patients with high initial scores, these decreased among the controls but not among those receiving the intervention. Conclusion: Psychological counselling should only be used in the context of trials rather than routine care.

Risk factors for non-haemorrhagic stroke in patients with coronary heart disease and the effect of lipid-modifying therapy with pravastatin

Objective To determine the relative importance of recognised risk factors for non-haemorrhagic stroke, including serum cholesterol and the effect of cholesterol-lowering therapy, on the occurrence of non-haemorrhagic stroke in patients enrolled in the LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) study. Design The LIPID study was a placebo-controlled, double-blind trial of the efficacy on coronary heart disease mortality of pravastatin therapy over 6 years in 9014 patients with previous acute coronary syndromes and baseline total cholesterol of 4-7 mmol/l. Following identification of patients who had suffered non-haemorrhagic stroke, a pre-specified secondary end point, multivariate Cox regression was used to determine risk in the total population. Time-to-event analysis was used to determine the effect of pravastatin therapy on the rate of non-haemorrhagic stroke. Results There were 388 non-haemorrhagic strokes in 350 patients. Factors conferring risk of future non-haemorrhagic stroke were age, atrial fibrillation, prior stroke, diabetes, hypertension, systolic blood pressure, cigarette smoking, body mass index, male sex and creatinine clearance. Baseline lipids did not predict non-haemorrhagic stroke. Treatment with pravastatin reduced non-haemorrhagic stroke by 23% (P= 0.016) when considered alone, and 21% (P= 0.024) after adjustment for other risk factors. Conclusions The study confirmed the variety of risk factors for non-haemorrhagic stroke. From the risk predictors, a simple prognostic index was created for nonhaemorrhagic stroke to identify a group of patients at high risk. Treatment with pravastatin resulted in significant additional benefit after allowance for risk factors. (C) 2002 Lippincott Williams Wilkins.

The therapeutic potential of dopamine modulators on the cardiovascular and renal systems

In the periphery, physiological dopamine increases renal blood flow, decreases renal resistance and acts on the kidney tubule to enhance natriuresis and diuresis. The loss of dopamine function may be involoved in the deterioration in kidney function associated with ageing and may have a role in the pathogenesis of hypertension and diabetes. Intravenous dopamine is used as a positive inotrope in the treatment of acute heart failure and cardiogenic shock and as a diuretic in renal failure. The clinical uses of dopamine are limited, as it must be given intravenously, and also has widespread effects. The levels of peripheral dopamine can be increased by the administration of L-dopa to increase synthesis, prodrugs to release dopamine (docarpamine, glu-dopa) or by inhibiting the breakdown of dopamine (nitecapone). Preliminary clinical trials suggest that docarpamine may be useful in patients with low cardiac output syndrome after cardiac surgery and in refractory cirrhotic ascites. Ibopamine is an agonist at dopamine D1 and D2 receptors, which may retard the progression of chronic renal failure. Gludopa is selective for the kidney thus avoiding widespread side effects. The early clinical studies with ibopamine as a diuretic in heart failure were favourable but the subsequent large mortality study showed that ibopamine increased mortality. Fenoldopam is a selective dopamine D1 receptor agonist. Intravenous fenoldopam may be useful in the treatment of hypertension associated with coronary artery bypass surgery or in hypertensive emergencies. Although our understanding of physiological and pathological roles of peripheral dopamine has been increasing rapidly in recent times, we still need more information to allow the design of clinically useful drugs that modify these roles. One priority is an orally-active selective dopamine D1 receptor agonist.

Present and future pharacotherapy for heart failure

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a β-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT1) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT1 antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of β-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional β-adrenoceptors, may give it additional benefits to selective β1-adrenoceptor antagonists. Celiprolol and bucindolol are not the β-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor α antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.

Angiotensin AT-1 receptor antagonism: complementary or alternative to ACE inhibition in cardiovascular and renal disease

Both angiotensin-converting enzyme (ACE) inhibitors and AT-1 receptor antagonists reduce the effects of angiotensin II, however they may have different clinical effects. This is because the ACE inhibitors, but not the AT-1 receptor antagonists, increase the levels of substance P, bradykinin and tissue plasminogen activator. The AT-1 receptor antagonists, but not the ACE inhibitors, are capable of inhibiting the effects of angiotensin II produced by enzymes other than ACE. On the basis of the present clinical trial evidence, AT-1 receptor antagonists, rather than the ACE inhibitors, should be used to treat hypertension associated with left ventricular (LV) hypertrophy. Both groups of drugs are useful when hypertension is not complicated by LV hypertrophy, and in diabetes. In the treatment of diabetes with or without hypertension, there is good clinical support for the use of either an ACE inhibitor or an AT-1 receptor antagonist. ACE inhibitors are recommended in the treatment of renal disease that is not associated with diabetes, after myocardial infarction when left ventricular dysfunction is present, and in heart failure. As the incidence of cough is much lower with the AT-1 receptor antagonists, these can be substituted for ACE inhibitors in patients with hypertension or heart failure who have persistent cough. Preliminary studies suggest that combining an AT-1 receptor antagonist with an ACE inhibitor may be more effective than an ACE inhibitor alone in the treatment of hypertension, diabetes with hypertension, renal disease without diabetes and heart failure. However, further trials are required before combination therapy can be recommended in these conditions.

The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET.) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ETA) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ETA receptor antagonism may have a role in the treatment of athero-sclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ETA receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the nonselective ET or selective ETA receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors tors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.

An investigation into the possible inhibitory effects of white cypress pine (Callitris glaucophylla) litter on the germination and growth of associated ground cover species

White cypress-pine stands typically support sparse densities of shrubs and grasses. The commonly held opinion is that leaching of allelopathic chemical compounds from cypress-pine litter partly facilitates this exclusion. Germination and growth of cypress pine seedlings do not appear to be similarly affected. This study set out to determine whether cypress litter had a differential effect on germination and growth of cypress-pine seedlings and on associated ground-cover species. Glasshouse trials comparing seedling emergence under cypress- and artificial-litter layers were undertaken. Cypress-pine litter did not have an inhibitory effect on the germination or growth of ground-cover species. In most cases, seedling emergence was facilitated by the application of cypress-pine litter due to its ability to increase the water holding capacity of the underlying soil. Cypress litter did not promote growth of its own seedlings over its competitors except on coarse-textured soils where it provided an ameliorative function to water stress due to the soil's reduced water holding capacity. The inhibition of ground-cover species' germination and growth in pure cypress stands was suggested to be the result of high below-ground resource competition due to the pine's expansive root morphology.

Dysarthria and dysphagia following treatment for a fourth ventricle choroid plexus papilloma

The present case report describes the presence of a persistent dysarthria and dysphagia as a consequence of surgical intervention for a choroid plexus papilloma (CPP). WM was a nine year ten month old male who at the time of the present study was seven years post-surgery. A comprehensive perceptual and instrumental test battery was used to document the nature of the dysarthria incorporating all components of speech production including respiration, phonation, resonance, articulation, and prosody. The nature of the dysphagia was evaluated through the use of videofluoroscopic evaluation of swallowing (VFS). Assessments confirmed the presence of a LMN dysarthria, marked by deficits in phonation, respiration, and prosody. Dysphagia assessment revealed deficits in oral preparatory, oral and pharyngeal stages of the swallow. The presence of persistent dysarthria and dysphagia in this case has a number of important implications for the management of children undergoing surgery for fourth ventricle CPPs, in particular the need for appropriate treatment, as well as counselling prior to surgery of the possible negative outcomes related to speech and swallowing. (C) 2003 Elsevier Science Ltd. All rights reserved.