Repeated measurements of motor activity in rats in long-term toxicity studies.

INTRODUCTION: In the light of 3R (replace, reduce, refine) principles in animal experimentation and increased focus on delayed effects of treatment on central nervous system, the incorporation of behavioural tests into standard toxicology studies as a complement or substitution of a stand-alone safety pharmacology study appears very attractive, but poses some challenges. In the present study, we evaluated the results of an open field test (standard part of the behavioural test batte- ries) incorporated into the 3-month regulatory toxicology study. METHODS: The study was performed in two rat strains most commonly used in toxicology studies (Wistar and Sprague Dawley (SprD)). Open field test was performed according to the standard protocol for stand-alone behavioural test (modified Irwin test) before the start of treat- ment (Day-7, "naïve" animals), on Day 2, inWeek 6 and inWeek 13 of treatment with saline. RESULTS AND DISCUSSION: There was no overall difference between strains, and only minor differences were detected at the individual time points. With regard to time effect, the average values for most of the parameters were comparable throughout the study but individual variability in the performance in the arena was increased at repeated measurements compared to the start. In conclusion, performance in the open field arena did not differ principally between Wistar and SprD rats of both genders. However, individual variability in the behaviour in the open field arena increased with time. This has clear implications for deciding the appropriate group size for this type of study and has to be taken into account in the design of a toxicology study with integrated safety pharmacology endpoints.

[Comparative data about cryosupernatant and fresh frozen plasma use in treatment of disseminated intravascular coagulation in patients with generalized peritonitis].

PURPOSE OF THE STUDY: To compare the complex treatment of peritonitis with cryosupernatant and with fresh frozen plasma. MATERIALS AND METHODS: Outcomes of treatment were studied in 88 patients receiving cryosupernatant and in 112 receiving fresh frozen plasma. RESULTS: Cryosupernatant application provides better dynamics of hemostasis, decreases a risk of thrombosis and mortality and improves outcomes of treatment. CONCLUSIONS: Cryosupernatant can be used instead of fresh frozen plasma in complex treatment of disseminated intravascular coagulation in patients with generalized peritonitis.

Swine as models in biomedical research and toxicology testing.

Swine are considered to be one of the major animal species used in translational research, surgical models, and procedural training and are increasingly being used as an alternative to the dog or monkey as the choice of nonrodent species in preclinical toxicologic testing of pharmaceuticals. There are unique advantages to the use of swine in this setting given that they share with humans similar anatomic and physiologic characteristics involving the cardiovascular, urinary, integumentary, and digestive systems. However, the investigator needs to be familiar with important anatomic, histopathologic, and clinicopathologic features of the laboratory pig and minipig in order to put background lesions or xenobiotically induced toxicologic changes in their proper perspective and also needs to consider specific anatomic differences when using the pig as a surgical model. Ethical considerations, as well as the existence of significant amounts of background data, from a regulatory perspective, provide further support for the use of this species in experimental or pharmaceutical research studies. It is likely that pigs and minipigs will become an increasingly important animal model for research and pharmaceutical development applications.

Swallowing problems and dementia in acute hospital settings: practical guidance for the management of dysphagia.

There is little evidence to support tube feeding in advanced dementia although it is still frequently used in acute hospital settings. Patients present with complex problems and are often unable to make decisions about their healthcare needs. Multidisciplinary teams may be challenged by the difficult ethical decisions they are required to make in the best interests of their patients. This paper guides decision making in the management of patients with dementia and dysphagia in the acute hospital setting. A structured approach to information gathering, assessment and management is outlined with practical application of recent published guidelines and research evidence, which ensures appropriate individualised care.

Can we use mid upper arm anthropometry to detect malnutrition in medical inpatients? A validation study.

BACKGROUND AND AIMS: Mid upper arm anthropometry (MUAA) is often used as a measure of nutritional status to detect changes in body composition. The aim of this study was to investigate the reliability and validity of MUAA including mid arm circumference (MAC) and triceps skin fold thickness (TSFT) to determine the usefulness in clinical practice. METHOD: We measured MUAA in 158 consecutive admissions along with subjective global assessment (SGA) and body mass index (BMI). Inter- and intra-rater reliability was evaluated in an additional 50 patients. RESULTS: The sensitivity and specificity of MUAA <5th percentile was compared with SGA and BMI. MAC and TSFT had a low sensitivity and a high specificity with low positive predictive values when compared with criterion values which were BMI

Propofol intravenous conscious sedation for anxious children in a specialist paediatric dentistry unit.

OBJECTIVES: To report on both the use and dosage of propofol, as a new intravenous (IV) conscious sedative agent, for anxious children referred to a specialist paediatric dentistry service. SETTING: Paediatric Dentistry Unit, Glasgow Dental Hospital and School. SAMPLE: Thirty-four children, 25 females and 9 males, mean age 12 years 10 months, with a mean weight of 54.6 kg (range 30-110 kg). METHODS: Report from 34 patients receiving intravenous sedation for the first time in respect of weight dose and amount of treatment completed. RESULTS: Thirty-two children successfully accepted operative dental care on their first visit, they received a mean total dose of 146.25 mg of propofol (range 10 mg to 356 mg); in relation to body weight, the mean was 2.5 mg/kg (range 0.2-5.4 mg/kg). The treatment that they received included fissure sealants, amalgam and adhesive restorations, root canal therapy and single and multiple extractions. Their sedation and recovery were uneventful. CONCLUSIONS: Sub-anaesthetic doses of propofol used for IV conscious sedation infusion facilitated operative dental treatment in anxious children.

Treatment of hypertension in peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) causes considerable morbidity and mortality. Hypertension is a risk factor for PAD. Therefore, treatment for hypertension must be compatible with the symptoms of PAD. Controversy regarding the effects of beta blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-blockers. Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD. OBJECTIVES: To determine the effects of anti-hypertensive drugs on the: cardiovascular events and death in patients with hypertension and PAD; symptoms of claudication and critical leg ischaemia; progression of PAD, and revascularisation, or amputations. SEARCH STRATEGY: Trials were sought via the Specialised Register of the Cochrane Peripheral Vascular Diseases Group (last searched July 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 2, 2003), and the NHS Database of Abstracts of Reviews of Effectiveness (DARE) (last searched August 2002). There were no language restrictions. Abstracts of cardiology meetings were studied. Reference lists of papers were also examined. SELECTION CRITERIA: Randomised controlled trials of at least one anti-hypertensive treatment against placebo, or two anti-hypertensive medications against each other, with interventions lasting at least one month. Trials had to include patients with symptomatic PAD. Trials of poor quality and execution were excluded, as were cross-over trials. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and checked by the other. Eligible studies were excluded when presentation prevented adequate extraction of data, and enquiries to authors did not yield the raw data. MAIN RESULTS: Two studies were included in the review. In one trial using perindopril in small numbers of patients with PAD, there was a marginal increase in claudication distance (weighted mean difference (WMD) 8.0, 95% confidence interval (CI) -30.66 to 46.66), but no change in ankle brachial pressure index (ABPI), (WMD 0, 95% CI -0.14 to 0.14), and a reduction in walking distance (WMD -46, 95 % CI -169.24 to 77.24). In patients undergoing angioplasty, a second trial suggested that the calcium antagonist verapamil reduced restenosis, although this was not reflected in the maintenance of a high ABPI. REVIEWER'S CONCLUSIONS: The evidence for various anti-hypertensive drug classes in PAD is poor, so that it is unknown whether significant benefit or risk accrues from their use. In view of this, no definite recommendations on use or avoidance can be made from the available data.

Measurement of the soluble angiopoietin receptor tie-2 in patients with coronary artery disease: development and application of an immunoassay.

BACKGROUND: The angiopoietin family has emerged as a group of crucial growth factors to normal angiogenesis. They are essential to the development of the mature vessel wall and interact with the endothelium via endothelial cell-specific tyrosine kinase receptors, tie-1 and tie-2. The role of the tie-2 receptor has been extensively examined in neovascularization associated with malignancy, but little is known about the role it may play in atherosclerosis, a condition whose pathophysiology also involves angiogenesis. Soluble tie-2 has been detected in the plasma of healthy controls, but this has yet to be applied to patients in the clinical setting. MATERIALS AND METHODS: We developed an ELISA to detect plasma tie-2 levels and applied these to a clinical setting. The intra- and interassay coefficients of variation for the assay were 4.7% and 9.6%, respectively. We then measured levels of tie-2, vascular endothelial growth factor (VEGF), another factor associated with angiogenesis, and the soluble VEGF receptor Flt-1 (sFlt-1) in 75 patients with coronary artery disease [25 with acute myocardial infarction (AMI), 25 with acute coronary syndromes (ACS) and 25 with stable angina] and 25 healthy controls. RESULTS: Median [IQR, interquartile range] levels of tie-2 were significantly higher in the coronary artery disease patients (AMI 12 [10-17] ng mL-1, ACS 10 [9-14] ng mL-1, stable angina 9 [3-11] ng mL-1) when compared with the controls (7.5 [7-9] ng mL-1P = 0.004). As expected, levels of VEGF and sFlt were significantly different from those in the healthy controls (P = 0.011 and P < 0.001, respectively). Significant correlations were found between levels of tie-2 and VEGF (Spearman r = 0.59, P < 0.001), tie-2 and sFlt-1 (r = 0.45, P < 0.001) and VEGF and sFlt-1 (r = 0.56, P < 0.001) in the whole study group. CONCLUSION: We suggest that tie-2 may be potentially used as a marker of angiogenesis in atherosclerosis and may help elucidate the role of the angiopoietin/tie-2 system in atherogenesis.

Ethnicity and peripheral vascular disease.

There are well-documented differences in the prevalence of coronary artery disease and carotid disease between caucasians, Afro-Caribbeans and Indo-Asians. Very little data are available on ethnic differences in peripheral vascular disease (PVD). To investigate this further, we surveyed 200 consecutive patients attending the vascular surgery service at a city centre hospital serving a multiethnic patient catchment population. All patients had proven PVD, with an ankle brachial pressure index of less than 0.8. Within this cohort, Afro-Caribbeans presented more frequently with PVD compared with the proportion of this ethnic group in the local population (p = 0.013), with a greater proportion with diabetes mellitus than in the other two ethnic groups. There did not appear to be a significant difference between the ethnic groups in any of the other established risk factors or associations (i.e. treated hypertension, smoking, previous history of ischaemic heart disease, atrial fibrillation, previous history of cerebrovascular accident or transient ischaemic attack) with PVD. As with coronary artery disease and carotid disease, there are ethnic differences in the prevalence of PVD, and the underlying risk factors, between caucasians, Afro-Caribbeans and Indo-Asians. Furthermore, patients of Afro-Caribbean origin present more frequently with symptomatic PVD than do either caucasians or Indo-Asians.

Ethnic differences in peripheral vascular disease.

The wide variation in the way coronary artery disease (CAD) affects different ethnic groups and the associated risk factor profiles of these groups have been extensively studied, but ethnic differences in the clinical manifestations of peripheral vascular disease (PVD) have been relatively neglected. The aim of the present review is to provide an overview of PVD in different ethnic groups and to explore possible pathophysiological factors accounting for these differences. Atherosclerotic PVD is generally less prevalent in Indo-Asians and Afro-Caribbeans than in caucasians, despite the 'classical' risk factors being as prevalent, if not more so, suggesting the possibility of as yet unidentified risk factors in these groups. Angiographic and microscopic evidence suggests that patients of African or Afro-Caribbean origin suffer from a different pattern of PVD, which primarily affects the distal arteries. In contrast, Indo-Asians tend to suffer from thromboangiitis obliterans (Buerger's disease) far more frequently than other ethnic groups; thus, their arterial disease appears to present much earlier and with greater severity. However, if this sub-category of patient is excluded, they seem to suffer much less from 'simple' atherosclerotic disease than their caucasian counterparts. Despite a higher prevalence of diabetes among Indo-Asians, the prevalence of intermittent claudication is considerably less in this ethnic group.

Peripheral vascular disease and hypertension: a forgotten association?

Peripheral vascular disease (PVD) is associated with a high cardiovascular morbidity and mortality. Intermittent claudication is the most common symptomatic manifestation of PVD, but is also an important predictor of cardiovascular death, increasing it by three-fold, and increasing all-cause mortality by two to five-fold. Hypertension is a common and important risk factor for vascular disorders, including PVD. Of hypertensives at presentation, about 2-5% have intermittent claudication, with this prevalence increasing with age. Similarly, 35-55% of patients with PVD at presentation also have hypertension. Patients who suffer from hypertension with PVD have a greatly increased risk of myocardial infarction and stroke. Apart from the epidemiological associations, hypertension contributes to the pathogenesis of atherosclerosis, the basic underlying pathological process underlying PVD. Hypertension, in common with PVD, is associated with abnormalities of haemostasis and lipids, leading to an increased atherothrombotic state. Nevertheless, none of the large antihypertensive treatment trials have adequately addressed whether a reduction in blood pressure causes a decrease in PVD incidence. There is therefore an obvious need for such outcome studies, especially since the two conditions are commonly encountered together.

Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose.

We studied the relationship between alcohol consumption and hepatotoxicity related to paracetamol ingestion both in cases of overdose with suicidal intent and in cases where paracetamol was apparently taken for therapeutic reasons. In a retrospective study of 553 patients admitted to a specialist liver unit between January 1987 and December 1993 with paracetamol-induced hepatotoxicity, there was no difference in the severity of the hepatotoxicity following either a deliberate or an inadvertent overdose. Heavy alcohol consumption was more common in males than females and more commonly associated with deliberate overdoses of >15 g. There was no correlation between alcohol consumption and severity of hepatotoxicity (mean INR and the serum creatinine levels over the first 7 days after the overdose). The significantly lower platelet count in heavy drinkers was probably the consequence of direct alcohol toxicity to the marrow. Overall there was a greater incidence of heavy alcohol consumption amongst therapeutic misadventure compared to deliberate overdose cases, but there was no difference between the two groups when amounts of <10 g/day were involved. Eleven (29%) patients in the therapeutic misadventure group were depressed, 10 of whom had previously attempted suicide. In conclusion, we were unable to demonstrate that heavy drinkers develop more severe hepatotoxicity following paracetamol overdose than non-drinkers, and from the material reported in this study, accidental overdose is a better defining term than therapeutic misadventure.