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Background and purposeThe reduction of delay between onset and hospital arrival and adequate pre-hospital care of persons with acute stroke are important for improving the chances of a favourable outcome. The objective is to recommend evidence-based practices for the management of patients with suspected stroke in the pre-hospital setting.MethodsThe GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to define the key clinical questions. An expert panel then reviewed the literature, established the quality of the evidence, and made recommendations.ResultsDespite very low quality of evidence educational campaigns to increase the awareness of immediately calling emergency medical services are strongly recommended. Moderate quality evidence was found to support strong recommendations for the training of emergency medical personnel in recognizing the symptoms of a stroke and in implementation of a pre-hospital code stroke' including highest priority dispatch, pre-hospital notification and rapid transfer to the closest stroke-ready' centre. Insufficient evidence was found to recommend a pre-hospital stroke scale to predict large vessel occlusion. Despite the very low quality of evidence, restoring normoxia in patients with hypoxia is recommended, and blood pressure lowering drugs and treating hyperglycaemia with insulin should be avoided. There is insufficient evidence to recommend the routine use of mobile stroke units delivering intravenous thrombolysis at the scene. Because only feasibility studies have been reported, no recommendations can be provided for pre-hospital telemedicine during ambulance transport.ConclusionsThese guidelines inform on the contemporary approach to patients with suspected stroke in the pre-hospital setting. Further studies, preferably randomized controlled trials, are required to examine the impact of particular interventions on quality parameters and outcome.Click for the corresponding questions to this CME article.

Prescribing in frail older people may be improved by application of the four tenets of medical ethics – beneficence, nonmaleficence, autonomy, justice – rather than solely those of evidence-based medicine. Evidence-based medicine provides data primarily on the efficacy of interventions. In younger adults, this is often sufficient to make a decision to prescribe medications. In frail older people, there are additional issues that need to be considered, such as individualisation of efficacy data, increased risk of adverse drug reactions, patients’ views on risk and benefit, difficulties in assessing capacity to understand risk and benefit, consent to treatment, and concerns about the cost-effectiveness of interventions in the very old. In such situations, evidence-based medicine can be useful in informing the prescriber about the ethical principle of beneficence. However, the decision to prescribe or withdraw medications is also influenced by the other three tenets of medical ethics: non-maleficence (adverse drug reactions, polypharmacy), autonomy (consent, competency) and justice (appropriate allocation of healthcare resources). J Pharm Pract Res 2010; 40: 148-52.

Aims Nitric oxide (NO) is involved in acute flow-mediated vasodilatation in various vascular beds. We determined whether acutely increasing flow in the human forearm of premenopausal women increases vascular NO activity. Methods Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Responses to brachial artery infusion of noradrenaline (a control vasoconstrictor, 20, 50, and 100 ng min−1, each for 5 min) and NG-monomethyl l-arginine (L-NMMA), an NO synthase inhibitor (200, 400, and 800 µg min−1, each for 5 min), were determined in eight premenopausal women before and following elevation of basal FBF with glyceryl trinitrate (GTN) on two separate occasions. Results Flow elevation with GTN increased responses to L-NMMA (summary measure 103±12 vs 65±12 arbitrary units, P

Aims Terodiline has concentration dependent QT prolonging effects and thus the potential for cardiotoxicity. Pharmacogenetic variation in terodiline metabolism could be responsible for cardiotoxicity. We sought to determine whether CYP2D6 (debrisoquine hydroxylase) or CYP2C19 (S-mephenytoin hydroxylase) status is a risk factor for terodiline cardiotoxicity. Methods Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes. Genotype prevalence was compared with that in published general population groups. Results One patient was a CYP2D6 poor metaboliser (CYP2D6*4 homozygous) and a second was heterozygous for CYP2D6*4, a slightly lower frequency for these genotypes compared with the general population (P = 0.31). In the case of CYP2C19, one patient was a poor metaboliser and four were heterozygous for the variant CYP2C19*2 allele, compared with general population frequencies of 2% and 23%, respectively (P = 0.035). Conclusions These findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity. However, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline. The present study demonstrates the feasibility of using spontaneous adverse drug reaction reporting schemes to determine the contribution of genotype for metabolizing enzymes to uncommon adverse drug reactions.

Aims β2-adrenoceptor agonists are generally considered to produce endothelium independent vasodilatation through adenylate cyclase. We determined whether nitric oxide contributes to β2-adrenoceptor vasodilatation in human arterial vasculature. Methods Forearm blood flow responses to brachial intra-arterial infusions of ritodrine (2.5–50 μg min−1 ), a selective β2-adrenoceptor agonist, were determined in 24 healthy, normotensive subjects (mean age 22 years, 5F) on two occasions with initial and concomitant administration of l-NMMA (800 μg min−1 ), an NO synthase inhibitor, or noradrenaline (5–30 ng min−1 ), a control constrictor not affecting basal NO activity. Responses to the endothelium dependent vasodilator serotonin (n=6) and an endothelium independent vasodilator GTN (n=9) were also determined. Results Maximal dilatation to ritodrine during l-NMMA infusion (310±32%; mean±s.e.mean) was reduced compared to that during noradrenaline infusion (417±41%, P

It is unclear whether the age-associated reduction in baroreflex sensitivity is modifiable by exercise training. The effects of aerobic exercise training and yoga, a non-aerobic control intervention, on the baroreflex of elderly persons was determined. Baroreflex sensitivity was quantified by the alpha-index, at high frequency (HF; 0.15-0.35 Hz, reflecting parasympathetic activity) and mid-frequency (MF; 0.05-0.15 Hz, reflecting sympathetic activity as well), derived from spectral and cross-spectral analysis of spontaneous fluctuations in heart rate and blood pressure. Twenty-six (10 women) sedentary, healthy, normotensive elderly (mean 68 years, range 62-81 years) subjects were studied. Fourteen (4 women) of the sedentary elderly subjects completed 6 weeks of aerobic training, while the other 12 (6 women) subjects completed 6 weeks of yoga. Heart rate decreased following yoga (69 +/- 8 vs. 61 +/- 7 min-1, P < 0.05) but not aerobic training (66 +/- 8 vs. 63 +/- 9 min-1, P = 0.29). VO2 max increased by 11% following yoga (P < 0.01) and by 24% following aerobic training (P < 0.01). No significant change in alpha MF (6.5 +/- 3.5 vs. 6.2 +/- 3.0 ms mmHg-1, P = 0.69) or alpha HF (8.5 +/- 4.7 vs. 8.9 +/- 3.5 ms mmHg-1, P = 0.65) occurred after aerobic training. Following yoga, alpha HF (8.0 +/- 3.6 vs. 11.5 +/- 5.2 ms mmHg-1, P < 0.01) but not alpha MF (6.5 +/- 3.0 vs. 7.6 +/- 2.8 ms mmHg-1, P = 0.29) increased. Short-duration aerobic training does not modify the alpha-index at alpha MF or alpha HF in healthy normotensive elderly subjects. alpha HF but not alpha MF increased following yoga, suggesting that these parameters are measuring distinct aspects of the baroreflex that are separately modifiable.

We have developed a computer-aided system (Bony Parts) to analyze periodic bands in fish otoliths (or other structures) for age estimation. The image analysis program first scans the image of a thin otolith section, perpendicular to the bands specified by the user. Adjacent scans are averaged and filtered with Fourier transformation or spatial domain convolution. Bands of higher density are detected and are marked and summed on the screen. We evaluated this new technique using subsamples of thin-sectioned otoliths from the bank rockfish Sebastes rufus. The time and effort for cleaning, preparation, sectioning, and mounting are the same for both traditional and computer-aided techniques. The computer-aided technique reduced the time and tedium of counting bands, yet still allowed the user to interactively make subjective decisions about aging criteria. Both approaches produced similar readings, but computer-aided estimates were more precise than traditional readings and required less analysis time...

An examination of the marketing practices and the regulation of the all terrain vehicle (ATV) industry during the 1980s is presented. This review includes a content analysis of ATV advertising, an examination of the Consumer Product Safety Commission's (CPSC) regulation of the ATV industry, a study of the consent decree regulating the marketing of ATVs, and an analysis of the costs and benefits to the ATV industry of providing additional information to consumers. The paper concludes that deaths and injuries from ATV-related accidents might have been reduced substantially if the CPSC had been more aggressive in informing the public about the safety hazards associated with ATV use. Cost/benefit analysis reveals that the profit-maximizing strategy for ATV manufacturers was to market ATVs aggressively even when faced with the prospects of lawsuits and regulatory action. What actions should have been taken by the Consumer Product Safety Commission (CPSC) when it learned that the use of all terrain vehicles (ATVs) was associated with a high incidence of adolescents' deaths and serious injuries? Did the ATV industry inform prospective purchasers through advertising, product labeling, dealers' salespeople, point-of-sale material, and training programs about the potential product hazards? Was it more profitable for ATV manufacturers to inform consumers about the hazards of ATV use or to downplay ATV risks and pay the resulting costs of products liability lawsuits? This research explores these questions by focusing on three objectives. First, it provides a history of the ATV industry, including an examination of ATV sales and of deaths and injuries from ATV accidents, and it includes a content analysis of ATV print advertising. Second, it examines whether consumers benefitted from the 1988 consent decree negotiated by Department of Justice (DOJ) and CPSC attorneys with the ATV industry. The agreement banned three-wheeled ATVs, required public service messages, and mandated point-of-sale and advertising disclosures. The regulatory analysis in this paper provides insights into how well the regulatory process worked to provide consumers with information about ATV hazards. Third, it contains a cost/benefit analysis of alternative approaches to informing consumers about ATV risks. This analysis examines the potential effect on industry profits of increasing consumers' awareness of the hazards associated with ATV use. ATV SALES AND ACCIDENTS ATVs are three- and four-wheeled motorized vehicles intended for use on nonpaved terrain and are characterized by large, low-pressure tires, a seat designed to be straddled, and handlebars for steering. During the early 1980s, there was a substantial increase in both ATV sales and accidents associated with ATV use. Since 1982, ATVs have been associated with over 800,000 injuries treated in emergency rooms and at least 2,650 deaths ("ATV Fatalities Reach 2,430 in Latest CPSC Statistical Update" 1993; CPSC 1994). The history of ATV sales is summarized in Table 1. There are three key findings that emerge from analysis of the data in this table. First, from 1980 through 1983, sales increased by more than 50 percent a year and peaked at more than 600,000 units in 1984 and 1985. In 1988, the year the consent decree was signed, ATV sales fell to 217,000 units. Sales declined to less than 130,000 units in 1990 and have increased by approximately ten percent per year since then. TABLE 1 Estimated Unit Sales and Estimated Total Stock of Three- and Four- Wheeled A TVs, 1972-1993 Unit Sales (1,000s) Percent Sales Year 3-Wheel 4-Wheel Total 3-Wheel 4-Wheel 1972-77 139 139 100.0 1978-79 154 154 100.0 1980 126 126 100.0 1981 188 188 100.0 1982 290 290 100. …

1. Nebivolol, a selective beta 1-adrenoceptor antagonist with antihypertensive effects, has haemodynamic effects suggestive of a direct vasodilator action. 2. The dorsal hand vein technique was used to determine whether nebivolol has venodilator action in vivo in man. 3. Nebivolol and atenolol were infused into the phenylephrine preconstricted superficial hand veins of 11 healthy male volunteers. In separate studies L-NMMA (0.1 microgram min-1) was pre- and co-infused with nebivolol to determine whether nitric oxide (NO) mediated mechanisms were present. Further studies with prostaglandin F2 alpha (PGF2 alpha) preconstriction were performed to exclude an alpha-adrenergic antagonistic effect of nebivolol. Effects of L-NMMA infusion on nitroglycerin venodilation were also determined. 4. Nebivolol produced a dose dependent venodilation, (72 +/- 18% maximum), whereas atenolol produced no significant venodilation. At doses of nebivolol producing plasma concentrations comparable with plasma levels achieved after standard oral dosing (10(-13)-10(-12) mol min-1) small (14 +/- 6% and 23 +/- 8%) but significant (P < 0.05) venodilation was observed. 5. The venodilator response to nebivolol was significantly reduced by infusion of L-NMMA (maximum dilation 18% vs 72%, P < 0.01). Venodilator responses to nitroglycerin were unaffected by L-NMMA infusion. A venodilator effect to nebivolol was also seen following preconstriction with PgF2 alpha (40 +/- 20% maximum). 6. Nebivolol has nitric oxide mediated, venodilator effects in man.

Background Epidemiological evidence on the effects of magnesium on blood pressure is inconsistent. Metabolic and experimental studies suggest that magnesium may have a role in the regulation of blood pressure. Objectives To evaluate the effects of magnesium supplementation as treatment for primary hypertension in adults. Search strategy We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. Selection criteria Inclusion criteria were: 1) RCTs of a parallel or crossover design comparing oral magnesium supplementation with placebo, no treatment, or usual care; 2) treatment and follow-up >/=8 weeks; 3) participants over 18 years old, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg; 4) SBP and DBP reported at end of follow-up. We excluded trials where: participants were pregnant; received antihypertensive medication which changed during the study; or magnesium supplementation was combined with other interventions. Data collection and analysis Two reviewers independently abstracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. Main results Twelve RCTs (n=545) with eight to 26 weeks follow-up met our inclusion criteria. The results of the individual trials were heterogeneous. Combining all trials, participants receiving magnesium supplements as compared to control did not significantly reduce SBP (mean difference: -1.3 mmHg, 95% CI: -4.0 to 1.5, I(2)=67%), but did statistically significantly reduce DBP (mean difference: -2.2 mmHg, 95% CI: -3.4 to -0.9, I(2)=47%). Sensitivity analyses excluding poor quality trials yielded similar results. Sub-group analyses and meta-regression indicated that heterogeneity between trials could not be explained by dose of magnesium, baseline blood pressure or the proportion of males among the participants. Authors' conclusions In view of the poor quality of included trials and the heterogeneity between trials, the evidence in favour of a causal association between magnesium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treatment. Larger, longer duration and better quality double-blind placebo controlled trials are needed to assess the effect of magnesium supplementation on blood pressure and cardiovascular outcomes.

The extent to which mitochondria are involved in the aging process is controversial; much of the reported decline in mitochondrial oxidations in human skeletal muscle may be due to disease and inactivity rather than age. To study true aging, mitochondrial respiratory chain function was studied in 9 young and 12 elderly athletes. No significant deterioration with age was observed. If mitochondria are involved in aging, it must be through a more subtle mechanism than a global decline in respiratory chain activity.

Textbooks of clinical pharmacology for medical students face two challenges. They need to provide concise information on the treatment of common diseases to enable the newly qualified doctor to acquire an adequate knowledge base to prescribe. Most textbooks succeed in this with varying ‘cost effectiveness’. The second more difficult task, more relevant to producing long-term professional competency in drug treatment, is to encourage students to think critically about drug use and the principles of clinical pharmacology and to encourage the acquisition of the skills required to practise ‘rational’ or ‘optimal’ therapeutics. Few student textbooks succeed in capturing this intellectual spirit of clinical pharmacology that separates it from the approach of other disciplines to drug treatment. The fourth edition of this textbook takes a traditional approach with the first section covering general principles, and the remaining 13 sections accounting for over 75% of the book, dealing with the treatment of common diseases (therapeutics). The book is attractively laid out, easy to read and has sufficient figures, tables, case histories and key points to hold the reader's attention, although the similarly priced ‘Integrated Pharmacology’ by Page et al. is better on visual presentation and layout. The principles of pharmacokinetics, pharmacodynamics and drug use in special groups (pregnancy, children and the elderly) are well covered at an appropriate level. This section would benefit from chapters on practical aspects of drug administration, particularly intravenous drug administration, writing prescriptions and the procedures and mindset necessary to avoid the ‘drug disasters’ that still too commonly occur in routine clinical practice. The importance of adherence to drug treatment, and its influencing factors, is not covered adequately, with only brief discussion in the chapters on the elderly and children. This approach will perpetuate the incorrect belief that poor adherence is a problem mostly in these patients. Inevitably textbooks are soon out of date and omit recent advances in therapeutics, and these sections should come with a ‘best before’ date. CD or web based updates are probably needed if textbooks are to avoid being completely replaced by electronic media. I was disappointed to see no mention of the use of thrombolysis and aspirin in acute ischaemic stroke, or beta-interferon as a treatment for multiple sclerosis. Although multiple risk factor assessment in cardiovascular risk is discussed, examples of how to use coronary risk prediction charts are not given. However, in general the therapeutics sections provide a lucid comprehensive account for students. This text is less successful in capturing the spirit of clinical pharmacology and outlining the principles and thinking which cultivate a ‘critical approach’ to the optimal use of drugs in clinical care. The North American text ‘Melmon and Morelli’s Clinical Pharmacology' is best in this respect, but it is little read in this country and too large to suit most students. This book is a reasonable recommendation to students as a core text for therapeutics teaching. Departments with integrated teaching of Pharmacology and Clinical Pharmacology and Therapeutics should probably consider other texts, which include more basic pharmacology.

Isoenzyme electrophoretic techniques were applied to the characterization of seven Sarcocystis spp. that had been identified by conventional morphological studies. Cystozoites were harvested from macroscopic cysts from sheep, cattle, and mice and from microscopic cysts from sheep, cattle, and goats. Soluble cystozoite extracts were subjected to cellulose acetate gel electrophoresis and characterized at 15 of the 39 enzyme loci examined. Genetic relationships among isolates were examined by simple phenetic clustering. Two different morphological types of macroscopic cysts from sheep, identified as S. gigantea (syn. S. ovifelis) and S. medusiformis, consistently differed at 40% of the loci examined. Such genetic divergence confirms their separate morphotypic classification. Both differed from microscopic cyst isolates from sheep at 87% of the loci examined; however, two different morphotypes of microscopic cysts were found in the sheep sampled (thick-walled and thin-walled cysts). Until sufficient numbers of each type can be isolated and examined separately, both were regarded as belonging to the species S. tenella (syn. S. ovicanis). Macroscopic and microscopic cysts from cattle consistently differed at 80% of the loci thereby supporting their separate classification as S. hirsuta (syn. S. bovifelis) and S. cruzi (syn. S. bovicanis), respectively. Isolates from goats (microscopic cysts identified as S. capracanis) differed from S. tenella and S. cruzi at 20% and 47% of the loci, respectively. All macroscopic cyst isolates from the various host animal species (including S. muris from mice) differed from each other at nearly all loci. Isoenzyme electrophoretic techniques therefore provided genetic evidence supporting the classification of these various Sarcocystis spp. by their morphological characteristics.

SUMMARY A total of 864 sheep sold for slaughter throughout South Australia were examined for infections with Sarcocystis spp using macroscopic, microscopic and immunoserological methods of detection. Macroscopic cysts were found in 6.7% of the sheep ranging in intensity from 1 to 64 cysts per carcase. Morphometric studies detected 2 types of macroscopic cysts which differed in their size and cyst wall morphology. Large ovoid cysts with thick primary cyst walls were identified as S. gigantea (syn. S. ovifelis) whereas small slender cysts with thin cyst walls were identified as S. medusiformis. The prevalence of each species was 4.5% and 3.1% respectively. In comparison, microscopic cysts were detected in 93.2% of the sheep and stereological calculations of the intensities of infection ranged from 20 to 32,700 cysts per unit volume of muscle. Two types of microscopic cysts were also identified by differences in their cyst wall morphology. Cysts with smooth thin walls were detected in 88.1% of the sheep whereas cysts with radially-striated thick walls were found in 74.7%. Although these 2 types appeared to conform to the original descriptions of S. tenella and S. ovicanis respectively, both were classified as S. tenella (syn. S. ovicanis) pending further taxonomic studies. Specific antibody was detected in 93.7% of the sheep by the complement fixation test and in 96.9% by the indirect fluorescent-antibody test (IFAT). A positive correlation was also found between the prevalence of IFAT antibody and the prevalence of infections by microscopic cysts.