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AIMS: To describe how changes in legislation to restrict paracetamol sales have affected overdose discharges and death associated with the drug in Scotland. METHODS: A descriptive analysis of routine death and hospital discharge data for the entire Scottish population between 1995 and 2004. Patients in Scotland participated who were discharged from hospital with a diagnosis of poisoning; deaths in Scotland from diagnosis of poisoning 1995-2003 were also analysed. Outcome measures were changes in mortality and overdose due to poisoning involving paracetamol. A comparison was made of in-hospital and out-of-hospital mortality in fatalities involving paracetamol. RESULTS: The majority of paracetamol-associated deaths were due to co-proxamol. Deaths associated with paracetamol alone or with ethanol occurred principally in hospital and were a minority of deaths overall. The proportion of in-hospital deaths attributed to paracetamol increased (post/pre ratio 1.347; 95% confidence interval 1.076, 1.639; P = 0.013). Overall numbers of cases discharged with poisoning fell. The proportion of these involving paracetamol in any form increased significantly in all groups except young men aged 10 to <20 years. CONCLUSIONS: Legislation has not reduced mortality or proportional use of paracetamol in overdose, both of which appear to have increased in Scotland since pack-size limitations. Other approaches are necessary to reduce the death rate from overdoses involving paracetamol.

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Neutralizing antibodies (Abs) are the principal protective mechanism against disease caused by reinfection with viruses. Ab-mediated neutralization of viruses is a complex process comprising multiple mechanisms. Every structural aspect of Abs is potentially capable of modulating the level of neutralizing activity or the mechanisms of neutralization. The focus of our laboratory is to understand the genetic and structural basis of Ab-mediated neutralization of human viral pathogens. We demonstrated the unexpected finding that virus antigen-binding fragments of Abs (Fabs) mediate potent virus neutralizing effects in vivo. This work has led to a broad investigation of the importance of the genetics, chemistry, and structure of the combining site to the neutralizing activity of antiviral Abs. Ongoing work in our laboratory reveals that effect or functions specified by the Ab isotype such as polymer formation, interactions with complement, interactions with Fc receptors, and the ability to transcytose mucosal epithelia, also modulate the mechanism and level of neutralizing effects mediated by antiviral Abs.

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AIMS: In man a neurokinin-1 (NK1) receptor antagonist has previously been shown to be ineffective in the prevention of motion-induced nausea. The antiemetic efficacy of NK1 receptor antagonists against chemotherapy-induced emesis is, however, enhanced when combined with a 5-HT3 receptor antagonist. Hence the efficacy of the NK1 antagonist GR205171 in combination with the 5-HT3 antagonist ondansetron (Zofrantrade mark) was assessed in motion-induced nausea. METHODS: GR205171 25 mg i.v., with and without concomitant administration of ondansetron 8 mg i.v., and hyoscine hydrobromide 0. 6 mg orally (positive control) were compared with placebo in a model of motion-induced nausea. The study was performed to a four-period, randomized, balanced, double-blind, crossover design in 16 healthy subjects. The end-point was the exposure to the motion stimulus required to produce moderate nausea in the subjects. RESULTS: The motion stimulus required to produce moderate nausea was significantly greater for the positive control than placebo (P < 0. 001). There was no significant difference between either GR205171 or GR205171 plus ondansetron and placebo (P = 0.648 and 0.342, respectively). CONCLUSIONS: The enhancement of NK1 receptor antagonist antiemetic activity through combination with a 5-HT3 receptor antagonist is not replicated in motion-induced nausea.

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1. Alterations in vasoreactivity and endothelial cell function could underlie some of the vascular abnormalities in diabetes. To examine aspects of these phenomena we studied the effects of 4-6 weeks streptozotocin-induced diabetes in the rat on basal and angiotensin II (AII)-stimulated prostacyclin release from isolated lung, perfused at constant flow. In addition, pressure was monitored throughout the lung perfusion as an index of vasomotor tone. 2. The experiment also included lungs from groups of diabetic rats treated with either insulin or an aldose reductase inhibitor (imirestat), to determine whether these treatments influenced the development of any defects seen in untreated diabetes. 3. Despite some indication of a trend towards reduced prostacyclin release in lungs from diabetic rats, neither the basal nor AII-stimulated release was significantly different from that seen in tissues from control animals. There were no significant differences between groups in the average basal perfusion pressure and in either the absolute pressure response to AII or the time of this peak. 4. The area under the perfusion pressure curve during AII infusion was greater in lungs from diabetic animals than in controls indicating a prolonged vasoconstrictor response. This increased pressor response may indicate increased sensitivity of diabetic tissue to AII or a reduced production of vasodilators in response to the vasoconstriction. 5. Whichever mechanism was responsible, this alteration was prevented by insulin treatment but not by aldose reductase inhibition, implicating mechanisms probably unrelated to exaggerated polyol pathway flux.

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Perturbation of the T lymphocyte antigen receptor/CD3 complex or phorbol ester stimulation leads to activation of phospholipase D in the Jurkat T lymphocyte cell line. These observations suggested that phospholipase D activation might result from activation of protein kinase C. In other systems, phospholipase D activity has been shown to be under G-protein or protein kinase C control. Studies detailed here demonstrate that commonly used inhibitors of protein kinase C had unrelated, diverse effects on phospholipase D activity in T lymphocytes. However, protein kinase C down-regulation resulting from prolonged cellular exposure to phorbol esters led to abrogation of anti-CD3-stimulated phospholipase D activation. The results presented underline the complexity of studies employing inhibitors of protein kinase C, suggest interesting approaches to isolation of phospholipase D dependent signalling pathways, confirm that T cell antigen receptor-linked activation of phospholipase D is dependent upon protein kinase C activity and suggest that distant events of T lymphocyte activation are dependent upon the establishment of a positive feedback loop involving protein kinase C and phospholipase D which would result in the prolonged activation of protein kinase C required for certain lymphokine production.

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Bacterial plaque which had accumulated for 0.5, 1, 2, 4, 7, 14 and 28 days was cultured from the labial surface of one of the central incisor teeth in 15 monkeys (Macaca fascicularis). Each sampling area was defined by a metal well contained within a custom-made removable acrylic block. The number (log10) of the total colony forming units (c.f.u.) increased significantly from 3.40 to 6.02 between 0.5 and 28 days. Similarly the number of streptococci increased from 2.80 to 4.79 during the same period, although when expressed as a percentage of the total c.f.u., the proportions decreased from 34.9 per cent at 1 day to 6.9 per cent at 7 days and then remained at that level. The number of micro-aerophilic actinomyces increased throughout the period of plaque accumulation and comprised 15.3 per cent of the total c.f.u. at 28 days. Neisseriae were infrequently isolated from 0.5- and 1-day-old plaque and were not recovered at more than 1 per cent of the total c.f.u. during any period of plaque accumulation. The fastest doubling time (median) of the total c.f.u. was 1.9 h (range 1.3-18.5 h). The rapid development of dental plaque after tooth cleaning emphasizes the importance of regular and meticulous oral hygiene to control the accumulation of potentially periodontopathic and cariogenic bacteria.

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A number of cellular signaling systems are called into play by interaction of the T lymphocyte antigen receptor/CD3 complex with its cognate antigen. Well-described signaling systems include phosphoinositide turnover, tyrosine phosphorylation, protein kinase C activation, and increased cytosolic calcium. We have explored the possibility that another recently described signaling system, activation of phospholipase D, may be operative. Data presented here demonstrate that stimulation of Jurkat T cells with anti-CD3 antibodies or phorbol esters resulted in activation of phospholipase D, as measured by production of phosphatidylethanol and phosphatidic acid. The combination of anti-CD3 antibody plus phorbol ester led to a greater than additive production of phosphatidylethanol and to the additive production of phosphatidic acid (in the absence of ethanol). Phorbol esters as a second stimulus with anti-CD3 antibody led to a additive increase in cellular diacylglycerol content but provided no increased production of inositol phosphates, suggesting that diacylglycerol production in these cells results from hydrolysis of noninositol containing lipids as well as from phosphinositides. Exogenous addition of phosphatidic acid led to increases in cytosolic calcium that, depending on the concentration used, resulted from release of an intracellular store of calcium and influx of extracellular calcium. Changes in cytosolic calcium occurred in the absence of inositol phosphates production. These studies establish a role for increased phospholipase D activity in T lymphocyte activation.

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We have developed a method for using short (30-42 base pair) synthetic oligonucleotide DNA probes in Northern blot assays. The method involves labeling the probes to high specific activity, very stringent hybridization and wash conditions, and the presence of several inhibitors of nonspecific binding in the hybridization buffer. We have tested this method with several probes obtained from local and commercial sources. The results with every probe used were high signal-to-noise ratios in an exposure time range of 30 min to 7 days.

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The generation of LTB4 by peripheral blood neutrophils (PMN) isolated before and for as long as 6 h after exercise-induced asthma (EIA) has been analyzed. Three and 6 h after the development of EIA, PMN isolated from 10 asthmatic subjects and stimulated in vitro by 2 x 10(8) and 4 x 10(8) zymosan particles per 2 x 10(6) PMN demonstrated a 12- and 4-fold enhancement, respectively, in the production of immunoreactive LTB4 as compared with PMN isolated before exercise. At 6 h after EIA, there was a redistribution of generated LTB4 such that 30 to 40% of LTB4 produced by zymosan-activated PMN was released extracellularly as compared with 10% before exercise. There was no significant enhancement in the generation of LTB4 by unstimulated PMN at any time point after exercise. Resolution by reverse-phase high performance liquid chromatography (HPLC) of products from [3H]arachidonic-acid-labeled and zymosan-activated PMN demonstrated that, in addition to LTB4, there was enhanced metabolism to 6-trans-LTB4, omega-oxidation metabolites of LTB4 and 5-HETE. Stimulation of PMN with 10 microM A23187 revealed a 2-, 6-, and 5-fold enhancement in the production of LTB4, 6-trans-LTB4, and 5-HETE, respectively, at 6 h after EIA, as measured by integrated ultraviolet absorbance after HPLC. There was no significant enhancement in LTB4 generation by PMN in 6 asthmatic subjects after methacholine-induced bronchospasm, and after exercise in 6 subjects who did not develop asthma. The augmentation of PMN LTB4 generation in EIA correlated with the extent of the early decrease in SGaw.(ABSTRACT TRUNCATED AT 250 WORDS)

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Serum neutrophil chemotactic activity (NCA) and plasma histamine concentrations were measured in 9 asthmatic subjects with exercise-induced asthma after inhalation challenge with ultrasonically nebulized 3.6% hypertonic saline, which was administered either in a dose-dependent manner (HSDR) or as a continuous single dose (HSC), and after cycle ergometer exercise. The mean decreases in FEV1 elicited by HSDR, HSC, and exercise were 26, 27, and 25%, respectively, and were not significantly different. There was an approximate 300% maximal increase in NCA detected after both HSC and exercise challenges. Gel filtration chromatography on columns of Ultragel ACA 34 indicated that the NCA released after HSC provocation and exercise were 600 to 700 kDa. There was an approximate 100% maximal increase in NCA after HSDR challenge, and this was significantly less (p = 0.016) than that after HSC and exercise. Exercise but not hypertonic challenge was associated with a basophilia and a significant increase in plasma histamine. There was a significant increase in plasma norepinephrine concentrations after exercise but not after HSC challenge in 7 asthmatics. Epinephrine concentrations did not change after exercise or HSC inhalation. NCA was measured in 5 subjects subjected to 2 HSC challenges that were separated by 60 min. There was an increase in NCA detected after both provocations. The increase after the second challenge was significantly greater (p = 0.27 x 10(-4)) than that observed after the initial provocation, despite a substantially reduced bronchoconstrictor response after the second challenge.

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Recruitment of inflammatory leucocytes to the airways may play a part in the pathogenesis of asthma. As dietary enrichment with fish oil lipids can suppress leucocyte function, the effect of these lipids on asthma control and neutrophil function was studied in 20 subjects with mild asthma. Twelve subjects received capsules containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid daily and eight subjects received placebo capsules containing olive oil for 10 weeks in a double blind fashion. Baseline specific airways conductance, airways responsiveness to histamine and exercise, diurnal peak expiratory flow, symptom scores, and bronchodilator use were measured. Neutrophil fatty acid composition was evaluated by gas chromatography, calcium ionophore induced neutrophil leukotriene (LT)B4 and LTB5 generation were measured by reverse phase high performance liquid chromatography and radioimmunoassay, and neutrophil chemotactic responses to formyl-methionyl-leucyl-phenylalanine (FMLP) and LTB4 were assessed by a microchemotaxis technique. Although the fish oil supplemented diet produced a greater than 10 fold increase in the eicosapentaenoic acid content of neutrophil phospholipids, there was no significant change in airways responsiveness to histamine or any change in any of the clinical measurements. After dietary supplementation with fish oil there was a 50% inhibition of total LTB (LTB4 + LTB5) generation by ionophore stimulated neutrophils and neutrophil chemotaxis was substantially suppressed. Neutrophil function remained unchanged in the placebo group. It is concluded that in subjects with mild asthma a fish oil enriched diet attenuates neutrophil function without changing the severity of asthma.

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Twelve patients with active rheumatoid arthritis supplemented their usual diet with 20 gm of Max-EPA fish oil, daily, for 6 weeks. Following this supplementation, the ratio of arachidonic acid to eicosapentaenoic acid in the patients' neutrophil cellular lipids decreased from 81:1 to 2.7:1, and the mean generation of leukotriene B4 (with calcium ionophore stimulation) significantly declined by 33%. The mean neutrophil chemotaxis to both leukotriene B4 and FMLP significantly increased toward the normal range at week 6. The generation of 5-lipoxygenase products by calcium ionophore-stimulated monocytes was not significantly suppressed, but a significant decline (37%) in platelet-activating factor generation was noted at week 6. The modulation of these measures of leukocyte inflammatory potential suggests that fish oil supplementation may have an antiinflammatory effect.

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Blood velocities have been measured transcranially, at small Doppler angles, in the middle cerebral artery of normal volunteers. Cerebral blood flow was changed by varying carbon dioxide tension. In four volunteers, the relationships between arterial pCO2 and percentage change in intensity weighted mean, median, and maximum Doppler-shifted frequencies in the internal carotid and middle cerebral arteries were linear with slopes of 2.5 and 2.8% per mm Hg change in pCO2. In 38 volunteers, the relationship between end-expiratory pCO2 and time-averaged maximum Doppler frequency was linear over the range of pCO2 20-60 mm Hg with slopes of 2.5 and 2.9 percentage change per mm Hg, for internal carotid and middle cerebral, respectively. These results are very similar to those reported using direct methods of measuring cerebral blood flow. As the transcranial Doppler method is reproducible, this indicates that changes in middle cerebral blood velocity may be used to monitor changes in flow.

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Using an Arabic version of the PSE, supplemented by CATEGO, we selected 48 patients with acute schizophrenia from the population of the Najd region of Saudi Arabia. Their life-event histories for the six months before onset or relapse were compared with those of 62 control subjects. A positive association between events and onset was established only for married women, although there was a parallel trend for men and single women suffering their first schizophrenic episode. The observed impact of life events was limited to the three weeks before onset. These findings are discussed in the light of Saudi culture.

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Plasma concentrations of glucagon, growth hormone and glucose were measured hourly during an ordinary treatment day in 11 Type 1 (insulin-dependent) diabetic patients with high glomerular filtration rate, 11 Type 1 diabetic patients with normal glomerular filtration rate matched for age, diabetes duration and sex, and five healthy control subjects, simultaneously with the measurement of the glomerular filtration rate using 51Cr EDTA clearance. Plasma glucagon profiles were not statistically distinguishable (p = 0.49) from control values in either group, although they were somewhat lower in the hyperfiltering group. Plasma growth hormone values were higher than control (p = 0.07) in both diabetic groups, but were not different between these two groups (p = 0.94). All indices of glycaemic control (glycosylated haemoglobin, urinary glucose excretion, and plasma glucose concentration) were higher in the hyperfiltering group, although no single index reached statistical significance. No correlations between concentrations of these substances and glomerular filtration rate were found. Elevated plasma concentrations of glucagon and growth hormone do not characterise those diabetic patients with high glomerular filtration rate.

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Axillary 5 alpha-androst-16-en-3-one (5 alpha-androstenone) levels were found to be significantly higher in men than in women but do not vary between left and right axillae, are not related to age, handedness or degree of hirsutism (in women) nor to anosmia to this steroid. In men (but not in women), levels are related linearly to axillary cholesterol concentrations but not to squalene. Olfactory thresholds for 5 alpha-androstenone varied widely, the lowest recorded being 0.2 ppb, but there was no difference in thresholds between men and women. Women (70%) found the smell 'repellant' but anosmia did not differ greatly between men and women (9-20%). Anosmia to the smell of 5 alpha-androst-16-en-3 alpha-ol was most marked in women (90%) rather than in men (45%). Axillary 5 alpha-androstenone values were generally consistent with the 'musky' or 'strong' smells of male axillary extracts, compared with the 'sweet' smell of those from female subjects.

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Detailed analyses were carried out in 207 fasting gastric juice samples obtained at endoscopy or with a nasogastric tube from 50 patients with partial gastrectomy, 43 with vagotomy, 20 with gastric carcinoma and 50 controls. Significantly higher mean pH, nitrite and N-nitroso compound (N-NO) concentrations and nitrate-reducing bacterial cultures were noted following partial gastrectomy compared with normal controls and comparable to findings in gastric cancer. A highly significant relationship (p less than 10(-6)) was also demonstrated between pH and N-NO concentrations, highest levels of which were seen following Billroth II gastrectomy, significantly higher (p = 0.02) than Billroth I, whereas the only change observed following proximal gastric vagotomy was a nearly threefold rise in N-NO compared with normal controls. However, vagotomy and pyloroplasty produced gastric juice changes comparable to those seen with gastrectomy and gastric carcinoma. Thus, the most marked changes were observed following surgical procedures involving increased enterogastric reflux and these findings lend further support to the possible involvement of N-nitroso compounds in the development of gastric cancer following both Billroth I and II gastrectomy and vagotomy with pyloroplasty.

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