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Uncontrolled host immunological reactions directed against tissue-trapped eggs precipitate a potentially lethal, pathological cascade responsible for schistosomiasis. Blocking schistosome egg production, therefore, presents a strategy for simultaneously reducing immunopathology as well as limiting disease transmission in endemic or emerging areas. We recently demonstrated that the ribonucleoside analogue 5-azacytidine (5-AzaC) inhibited Schistosoma mansoni oviposition, egg maturation and ovarian development. While these anti-fecundity effects were associated with a loss of DNA methylation, other molecular processes affected by 5-AzaC were not examined at the time. By comparing the transcriptomes of 5-AzaC-treated females to controls, we provide evidence that this ribonucleoside analogue also modulates other crucial aspects of schistosome egg-laying biology. For example, S. mansoni gene products associated with amino acid-, carbohydrate-, fatty acid-, nucleotide- and tricarboxylic acid (TCA)- homeostasis are all dysregulated in 5-AzaC treated females. To validate the metabolic pathway most significantly affected by 5-AzaC, amino acid metabolism, nascent protein synthesis was subsequently quantified in adult schistosomes. Here, 5-AzaC inhibited this process by 68% ±16.7% (SEM) in male- and 81% ±4.8% (SEM) in female-schistosomes. Furthermore, the transcriptome data indicated that adult female stem cells were also affected by 5-AzaC. For instance, 40% of transcripts associated with proliferating schistosome cells were significantly down-regulated by 5-AzaC. This finding correlated with a considerable reduction (95%) in the number of 5-ethynyl-2'-deoxyuridine (EdU) positive cells found in 5-AzaC-treated females. In addition to protein coding genes, the effect that 5-AzaC had on repetitive element expression was also assessed. Here, 46 repeats were found differentially transcribed between 5-AzaC-treated and control females with long terminal repeat (LTR) and DNA transposon classes being amongst the most significant. This study demonstrates that the anti-fecundity activity of 5-AzaC affects more than just DNA methylation in schistosome parasites. Further characterisation of these processes may reveal novel targets for schistosomiasis control., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database., Patients and Methods: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors., Results: Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04)., Conclusions: Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC., Patients and Methods: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome., Results: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02)., Conclusions: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

Considerable epidemiological, experimental and clinical data have amassed showing that the risk of developing disease in later life is dependent upon early life conditions. In particular, altered maternal nutrition, including undernutrition and overnutrition, can lead to metabolic disorders in offspring characterised by obesity and leptin resistance. The adipokine leptin has received significant interest as a potential programming factor; alterations in the profile of leptin in early life are associated with altered susceptibility to obesity and metabolic disorders in adulthood. Maintenance of a critical leptin level during early development facilitates the normal maturation of tissues and signalling pathways involved in metabolic homeostasis. A period of relative hypo- or hyperleptinemia during this window of development will induce some of the metabolic adaptations which underlie developmental programming. However, it remains unclear whether leptin alone is a critical factor for the programming of obesity. At least in animal experimental studies, developmental programming is potentially reversible by manipulating the concentration of circulating leptin during a critical window of developmental plasticity and offers an exciting new approach for therapeutic intervention., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Associations between vascular disease and ABO(H) blood groups have a long history, but no consensus exists regarding its magnitude and significance, or whether it relates to all disorders equally. An accurate calculation of risk would allow direct assessment of whether the effects of non-O status on thrombosis risk are of the magnitude predicted by its effect on von Willebrand factor/FVIII levels., Methods and Results: We conducted a systematic review and meta-analysis of studies reporting associations with non-O blood groups. This gave pooled odds ratios of 1.25 [95% confidence interval (CI) 1.14-1.36] for myocardial infarction (MI), 1.03 (95% CI 0.89-1.19) for angina, 1.45 (95% CI 1.35-1.56) for peripheral vascular disease, 1.14 (95% CI 1.01-1.27) for cerebral ischemia of arterial origin, and 1.79 (95% CI 1.56 to 2.05) for venous thromboembolism (VTE). However, restriction to prospective MI studies only did not confirm the association (OR 1.01; 95% CI 0.84-1.23), although these studies may have failed to capture early-onset disease. For VTE, using a combined group of OO/A(2)A(2)/A(2)O as index, the combination of A(1)A(1)/A(1)B/BB gave an OR of 2.44 (95% CI 1.79-3.33) and A(1)O/ BO/A(2)B an OR of 2.11 (95% CI 1.66-2.68)., Conclusions: This study confirms the historical impression of linkage between some vascular disorders and non-O blood group status. Although the odds ratios are similar to those predicted by the effect of ABO(H) on von Willebrand factor levels, further work is required to assess risk prospectively and to refine the effect of reducing O(H) antigen expression on thrombosis. However, as non-O and particularly A(1)A(1), A(1)B, BB constitute a significant proportion of the population attributable fraction of VTE, there may be a role for more widespread adoption of ABO(H) typing in testing strategies.

Background and Objectives: Patients with myeloproliferative disease (MPD) have an increased risk of thrombosis. We studied markers of platelet and coagulation activation in a large cohort of patients with MPD (n = 118) and related this to Janus Kinase 2 (JAK2) V617 F mutation status, a marker of clonality, and the presence of antiphospholipid antibodies (APA), all of which have been associated with thrombosis in MPD., Methods: D-dimer, thrombin-antithrombin complexes (TAT), prothrombin fragments 1 + 2 (F(1+2)), soluble E-selectin (sE-selectin), and soluble P-selectin (sP-selectin) levels were compared between patients and hypertensive controls (n = 127). Assays for lupus anticoagulant (LA), anticardiolipin antibodies (ACA), antibeta2 glycoprotein 1 antibodies (anti-beta(2)GP1), and antiprothrombin antibodies (alpha-Pro) were also performed. The JAK2 V617F mutation status was determined in the cohort using amplification refractory mutation system (ARMS) polymerase chain reaction. Disease clonality was determined in 54 patients using the HUMARA assay., Results: sP-selectin was significantly increased in patients with MPD (P

The only evidence in favour of the provision of assistance for anaesthesiologists seems to be that single-handed anaesthesiologists generate higher anaesthetic mortality than does a team system. In mainland Europe, the independent scope of the practice of nurse anaesthetists has been constrained while possible new roles for nurses have been suggested in the United Kingdom. In the USA, Anesthesiology Assistants are developing as an alternative to nurse anesthetists. The current fluidity will probably settle in Europe into a cadre of Assistant Anaesthetists, predominantly drawn from graduate nurses but with some graduates in biological or medical sciences, receiving a further 2-year specialist training. To attract people of this calibre, their role will have to offer some degree of clinical autonomy over the management of general anaesthesia. Considerations of safety will constrain this autonomy but the introduction of a monitor of anaesthetic depth and sophisticated communication systems will relieve anxiety about this development.

Skewed X-chromosome inactivation in peripheral blood granulocytes becomes more frequent with increasing age, affecting up to half of those over 75 years old. To investigate the mechanisms underlying this phenomenon, X-inactivation profiles in 33 monozygotic and 22 dizygotic elderly twin pairs were studied. Differential methylation-sensitive restriction enzyme cutting at a hypervariable locus in the human androgen receptor gene (HUMARA) was studied on purified granulocytes using T cells as controls. A large genetic effect on skewed granulocytic X inactivation was shown (P <.05); heritability was estimated to be 0.68. A minor part (SD.0151 relative allele frequency [ie, larger/smaller] units) of the observed variance is due to experimental error. A further contributor to acquired skewing is stochastic asymmetric stem cell division, which was modeled and shown as unlikely to account for a substantial part of variance. Two monozygotic twin pairs had X-inactivation ratios skewed markedly in opposite directions, evidence for a further stochastic mechanism, suggestive of a single overrepresented clone. In conclusion, all 3 suggested mechanisms contribute to acquired X inactivation but the dominant mechanism is genetic selection. The observed proportion of putatively clonal hematopoiesis is similar to the lifetime incidence of hematopoietic stem cell malignancy consistent with the concept that clonal hematopoiesis precedes stem cell malignancy.

Background: Previous work has suggested that the long-term regular use of inhaled beta2-agonist bronchodilators might lead to a deterioration in asthma control. The aim of TRUST (The Regular Use of Salbutamol Trial) was to study the effects of regular use of inhaled salbutamol, the most widely prescribed bronchodilator in the UK, on the control of asthma., Methods: A randomised, double-blind, placebo-controlled trial was undertaken in 983 patients with asthma being treated at least twice a week with short-acting beta2-agonist, alone or in combination with inhaled steroids (2 mg or less) daily. Patients were aged 18 years and over and were recruited from 115 general practices in the UK. 90% (881) of the patients used inhaled corticosteroid therapy, and all patients continued to use their usual inhaled beta2-agonist for symptomatic relief. Patients were randomised to receive 400 microg salbutamol or matched placebo via a Diskhaler four times per day for 12 months. The primary outcome measure was rate of exacerbations of asthma, with criteria based on data from diary cards completed daily by each patient, treatment with additional corticosteroids, or both., Findings: There were no differences in the annual rate, timing, or duration of exacerbations between the two groups. The mean morning peak expiratory flow was similar for the two groups. The mean evening peak expiratory flow (p<0.001) and the diurnal variation (p<0.001) were greater, and the use of rescue bronchodilator was less (p<0.001), in the group receiving regular salbutamol., Interpretation: There was no evidence that regular use of inhaled salbutamol 400 microg four times daily for a year increased the exacerbation rate of asthma in the population studied.

To evaluate new therapeutical concepts for male subfertility, we tested the effects of exogenous recombinant bovine growth hormone (rbGH) on various endocrine and metabolic parameters both in blood and in seminal plasma of bulls. Sperm quality was assessed morphometrically and by monitoring the number of successful artificial inseminations (AIs) defined as non-return rates (NRR). Aliquots of 450 semen samples were used from each bull and each experimental period (4 wk before, 14 weeks during and 6 wk after treatment). Six out of ten sires (average age 8.4 years) were treated every two weeks with 640-mg depot formulated rbGH (Eli Lilly). Four bulls received vehicle only. Blood plasma bGH, IGF-I, insulin and glucose concentrations were increased with rbGH treatment. In seminal plasma there was no effect of rbGH treatment on fructose and citrate or on testosterone concentrations. With one exception, rbGH-treated bulls had greater IGFBP-3 concentrations in seminal plasma. Motility of spermatozoa after freezing and thawing was increased compared with pretreatment rates. Most interestingly, the number of successful AIs was increased by an average of 6.0% NRR when ejaculates from rbGH-treated bulls were used.

It has recently been shown that short-term growth hormone (GH) treatment can increase the motility of spermatozoa in the GH-deficient dw/dw rat. To examine whether the effects of GH on motility of immature spermatozoa are mediated by an increase in plasma concentrations of IGF-I, we treated GH-deficient dw/dw rats with 2 microg/g/day of IGF-I using osmotic minipumps. Body weight (saline 227+/-5 g, IGF-I 253+/-4 g) and IGF-I concentrations in blood plasma (saline 472+/-19.9 ng/ml, IGF-I 986+/-43.6 ng/ml) and seminal vesicle fluid (saline 30.9+/-1.7 ng/ml, IGF-I 47.9+/-2.9 ng/ml) were significantly increased with IGF-I treatment (P<0.001), similar to the observed responses to GH therapy in our earlier study. While epididymal fluid IGF-I concentrations were not changed, IGF-I treatment significantly increased the number of immature motile spermatozoa (saline 14.4+/-3.5%, IGF-I 28.3+/-4.1%, P<0.05) and the number of spermatozoa with normal morphology (control 65.7+/-3.3%, IGF-I 75+/-1.9%, P<0.05). These data suggest that increasing the circulating concentrations of IGF-I in the GH-deficient rat can improve the motility and morphology of immature spermatozoa and thus mimic, at least in part, the effects of GH., (Copyright 1999 Harcourt Publishers Ltd.)

ND4 is a mitochondrially encoded component of NADH dehydrogenase (Complex I) of the respiratory chain. A cDNA encoding a fusion protein comprised of the N-terminus of GAL10 of Saccharomyces cerevisiae and an N-terminally truncated form of human ND4 was isolated by its ability to functionally complement the thymidine transport deficiency of S. cerevisiae grown under conditions of thymidylate starvation. Epitope-tagged GAL10-ND4 was shown by immunological methods to be present in the plasma membranes of yeast expressing the GAL10-ND4 encoding cDNA. The ability of the GAL10-ND4 fusion protein to induce uptake of thymidine raises the possibility that native ND4, which is predicted to have 12 transmembrane domains, may function as a transporter or channel in the mitochondrial inner membrane.

We hypothesized that the increased glomerular permeability to serum proteins in the nephrotic syndrome might lead to alterations of the somatotropic hormone axis, thereby contributing to growth failure and catabolism in the nephrotic state. The insulin-like growth factors (IGF)-I and -II and the IGF binding proteins (IGFBP)-1, -2 and -3 were analyzed in serum and urine of 21 children with the nephrotic syndrome and normal glomerular filtration rate. Mean age-related serum IGF-I levels by RIA (-0.53 +/- 0.34 SD) were slightly, but significantly (P < 0.05) decreased compared with the reference population, whereas mean age-related serum IGF-II levels (0.68 +/- 0.21 SD) were slightly, but significantly (P < 0.005) increased. The urinary excretion rate of both peptides was enhanced fivefold. By RIA, mean age-related serum IGFBP-1 (2.05 +/- 0.19 SD) and, even more pronounced, IGFBP-2 (5.97 +/- 0.65 SD) were clearly elevated despite a 12-fold and 2-fold increase of the respective urinary excretion rate. There was a tight and specific correlation between age-related serum IGFBP-2 levels and the degree of the nephrotic syndrome, as estimated by serum albumin levels (r = -0.78, P < 0.0001). Serum immunoreactive IGFBP-3 levels were also elevated (1.79 +/- 0.33 SD) in nephrotic serum, due to an increase of low-molecular weight IGFBP-3 fragments. By FPLC analysis, there was a decrease of the 150 kDa IGFBP ternary complex in nephrotic serum, which in the presence of normal concentrations of the acid-labile subunit by RIA appears to be due to a reduction of intact IGFBP-3. Serum levels of the high-affinity GH binding protein that presumably reflects GH receptor status in tissues were normal. In summary, total serum IGFs in children with the nephrotic syndrome are normal, but the binding of IGFs to IGFBPs in the circulation is altered with a shift from the 150 kDa IGFBP complex to an excess of low molecular weight IGFBPs. Because increased unsaturated high-affinity IGFBPs in nephrotic serum have the ability to inhibit IGF action on target tissues by competing with the type 1 IGF receptor for IGF binding, this alteration is likely to contribute to growth failure and tissue catabolism in the nephrotic state.

Intermittent injection of liquid anaesthetic into a closed breathing system is particularly suitable in countries with limited resources. A method of calculating appropriate times and magnitudes of the injected doses was described by Lowe but the method has never been assessed rigorously. Such an assessment was the purpose of this study. The technique was used in a double-blind, randomized comparison of halothane, enflurane and isoflurane in oxygen-air, with 20 ASA I or II patients in each group, undergoing superficial or abdominal surgery. The prescribed times of injection were adhered to, but the doses, after the first two, were adjusted to maintain systolic arterial pressure within 20% of the reference preoperative value. Partial pressures of the anaesthetics were monitored but concealed from the investigator-anaesthetist. The mean doses found necessary for each anaesthetic were within 33% of those calculated to produce 1.3 MAC. However, end-tidal partial pressure (just before each dose) stabilized at a steady level of only 0.97, 0.42 and 0.77 MAC for halothane, enflurane and isoflurane, respectively. Recovery from enflurane was much more rapid than that from the other agents but no patient admitted to any dreams. We conclude that the rate of uptake of anaesthetic declines more slowly than predicted and that the patients receiving enflurane were less deeply anaesthetized because the greater hypotensive effect of enflurane led to the use of smaller doses.

We have compared propofol concentrations in arterial and arterialized venous blood (from the radial artery at the wrist and a vein in the opposite forearm) in five volunteers during a sub-anaesthetic increasing infusion regimen designed to produce pseudo-steady-state arterial concentrations of 0.06, 0.17 and 0.43 micrograms ml-1. As in a previous study, we found no statistically significant difference between sampling sites (P = 0.66). However, changes in the method of arterialization yielded a reduction in the observed variability, with the arterialized venous propofol concentration lying within +/- 23% (95% reference interval) of the corresponding arterial concentration compared with 1 +/- 43%, as reported previously.

We have investigated the effects of 9.5% and 14.1% MAC concentrations of isoflurane on some psychometric measurements. Both concentrations depressed peak saccadic velocity (P < 0.01), choice reaction time (P < 0.05) and visual analogue scores for sedation (P < 0.05), but not the critical flicker fusion threshold. The incidence of errors in saccade tasks increased in a dose-related fashion, which made analysis of peak saccadic velocity less accurate at more than 10% MAC. The percentage error itself was an indicator of the depth of sedation. All the objective measures correlated highly with the estimated brain tension of isoflurane (r2 = 0.86-0.96), but not the visual analogue score for sedation (r2 = 0.51). This suggests that a combination of peak saccadic velocity, percentage error and choice reaction time is a potentially useful batch of tests to measure recovery from anaesthesia.

Obesity is a complex health problem and, because of the incidence of obesity in women, a common concern for providers of women's health care. For many women, obesity becomes an obsession that leads to physiologic, psychologic, and social problems. To address the needs of the obese client better, nurses must acquire a comprehensive, research-based understanding of obesity. To develop a nursing care plan, the nurse must assess the client's diet history, level of motivation to effect a change in life-style, self-image, and self-esteem.

We have investigated the effect of 4.7 and 8.8% MAC of cyclopropane, and 5.3 and 9.3% MAC of halothane on the peak velocity of saccadic eye movements (PSV) in six healthy volunteers. Both concentrations of cyclopropane and halothane significantly depressed PSV (P less than 0.01) compared with air, in a dose-related fashion. Halothane depressed PSV significantly more than cyclopropane (P less than 0.05). PSV returned to baseline within 5 min after discontinuation of the agents. There was no significant difference between cyclopropane, halothane and air in subjective assessment of sedation.

Seven patients received a series of low-dose propofol infusions designed to produce three successive pseudo-steady states of arterial blood concentration: 0.06, 0.17 and 0.43 micrograms ml-1. Arterial and arterialized venous blood samples were obtained simultaneously at the end of each infusion. The results indicate that 95% of the arterialized venous concentrations may be expected to lie within 1 +/- 43% of the corresponding arterial concentration, or -5 +/- 35% if one set of measurements with poor agreement between duplicate aliquots is omitted.

Peak velocity of saccadic eye movements was studied in six healthy volunteers who were each given, on separate days, 5% and 10% MAC of nitrous oxide (5% and 10% end-tidal) or of isoflurane (0.06% and 0.12% end-tidal) or air, each gas for 25 min. Subjective assessment following each treatment was also undertaken. No significant difference was found between air and either 5% or 10% nitrous oxide. However, significant differences occurred at 15 and 25 min after 0.06% isoflurane compared with air (P less than 0.05) and highly significant differences were present 5, 15 and 25 min after 0.12% isoflurane when compared with air and nitrous oxide (P less than 0.01). In contrast, there was little difference between the three gases by subjective assessment.

We describe a family in which alpha-thalassemia occurs in association with a deletion of 62 kilobases from a region upstream of the alpha globin genes. DNA sequence analysis has shown that the transcription units of both alpha genes downstream of this deletion are normal. Nevertheless, they fail to direct alpha globin synthesis in an interspecific hybrid containing the abnormal (alpha alpha)RA chromosome. It seems probable that previously unidentified positive regulatory sequences analogous to those detected in a corresponding position of the human beta globin cluster are removed by this deletion.

The incidence of postoperative respiratory apnoea was compared between five patients receiving a continuous i.v. infusion of morphine (mean 73.6 mg) and five patients receiving a continuous extradural infusion of 0.25% bupivacaine (mean 192 mg) in the 24-h period following upper abdominal surgery. Monitoring consisted of airflow detection by a carbon dioxide analyser, chest wall movement detected by pneumatic capsules, and continuous electrocardiograph recorded with a Holter ambulatory monitor. Both obstructive (P less than 0.05) and central apnoea (P less than 0.05) occurred more frequently in patients who had a morphine infusion. There was also a higher incidence of tachyarrhythmias (P less than 0.05) and ventricular ectopic beats (P less than 0.05) in the morphine infusion group.

Meptazinol and pethidine were compared under double-blind conditions in 20 patients, using an on-demand analgesic system to provide pain relief after upper abdominal surgery. The degree of analgesia, subjectively assessed, was good with both meptazinol and pethidine; although meptazinol produced significantly more nausea than did pethidine (P less than 0.01), there was no statistically significant difference in the frequency of other side-effects. Over 24 h average consumption of meptazinol was 2.4 times that of pethidine, suggesting that, when given by i.v. injection, meptazinol is less potent that pethidine.

A double-blind comparison between buprenorphine and pentazocine was performed in 20 patients using an on demand analgesic system to provide analgesia after operation. The quality of analgesia, assessed subjectively, was good with both drugs and drug consumptions were compatible with previous potency estimates. The mean doses demanded in 24 h of buprenorphine (1.68 mg) and of pentazocine (382 mg) are consistent with those found in other trials although the between-patient variation was five- or six-fold. There was no significant difference in side-effects between the two groups. Buprenorphine and pentazocine may be used successfully in an on demand system to provide relief of severe pain after operation.

Three comparable groups of surgical patients were given nefopam 0.2 mg kg-1 or 0.4 mg kg-1 or morphine 0.15 mg kg-1 for pain relief after operation. Nefopam 0.4 mg kg-1 was equi-analgesic with morphine 0.15 mg kg-1 and produced no obvious cardiovascular or respiratory side-effects.

Premedication with nalbuphine and morphine delayed gastric emptying in the period after operation, but oral diazepam did not. All three drugs delayed co-ordinated intestinal motility, although nalbuphine did so for less than half as long as morphine. This property of nalbuphine, if confirmed, could make it a valuable analgesic drug in the period after operation.

Temazepam 0.5, 1.0 and 1.5 mg kg-1 in an elixir formulation (Euhypnos Elixir), was compared with trimeprazine tartrate 3 mg kg-1 in a syrup (Vallergan Forte Syrup), as premedication in 220 children (ASA grade I) undergoing tonsillectomy and associated procedures. Each patient was randomly allocated to one of the four treatments. The administration was blind to the observers in theatre, recovery room and postoperative ward, who assessed each patient according to a total of 14 criteria. A modelling technique allowed account to be taken of the effects of concomitant variables (e.g. age and duration of anaesthesia) where appropriate. No statistically significant difference was found between the efficacy of the treatments. The only statistically significant differences were that temazepam was associated with more ectopic beats under anaesthesia (P = 0.03 or 0.002, depending on the test applied), more postoperative vomiting (P = 0.04) and more postoperative restlessness (P less than 0.0001).

In 40 patients anaesthetized with thiopentone, 66% nitrous oxide and 1% halothane, the effects of a single i.v. dose of nalbuphine 4.5, 8, 15, 25 or 50 mg/70 kg or morphine 3, 5, 10 or 17.5 mg/70 kg on total ventilation and end-tidal carbon dioxide concentration have been measured. Depression of respiration occurred with both drugs and with all doses. The lower doses of nalbuphine produced more depression than equianalgesic doses of morphine. Conventional equianalgesic doses produced similar degrees of depression. With the highest dose of morphine, respiratory impairment progressed to apnoea whereas, with nalbuphine, apnoea did not occur in any patient. With increasing dosage of nalbuphine there appeared to be a limit to the extent of respiratory depression. The highest dose of nalbuphine produced less depression than some lower doses, suggesting a reversal effect.

An animal preparation has been developed to test therapeutic agents in the extradural and intradural spaces. Under anaesthesia a hole was drilled in the penultimate lumbar vertebra of male Wistar rats and the appropriate space cannulated. The catheter was tunnelled subcutaneously to emerge at the neck. There was no spinal cord or meningeal reaction after 1 month. Catheters remained patent for 3 months. The method of cannulation allowed free rostral spread of drugs. Using plain 2% lignocaine, paralysis and anesthesia of the hind limbs required an intradural volume of 32 +/- 3 mulitre: the required volume on extradural injection was 46 +/- 2 mulitre (P less than 0.01). Paralysis of all limbs required an intradural volume of 115 +/- 12 mulitre. Respiratory arrest and death required a mean intradural volume of 179 +/- 15 mulitre.

A high degree of safety from fires and explosions exists in operating theatres in the U.K. and this is reflected in the extremely low number of fatal and non-fatal accidents which occur. This has been achieved by safety precautions which in some respects have been over-careful and overexpensive. Antistatic precautions applied to the breathing circuit seem to have been the crucial factor in achieving this level of safety.