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Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (-28-30%), adipose tissue (-45-50%) weights and serum insulin (-22-25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes (Acaca, Fasn). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor (Fxr) signalling in the intestine and liver, and hepatic expression of fatty acid transporters (Fabp4, Vldlr, Cd36) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Osteogenesis imperfecta (OI) is an inherited disorder, which causes brittle bones resulting in recurrent fractures. The associated poor mobility of children with OI increases susceptibility to obesity, and obesity further dramatically limits mobility and increases fracture risk., Objectives: The aim of this report is to describe outcomes of weight loss surgery (WLS) in 2 adolescents with severe obesity and OI., Setting: Two University Hospitals (in the United Kingdom and in the United States)., Methods: Two cases of OI treated with WLS were identified. Pre- and postoperative anthropometric and biochemical data and clinical course were reviewed., Results: In these 2 cases, preoperative Body Mass Index (BMI) values were 38 and 46 kg/m 2 . Following laparoscopic sleeve gastrectomy (LSG), BMI decreased by 55% and 60% by 26 and 24 months, respectively. There were no surgical complications, and both patients experienced improvement in their mobility and ability to perform activities of daily living., Conclusion: WLS effectively treated severe obesity in 2 OI patients and substantially improved mobility and quality of life, theoretically reducing fracture risk., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Effective treatment of acute bleeding episodes in patients with hemophilia B relies on factor IX recovery, with higher levels being more desirable, whereas prevention of bleeds with a prophylactic regimen depends on the half-life of the product. Lower recovery values have been reported following administration of recombinant FIX (rFIX) than following administration of plasma-derived FIX (pdFIX)., Objectives: To compare the pharmacokinetic and pharmacodynamic properties of rFIX and pdFIX in patients with hemophilia B., Methods: A prospective crossover study of nine patients with moderate to severe hemophilia B was performed. Following a washout period, 50 U kg(-1) FIX was administered, and blood samples were taken as per protocol up to 48 h postinfusion. Paired data were analyzed with the Wilcoxon signed rank test., Results: Mean peak recovery at 10 min postinfusion was 62.14 IU dL(-1) with pdFIX and 52.7 IU dL(-1) with rFIX (P = 0.08). Mean half-life was 16.6 h with pdFIX and 17.5 h with rFIX (P = 0.55). Maximum peak thrombin generation (PTG) was 35.9 nm with pdFIX and 28.9 nm with rFIX (P = 0.21). Administration of rFIX resulted in early PTG, whereas administration of pdFIX resulted in slightly later and sustained PTG. At 48 h, PTG was similar with pdFIX (19.0 nm) and rFIX (19.4 nm) (P = 0.91)., Conclusions: Patients experienced better recovery with pdFIX than with rFIX. pdFIX and rFIX had similar half-lives. Maximum PTG was higher for pdFIX; however, this difference did not reach statistical significance. The clinical impact of the slightly increased, delayed and sustained PTG with pdFIX requires further investigation., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: Factor VII polymorphisms have been suggested in some studies to show an association with some aspects of coronary disease, and there is a known association between FVII levels and polymorphic variants in the gene. The aim of the study was to assess whether Factor VII polymorphism R353Q is associated with the extent of coronary artery disease in patients with chronic stable angina., Methods and Results: There is evidence that Factor VII polymorphisms are markers of susceptibility to coronary artery disease (CAD), but two studies have suggested that there is no association between the degree of vessel disease and these polymorphisms. One of these studies did not exclude patients with unstable angina or MI. We therefore set up a prospective cohort study to determine Factor VIIa, VIIc and VIIAg levels, genotype for R353Q, lipid status, smoking history and the degree of vessel disease, in patients attending the hospital for routine day case angiography over a 20 month period. From 519 cases, 400 had no previous MI or revascularisation, including 153 with zero vessel disease, and were successfully genotyped: 9 (2%) QQ, 78 (20%) RQ and 313 (78%) RR. Compared with RR subjects, heterozygotes were 2.7 years older (95% CI: 0.3, 5.0; p=0.027), but were not significantly different regarding gender, cholesterol, extent of vessel disease or smoking history. If those with vessel disease were considered, then the heterozygotes were 3.5 years older than the RR homozygotes (95% CI: 0.6-6.4, p=0.016). There was a significant association between all measures of Factor VII and the R353Q polymorphism, with the Q allele associating with lower levels. There was no significant association between the degree of vessel disease and genotype., Conclusions: The degree of vessel disease as seen at day case angiography is independent of polymorphism status, but there appears nonetheless to be a moderate protective effect of the Q allele against stable angina, in that angiographic investigation occurs a few years later for RQ heterozygotes than RR homozygotes. The effect may be mediated by reduced levels of Factor VII.

This paper reviews the available data on the prevalence of thrombophilia defects in patients with peripheral vascular disease (PVD) and attempts to delineate the risk of failure of vascular intervention in these patients. The prevalence of thrombophilia in stable claudicants is 25% and increases to 40% in those requiring revascularisation, compared to only 11% in the control group. The overall prevalence of thrombophilia defects in patients with premature atherosclerosis appears to be between 15 and 30%. The prevalence in the typical cohort of patients with PVD appears to be similar. All these studies have recruited patients with symptoms significant enough to warrant intervention. The overall prevalence of thrombophilia calculated from these trials, therefore, may not be truly indicative of the general vascular population who may not even present primary or secondary healthcare. The risk of thrombotic occlusion following arterial revascularisation in patients with an identified thrombophilia defect appears to be almost three times that of patients with no evidence of a thrombophilia defect. The best management of these patients has not been determined and needs to be evaluated by prospective randomized trials.

Treatment of painful episodes in sickle cell disease (SCD) is sometimes complicated by disputes between patients and staff and patient behaviors that raise concerns about analgesic misuse. Those concern-raising behaviors could indicate either drug seeking caused by analgesic dependence or pseudoaddiction caused by undertreatment of pain. To make a systematic assessment of concern-raising behaviors and examine their associations with other factors, including DSM-IV symptoms of substance dependence, individual, in-depth interviews with SCD patients were conducted to apply pre-established criteria for concern-raising behaviors. These included disputes with staff tampering with analgesic delivery systems, passing prescribed analgesics from one person to another, being suspected or accused of analgesic misuse, self-discharging from hospital, obtaining analgesic prescriptions from multiple sources, using illicit drugs, and injecting analgesics. Assessments were also made of pain-related symptoms of substance dependence (where behaviors resemble substance dependence but reflect attempts to manage pain, increasing the risk of pseudoaddiction), non-pain-related symptoms of substance dependence (where substance dependence reflects analgesic use beyond pain management), and pain coping strategies (using the Pain Coping Strategies Questionnaire). Inter-rater reliability for the assessment of concern-raising behaviors was high, with Kappa coefficients of 0.63 to 1.0. The most frequent concern-raising behaviors were disputes with staff about pain or analgesics. The least frequent were tampering with analgesic delivery systems and passing analgesics between patients in hospital. The odds of concern-raising behaviors in hospital were raised eightfold by less use of ignoring pain as a coping strategy, and more than doubled by each additional pain-related symptom of substance dependence. Non-pain-related symptoms of substance dependence had no independent effect on concern-raising behaviors. Concern-raising behaviors were more closely associated with pain behaviors that make patients vulnerable to misperceptions of substance dependence than they were with genuine substance dependence. The results show how pseudoaddiction can adversely influence hospital pain management, and suggest that more emphasis should be placed on patients' pain and analgesic needs when responding to concern-raising behaviors in hospital.

A number of studies have shown elevated matrix metalloproteinase expression in chronic wound fluid compared to an acute wound; however, little has been done to characterize animal models in a similar manner and thus determine their usefulness. The diabetes mouse is an animal model of type II diabetes that shows impaired dermal wound healing and has been proposed as a model of human impaired wound healing. In this study we have determined the mRNA and protein expression profiles of matrix metalloproteinases 2, 3, and 9 during the first 10 d of dermal healing for the diabetes mouse and its normally healing littermate. Additionally, human wound fluid from diabetic chronic wounds and acute surgical wounds were studied to enable a comparison of the model to the human condition. We show that during the early stages of wound healing the diabetes mouse possesses significantly reduced protein levels of pro-matrix metalloproteinases 2 and 9 within the wound tissue and active matrix metalloproteinase 3 within the fluid. Pro-matrix metalloproteinase 3 levels are also significantly reduced in the diabetes mouse during the later stages of healing. These differences may be contributing to the impaired healing of the diabetes mouse; however, they differ from the human data presented here, which show elevated matrix metalloproteinase 2 and reduced matrix metalloproteinase 9 in human diabetic chronic wound fluid compared to acute wound fluid. Therefore, although clearly showing the importance of appropriate matrix metalloproteinase regulation for normal acute wound healing to occur, the diabetes mouse may not be an ideal model for study of matrix metalloproteinase involvement in human chronic wound healing.

Heparin is the standard anticoagulant for patients undergoing cardiopulmonary bypass. There are some patients for whom heparin is unsuitable and ancrod (a defibrinogenating enzyme) has been used as an alternative. We present a patient with heparin-induced thrombocytopenia in whom treatment ancrod was ineffective. The addition of danaparoid sodium (a heparinoid) allowed safe cardiopulmonary bypass. We discuss the reasons for this and suggest that the combination of ancrod and danaparoid sodium is a logical one in such cases.

For more than 40 years, succinylcholine has been the traditional choice of muscle relaxant to facilitate tracheal intubation, particularly for anesthesia in the emergency patient with a full stomach. This presentation reviews factors that determine the onset of neuromuscular blockade, particularly with regard to tracheal intubation. Measurement of neuromuscular block, both clinical and via nerve stimulators, is described and compared, and correlations with intubating conditions are attempted. The onset of action of different muscle groups in humans is examined in an attempt to explain timing differences leading to the more rapid onset of block seen in the laryngeal and ventilatory muscles than in the muscles of the hand, which are the usual site of neuromuscular monitoring. The onset of different relaxants is compared, and attempts are made to relate the differences to neuromuscular pharmacology so as to understand the reasons for the rapid onset of succinylcholine (rapid metabolism) and rocuronium (poor potency). None of the currently available drugs, or those undergoing clinical investigation, possesses the rapid onset and prompt recovery of succinylcholine. Despite the formidable side effect profile of succinylcholine, it has not been replaced by a nondepolarizing agent for use in emergency conditions. However, the alternatives, particularly rocuronium and mivacurium, are drugs with a greater safety profile that, in many circumstances, can substitute for succinylcholine.

Objectives: To determine whether preoperative hypercoagulable abnormalities are independent risk-factors for the failure of arterial reconstruction in leg ischaemia., Methods: Sixty consecutive patients were studied before, and for 1 year following, elective peripheral revascularisation. Antithrombin III, protein C and protein S levels, and tests for lupus anticoagulant were performed preoperatively, and then repeated on the first and third postoperative days and after 1 and 6 months. Heparin-associated thrombocytopenia was also investigated if there was a postoperative fall in platelet count greater than 100 x 10(9)/l., Results: Forty-six (77%) procedures were performed for critical ischaemia and 15 (25%) involved infrapopliteal reconstruction. The nature of surgery or accepted risk factors for occlusion were comparable between the 40 (67%) patients with patent reconstructions at 1 year and the 20 (33%) who had suffered failure. Preoperative hypercoagulable abnormalities were detected in 21 (35%) patients, with a three times greater incidence in those whose reconstructions failed (65% vs. 20%, p < 0.01), and in 11 of 12 patients suffering early (within 1 month) occlusion. The lupus anticoagulant was more frequently detected when prosthetic grafts were already present (p < 0.05) and carried a positive predictive value for reocclusion of 67% (p < 0.01). All three postoperative deaths occurred in patients with low protein S levels before surgery., Conclusions: Hypercoagulable abnormalities are common prior to arterial revascularisation and are independently associated with subsequent failure.

Background: Many patients with circulating antibodies to human leucocyte antigens (anti-HLA) are highly sensitised against renal transplantation and are liable to immediate graft loss through hyperacute rejection. Our aim was to find out whether removal of anti-HLA immediately before renal transplantation prevented hyperacute graft rejection., Methods: 13 highly sensitised patients underwent cadaveric renal transplants immediately after immunoadsorption (IA) treatment to remove anti-HLA. Before IA, 12 patients had a positive crossmatch against donor cells either by cytotoxic or flow-cytometric assay; results for one patient were equivocal., Findings: Renal biopsy samples were obtained 20 min after removal of the vascular clamps in nine patients. There was no evidence of hyperacute rejection in six of the nine patients; the other three patients showed glomerular thrombosis but no other evidence of hyperacute rejection. Two of these three grafts were functioning at 31 months of follow-up. Six episodes of acute rejection occurred in five patients during the first month after transplantation and overall there were 13 rejection episodes in nine patients. At latest follow-up (median 26 months, range 9-42), 12 of 13 patients were alive and seven of 13 grafts were surviving with a median plasma creatinine concentration of 185 mumol/L (range 106-296) in the functioning grafts. No graft was lost as a result of classic hyperacute rejection., Interpretation: Immediate pretransplant IA can prevent hyperacute rejection and provide an opportunity for successful transplantation in highly sensitised patients.

The molecular genetic analysis of protein S deficiency has been hampered by the complexity of the protein S (PROS) gene and by the existence of a homologous pseudogene. In an attempt to overcome these problems, a reverse transcript-polymerase chain reaction (RT-PCR) mutation screening procedure was developed. However, the application of this mRNA-based strategy to the detection of gene lesions causing heterozygous type I protein S deficiency appears limited owing to the high proportion of patients exhibiting absence of mRNA derived from the mutation-bearing allele ("allelic exclusion"). Nevertheless, this strategy remains extremely effective for rapid mutation detection in type II/III protein S deficiency. Using the RT-PCR technique, a G-to-A transition was detected at position +1 of the exon IV donor splice site, which was associated with type I deficiency and resulted in both exon skipping and cryptic splice site utilization. No abnormal protein S was detected in plasma from this patient. A missense mutation (Asn 217 to Ser), which may interfere with calcium binding, was also detected in exon VIII in a patient with type III protein S deficiency. A further three PROS gene lesions were detected in three patients with type I deficiency by direct sequencing of exon-containing genomic PCR fragments: a single base-pair (bp) deletion in exon XIV, a 2-bp deletion in exon VIII, and a G0to-A transition at position -1 of the exon X donor splice site all resulted in the absence of mRNA expressed from the disease allele. Thus, the RT-PCR methodology proved effective for further analysis of the resulting protein S-deficient phenotypes. A missense mutation (Met570 to Thr) in exon XIV of a further type III-deficient proband was subsequently detected in this patient's cDNA. No PROS gene abnormalities were found in the remaining four subjects, three of whom exhibited allelic exclusion. However, the father of one such patient exhibiting allelic exclusion was subsequently shown to carry a nonsense mutation (Gly448 to Term) within exon XII.

Splenic lymphoma with villous lymphocytes (SLVL) is a monoclonal B-lymphoproliferative disorder characterised by splenomegaly and distinctive villous lymphocytes in the peripheral blood. It has not previously been reported from Africa, but we describe ten Ghanaian patients with SLVL seen at one hospital during a 4-year period. The clinical presentation is similar in Africa and in temperate regions, though the lymphocyte count is higher in African patients and the disorder predominantly affects middle-aged women rather than elderly men. It is likely that SLVL has previously been classified as splenic chronic lymphocytic leukaemia or hyper-reactive malarial splenomegaly.

Noonan's syndrome is characterised by a dysmorphic facies, congenital heart disease, and short stature, and is inherited as an autosomal dominant trait. Because abnormal bleeding has also been reported, we investigated a group of patients for coagulation-factor deficits. Of the 72 individuals studied (37 male, 35 female, mean age 11.4 years), 47 (65%) had a history of abnormal bruising or bleeding. 29 patients (40%) had a prolonged activated partial thromboplastin time. Specific abnormalities in the intrinsic pathway of coagulation (partial factor XI:C, XII:C, and VIII:C deficiencies) were found in 36 patients (50%). Multiple abnormalities among these 36 patients included combined factor XI:C and XII:C deficiencies (4 patients) and factor XI:C and VIII:C deficiencies (4), and 1 patient had combined factor VIII:C, XI:C, and XII:C deficiency. There was poor correlation between a history of abnormal bleeding and coagulation-factor deficit. In five families, similar coagulation-factor deficiencies were present in first-degree relatives with the syndrome. The pattern of inherited bleeding abnormalities seen in Noonan's syndrome suggests autosomal regulation of the intrinsic coagulation pathway.

A high-performance liquid chromatographic assay coupled with electrochemical detection has been developed for the determination of vecuronium and its three putative deacetylated metabolites in human plasma. A novel solid-phase extraction procedure allowed good recovery of both vecuronium and its metabolites, together with ease and speed of execution. This method was sensitive, reproducible and accurate over the therapeutic range of concentrations of vecuronium and its metabolites, and was applied successfully to a study of the pharmacokinetics of vecuronium in anaesthetized patients.

Suxamethonium increases neuromuscular block produced by non-depolarizing agents administered subsequently. To determine if this effect has a pharmacokinetic or pharmacodynamic origin, 18 ASA physical status I or II adults received atracurium 0.2 mg kg-1, with (n = 10) or without (n = 8) previous injection of suxamethonium 1 mg kg-1, during a thiopentone-nitrous oxide-isoflurane (0.5% end-tidal) anaesthetic. Arterial blood samples were obtained and plasma atracurium concentration measured by HPLC. Train-of-four stimulation was applied to the ulnar nerve and the force of contraction of the adductor pollicis muscle was recorded. Mean (SEM) volume of distribution was slightly greater with previous suxamethonium (143 (13) ml kg-1) than without (109 (5) ml kg-1) (P less than 0.04). Mean elimination half-life was unaffected (20.3 (0.8) min and 20.4 (1.6) min, respectively). Neuromuscular block was more intense and recovery was slower with previous administration of suxamethonium. Atracurium concentration at 50% block (Cpss50) was 305 (30) ng ml-1 with and 454 (25) ng ml-1 without previous suxamethonium (P less than 0.01). It is concluded that suxamethonium may be associated with a slight increase in the volume of distribution of atracurium, but this effect is more than compensated by a decrease in atracurium concentration required for a given effect.

In Africa, hyper-reactive malarial splenomegaly (HMS), which is also known as tropical splenomegaly syndrome, can be associated with a prominent lymphocytosis in blood and bone marrow that is difficult to distinguish clinically from chronic lymphocytic leukaemia (CLL). The observation that some patients with HMS become resistant to treatment with anti-malarial drugs has led to the suggestion that HMS may evolve into a malignant lymphoproliferative disorder. To test this hypothesis, 22 Ghanaian patients with HMS and/or lymphocytosis were categorised by degree of response to proguanil according to standard clinical criteria, and DNA was extracted from peripheral blood cells and screened for rearrangements of the Jh region of the immunoglobulin gene with a DNA probe. Clonal rearrangements of the Jh region were found in all 3 patients with no response, in none of 13 patients with sustained response, and in 2 of 6 patients with moderate response or relapse on proguanil therapy. The detection of such rearrangements, and hence clonal lymphoproliferation in individuals with clinical features intermediate between HMS and CLL, supports the hypothesis that HMS may evolve into a malignant lymphoproliferative disorder.

We have studied the effect of prior administration of non-depolarizing neuromuscular blocking drugs on suxamethonium-induced increases in masseter muscle tension in 21 children aged 3-10 yr, anaesthetized with nitrous oxide and halothane using supramaximal stimulation of the ulnar nerve and the nerve to masseter. Resting tension and isometric force of contraction were measured in the adductor pollicis and masseter muscles. A sub-paralysing dose of tubocurarine 0.05 mg kg-1, a paralysing dose of atracurium 0.5 mg kg-1 or saline was given, followed 3 min later by suxamethonium 1 mg kg-1. Onset times of suxamethonium and atracurium block were shorter in the masseter than in the adductor pollicis muscle. When preceded by a sub-paralysing dose of tubocurarine, suxamethonium produced an increase in masseter tension (47 (SEM 15) g) similar to that produced by suxamethonium alone (59 (13) g). Prior administration of a paralysing dose of atracurium almost abolished this increase in tension (2.5 (2.5) g) (P less than 0.05 vs saline). The tension increase in adductor pollicis was 0, 3.2 (2.2) and 5.9 (1.1) g in the atracurium, tubocurarine and saline groups, respectively. Tubocurarine and atracurium prevented muscle fasciculations in all patients. It was concluded that increased muscle tone is a normal response to suxamethonium and is greater in the masseter than adductor pollicis. Sub-paralysing doses of non-depolarizing neuromuscular blockers have little effect, in contrast with paralysing doses. This suggests that the effect is mediated via postsynaptic receptors.

To determine the influence of enflurane on the ability of edrophonium to antagonize atracurium block, dose-response curves were constructed for edrophonium in the presence of 0%, 1% and 2% enflurane, and for 2% enflurane discontinued at the time of administration of edrophonium. One hundred ASA Physical Status I or II patients (four groups of 25), selected randomly and undergoing elective surgery, received atracurium 0.5 mg kg-1, with thiopentone, nitrous oxide and enflurane. Supplementary doses of fentanyl were given if needed. Train-of-four (TOF) stimulation was applied every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When first twitch height (T1) had recovered spontaneously to 10% of initial value, edrophonium 0.1, 0.2, 0.4 or 1 mg kg-1 was administered by random allocation. Enflurane concentrations remained constant, except that enflurane was discontinued in 50% of the patients who had received 2% enflurane. Monitoring was continued for at least 10 min, at which time T1 and TOF ratio (T4/T1) were measured. The ED80 for T1 recovery depended on the dose of enflurane: 0.08 (SEM 0.03), 0.21 (0.06) and 0.42 (0.18) mg kg-1 for 0%, 1% and 2% enflurane, respectively (P less than 0.005). With enflurane 2% discontinued, the ED80 was 0.095 (0.050) mg kg-1 (P less than 0.02 compared with 2% enflurane).(ABSTRACT TRUNCATED AT 250 WORDS)

Neuromuscular transmission was measured using train-of-four stimulation, during and after anaesthesia, in 20 patients with end-stage renal failure. Neuromuscular blockade was provided with pancuronium in single doses of either 3 or 6 mg per 70 kg, and antagonized at 10% recovery with atropine and neostigmine 2.5 mg per 70 kg. Reversal was followed by progressive recovery of muscle twitch in every patient during the 3 h of the study. Recovery was more rapid after the smaller dose of pancuronium and was inversely correlated with the duration of blockade. It is concluded that, when pancuronium is antagonized with neostigmine in patients with renal failure, neuromuscular transmission recovers without evidence of recurarization. However, when large doses of pancuronium are antagonized with neostigmine 2.5 mg, recovery may be insufficient to ensure normal ventilatory function.

The anaesthetic management and postoperative complications of 110 grossly obese patients undergoing weight-reducing surgery have been reviewed. The major problems were technical, related to the bulk of the patient, and respiratory, caused by alterations in pulmonary physiology. Extradural catheters were placed in 70 patients before induction of general anaesthesia. In all patients the trachea was intubated during anaesthesia and the lungs ventilated with large tidal volumes and appropriate inspired oxygen concentrations. Muscle relaxation was achieved with extradural block in 35 patients; the remainder received pancuronium i.v. Extradural analgesia with bupivacaine provided excellent analgesia after surgery and greatly facilitated nursing care.

Malignant lymphoma complicating coeliac disease has been characterised on morphological and immunocytochemical grounds as malignant histiocytosis of the intestine (MHI). Fresh tissue from four cases of MHI was studied by means of a panel of monoclonal antibodies; in three cases tumour DNA was studied for immunoglobulin and T-cell receptor (TCR) gene rearrangement. Immunocytochemistry showed a T-cell phenotype in all four cases, confirmed by the demonstration of a rearranged TCR beta-chain gene in the three cases studied. Lymphoma complicating coeliac disease thus appears to be of T-cell, rather than histiocyte, origin.

The fluorescence yield of benzo[a]pyrene (BP) increases dramatically upon its transfer from the surface of particulates to rat liver microsomes. Adsorption of BP to Canadian chrysotile, anthophyllite, hematite and silica results in greatly enhanced uptake rates into microsomes when compared to uptake from a microcrystalline dispersion of BP. The fibrous minerals chrysotile and anthophyllite were more effective than silica and hematite in enhancing BP uptake. Simple mixtures of BP microcrystals and particles did not display enhanced transport, indicating that adsorption of BP to the particulate surface is necessary for enhanced microsomal uptake. BP was not released into microsomes from carbon black. We suggest that particulate-enhanced availability of BP may be of significance in the co-carcinogenesis between particulates and polynuclear aromatic hydrocarbons. However, other mechanisms are also possible, and are not excluded by our experiments. The fluorescence methodology, described in this paper provides a novel and convenient means to quantify microsomal uptake of BP and thereby investigate further the mechanisms of cocarcinogenesis.

Equipotent, paralysing doses of pancuronium and tubocurarine were administered to 40 patients, aged from 1 day to 12 months, during nitrous oxide, oxygen and fentanyl anaesthesia. Neuromuscular activity was measured during onset and recovery from paralysis using train-of-four stimulation. At the same depression of the first stimulus of the train, the train-of-four ratio was decreased more during recovery than during onset with each drug and more with tubocurarine than with pancuronium. These results are qualitatively similar to those found in adults, but the decrease in train-of-four ratio was less in infants. Thus, it is concluded that prejunctional neuromuscular activity, recognized as fade in response to train-of-four stimulation, can be detected after administration of pancuronium or tubocurarine to infants, but that it is less marked than in adults.

The study was designed to determine whether the onset of action of pancuronium in infants and children could be accelerated by its administration in divided doses. Sixty paediatric patients (0-1 yr (n = 20); 1-3 yr (n = 20); 3-10 yr (n = 20)) were studied during nitrous oxide-oxygen-halothane anaesthesia using train-of-four stimulation, and the results were compared with data obtained previously in adults. The time to onset correlated with the patient's age, and an additional, small acceleration was produced following divided doses which did not alter the duration or pattern of neuromuscular blockade. It was concluded that, in children, divided doses of pancuronium are unlikely to offer important clinical advantages.

Mechanisms of co-carcinogenicity of particulates, such as iron oxide and asbestos, and benzo[a]pyrene (B[a]P) are not completely understood. Particulates dramatically alter rates of uptake of B[a]P into membranes, a factor which could account for co-carcinogenicity. However, B[a]P must be activated to reactive forms to be carcinogenic and mutagenic so alterations in metabolism of B[a]P by particulates also could result in co-carcinogenesis. To elucidate mechanisms of particulate-B[a]P co-carcinogenesis, we have correlated rates of uptake of B[a]P into microsomes with metabolism of B[a]P and with mutagenicity of B[a]P in the Ames test. In general, aryl hydrocarbon hydroxylase (AHH) activity paralleled rates of uptake of B[a]P, though some inhibition of AHH activity by particulates which was not attributable to availability of B[a]P was evident. This inhibition was studied further by assaying separately mixed function oxidase and epoxide hydrase activities in the presence of particulates. Both chrysotile and iron oxide inhibited O-deethylation of 7-ethoxyresorufin and hydration of B[a]P-4,5-oxide. To determine effects of this inhibition on activation of B[a]P to reactive forms, we studied profiles of metabolites of B[a]P and mutagenicity of B[a]P. The only alteration in profiles of B[a]P metabolites produced by particulates was that due to effects on rates of uptake. Similarly, mutagenicity of B[a]P was positively correlated with rates of uptake into microsomes. We conclude that the predominant effects of chrysotile and iron oxide are in altering rates of uptake of particle-adsorbed B[a]P. Changes in uptake rates then result in alterations of B[a]P metabolism and mutagenicity.

The chromosome 22 derivative, the Philadelphia (Ph) chromosome, results from a reciprocal translocation t(9;22) (q34;q11) and is associated with chronic myeloid leukemia (CML). The translocation can be identified at the DNA level in Ph-positive CML by using a probe to the breakpoint cluster region (bcr). In addition, as a result of this translocation an abl-related 210-kd protein with protein tyrosine kinase (PTK) activity is produced. We analyzed 28 cases of Ph-negative CML for rearrangement of the chromosome 22 sequences and found that eight of the 28 show rearrangement of the bcr. When 12 of the Ph-negative cases were independently reviewed, five were indistinguishable from Ph-positive CML on the basis of morphology, peripheral blood film and clinical details. These five also showed bcr rearrangement. The other seven were reclassified as six atypical CML (aCML) and one chronic myelomonocytic leukemia (CMML). None of these seven showed bcr rearrangement. In addition 11 cases of bcr- CML were assayed for abl-related PTK, and no detectable activity was present, whereas p210 phl/abl PTK was observed both in Ph-positive (three cases examined) and Ph-negative, bcr + (four cases examined) CML. Therefore, bcr + CML, whether or not the Ph chromosome is cytogenetically apparent, involves a similar molecular alteration and produces the 210-kd protein with enhanced PTK activity. Furthermore, these cases can be distinguished from Ph-negative bcr- CML by careful evaluation of clinical and hematologic data.

Train-of-four stimulation was applied to the ulnar and phrenic nerves in 18 adult patients anaesthetized with nitrous oxide and halothane in oxygen. The response of the adductor pollicis and the diaphragm were measured. Incremental doses of atracurium and vecuronium were given, with an infusion to replace drug lost by elimination or distribution. The mean (SEM) doses of atracurium associated with 50% and 90% depression of response to the first stimulation in the train-of-four (ED50 and ED90) were 90 (9) and 133 (10) micrograms kg-1 at the adductor pollicis, and 130 (9) and 245 (17) micrograms kg-1 at the diaphragm, respectively. The mean (SEM) ED50 and ED90 of vecuronium were 25 (2) and 38 (4) micrograms kg-1 at the adductor pollicis and 34 (3) and 58 (5) micrograms kg-1 at the diaphragm, respectively. The mean (SEM) ED50 ratios were 1.56 (0.16) for atracurium and 1.47 (0.16) for vecuronium. ED90 ratios were 1.93 (0.29) and 1.55 (0.17) for atracurium and vecuronium, respectively. It is concluded that both atracurium and vecuronium exhibit a similar degree of sparing of the diaphragm.

The capacity of Zn2+, Cd2+, or Hg2+ to induce fusion of phospholipid vesicles composed of 50%/50%, 60%/40%, or 80%/20% dipalmitoyl phosphatidylcholine (DPPC)/bovine brain phosphatidylserine (PS) was investigated and compared to that of Ca2+ and Mg2+. In vesicles composed of 50%/50% or 60%/40% DPPC/PS, Zn2+ and Cd2+-induced fusion at concentrations considerably lower than were required for Ca2+-induced fusion. Only limited fusion of 80%/20% DPPC/PS vesicles occurred and Zn2+ was more effective than Ca2+ or Cd2+ in inducing fusion of these vesicles. Mg2+ and Hg2+ did not induce fusion in any of the vesicle systems.

Single twitch and train-of-four stimulation were applied at 0.08 Hz to each ulnar nerve and the force of contraction of the adductor pollicis was recorded during onset of and recovery from neuromuscular blockade by suxamethonium 1 mg kg-1 or atracurium 0.4 mg kg-1. Times to 90% first twitch blockade of train-of-four were (mean +/- SEM) 0.82 +/- 0.08 and 1.98 +/- 0.18 min for suxamethonium and atracurium, respectively, compared with times to 90% single twitch blockade of 1.00 +/- 0.07 and 3.35 +/- 0.37 min, respectively (P less than 0.05 in both cases). Apparent onset time also depended on how long train-of-four stimulation had been applied before injection of atracurium. The mode of stimulation had little effect on time to 10% recovery. The results are consistent with stimulation-induced augmentation in muscle blood flow, which increased delivery of the drug to the neuromuscular junction.

The neuromuscular blockade produced by a prolonged (greater than 90 min) continuous infusion of suxamethonium and measured with train-of-four stimulation was studied in 20 infants and 20 children during nitrous oxide and halothane in oxygen anaesthesia. The results were compared with a previous study in adults. Suxamethonium requirement was increased in infants and children. Mean peak infusion rates were 297 and 284 micrograms kg-1 min-1 in infants and children, compared with 134 micrograms kg-1 min-1 in adults. An initial tachyphylaxis was followed by bradyphylaxis, and the peak requirement occurred earlier in infants than in children and adults (40 v. 80-100 min). Phase II block developed during the tachyphylaxis. Recovery of neuromuscular activity commenced after stopping the infusion and was accelerated with neostigmine.

We have compared the rates of recovery of pancuronium-induced neuromuscular blockade after administration of neostigmine during anaesthesia maintained with nitrous oxide and intermittent narcotics, halothane or enflurane. Thirty patients were studied in whom anaesthesia was maintained with 70% nitrous oxide in oxygen with: fentanyl or thiopentone, halothane (0.55-0.65% end-tidal), or enflurane (1.3-1.4% end-tidal). Muscle twitch response was measured using train-of-four stimulation. Pancuronium 3 mg/70 kg was antagonized with neostigmine 2.5 mg/70 kg at 10% spontaneous recovery of the first twitch of the train compared with control. There were no significant differences between the times to 10% spontaneous recovery of the first twitch or the rates of train-of-four recovery after neostigmine when the narcotic and halothane groups were compared. However, enflurane anaesthesia, in comparison with fentanyl, was associated with a significant increase in the time to 10% recovery (57.9 +/- 6.0 min v. 35.4 +/- 7.0 min) and with decreases in the train-of-four recoveries at 4, 5, 10, 20 and 30 min after neostigmine. We conclude that, under the conditions of this study, the antagonism of pancuronium-induced neuromuscular blockade with neostigmine was impaired during enflurane but not halothane anaesthesia.

The effects of positive and negative end expiratory pressure on renal function have been studied in adult greyhounds with a normal blood volume and without evidence of cardiorespiratory disease. Positive expiratory pressure (+ 10 cm H2O) resulted in a decrease of urine volume, glomerular filtration rate and renal blood flow which returned towards normal following removal of the positive pressure. Negative expiratory pressure (-6 cm H2O) resulted in opposite changes in renal function.

The neuromuscular blockade produced by a prolonged infusion of suxamethonium was studied using train-of-four stimulation in 40 patients receiving either halothane-nitrous oxide or fentanyl-nitrous oxide anaesthesia. Initially, a depolarizing (phase I) block was observed in all patients followed by phase II block which was associated with tachyphylaxis to suxamethonium; the latter changes occurring more rapidly in the halothane group. Infusions were continued for more than 150 min in 17 patients and there was a late decrease in suxamethonium requirement in those who received halothane, but not fentanyl. Ten minutes after the suxamethonium infusion was stopped, most patients received neostigmine which was followed by rapid recovery of neuromuscular transmission.

A method to study elution of benzo[a]pyrene (B[a]P) from carbonaceous particulates into phospholipid vesicles composed of dimyristoyl phosphatidylcholine (DMPC) was developed. Recoveries of B[a]P at each step of the procedure were quantified, with overall recoveries being 81%. Application of the technique to elution of B[a]P from woodstove particulate revealed that 25% of B[a]P associated with the particulate was eluted into DMPC vesicles in 18 h. From data obtained, it also was possible to evaluate elution of another polycyclic aromatic hydrocarbon (PAH), benzo[k]fluoranthene (B[k]F). Of the total B[k]F associated with woodstove particulate, 68% was eluted. This technique provides a convenient method for evaluating the potential bioavailability of PAH associated with other carbonaceous particulates which occur in the environment.