Search

Objective: Hypnosis is an adjunctive, noninvasive treatment with few side effects that can be useful in the management of chronic pain. However, it has fallen into disfavor in recent years and is often perceived by physicians as simple charlatanism. We evaluated the efficacy of this treatment as used clinically in a large, mostly rural, pain management center.Methods: We conducted a chart review of 300 pain patients from the Pain Treatment Center of the Bluegrass who had undergone hypnosis for their pain concerns. A chart audit tool was developed consisting of basic demographics, pre- and posthypnosis pain ratings, a rating of relaxation achieved posthypnosis, and scores on the Beck Depression Inventory, Perceived Disability Scale, and the Pain Anxiety Symptom Scale.Results: The sample consisted of 79 men (26.3%) and 221 women (73.7%) with a mean age of 46.3 years (SD = 9.9, range = 19-78). Pain levels recorded pre- and posthypnosis revealed significant improvement as a result of the intervention (mean difference = 2.5, t (1,298) = 25.9, p < .001). Patients reported an average of 49.8% improvement in relaxation level posthypnosis (SD = 24.2%) and had a mean score of 19.0 on the Beck Depression Inventory (SD = 9.9), indicating moderate levels of depression. Also, patients saw themselves as severely disabled regarding their ability to engage in physical (8.3/10) or job-related (7.7/10) activities. Attempts to identify predictors of hypnosis success were not fruitful with one exception. "Poor" responders to hypnosis reported greater levels of perceived dysfunction in their sexual functioning compared to the "good" responders, F(1,187) = 7.2, p < .01.Significance Of Results: Hypnosis appears to be a viable adjunct for pain management patients, including those from rural and relatively disadvantaged backgrounds. Prospective trials are needed to examine the utility of this modality in end-of-life and palliative care patients. [ABSTRACT FROM AUTHOR]

Using 7-ethoxycoumarin as a probe substrate, microsomal monoxygenase activity has been measured in liver tissue from patients with primary biliary cirrhosis (PBC) of varying histological severity, and in histologically normal control tissue. Interindividual variation in enzyme activity was considerable, and in no histological category was the activity significantly different to control. We conclude that: (a) in PBC, hepatic microsomal monoxygenase activity is determined primarily by factors other than the histological severity of the liver disease, and (b) studies of xenobiotic metabolism in patients with liver disease should specify the nature of the underlying disease process. [ABSTRACT FROM AUTHOR]

Abstract: Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn's disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Potential pronociceptive mediators were identified based on gene upregulation in IBD biopsy tissue and cognate receptor expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt , which encode the precursor to angiotensin II (Ang II), in samples from UC patients ( P = 3.2 × 10 -8 ). Consistent with the marked expression of the angiotensin AT 1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca 2+ in capsaicin-sensitive, voltage-gated sodium channel subtype Na V 1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT 1 receptor antagonist valsartan. Findings from our study identify AT 1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

TRAAK (KCNK4, K2P4.1) is a mechanosensitive two-pore domain potassium (K2P) channel. Due to its expression within sensory neurons and genetic link to neuropathic pain it represents a promising potential target for novel analgesics. In common with many other channels in the wider K2P sub-family, there remains a paucity of small molecule pharmacological tools. Specifically, there is a lack of molecules selective for TRAAK over the other members of the TREK subfamily of K2P channels. We developed a thallium flux assay to allow high throughput screening of compounds and facilitate the identification of novel TRAAK activators. Using a library of ∼1200 drug like molecules we identified Aprepitant as a small molecule activator of TRAAK. Aprepitant is an NK-1 antagonist used to treat nausea and vomiting. Close structural analogues of Aprepitant and a range of NK-1 antagonists were also selected or designed for purchase or brief chemical synthesis and screened for their ability to activate TRAAK. Electrophysiology experiments confirmed that Aprepitant activates both the 'long' and 'short' transcript variants of TRAAK. We also demonstrated that Aprepitant is selective and does not activate other members of the K2P superfamily. This work describes the development of a high throughput assay to identify potential TRAAK activators and subsequent identification and confirmation of the novel TRAAK activator Aprepitant. This discovery identifies a useful tool compound which can be used to further probe the function of TRAAK K2P channels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Two-pore domain potassium (K2P) channels carry background (or leak) potassium current and play a key role in regulating resting membrane potential and cellular excitability. Accumulating evidence points to a role for K2Ps in human pathophysiologies, most notably in pain and migraine, making them attractive targets for therapeutic intervention. However, there remains a lack of selective pharmacological tools. The aim of this work was to apply a "target class" approach to investigate the K2P superfamily and identify novel activators across all the described subclasses of K2P channels. Target class drug discovery allows for the leveraging of accumulated knowledge and maximizing synergies across a family of targets and serves as an additional approach to standard target-based screening. A common assay platform using baculovirus (BacMam) to transiently express K2P channels in mammalian cells and a thallium flux assay to determine channel activity was developed, allowing the simultaneous screening of multiple targets. Importantly, this system, by allowing precise titration of channel function, allows optimization to facilitate the identification of activators. A representative set of channels (THIK-1, TWIK-1, TREK-2, TASK-3, and TASK-2) were screened against a library of Food and Drug Administration (FDA)-approved compounds and the LifeArc Index Set. Activators were then analyzed in concentration-response format across all channels to assess selectivity. Using the target class approach to investigate the K2P channels has enabled us to determine which of the K2Ps are amenable to small-molecule activation, de-risk multiple channels from a technical point of view, and identify a diverse range of previously undescribed pharmacology.

Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.

TREK2 (KCNK10, K 2P 10.1) is a two-pore domain potassium (K2P) channel and a potential target for the treatment of pain. Like the majority of the K2P superfamily, there is currently a lack of useful pharmacological tools to study TREK2. Here we present a strategy for identifying novel TREK2 activators. A cell-based thallium flux assay was developed and used to screen a library of drug-like molecules, from which we identified the CysLT1 antagonist Pranlukast as a novel activator of TREK2. This compound was selective for TREK2 versus TREK1 and showed no activity at TRAAK. Pranlukast was also screened against other members of the K2P superfamily. Several close analogues of Pranlukast and other CysLT1 antagonists were also tested for their ability to activate K2P channels. Consistent with previous work, structure activity relationships showed that subtle structural changes to these analogues completely attenuated the activation of TREK2, whereas for TREK1, analogues moved from activators to inhibitors. Pranlukast's activity was also confirmed using whole-cell patch clamp electrophysiology. Studies using mutant forms of TREK2 suggest Pranlukast does not bind in the K2P modulator pocket or the BL-1249 binding site. Pranlukast therefore represents a novel tool by which to study the mechanism of TREK2 activation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K + channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators. After screening a library of 1000 compounds, including drug-like and FDA approved molecules, we identified Terbinafine as an activator of TASK3. In a thallium flux assay a pEC50 of 6.2 ( ±0.12) was observed. When Terbinafine was screened against TASK2, TREK2, THIK1, TWIK1 and TRESK no activation was observed in thallium flux assays. Several analogues of Terbinafine were also purchased and structure activity relationships examined. To confirm Terbinafine's activation of TASK3 whole cell patch clamp electrophysiology was carried out and clear potentiation observed in both the wild type channel and the pathophysiological, Birk-Barel syndrome associated, G236R TASK3 mutant. No activity at TASK1 was observed in electrophysiology studies. In conclusion, we have identified the first selective activator of the two-pore domain potassium channel TASK3., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Kir7.1 is an inwardly rectifying potassium channel that has been implicated in controlling the resting membrane potential of the myometrium. Abnormal uterine activity in pregnancy plays an important role in postpartum hemorrhage, and novel therapies for this condition may lie in manipulation of membrane potential. This work presents an assay development and screening strategy for identifying novel inhibitors of Kir7.1. A cell-based automated patch-clamp electrophysiology assay was developed using the IonWorks Quattro (Molecular Devices, Sunnyvale, CA) system, and the iterative optimization is described. In total, 7087 compounds were tested, with a hit rate (>40% inhibition) of 3.09%. During screening, average Z' values of 0.63 ± 0.09 were observed. After chemistry triage, lead compounds were resynthesized and activity confirmed by IC50 determinations. The most potent compound identified (MRT00200769) gave rise to an IC50 of 1.3 µM at Kir7.1. Compounds were assessed for selectivity using the inwardly rectifying potassium channel Kir1.1 (ROMK) and hERG (human Ether-à-go-go Related Gene). Pharmacological characterization of known Kir7.1 inhibitors was also carried out and analogues of VU590 tested to assess selectivity at Kir7.1., (© 2015 Society for Laboratory Automation and Screening.)

TRESK is a two-pore domain potassium channel. Loss of function mutations have been linked to typical migraine with aura and due to TRESK’s expression pattern and role in neuronal excitability it represents a promising therapeutic target. We developed a cell based assay using baculovirus transduced U20S cells to screen for activators of TRESK. Using a thallium flux system to measure TRESK channel activity we identified Cloxyquin as a novel activator. Cloxyquin was shown to have an EC50 of 3.8 μM in the thallium assay and displayed good selectivity against other potassium channels tested. Activity was confirmed using whole cell patch electrophysiology, with Cloxyquin causing a near two fold increase in outward current. The strategy presented here will be used to screen larger compound libraries with the aim of identifying novel chemical series which may be developed into new migraine prophylactics.

Background: Alveolar macrophages are one of the first lines of defence against invading pathogens and play a central role in modulating both the innate and acquired immune systems. By responding to endogenous stimuli within the lung, alveolar macrophages contribute towards the regulation of the local inflammatory microenvironment, the initiation of wound healing and the pathogenesis of viral and bacterial infections. Despite the availability of protocols for isolating primary alveolar macrophages from the lung these cells remain recalcitrant to expansion in-vitro and therefore surrogate cell types, such as monocyte derived macrophages and phorbol ester-differentiated cell lines (e.g. U937, THP-1, HL60) are frequently used to model macrophage function., Methods: The availability of high throughput gene expression technologies for accurate quantification of transcript levels enables the re-evaluation of these surrogate cell types for use as cellular models of the alveolar macrophage. Utilising high-throughput TaqMan arrays and focussing on dynamically regulated families of integral membrane proteins, we explore the similarities and differences in G-protein coupled receptor (GPCR) and ion channel expression in alveolar macrophages and their widely used surrogates., Results: The complete non-sensory GPCR and ion channel transcriptome is described for primary alveolar macrophages and macrophage surrogates. The expression of numerous GPCRs and ion channels whose expression were hitherto not described in human alveolar macrophages are compared across primary macrophages and commonly used macrophage cell models. Several membrane proteins known to have critical roles in regulating macrophage function, including CXCR6, CCR8 and TRPV4, were found to be highly expressed in macrophages but not expressed in PMA-differentiated surrogates., Conclusions: The data described in this report provides insight into the appropriate choice of cell models for investigating macrophage biology and highlights the importance of confirming experimental data in primary alveolar macrophages.

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disease. Approximately 20 percent of familial ALS cases are caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Rodents expressing mutant SOD1 transgenes develop progressive, fatal motor neuron disease and disease onset and progression is dependent on the level of SOD1. We investigated the possibility that a reduction in SOD1 protein may be of therapeutic benefit in ALS and screened 30,000 compounds for inhibition of SOD1 transcription. The most effective inhibitor identified was N-{4-[4-(4-methylbenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboxamide (Compound ID 7687685), which in PC12 cells showed an EC50 of 10.6 microM for inhibition of SOD1 expression and an LD50 more than 30 microM. This compound was subsequently shown to reduce endogenous SOD1 levels in HeLa cells and to exhibit a modest reduction of SOD1 protein levels in mouse spinal cord tissue. These data suggest that the efficacy of compound 7687685 as an inhibitor of SOD1 gene expression is not likely to be clinically useful, although the strategy reported could be applied broadly to screening for small molecule inhibitors of gene expression.

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are detected in 20% of familial and 3% of sporadic amyotrophic lateral sclerosis (ALS) cases. Although mutant SOD1 is known to induce motor neuron death via multiple adverse acquired functions, its exact pathogenic mechanism is not well defined. SOD1 toxicity is dose dependent; levels of mutant SOD1 protein in transgenic mice determine disease susceptibility, onset and rate of progression. We therefore sought to identify small molecules that reduce SOD1 levels by inhibiting the SOD1 promoter. We tested pyrimethamine (previously reported to suppress SOD1 expression), several compounds currently in trials in human and murine ALS, and a set of 1040 FDA-approved compounds. In a PC12 cell-based assay, no compounds reduced SOD1 promoter activity without concomitant cytotoxicity. Additionally, pyrimethamine failed to repress levels of SOD1 protein in HeLa cells or homogenates of liver, spinal cord and brain of wild-type mice. Thirty-four compounds (including riluzole, ceftriaxone, minocyclin, PBA, lithium, acetylcysteine) in human and mouse ALS trials and an additional set of 1040 FDA-approved compounds also showed no effect on SOD1 promoter activity. This present study thus failed to identify small molecule inhibitors of SOD1 gene expression., ((c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Novel immune-type receptors (NITRs) are encoded by large multi-gene families and share structural and signaling similarities to mammalian natural killer receptors (NKRs). NITRs have been identified in multiple bony fish species, including zebrafish, and may be restricted to this large taxonomic group. Thirty-nine NITR genes that can be classified into 14 families are encoded on zebrafish chromosomes 7 and 14. Herein, we demonstrate the expression of multiple NITR genes in the zebrafish ovary and during embryogenesis. All 14 families of zebrafish NITRs are expressed in hematopoietic kidney, spleen and intestine as are immunoglobulin and T cell antigen receptors. Furthermore, all 14 families of NITRs are shown to be expressed in the lymphocyte lineage, but not in the myeloid lineage, consistent with the hypothesis that NITRs function as NKRs. Sequence analyses of NITR amplicons identify known alleles and reveal additional alleles within the nitr1, nitr2, nitr3, and nitr5 families, reflecting the recent evolution of this gene family.

This paper describes the work undertaken by the Postgraduate Primary Care Trust (PCT) Dental Tutor for South Yorkshire and East Midlands Regional Postgraduate Dental Education Office during the first year of a two-year pilot. The tutor has special responsibility for facilitating the writing of Personal Development Plans (PDPs) and the introduction of Significant Event Analysis to the 202 general dental practitioners in the four Sheffield PCTs. Data were collected on significant events and the educational needs highlighted as a result. A hands-on workshop format was used in small practice groups and 45% of Sheffield general dental practitioners now have written PDPs compared with a 16% national average. A library of significant events has also been collated from the data collected.

Infective endocarditis (IE) is an elusive systemic disorder that is often associated with neurologic complications. The contribution of brain magnetic resonance imaging (MRI) to the diagnosis of IE and the spectrum of such findings has been only sparsely described previously. The authors report cranial MRI findings in 12 patients with IE. Each of the patients had MRI evidence of cerebral embolization, with multiple brain lesions noted in most patients (n = 10). Cortical branch infarction was the most common lesion (n = 8), which usually involved the distal middle cerebral artery tree. The next most common finding (n = 7) was numerous small embolic lesions which typically lodged in the supratentorial gray-white junction, some of which were clinically silent and many of which enhanced (probable microabscesses). Brain hemorrhages were noted in four patients, most commonly subarachnoid hemorrhage (n = 3). Two patients developed multiple frank parenchymal macroabscesses/cerebritis lesions. A previously unreported finding in septic embolization, a stroke that became infected with abscess formation ("septic infarction"), was noted in two patients. MRI showed orbital cellulitis in two patients. Most patients studied with gadolinium showed enhancement of lesions (n = 5/8). The authors conclude that cranial MRI may be a valuable tool in the evaluation of patients with IE. The presence of characteristic cranial MRI lesions, especially of multiple types, may prompt early diagnosis and treatment.

Static headspace gas chromatography was investigated for the analysis of residual solvents in size-limited samples. The advantages of improved limits of detection at low ppm levels and decreased sample size requirements were realized. This methodology allows the measurement of 18 common residual solvents in 6 min using 1 mg or less of sample. Greater recovery of analytes from pure dissolution solvents without the use of salts became possible when smaller preparations of samples were combined with the use of smaller vials. Rapid equilibration of the static headspace sample preparations was an additional benefit of this modification. Optimized chromatography was developed to take advantage of the shorter equilibration time and to increase instrument productivity.

Objective: To compare the three month outcome of open and laparoscopic cholecystectomy., Design: Prospective assessment of outcome for a series of patients encompassing the introduction of the laparoscopic technique., Setting: One teaching hospital., Patients: 269 patients admitted for open cholecystectomy between January 1989 and March 1992 and 122 admitted for laparoscopic cholecystectomy between January 1991 and March 1992., Main Measures: Patients' reported symptoms and self assessed scores with the Nottingham health profile before operation and at three month follow up. Incidence of complications and adverse events after discharge., Results: Similar improvements in symptom rates and health scores were seen regardless of surgical technique. A lower rate of postoperative complications was seen in the patients given laparoscopic surgery (6/95(6%) v 45/235(19%)), and their mean length of stay was lower (4.5 v 9.8 days). Similar results were obtained when the analysis was restricted to a subset of fairly uncomplicated cases (patients aged 60 or less without other illnesses on admission who were not undergoing emergency or urgent surgery), which constituted a larger proportion of the group given laparoscopy (35/95(37%) v 40/235(17%)). Between these two groups no significant difference was seen in the frequency of relevant readmissions to hospital or visits to general practitioners or accident and emergency departments., Conclusion: Ideally, a new surgical technique would be evaluated in a randomised trial. In the absence of such a trial, this observational study provides some evidence that the switch from open to laparoscopic cholecystectomy has brought benefits, particularly in terms of reduced length of stay in hospital. A range of clinical and patient derived indicators suggests that these gains have not been associated with a reduction in the quality of the outcome at three months.

Objective: To assess the validity of the Nottingham health profile (NHP) as an indicator of short term outcome of cholecystectomy., Design: Prospective assessment of outcome., Setting: One teaching hospital. Patients--161 consecutive patients admitted for cholecystectomy between January 1989 and September 1990., Main Measures: Patients' reported symptoms and self assessed NHP scores before cholecystectomy and at follow up at three and 12 months (76 patients); assessment before admission (19)., Results: Complete data were obtained preoperatively and at three months' follow up from 154 patients; seven did not respond to the follow up questionnaire. 76/84(90%) patients in the study 12 months or more answered the 12 month follow up questionnaire; eight did not respond. Significant changes in score before and at three months after the operation were observed for four of the six dimensions: energy (35.34 v 19.53, p < 0.0001), pain (27.38 v 9.8, p < 0.0001), sleep (26.99 v 17.51, p = 0.0002), and emotional reactions (16.12 v 7.56, p = 0.001). The mean scores for 76 patients followed up at three and 12 months showed little subsequent change. Scores in readmitted patients were all significantly higher, suggesting poor health. Patients with five reported symptoms had significantly worse scores for all dimensions. Scores were similar before cholecystectomy whether the questionnaire was completed before or after admission., Conclusion: The NHP is an appropriate tool for monitoring changes in health after cholecystectomy.

Forty patients with widely disseminated or locally advanced malignant obstruction of the middle or lower third of the oesophagus underwent endoscopic treatment by either NdYAG laser recanalization or intubation. Groups were matched on the basis of tumour location and swallowing was graded clinically before and after treatment. Technical success was achieved in 17 of 20 laser treated and 18 of 20 intubated patients. Pretreatment swallowing ability, histology, tumour location and overall length were unrelated to functional outcome in both groups. However, circumferential tumour length identified endoscopically strongly influenced the quality of swallowing after laser recanalization. Patients with excellent swallowing quality (n = 7) had significantly shorter circumferential tumour lengths, 3.1(1.0) cm, than those with poorer quality swallowing (n = 10), 6.3(1.6)cm, (P less than 0.001). Both methods of treatment had low complication rates and there was one death in the series in the laser-treated group. Laser recanalization provides a better functional result than intubation for short (less than 4 cm) circumferential tumour. Intubation at a single session seems more appropriate than repeated laser therapy when tumour length exceeds 4 cm.

Whole-body protein metabolism was determined by a primed constant-rate infusion of L-[ 1-14C ]leucine in patients before and after elective surgery, the nutritional intake being carefully controlled and the surgical stress in individuals being assessed. Pre-operatively, whole-body protein flux (P less than 0.05) and synthesis (P less than 0.05), along with amino acid oxidation (P less than 0.01), increased with nutritional intake whereas protein breakdown remained unaltered. Whole-body protein balance also correlated with intake (P = 0.001). Postoperatively, whole-body protein metabolism was determined with patients either fasted (group 1) or fed (group 2) and the change in metabolism in each individual from a pre-operative study, carried out in the fed state, was calculated. Whole-body protein breakdown increased in both groups (group 1, + 0.91 +/- 0.74 g day-1 kg-1; mean +/- SD, n = 7: group 2, + 0.47, + 0.63 and + 1.01 g day-1 kg-1, n = 3), the change being significant in those fasted after surgery (P less than 0.05). However, the pattern of change in whole-body protein synthesis was entirely different in each group, rising in those fed throughout (+ 0.32, + 0.41 and + 0.66 g day-1 kg-1, n = 3) but falling in those fasted after surgery (-0.38, -0.80 and -1.33 g day-1 kg-1, n = 3). The changes in metabolism appeared more marked in those undergoing greatest surgical stress. Some of the factors involved in the calculations are discussed and their effects on the overall conclusions are considered. A concept of whole-body protein metabolism in the metabolic response to trauma is advocated whereby protein breakdown is largely obligatory to the response, whereas synthesis responds to substrate availability.

Glucose metabolism is affected by various pathologic states including tumors. In this project, glucose turnover and recycling rates in 11 patients with colorectal carcinoma were measured using a double-labelled 3-3H and 1-14C glucose injection technique. Fasting blood glucose, lactate, pyruvate, alanine, glycerol, 3-hydroxybutyrate, acetoacetate, plasma cortisol, and plasma insulin concentrations were also measured. No patient in the study had a history of diabetes mellitus or endocrine disorders, nor any abnormal liver function tests. The findings demonstrated a significantly elevated glucose turnover rate in patients with Dukes C and D lesions in comparison to patients with Dukes B lesions. Cori recycling rates were not significantly different between Dukes B vs. Dukes C and D patients. There were no differences between Dukes B and Dukes C and D patients in any of the metabolites measured. Furthermore, there were no significant differences in glucose turnover or recycling rates as a function of pre-illness weight loss. These data suggest that, when colorectal carcinoma extends beyond the limits of the bowel wall, glucose metabolism is significantly altered.

Body protein metabolism and plasma amino acids were measured in 37 patients with stable cirrhosis of the liver to assess the effect of disease severity (Child's classification). Thirty two patients underwent a second series of measurements while nutrition was administered intravenously as one of five different infusions. Four infusions were formulations of amino acids with dextrose of varying branched chain amino acid content (100%, 53%, 35% and 16% branched chain to total amino acids). The fifth infusion was dextrose alone. No differences were detected in body protein synthesis and breakdown between patients on the basis of disease severity although some small differences were noted in the plasma amino acids. Infusion of dextrose alone and the 16% BCAA solution led to negative protein balance and a lowering of the plasma branched chain amino acid concentrations. Improved protein balance was observed with 35% BCAA, this solution also lowered the levels of methionine and aromatic amino acids. In those patients given 53% BCAA protein balance was achieved and the plasma branched chain amino acids elevated. Protein balance also occurred with 100% BCAA, in association with marked increases in underlying protein synthesis and breakdown and with this infusion there were marked elevations in the plasma branched chain amino acids and depression of the other plasma amino acids. The increase in protein breakdown with this last formulation was unexpected and may be harmful. On the basis of these findings it is suggested that the composition of the 53% and 35% solutions may be optimal to protein metabolism and manipulation of plasma amino acids in this group of patients.

The activities of carnitine acyltransferases and acyl-CoA hydrolases were determined in human and rat liver to establish the validity of extrapolating from studies on rats to human metabolism. In human liver, carnitine acetyltransferase activity was 10-14 times higher and carnitine octanoyltransferase 1.7-2.4 times higher than in rat liver, while carnitine palmitoyltransferase activity was similar in human and rat. Acetyl-CoA hydrolase and octanoyl-CoA hydrolase activities were lower in human (42-57%) than in rat liver, but palmitoyl-CoA hydrolase activity was similar in both species. The activity of citrate synthase was lower (44%) in human than in rat liver. The low citrate synthase activity and the high carnitine acetyltransferase in human liver suggest that in man acetylcarnitine might be more important as a vehicle for export of acetyl units from mitochondria than citrate. The high activity of carnitine acetyltransferase in human liver is consistent with the observation that acetylcarnitine is the predominant acylcarnitine excreted in diabetic ketosis in man. It is concluded that the rat may not be a valid model for carnitine metabolism in man, and that in human liver carnitine may have an important role in transfer of acetyl groups out of mitochondria and possibly also to extra-hepatic tissues.

We report a comparison of continuous intraperitoneal insulin infusion (CIPII) and continuous intravenous insulin infusion (CIVII) in 6 diabetic patients in whom severe hyperglycaemia and ketoacidosis could not be prevented with subcutaneous or intramuscular insulin. In the short term both methods were equally effective in maintaining glycaemic control. Blood glucose, glycerol, and 3-hydroxybutyrate levels were normal but lactate and pyruvate levels remained elevated with both treatments. Insulin requirements were significantly lower on CIPII than CIVII (70 vs 113 U/day, p less than 0.01). Intraperitoneal insulin delivery was associated with near physiological peripheral plasma insulin profiles in 3 patients. In the longer term CIVII was associated with frequent septicaemia and thrombosis, and was successful in preventing hospitalization for 6 months or more in only one patient. Despite technical problems with CIPII complications were less serious and hospital admission due to metabolic decompensation was prevented for 6 months or more in 3 patients. When subcutaneous insulin delivery is unsuccessful in the management of brittle diabetes, CIPII should be considered rather than CIVII because it is more likely to be successful and less likely to cause serious complications.

Fasting blood glucose is elevated and the rate of disappearance of a glucose load is reduced after major surgery. Resistance to insulin is considered to play a part in post-traumatic glucose intolerance. Fructose metabolism is partly independent of insulin. Glucose and fructose clearance were compared in two groups of 6 matched male patients with normal glucose tolerance who were studied before and after major vascular surgical operations of the same severity. Fructose or glucose (25 g) was given intravenously over a 2-min period before, during and at intervals for 8 days after surgery. The rate of clearance of fructose increased significantly during operation (P less than 0.01), but returned to the preoperative level by the first postoperative day. Glucose clearance, in contrast, was reduced during and throughout the 8 days of the study. The fructose load produced a brisk insulin response before operation which was diminished and delayed during surgery. These findings suggest that administered fructose may be removed more rapidly than glucose during and immediately after surgical operation.

To clarify the changes in glucose homeostasis which occur following injury, pigs were subjected to hemorrhagic shock. During shock increased levels of free glucose occurred in red blood cells and muscle tissue, suggesting that inhibition of glucose phosphorylation was occurring. Simultaneously systemic plasma glucose levels were noted to be higher than portal plasma glucose levels while levels of free glucose within the liver fell, indicating that the liver was mobilizing glucose. Plasma insulin and phosphate levels were observed to rise throughout the experiment. From this study it was concluded that the hyperglycemia of injury in these animals was caused by a combination of decreased cellular glucose utilization due to diminished phosphorylation and increased mobilization of glucose by the liver.

The results of 61 consecutive patients treated for bleeding esophageal varices with a coordinated multidisciplinary protocol are described. The primary form of treatment after vigorous resuscitation was fiberoptic endoscopic injection sclerotherapy under general anesthetic. Thirteen patients failed to be controlled by injection, and eight were able to be treated by percutaneous transhepatic embolization. Those patients who were unable to undergo embolization or whose bleeding did not stop after embolization were controlled by surgery. The overall mortality rate with the 2-year limit was 29 patients (47%); however, only 18 deaths (29%) were related to the hospital admission for bleeding. Only one patient died of continued variceal bleeding. All of the other deaths were from later liver failure or unrelated disease. The results of the study confirmed the high mortality rate in patients with severe liver disease (Child's grade C) undergoing surgical control of bleeding, and it was shown that when control was obtained with injection sclerotherapy and embolization, the 1-year survival rate of a similar group of patients may be as high as 32%.

Hormonal and substrate profiles and urinary nitrogen and urea excretion were measured in 78 underweight patients admitted for surgical investigation, who were placed into either a normo- or a hyperketonemic group, depending upon their levels of acetoacetate and beta-hydroxybutyrate. The two groups were otherwise similar in terms of weight loss, arm muscle circumference, triceps skinfold thickness, and serum protein levels. Before surgery only one-quarter of them were hyperketonemic displaying mean glucose, insulin, and glucagon levels characteristic of starvation-adaption, and excreted significantly less urinary nitrogen than in normoketonemic group. Those patients who underwent surgery tended to retain their presurgery hormonal and substrate profile. The normoketonemic group excreted significantly greater amounts of urinary nitrogen, depleted body protein to a greater extent as evidenced by larger changes in arm muscle circumference and serum protein levels, and mortality was greater. Interference with insulin-glucagon balance by sepsis and disease is suggested as a possible explanation for the failure of three-quarters of the patients to become starvation-adapted. The implications of this finding on the parenteral feeding of undernourished patients are discussed.

A program to calculate the 24-h intravenous requirements of water, nitrogen, energy and six electrolytes on a card-programmable pocket calculator is described. Comparison of calculator-generated requirements with intravenous feeding regimens prescribed by junior clinicians for 8 ill patients suggests that the clinicians provide too much water and too little nitrogen and energy. Certain program modifications are necessary to widen the useful clinical application of the calculator, but in general it is a useful bedside tool capable of further application to suitable medical tasks.

A patient with carcinoid syndrome on long-term antiserotonin therapy with parachlorophenylalanine, experienced a flushing attack with hypotension during the prophylactic administration of aprotonin prior to the induction of anaesthesia. When she was subsequently prepared with a long-acting somatostatin analogue, octreotide (Sandostatin, Sandoz SMS 201-995), plasma levels of tumour-released hormones were reduced and anaesthesia for resection of hepatic metastases was uneventful. The advantages of an anaesthetic approach based on inhibition of carcinoid tumour activity, rather than antagonism of released hormones, are discussed.

Forty men who had sustained head injury were randomly assigned to one of five groups to receive 0.2 g nitrogen/kg body weight/day as either an elemental or a whole-protein diet. Three proprietary elemental and two whole-protein diets were compared. The mean daily nitrogen intake was below 0.2 g/kg in all groups, and was significantly lower in the groups receiving elemental compared with whole-protein diets. Energy intake was significantly different only between one group receiving an elemental and one receiving a whole-protein diet. Mean daily urinary nitrogen excretion was significantly lower in the groups receiving elemental diets, and mean daily nitrogen balance was negative in all groups except one receiving a whole-protein diet. Reduced nitrogen intakes occurred particularly with the elemental diets, which often provoked reflex vomiting or gastric stasis. The need to introduce diets at reduced strength made a negative balance almost inevitable, but nutritional balance seemed to be more readily achieved with the whole-protein diets. More work is needed to assess the relative merits of these proprietary diets compared with tube feeds prepared in hospitals.

To examine the effect of increased nonesterified fatty acid concentration on glucose storage in human muscle, an in vitro method for study of glycogen synthesis in this tissue has been established. Muscle strips obtained from rectus abdominus during elective abdominal surgery were clamped at resting length, and adenosine triphosphate/total adenosine nucleotide ratios remained constant for 3 hours ex vivo. Leakage of enzyme markers of muscle damage was minimal, and electron microscopy showed preserved myofibril ultrastructure. Insulin stimulation brought about a dose-dependent increase in rates of glycogen synthesis with a half-maximal effect at 9 x 10(-10) mol/L insulin. In 15 consecutive studies, basal rates of glycogen synthesis were 4.1 +/- 0.5, 3.2 +/- 0.7, and 3.0 +/- 0.3 nmol glucose/25 mg/h in the absence of palmitate, with 1.4 mmol/L and 2.8 mmol/L palmitate, respectively. Insulin-stimulated rates of glycogen synthesis were 8.6 +/- 1.2, 6.0 +/- 1.8, and 5.8 +/- 0.8 nmol glucose/25 mg/h. Thus, increasing fatty acid concentrations decreased rates of glycogen synthesis both basally and with insulin stimulation. The insulin signal itself was not affected as the percentage stimulation over basal rates remained approximately constant in the presence or absence of fatty acid (2.1-, 1.9- and 1.9-fold, respectively). Insulin sensitivity in vivo is usually expressed as absolute rates of glucose uptake during euglycemic hyperinsulinemia, and if plasma fatty acid elevation were to be studied in vivo an erroneous conclusion may be reached of resistance to hormone action per se.(ABSTRACT TRUNCATED AT 250 WORDS)

1. A method is proposed for the determination of the rate of oxidation of 14C-labelled substrates in man from blood sampling only. 2. The method was verified by simulating release of 14C into the bicarbonate pool of patients by using a constant-rate infusion of sodium [14C]bicarbonate, the plasma level of total 14CO2 (d.p.m. ml-1 70 kg-1) correlating well (r = 0.878, P = 0.001) with the infusion rate (microCi/h). 3. Techniques involved in employing this method are discussed, particularly in the light of errors involved.

Two severely brittle diabetic patients were treated with "Infusaid" implantable insulin infusion pumps. Both were young females with recurrent ketoacidosis, prolonged or repeated hospital admissions, and subcutaneous insulin resistance. They also had psychological problems, and had seriously interfered with their treatment to induce glycaemic instability. Delivery of insulin from the pumps was intravenous (i.v.) in one patient, and intraperitoneal (i.p.) in the other. Following implantation, there was a marked improvement in glycosylated haemoglobin level (HbA1), fasting blood glucose (BG), daily insulin dose and hospitalizations. The beneficial effect has continued to date (9 months, and 12 months follow-up) with no major problems.

Thirty seven patients with established cirrhosis of the liver were subjected to measurement of body protein metabolism using L-(1-14C) labelled leucine as a tracer. The effects of disease severity and those of solutions containing 0%, 16%, 35%, 53%, and 100% branched chain amino acids were evaluated. Significant increases in protein synthesis were noted with solutions containing 35%, 53%, and 100% branched chain amino acids, but in patients receiving 100% branched chain amino acids without additional essential amino acid supplement the increase in synthesis was matched by a significant increase in protein breakdown. Protein balance was thus improved only in patients receiving 35% and 53% branched chain amino acids. It was concluded that the high increase in protein breakdown in patients receiving 100% branched chain amino acids was undesirable, and such a solution should not be recommended for clinical use.

A number of metabolic abnormalities associated with cancer may interfere with normal starvation-adaption to alter the pattern of tissue loss in individuals with cancer. The cachexia thus produced is said to differ from simple under-nutrition and may therefore be detectable using simple clinical methods. Seven measurements commonly used for nutritional assessment were made before treatment in 72 patients with cancer and 89 patients who were undernourished but cancer-free. Body weight as a percentage of ideal weight, arm muscle circumference, triceps skinfold thickness, plasma protein, albumin and transferrin and the peripheral blood lymphocyte count did not differ significantly between the groups. If body composition in cancer cachexia differs from that found in comparable simple undernutrition then such variations are not detectable by a standard nutritional assessment.

Direct measurement of body protein metabolism using L-(1-14C) leucine during total parenteral nutrition following cholecystectomy demonstrated no significant difference between isocaloric isonitrogenous regimens containing glucose alone (n = 5) or with a fat emulsion (n = 5) as the energy substrates. It would appear that providing the obligatory requirement for glucose is met (about 150g d(-1)), fat and carbohydrate calories are inter-changeable with regards to fueling protein metabolism in the early period following moderately severe trauma.

Following injury there is increased synthesis of several plasma proteins. During a constant rate infusion of 1-(1-14C) leucine some of the labeled amino acid became incorporated into plasma proteins, the amount being readily determined after precipitation with perchloric acid. This value was correlated with the clinical state of the patient to see if an index of severity of injury could be derived. Before operation 6.7 +/- 0.5% (mean +/- SD, n = 16) of the infused labeled amino acid was incorporated in asymptomatic patients, irrespective of their dietary intakes, while in the presence of symptomatology this value rose, correlating with tumor staging in patients with colorectal neoplasia (r = 0.988, p = 0.001). It returned to normal following tumor resection, but was elevated in the presence of recurrence or residual disease. After operation it also rose, being maximal in the early postoperative period and following the more major surgical procedures, the increase correlating with the change in cortisol level in patients following cholecystectomy (r = 0.84, p less than 0.01; n = 8). The pattern of distribution of the label among the plasma proteins did not change with increased incorporation. The increase in incorporation of 1-(1-14C) leucine into plasma proteins would appear to offer a good index for severity of injury of activity of a disease state.