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Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle. Am J Physiol Endocrinol Metab 283: E38-E43, 2002. First published March 12, 2002; 10.1152/ajpendo.00387.2001.--Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurments confirmed the changes in transcript levels of cytochrome-c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR. rat muscle; microarrays and mitochondrial adenosine 5'triphosphate production

High-fat diets are reported to increase oxidative stress in a variety of tissues, whereas antioxidant supplementation prevents many diseases attributed to high-fat diet. Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage. We hypothesized that the effects of a high-fat diet on skeletal muscle DNA functions would be attenuated or partially reversed by antioxidant supplementation. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle from male rats after feeding one of three diets (control, high-fat diet with or without antioxidants) for 36 wk. The high-fat diet altered transcript levels of 18 genes of 800 surveyed compared with the control-fed rats. Alterations included reduced expression of genes involved in free-radical scavenging and tissue development and increased expression of stress response and signal transduction genes. The magnitude of these alterations due to high-fat diet was reduced by antioxidant supplementation. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome c oxidase subunit III and superoxide dismutase-1 and -2 noted by microarray approach. Mitochondrial ATP production was unaltered by dietary changes or antioxidant supplemention. It is concluded that the high-fat diet increases the transcription of genes involved in stress response but reduces those of free-radical scavenger enzymes, resulting in reduced DNA repair/metabolism (increased DNA damage). Antioxidants partially prevent these changes. Mitochondrial functions in skeletal muscle remain unaltered by the dietary intervention due to many adaptive changes in gene transcription. antioxidants; gene expression; mitochondrial adenosine triphosphate production

We determined the effect of hyperandrogenemia as observed in polycystic ovary syndrome (PCOS) on fasting and glucose-stimulated proatherogenic inflammation markers in lean healthy reproductive-age women. Sixteen lean healthy ovulatory reproductive-age women were treated with 130 mg of DHEA or placebo (n = 8 each) for 5 days. Interleukin-6 (IL-6) mRNA and IL-6 release from mononuclear cells (MNC), plasma IL-6 and C-reactive protein (CRP), and MNC-derived (matrix metalloproteinase-2) MMP-2 protein were quantified in the fasting state and 2 h after glucose ingestion, before and after treatment. Before treatment, subjects receiving dehydroepinadrosterone (DHEA) or placebo exhibited no differences in androgens, or any proatherogenic inflammation markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-sulfate (DHEA-S), and increased the percent change from baseline in fasting IL-6 mRNA, IL-6 release, plasma IL-6, and CRP and MMP-2 protein. However, there were no differences in any of the proatherogenic inflammation markers following glucose ingestion after DHEA administration. We conclude that in lean reproductive-age women, proatherogenic inflammation in the fasting state increases after raising circulating androgens to levels observed in PCOS. However, this hyperandrogenemia- induced MNC activation does not provoke a similar response to subsequent glucose ingestion. [ABSTRACT FROM AUTHOR]

Direct interactions between tumor and immune cells mediate the antitumor effect of all modern cancer immunotherapeutic agents. Simultaneously, tumor cells have evolved mechanisms of evasion including the downregulation of HLA-I potentially disrupting the mechanism of action employed by many immune checkpoint inhibitors. And yet the in situ interplay between these cells within the tumor immune microenvironment (TIME) remains elusive. Recent advances in histologic multiplex bioimaging platforms have enabled in-depth molecular characterization of single cells within spatially-preserved and clinically archived tumor tissues. Herein, we applied multiplex immunofluorescence (MxIF) to excisional lymph node biopsies from 14 patients with metastatic melanoma who experienced clear objective responses to immunotherapy (7 complete response; 7 progressive disease) to determine distinguishing features of the TIME in the pretreatment setting. Distinct regions of the TIME were evaluated using 35 proteins probing tumor, immune and vasculature components across 323 fields of view. Single cell compositional analysis confirmed established prognostic immune cell types including increased prevalence of cytotoxic T cells within the tumor core FOVs of responders. Integrating single cell quantification with the spatial arrangement of cellular neighborhoods surrounding tumor cells revealed novel, spatial immune signatures capable of stratifying TIME based on clinical response. Our analysis revealed dynamic cellular composition of the TCCN based on anatomical subregion, functional expression of HLA-I by the index tumor cell and ultimately clinical response to immunotherapy. Overall, this study provides an analytical framework to resolve the cellular complexity of the TIME, increasingly relevant to the outcomes of modern cancer immunotherapy., Competing Interests: Conflict of Interest Statement: The authors declare no potential conflicts of interest.

Background & Aims: Amino acid (AA) availability is critical to maintain protein homeostasis and reduced protein intake causes a decline in protein synthesis. Citrulline, an amino acid metabolite, has been reported to stimulate muscle protein synthesis in malnourished rats., Methods: To determine whether citrulline stimulates muscle protein synthesis in healthy adults while on a low-protein diet, we studied 8 healthy participants twice in a cross-over study design. Following a 3-days of low-protein intake, either citrulline or a non-essential AA mixture (NEAA) was given orally as small boluses over the course of 8 h. [ring-(13)C6] phenylalanine and [(15)N] tyrosine were administered as tracers to assess protein metabolism. Fractional synthesis rates (FSR) of muscle proteins were measured using phenylalanine enrichment in muscle tissue fluid as the precursor pool., Results: FSR of mixed muscle protein was higher during the administration of citrulline than during NEAA (NEAA: 0.049 ± 0.005; citrulline: 0.060 ± 0.006; P = 0.03), while muscle mitochondrial protein FSR and whole-body protein turnover were not different between the studies. Citrulline administration increased arginine and ornithine plasma concentrations without any effect on glucose, insulin, C-peptide, and IGF-1 levels. Citrulline administration did not promote mitochondria protein synthesis, transcripts, or citrate synthesis., Conclusions: Citrulline ingestion enhances mixed muscle protein synthesis in healthy participants on 3-day low-protein intake. This anabolic action of citrulline appears to be independent of insulin action and may offer potential clinical application in conditions involving low amino acid intake., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Insulin action on protein synthesis (translation of transcripts) and post-translational modifications, especially of those involving the reversible modifications such as phosphorylation of various signaling proteins, are extensively studied but insulin effect on transcription of genes, especially of transcriptional temporal patterns remains to be fully defined., Methodology/principal Findings: To identify significant transcriptional temporal patterns we utilized primary differentiated rat skeletal muscle myotubes which were treated with insulin and samples were collected every 20 min for 8 hours. Pooled samples at every hour were analyzed by gene array approach to measure transcript levels. The patterns of transcript levels were analyzed based on a novel method that integrates selection, clustering, and functional annotation to find the main temporal patterns associated to functional groups of differentially expressed genes. 326 genes were found to be differentially expressed in response to in vitro insulin administration in skeletal muscle myotubes. Approximately 20% of the genes that were differentially expressed were identified as belonging to the insulin signaling pathway. Characteristic transcriptional temporal patterns include: (a) a slow and gradual decrease in gene expression, (b) a gradual increase in gene expression reaching a peak at about 5 hours and then reaching a plateau or an initial decrease and other different variable pattern of increase in gene expression over time., Conclusion/significance: The new method allows identifying characteristic dynamic responses to insulin stimulus, common to a number of genes and associated to the same functional group. The results demonstrate that insulin treatment elicited different clusters of gene transcript profile supporting a temporal regulation of gene expression by insulin in skeletal muscle cells.

Objective: To determine the type of Irish dance injuries requiring evaluation and treatment by a sports medicine physician., Design: Cross-sectional retrospective chart review., Setting: Academic sports medicine center in the Midwest., Participants: Female Irish dancers who presented at an academic sports medicine center from June 2002 to September 2009., Main Outcome Measures: This was a retrospective chart review identifying injuries sustained to female Irish dancers in a single Irish dance company in a major metropolitan area. Dancers were evaluated and injuries were diagnosed by one sports medicine physician at an academic sports medicine center., Results: Sixty-nine female Irish dancers, ages 8 to 23 years, sustained 217 recorded injuries. The top injuries included stress fractures (29.9%), patellofemoral pain syndrome (11.1%), Sever condition (6.0%), ankle sprains (5.1%), posterior tibialis tendonitis (4.6%), and plantar fasciitis (4.6%). The most common site for stress fractures were the sesamoids, comprising 27.7% of all stress fractures and 8.3% of total injuries. The majority of injuries were in the lower extremities (94.9%), remaining injuries involved the lumbosacral spine and pelvis (5.1%). Most dancers (79.7%) had multiple injuries. The number of injuries per dancer increased as the dancer's level increased. There was a trend for the average age of the dancers to decrease as the level of skill increased., Conclusion: Lower extremity injuries comprised the majority of Irish dance injuries. Stress fractures (29.9%), patellofemoral pain syndrome (11.1%), and Sever condition (6.0%) were the most common injuries., (Copyright © 2010 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Context: Although GH promotes growth and protein anabolism, which are ATP-dependent processes, the GH effect on mitochondrial regulation remains to be determined., Objective: Our objective was to determine the acute effect of GH on mitochondrial oxidative capacity in skeletal muscle of healthy subjects., Design and Setting: The study was a randomized crossover design at an academic medical center., Participants: Nine healthy men and women completed the study., Intervention: GH (150 microg/h) or saline was infused for 14 h on separate days, and muscle biopsies were obtained., Main Outcome Measures: Outcome measures included mitochondrial function, gene expression, and protein metabolism., Results: The 4-fold increase in plasma GH caused elevations in plasma IGF-I, insulin, glucose, and free fatty acids and a shift in fuel selection, with less carbohydrate (-69%) and leucine (-43%) oxidation and 29% more fat oxidation. Muscle mitochondrial ATP production rate and citrate synthase activity were increased 16-35% in response to GH. GH also resulted in higher abundance of muscle mRNAs encoding IGF-I, mitochondrial proteins from the nuclear (cytochrome c oxidase subunit 4) and mitochondrial (cytochrome c oxidase subunit 3) genomes, the nuclear-derived mitochondrial transcription factor A, and glucose transporter 4. Although GH increased whole-body protein synthesis (nonoxidative disposal of leucine), no effect on synthesis rate of muscle mitochondrial proteins was observed., Conclusions: These results demonstrate that acute GH action promotes an increase in mitochondrial oxidative capacity and abundance of several mitochondrial genes. These events may occur through direct or indirect effects of GH on intracellular signaling pathways but do not appear to involve a change in mitochondrial protein synthesis rate.

Objective: Muscle mitochondrial dysfunction occurs in many insulin-resistant states, such as type 2 diabetes, prompting a hypothesis that mitochondrial dysfunction may cause insulin resistance. We determined the impact of insulin deficiency on muscle mitochondrial ATP production by temporarily depriving type 1 diabetic patients of insulin treatment., Research Design and Methods: We withdrew insulin for 8.6 +/- 0.6 h in nine C-peptide-negative type 1 diabetic subjects and measured muscle mitochondrial ATP production and gene transcript levels (gene array and real-time quantitative PCR) and compared with insulin-treated state. We also measured oxygen consumption (indirect calorimetry); plasma levels of glucagon, bicarbonate, and other substrates; and urinary nitrogen., Results: Withdrawal of insulin resulted in increased plasma glucose, branched chain amino acids, nonesterified fatty acids, beta-hydroxybutyrate, and urinary nitrogen but no change in bicarbonate. Insulin deprivation decreased muscle mitochondrial ATP production rate (MAPR) despite an increase in whole-body oxygen consumption and altered expression of many muscle mitochondrial gene transcripts. Transcript levels of genes involved in oxidative phosphorylation were decreased, whereas those involved in vascular endothelial growth factor (VEGF) signaling, inflammation, cytoskeleton signaling, and integrin signaling pathways were increased., Conclusions: Insulin deficiency and associated metabolic changes reduce muscle MAPR and expression of oxidative phosphorylation genes in type 1 diabetes despite an increase in whole-body oxygen consumption. Increase in transcript levels of genes involved in VEGF, inflammation, cytoskeleton, and integrin signaling pathways suggest that vascular factors and cell proliferation that may interact with mitochondrial changes occurred.

Phase 2 studies suggest that the monoclonal antibody rituximab may improve the prognosis of patients with follicular lymphoma (FL) when it is added to chemotherapy. In the current study, 428 patients with untreated, advanced-stage FL were randomly assigned for therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone (n = 205) or CHOP combined with rituximab (R-CHOP) (n = 223). R-CHOP reduced the relative risk for treatment failure by 60% and significantly prolonged the time to treatment failure (P < .001). In addition, a significantly higher overall response rate (96% vs 90%; P = .011) and a prolonged duration of remission (P = .001) were achieved. In spite of a relatively short observation time, these beneficial effects even translated to superior overall survival (P = .016), with 6 deaths in the R-CHOP group compared with 17 deaths in the CHOP group within the first 3 years. The predominant treatment-related adverse effect was myelosuppression. Severe granulocytopenia was more frequently observed after R-CHOP (63% vs 53%; P = .01). However, severe infections were rare and of similar frequency after R-CHOP and CHOP (5% and 7%). Hence, adding rituximab to CHOP significantly improves the outcome for patients with previously untreated advanced-stage FL and does not induce major adverse effects.

Cumulative mtDNA damage occurs in aging animals, and mtDNA mutations are reported to accelerate aging in mice. We determined whether aging results in increased DNA oxidative damage and reduced mtDNA abundance and mitochondrial function in skeletal muscle of human subjects. Studies performed in 146 healthy men and women aged 18-89 yr demonstrated that mtDNA and mRNA abundance and mitochondrial ATP production all declined with advancing age. Abundance of mtDNA was positively related to mitochondrial ATP production rate, which in turn, was closely associated with aerobic capacity and glucose tolerance. The content of several mitochondrial proteins was reduced in older muscles, whereas the level of the oxidative DNA lesion, 8-oxo-deoxyguanosine, was increased, supporting the oxidative damage theory of aging. These results demonstrate that age-related muscle mitochondrial dysfunction is related to reduced mtDNA and muscle functional changes that are common in the elderly.

Background: Unpredictable and severe diarrhea (NCI grade > or =3) remains a life-threatening adverse event in patients treated with irinotecan (CPT-11). The aim of this study was to evaluate the efficacy and safety of orally administered budesonide for prevention of CPT-11-induced delayed diarrhea in patients with advanced colorectal cancer., Patients and Methods: A total of 56 patients with advanced colorectal cancer receiving CPT-11 therapy (125 mg/m2 once weekly) were enrolled in this multicenter trial. Patients were randomly treated with 3 mg budesonide orally 3 times daily versus placebo. Detailed assessment of diarrhea by monitoring stool frequency, stool consistency and loperamide rescue medication was made by keeping a diary., Results: Diarrhea, defined as number of stools >4 occurring on a single day during the study period, could be prevented in 58.3% of the budesonide-treated patients compared to 38.5% of the patients under placebo. Patients in the budesonide group had less episodes (0.7 vs. 2.2 episodes) and a considerably shorter total duration of diarrhea (1.8 vs. 4.2 days) episodes than patients in the placebo group. Loperamide use was more frequent in the placebo than in the budesonide arm (55.6 vs. 41.7%). Also, exposure to rescue medication of loperamide was higher for placebo (36.2 capsules) than for budesonide (24.9 capsules). A superior prevention of diarrhea was observed for budesonide compared to placebo in the first cycle (14 vs. 10; p = 0.257), with more failures observed in the placebo group (16 vs. 10)., Conclusion: This double-blind randomized trial failed to show that budesonide has a significant benefit in preventing CPT-11-induced diarrhea. While a trend exists, further trials are warranted., ((c) 2005 S. Karger AG, Basel)

This study was aimed at evaluating the feasibility, effectiveness, and toxicity of palliative chemotherapy/supportive care in patients with advanced pancreatic cancer being treated on an outpatient basis. A retrospective analysis was performed on 127 consecutive, unselected patients with advanced pancreatic cancer in four community-based oncology group practices. Median age was 63 years and WHO performance status ranged from 0 to 3. Forty-three patients (34%) had locally advanced disease, and 84 patients (66%) had distant metastases; 94 patients (74%) received cytotoxic treatment during the course of their disease, and 33 (26%) received best supportive care only. First-line treatment consisted of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) in 81 patients (86%), 5-fluorouracil (5-FU) in 8 patients (9%), radiochemotherapy in 4 patients (4%), and radiation therapy only in 1 patient (1%). A total of 1,501 gemcitabine treatments were given during the study period. Toxicity was moderate. Four patients (3%) required hospitalization for treatment-related side effects, and 111 patients (88%) died during the observation period. Symptom control, as measured by reduction of pain medication, was seen in 25% of patients receiving gemcitabine, whereas no reduction in pain medication was seen in the best supportive care group. The median survival of patients receiving cytotoxic treatment (mainly gemcitabine) was 42 weeks, and the median survival of patients receiving best supportive care was 21 weeks. The overall survival rate at 6, 12, 24, and 36 months was 65%, 32%, 14%, and 7%, respectively. Based on these outcomes, it appears that patients with locally advanced and metastatic pancreatic cancer benefit from adequate palliative treatment, including cytotoxic chemotherapy with gemcitabine, and this can be accomplished on an outpatient basis.

Experimental evidence indicates that a lower synthesis rate of muscle contractile protein myosin heavy chain (MHC) occurs in age-related muscle wasting and weakness. To determine the molecular mechanism of this lower synthesis of MHC, we measured transcript levels of isoforms of MHC (MHCI, MHCIIa, and MHCIIx) in muscle biopsy samples of 7 young (20-27 yr), 12 middle-aged (47-60 yr), and 14 older (>65 yr) people. We further determined the effect of 3 mo of resistance exercise training (exercise) vs. nonintervention (control) on transcript levels of MHC isoforms on these subjects and the fractional synthesis rate (FSR) of MHC in 39 people aged 46-79 yr. MHCI mRNA levels did not significantly change with age, but MHCIIa decreased 38% (P < 0.05) from young to middle age and further decreased 50% (P < 0.05) from middle to old age. MHCIIx decreased 84% (P < 0.05) from young to middle age and 48% from middle to old age (P < 0.05). Exercise increased FSR of MHC by 47% (P < 0.01) and mixed muscle protein by 56% (P < 0.05). Exercise training results in an increase (85%) in transcript levels of MHCI and a decrease in the transcript levels of MHCIIa and MHCIIx. In conclusion, an age-related lowering of the transcript levels of MHCIIa and MHCIIx is not reversed by exercise, whereas exercise results in a higher synthesis rate of MHC in association with an increase in MHCI isoform transcript levels.

Insulin-like growth factor-I and -II (IGF-I and IGF-II) and their binding proteins are important components in growth promotion and tissue maintenance. We determined the presence of IGF-I, -II, and binding protein 5 (IGFBP-5) gene expression in human skeletal muscle and that mRNA abundance is not altered by nutrients and insulin. In the first protocol, (control) subjects were given water. In the second protocol, half of these subjects drank Polycose (carbohydrate) and the remaining subjects drank equal calories as a mixed meal. Quadriceps muscle biopsies were taken at 10 h. A semi-quantitative polymerase chain reaction was designed to measure gene expression. IGF-I, IGF-II and IGFBP-5 mRNA are present in adult human skeletal muscle, but no significant changes between meal groups were observed for IGF-I, IGF-II or IGFBP-5 mRNA levels, indicating that the expression of these genes are not altered acutely by nutrients and insulin., (Copyright 1999 Harcourt Publishers Ltd.)

The presence of endotoxin from Gram-negative bacteria signals the innate immune system to up-regulate bacterial clearance and/or killing mechanisms. Paradoxically, such responses also contribute to septic shock, a clinical problem occurring with high frequency in Gram-negative septicemia. CD14 is a receptor for endotoxin (lipopolysaccharide, LPS) and is thought to have an essential role in innate immune responses to infection and thereby in the development of septic shock. Using a novel rabbit model of endotoxic shock produced by multiple exposures to endotoxin, we show that anti-rabbit CD14 mAb, which blocks LPS-CD14 binding, protects against organ injury and death even when the antibody is administered after initial exposures to LPS. In contrast, anti-rabbit tumor necrosis factor mAb treatment fails to protect when administered after LPS injections. These results support the concept that anti-CD14 treatment provides a new therapeutic window for the prevention of pathophysiologic changes that result from cumulative exposures to LPS during septic shock in man.

Previous work has shown that the avian retina receives two types of centrifugal fibers from the brain. These types can be distinguished based on the size and the morphology of their terminal endings and have been termed convergent and divergent. The centrifugal fibers arise from the isthmooptic nucleus (ION) and the surrounding ectopic cell region (ECR). We used injections of anterograde tracers either to the ION/ECR or to the ECR only to determine the morphology, depth of termination, and regional distribution of the centrifugal fibers arising from each. We found that the ECR gives rise only to the divergent type of the centrifugal fiber, whereas the ION gives rise mainly to the convergent type but may also send some fibers of the divergent type. Most of the fibers project contralaterally, although a few from the ECR project ipsilaterally. The terminals of either type are not uniformly distributed throughout the retina; instead, they are found mainly in the inferior, midtemporal, to nasal portion of the retina and appear to avoid the fovea and most of the red field. By comparison, the ION receives a major projection from portions of the tectum that receive input from the fovea and the red field in a type of neural loop. The neural loop does not project to the same point (homotopic), but projects from the red field to the inferior retina (heterotopic), as was recently proposed by Holden (1990; Vis. Neurosci. 4:493-497). The distribution of centrifugal axons corresponds to displaced ganglion cells that selectively innervate the nuclei of the accessory optic system (AOS), including the nucleus of the basal optic root (dorsal, ventral, and lateral) and the nucleus lentiformis mesencephali, pars magnocellularis. We suggest that the centrifugal axons act by increasing the gain on the AOS, thereby enhancing retinal stabilization of gaze with improved accuracy of pecking of small objects.

Background: Opioid and spinal monoaminergic agonists have distinct analgesic properties, which may potentiate each other. Tramadol has both opioid and monoaminergic agonist actions. This initial study compared the analgesic and toxic effects of tramadol and morphine in patients with strong cancer pain., Patients and Methods: Pain control and side-effects with tramadol and morphine were compared in 20 cancer patients hospitalised for the treatment of strong pain. Doses of oral solutions of tramadol or morphine were individually titrated in the double-blind, randomized, cross-over study. Cross-over was after day 4, the day of statistical evaluation., Results: The mean pain intensity (+/- SD) on a verbal rating scale (0 = none, 4 = unbearable) was similar with morphine (1.6 +/- 1.2, n = 17) and with tramadol (1.5 +/- 1.3, n = 16) on the fourth day of dosing. The mean daily doses on day 4 were 101 +/- 58 mg of morphine and 375 +/- 135 mg of tramadol, indicating a relative potency of 4:1 with oral dosing. The total number of side-effects per person was lower on the fourth day with tramadol (p < 0.05), as was the severity of nausea (p < 0.05) and constipation decreased with tramadol (p < 0.05). Three patients dropped out of the morphine group due to side-effects and 4 out of the tramadol group due to inadequate analgesia. Overall, 8 patients (40%) preferred morphine, 3 (15%) favoured tramadol and 9 (45%) expressed no distinct choice. Nurses rated pain control better with morphine (p < 0.03), but the tolerability of tramadol was judged superior (p < 0.002)., Conclusions: In certain cancer patients with strong pain, tramadol achieved good pain control with fewer side-effects than morphine. The non-opioid mode of action may result in a different spectrum of analgesia and side-effects. Longterm studies are required to confirm this study of brief duration.

The influence of prostacyclin (PGI2) alone or in combination with intraaortic balloon pumping (IABP) on the levels of energy-rich phosphate compounds was investigated before and after coronary artery ligation in canine myocardium. There was a higher level in creatine phosphate in the ischemic as well as non-ischemic areas of the myocardium after treatment with PGI2, however the most protective effect was registered after a combination of PGI2 and IABP. PGI2 also reduces the release of cathepsin D activity into the blood independently whether or not a mechanical support of the heart after coronary artery ligation was performed.

Delayed nausea and emesis are common after cancer chemotherapy, especially cisplatin-containing regimens. Often no, or inadequate, prophylactic antiemetic cover is prescribed in these usually ambulant patients. Metoclopramide is a very effective drug in preventing the acute emetic and nauseating effects of cisplatin. The long-acting metoclopramide formulations (in the present study: Gastrosil retard) may be effective in preventing the delayed toxicity. 12-hourly dosing of 60 mg long-acting metoclopramide in a typical oncology ward situation led to stable metoclopramide levels of approximately 100ng/ml in the observed 74 h in 18 patients, with the well-known wide plasma concentration variability. The clinical efficacy of long-acting metoclopramide in this indication remains to be evaluated.