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Selected AbstractsEffects of repeated injections of fibroblast-stimulating lipopeptide-1 on fever, formation of cytokines, and on the responsiveness to endotoxin in guinea-pigsACTA PHYSIOLOGICA, Issue 1 2009A. Greis Abstract Aims:, We investigated, whether the Toll-like receptors (TLRs)-2/6-agonist fibroblast-stimulating lipopeptide-1 (FSL-1), like the TLR-4 agonist lipopolysaccharide (LPS), induces a state of tolerance. We further tested the influence of repeated pre-treatment with FSL-1 on the animals' responsiveness to LPS. Methods:, Abdominal temperature was recorded in unrestrained guinea-pigs with intra-abdominally implanted radiotransmitters. Circulating concentrations of tumour necrosis factor (TNF) and interleukin-6 (IL-6) were measured with specific bioassays. We tested the effects of intra-arterial (i.a.) or intraperitoneal (i.p.) injections of 100 ,g kg,1 FSL-1, repeated five times at intervals of 3 days. The animals' responses to i.a. or i.p. injections of 10 ,g kg,1 LPS were determined another 3 days later and compared to those of naďve guinea-pigs. Results:, The FSL-1-induced TNF peak was significantly attenuated starting with the third i.a. administration, while fever was unimpaired and the IL-6-peak just tended to decrease. Fever and IL-6 in response to i.a. injections of LPS were identical in both groups, while circulating TNF was higher in naďve compared to FSL-1 pre-treated animals. The effects of repeated i.p. injections of FSL-1 were more pronounced resulting in attenuation of fever as well as circulating TNF and IL-6, the strongest reduction observed after the third stimulation with FSL-1. Repeated i.p. pre-treatment with FSL-1 induced hyporesponsiveness to i.p. administration of LPS compared to naďve animals with regard to fever and especially with regard to LPS-induced formation of cytokines. Conclusions:, There is a development of tolerance to FSL-1 and cross-tolerance between FSL-1 and LPS depending on the route of administration of the respective TLR-2/6 and TLR-4 agonists. [source] Circulating adipocytokines in non-diabetic and Type 1 diabetic children: relationship to insulin therapy, glycaemic control and pubertal developmentDIABETIC MEDICINE, Issue 6 2006F. Celi Abstract Aim To determine the influence of Type 1 diabetes mellitus on circulating adipocytokines in children. Methods The circulating concentrations of leptin, adiponectin, resistin and tumour necrosis factor (TNF)-, were measured in 91 children, aged 11.1 ± 2.7 years, with Type 1 diabetes mellitus (T1DM). Ninety-one healthy children were selected as control subjects. Results Body mass index-adjusted leptin concentrations were higher in the pubertal diabetic children compared with the control children. There was a significant positive correlation between leptin and daily insulin dose in the diabetic group. Circulating adiponectin concentrations were higher in the prepubertal diabetic children and were positively associated with HbA1c. Resistin concentrations were lower in the prepubertal non-diabetic subjects compared with the pubertal non-diabetic children, whose values were higher than those of the diabetic children. TNF-, concentrations were similar in non-diabetic and diabetic children. Conclusions Circulating concentrations of adipocytokines are abnormal in Type 1 diabetic children, although the direction of change differs by cytokine. Pubertal development, in addition to insulin treatment and glycaemic control, also influences the concentrations. [source] Adrenocortical and Pituitary Glucocorticoid Feedback in Abstinent Alcohol-Dependent WomenALCOHOLISM, Issue 5 2010Bryon Adinoff Background:, The long-term ingestion of alcohol diminishes hypothalamic,pituitary,adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone. Methods:, Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 age-matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 ,g/kg), a synthetic ACTH (1,24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes. Results:, Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone. Conclusion:, Significant differences in pituitary,adrenal function were not apparent between alcohol-dependent women and matched controls. Despite the small n, it appears that alcohol-dependent women do not show the same disruptions in HPA activity as alcohol-dependent men. These findings may have relevance for gender-specific treatment effectiveness. [source] Primate models in women's health: inflammation and atherogenesis in female cynomolgus macaques (Macaca fascicularis)AMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009Thomas C. Register Abstract Female cynomolgus monkeys are excellent models for understanding cardiovascular disease and the relationships between inflammatory processes and conditions such as atherogenesis. This review summarizes published research findings obtained through comprehensive, multidisciplinary, multi-investigator studies in nonhuman primates over the past two decades. These studies examined the effects of exogenous estrogens and dietary soy protein/isoflavones (IFs) on atherosclerosis, circulating biomarkers, and tissue inflammation in pre- and postmenopausal female cynomolgus monkeys. Inflammation may play a role in the initiation and progression of disease, be a consequence of the disease, or both. Circulating and tissue biomarkers with inflammatory and anti-inflammatory characteristics (including adhesion molecules such as e-selectin, VCAM-1, and ICAM-1, chemokines such as MCP-1, cytokines such as interleukins, and acute phase reactants such as CRP, and others) may be useful indicators of disease status. Treatment of postmenopausal subjects with estrogen resulted in significant reductions in several key inflammatory mediators as well as atherosclerosis, while dietary IF had a more limited effect on inflammation and atherogenesis. Circulating concentrations of key inflammatory proteins, including monocyte-chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), were associated with atherosclerosis and lesion characteristics in these animals. In premenopausal female monkeys, a diet enriched in soy protein reduced arterial inflammation as well as atherogenesis in comparison to a diet enriched in casein-lactalbumin. Expression levels of arterial inflammation associated genes (MCP-1, ICAM-1) and markers for inflammatory cell types (macrophages and T cells) correlated with plaque size, were differentially influenced by treatments, and represent potential targets for interventions. Arterial expression of estrogen receptor ,, the key mediator of estrogenic effects, was inversely correlated with plaque size and indices of inflammation, suggestive of an atheroprotective role. The findings provide additional evidence that circulating inflammatory markers (particularly MCP-1) may be useful indicators of atherosclerotic disease progression and responses to treatment in female primates, and that estrogens and dietary soy may inhibit atherogenesis in part through anti-inflammatory mechanisms. Am. J. Primatol. 71:766,775, 2009. © 2009 Wiley-Liss, Inc. [source] Preoperative but not postoperative systemic inflammatory response correlates with survival in colorectal cancer,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 8 2007J. E. M. Crozier Background: The aim of the present study was to evaluate the relationship between the preoperative and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for colorectal cancer. Methods: One hundred and eighty patients with colorectal cancer were studied. Circulating concentrations of C-reactive protein (CRP) were measured before surgery and in the immediate postoperative period. Results: The peak in CRP concentration occurred on day 2 (P < 0·001). During the course of the study 59 patients died, 30 from cancer and 29 from intercurrent disease. Day 2 CRP concentrations were dichotomized. In univariable analysis, advanced tumour node metastasis stage (P = 0·002), a raised preoperative CRP level (P < 0·001) and the presence of hypoalbuminaemia (P = 0·043) were associated with poorer cancer-specific survival. Conclusion: Preoperative but not postoperative CRP concentrations are associated with poor tumour-specific survival in patients undergoing potentially curative resection for colorectal cancer. Copyright © 2007 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Serum markers of lamellar basement membrane degradation and lamellar histopathological changes in horses affected with laminitisEQUINE VETERINARY JOURNAL, Issue 6 2000P. J. JOHNSON Summary In order better to evaluate the extent to which degradation of the lamellar basement membrane (LBM) by matrix metalloproteinases (MMP) occurs in equine laminitis, we determined the concentration of type IV collagen and laminin in normal and laminitic horses, using specific immunoassays. Blood samples were obtained from both the jugular and the cephalic veins of horses (n = 10) before and after the induction of acute alimentary laminitis by carbohydrate overload. Jugular and cephalic venous blood samples were also obtained from horses affected with naturally occurring laminitis (n = 16) and nonlaminitic controls (n = 8). The serum collagen IV concentration was not changed following the induction of laminitis in the experimental group. Serum collagen IV concentration was increased in jugular venous blood obtained from cases of naturally occurring laminitis (mean ± s.e. 218.04 ± 18.59 ng/ml) compared with nonlaminitic controls (157.50 ± 10.93 ng/ml) (P<0.05). Serum collagen IV concentration was also increased in jugular venous blood obtained from severely laminitic horses (219.50 ± 18.18 ng/ml) compared with nonlaminitic controls (157.50 ± 10.93 ng/ml) (P<0.05). A difference in serum concentration of collagen IV was not identified based on chronicity of naturally occurring laminitis. Serum laminin concentration did not differ between laminitic and nonlaminitic horses. Differences in serum laminin concentration were not identified based on sampling location (jugular orcephalic vein), severity of laminitic pain, or chronicity of spontaneous laminitis. In conclusion, the circulating concentration of collagen IV was increased in horses affected with naturally occurring laminitis. The potential role for serum collagen IV assay for characterisation of equine laminitis warrants further investigation. [source] Changes in direct current (DC) potentials and infra-slow EEG oscillations at the onset of the luteinizing hormone (LH) pulseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Lisa Marshall Abstract An essential function of the neuroendocrine system lies in the coordination of hypothalamo-pituitary secretory activity with neocortical neuronal activity. Cortical direct current (DC) potential shifts and EEG were monitored in conjunction with the circulating concentration of luteinizing hormone (LH) in humans while asleep to assess a hypothalamic,neocortical interaction. The onset of an LH pulse was accompanied (i) at frontocortical locations by a transient positive DC potential shift of ,,3 min duration and peak amplitude 50 ,V; (ii) at frontal and central locations by an increase in power of infra-slow EEG oscillations for periodicities between 64 and 320 s. Results uniquely demonstrate a coupling of hypothalamo-pituitary activity with regulation of neocortical excitability. [source] Chemical form of dietary l -Carnitine affects plasma but not tissue Carnitine concentrations in male Sprague,Dawley ratsJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 2 2009B. D. Lambert Summary In Experiment 1, rats (n = 54) were randomly assigned to control or one of the four sources of l -Carnitine supplemented at either 100 or 200 ,mol/kg/day and were allowed to acclimate for 14 days. Following a 12-h fast, plasma samples were obtained at 0, 5, 10, 15, 30, 60, 120, 240, 480 and 720 min after l -Carnitine feeding and assayed for free l -Carnitine concentration. Plasma-free l -Carnitine levels were affected by time after treatment intake (p < 0.0001) and l -Carnitine source (p < 0.0001). The time × source interaction was not statistically significant (p = 0.99). In Experiment 2, rats (n = 54) were randomly assigned to control or one of the four sources of l -Carnitine at either 100 or 200 ,mol/kg/day and were acclimated as in experiment 1. Rats were sacrificed 120 min after feeding. Samples of liver and skeletal muscle were obtained and assayed for free l -Carnitine concentration. Neither skeletal muscle (p = 0.44) or liver (p = 0.59) tissue concentrations of l -Carnitine were affected by any l -Carnitine source as compared with the control. We conclude that some differences exist in plasma concentrations of free l -Carnitine following ingestion of different chemical forms of l -Carnitine. It is unclear if these differences in the circulating concentration of free l -Carnitine translate into any physiological differences for the animal. In this study, chemical form of l -Carnitine had no effect on skeletal muscle or liver tissue concentrations of l -Carnitine in young male Wistar rats. [source] Prognostic value of serum angiogenic activity in colorectal cancer patientsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2007Francisco-Jesus Gonzalez Abstract Angiogenesis, resulting from an imbalance between angiogenic activator factors and inhibitors, is required for tumour growth and metastasis. The determination of the circulating concentration of all angiogenic factors (activators and inhibitors) is not feasible at present. We have evaluated diagnostic and prognostic values of the measurement of serum angiogenic activity in colorectal carcinoma (CRC) patients. Serum proliferative activity (PA) on human umbilical vein endothelial cells (HUVEC) in vitro, and serum vascular endothelial growth factor (VEGF) levels were determined by ELISA in 53 patients with primary CRC, 16 subjects with non-neoplastic gastrointestinal disease (SC) and 34 healthy individuals. Data were compared with clinical outcome of the patients. Although serum from CRC patients significantly increased the PA of HUVEC, compared to culture control (HUVEC in medium + 10% foetal bovine serum (FBS); P < 0.001); our results indicate that serum PA in CRC patients was similar to that of SC or healthy individuals. There was no correlation between serum PA and circulating VEGF concentrations. Surgery produced a decrease of PA at 8 hrs after tumour resection in CRC patients compared to pre-surgery values (186 ± 47 versus 213 ± 41, P < 0.001). However, an increase in serum VEGF values was observed after surgery (280 [176,450] versus 251 [160,357] pg/ml, P = 0.004). Patients with lower PA values after surgery showed a worse outcome that those with higher PA values. Therefore, this study does not support a diagnostic value for serum angiogenic activity measured by proliferative activity on HUVEC but suggests it could have a prognostic value in CRC patients. [source] Fasting concentrations of nesfatin-1 are negatively correlated with body mass index in non-obese malesCLINICAL ENDOCRINOLOGY, Issue 4 2010Takafumi Tsuchiya Summary Background, We recently identified a novel anorexigenic protein, nesfatin-1, which is processed from nesfatin/nucleobindin-2 (NUCB2). However, the clinical importance of this protein has not been determined. Objective, To investigate its clinical significance in humans, we have established a new specific enzyme-linked immunosorbent assay (ELISA) for human nesfatin-1 in peripheral blood and measured its circulating concentration in healthy subjects. Design, The new sandwich-type ELISA method was validated and then used to measure nesfatin-1 levels in plasma samples, under overnight fasting conditions, followed by oral glucose tolerance and meal tests. Patients and measurements, A total of 43 nonobese males (age: 24·5 ± 0·6 , body mass index (BMI); 21·1 ± 0·3 kg/m2) were recruited to the study for evaluating fasting concentrations of nesfatin-1. In those, fifteen subjects underwent a 75- g oral glucose tolerance test (OGTT) and another 15 underwent a meal test. In addition, fasting concentrations of nesfatin-1 were measured in nine males with high BMI (age: 32·4 ± 3·7 , BMI; 37·3 ± 3·8 kg/m2). Results, Peripheral concentrations of nesfatin-1 showed a significant negative correlation with BMI, percentage body fat, body fat weight and blood glucose (P < 0·05). Nesfatin-1 concentrations were not significantly changed during OGTT and meal tests. Fasting nesfatin-1 levels were significantly lower in subjects with high BMI compared to nonobese subjects (P < 0·05). Conclusions, A new specific and sensitive ELISA for nesfatin-1 was established. Further accumulation of clinical observations is necessary to clarify the role of circulating nesfatin-1 in various metabolic disorders. [source] Equine laminitis: Ultrastructural lesions detected in ponies following hyperinsulinaemiaEQUINE VETERINARY JOURNAL, Issue 7 2009A. R. NOURIAN Summary Reasons for performing study: Anatomical changes in the hoof lamellar tissue induced by prolonged hyperinsulinaemia have not been described previously. Analysis of the induced lesions may promote understanding of hyperinsulinaemic laminitis pathogenesis and produce clinical benefit. Objectives: To use light and transmission electron microscopy (TEM) to document hoof lamellar lesions in ponies clinically lame after prolonged hyperinsulinaemia. Methods: Nine clinically normal, mature ponies were allocated randomly to either a treatment group (n = 5) or control group (n = 4). The treatment group received insulin via a modified, prolonged euglycaemic hyperinsulinaemic clamp technique (EHCT) and were subjected to euthanasia when clinical signs of Obel grade II laminitis occurred. The control group was sham treated with an equivalent volume of 0.9% saline and killed at 72 h. Lamellar tissues of the right front feet were harvested and processed for TEM. Results: Lamellae from insulin treated ponies were attenuated and elongated with many epidermal basal cells (EBC) in mitosis. Unlike carbohydrate induced laminitis in horses there was no global separation at the lamellar dermal/epidermal interface among ponies. Sporadic EBC basement membrane (BM) separation was associated with the proximity of infiltrating leucocytes. In 2 ponies, the lamellar BM was thickened. The number of hemidesmosomes/,m of BM was decreased in all insulin treated ponies. Conclusions: Prolonged hyperinsulinaemia causes unique lamellar lesions normally characteristic of acute and chronic laminitis. Lamellar proliferation may be an insulin effect through its mitogenic pathway. Aberrant lamellar mitosis may lengthen and weaken the lamellar, distal phalanx attachment apparatus and contribute to the clinical signs that developed. Potential relevance: The study shows that insulin alone, in higher than normal circulating concentrations, induces profound, changes in lamellar anatomy. Medical control of insulin resistance and hyperinsulinaemia may ameliorate lesions and produce clinical benefit. [source] Seasonal Variation in Serum Concentrations of Selected Metabolic Hormones in HorsesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2010N.J. Place Background: Determination of adrenocorticotropic hormone (ACTH) concentration is a commonly used test in the evaluation of endocrine causes of equine laminitis, but the concentration in healthy horses can be high at certain times of year, which alters the specificity of the ACTH test. Objective: To determine if circulating concentrations of ACTH, cortisol, glucose, insulin, and thyroxine vary month to month in healthy horses and in horses with equine metabolic syndrome (EMS). Animals: Nine healthy adult horses were studied on their farm/stable over the course of 1 year. After the diagnosis of EMS, 10 laminitic horses residing at the same farm/stable were also studied. Methods: Prospective study of healthy and laminitic horses. Plasma/serum samples were analyzed for concentrations of hormones and glucose. Results: ACTH was the only analyte to show a discrete seasonal pattern, with concentrations in healthy and EMS horses frequently outside of the reference range (9,35 pg/mL) in August through October. Insulin was elevated (>40 ,IU/mL) in EMS horses during most months and median serum glucose was generally higher in EMS horses (100 mg/dL, range, 76,163 mg/ dL) than in controls (94 mg/dL, range, 56,110 mg/dL), but no seasonal patterns for insulin or glucose were found. Conclusions and Clinical Importance: An increased ACTH concentration in horses in late summer or autumn should be interpreted with caution. In contrast, insulin concentration is maintained within the reference range throughout the year in healthy horses, thus an increased insulin concentration at any time of year should raise suspicions of EMS, ECD, or both. [source] Role of circulating neurotoxins in the pathogenesis of hepatic encephalopathy: potential for improvement following their removal by liver assist devicesLIVER INTERNATIONAL, Issue 2003Roger F. Butterworth Abstract Both acute and chronic liver failure result in impaired cerebral function known as hepatic encephalopathy (HE). Evidence suggests that HE is the consequence of the accumulation in brain of neurotoxic and/or neuroactive substance including ammonia, manganese, aromatic amino acids, mercaptans, phenols, short-chain fatty acids, bilirubin and a variety of neuroactive medications prescribed as sedatives to patients with liver failure. Brain ammonia concentrations may attain levels in excess of 2 mm, concentrations which are known to adversely affect both excitatory and inhibitory neurotransmission as well as brain energy metabolism. Manganese exerts toxic effects on dopaminergic neurones. Prevention and treatment of HE continues to rely heavily on the reduction of circulating ammonia either by reduction of gut production using lactulose or antibiotics or by increasing its metabolism using l -ornithine- l -aspartate. No specific therapies have so far been designed to reduce circulating concentrations of other toxins. Liver assist devices offer a potential new approach to the reduction of circulating neurotoxins generated in liver failure. In this regard, the Molecular Absorbents Recirculating System (MARS) appears to offer distinct advantages over hepatocyte-based systems. [source] Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to ,-adrenergic stimulationTHE JOURNAL OF PHYSIOLOGY, Issue 15 2010Jennifer C. Richards Sprint interval training (SIT) and traditional endurance training elicit similar physiological adaptations. From the perspective of metabolic function, superior glucose regulation is a common characteristic of endurance-trained adults. Accordingly, we have investigated the hypothesis that short-term SIT will increase insulin sensitivity in sedentary/recreationally active humans. Thirty one healthy adults were randomly assigned to one of three conditions: (1) SIT (n= 12): six sessions of repeated (4,7) 30 s bouts of very high-intensity cycle ergometer exercise over 14 days; (2) sedentary control (n= 10); (3) single-bout SIT (n= 9): one session of 4 × 30 s cycle ergometer sprints. Insulin sensitivity was determined (hyperinsulinaemic euglycaemic clamp) prior to and 72 h following each intervention. Compared with baseline, and sedentary and single-bout controls, SIT increased insulin sensitivity (glucose infusion rate: 6.3 ± 0.6 vs. 8.0 ± 0.8 mg kg,1 min,1; mean ±s.e.m.; P= 0.04). In a separate study, we investigated the effect of SIT on the thermogenic response to beta-adrenergic receptor (,-AR) stimulation, an important determinant of energy balance. Compared with baseline, and sedentary and single-bout control groups, SIT did not affect resting energy expenditure (EE: ventilated hood technique; 6274 ± 226 vs. 6079 ± 297 kJ day,1; P= 0.51) or the thermogenic response to isoproterenol (6, 12 and 24 ng (kg fat-free mass),1 min,1: %,EE 11 ± 2, 14 ± 3, 23 ± 2 vs. 11 ± 1, 16 ± 2, 25 ± 3; P= 0.79). Combined data from both studies revealed no effect of SIT on fasted circulating concentrations of glucose, insulin, adiponectin, pigment epithelial-derived factor, non-esterified fatty acids or noradrenaline (all P > 0.05). Sixteen minutes of high-intensity exercise over 14 days augments insulin sensitivity but does not affect the thermogenic response to ,-AR stimulation. [source] Actions of Tumor Necrosis Factor-, on Oocyte Maturation and Embryonic Development in Cattle,AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2003P. Soto Problem:, Infertility can accompany mastitis in cattle. Involvement of tumor necrosis factor- , (TNF- ,) in this phenomenon is suggested by observations that circulating concentrations of TNF- , are elevated after intramammary infection or infusion of endotoxin. It was hypothesized that (1) TNF- , acts on the oocyte during maturation to decrease the percent of oocytes that cleave and develop following fertilization; (2) exposure of embryos to TNF- , after fertilization reduces development to the blastocyst stage; and (3) TNF- , increases the proportion of blastomeres that undergo apoptosis in a stage-of-development dependent manner. Method of study:, In one experiment, oocytes were matured with various concentrations of TNF- , and then fertilized and cultured without TNF- ,. In another study, embryos were cultured with TNF- , for 8 days beginning after fertilization. Finally, embryos were collected at the two or four-cell stage (at 28,30 hr after insemination) or when ,9-cells (at day 4 after insemination) and cultured ± TNF- , for 24 hr. The proportion of blastomeres undergoing apoptosis was then determined by the TUNEL procedure. Results:, Addition of TNF- , to maturation medium did not affect the proportion of oocytes that cleaved. However, the percent of oocytes that developed to the blastocyst stage at day 8 after insemination was reduced (P = 0.05) at all TNF- , concentrations tested (0.1,100 ng/mL). When added during embryo culture, there was no significant effect of TNF- , on the proportion of oocytes that became blastocysts. In addition, TNF- , did not induce apoptosis in two and four-cell embryos. For embryos ,9-cells, however, 10 and 100 ng/mL TNF- , increased (P < 0.05) the percent of blastomeres labeling as TUNEL-positive. Conclusion:, TNF- , can have deleterious actions on oocyte maturation that compromise development of the resultant embryo. While exposure of fertilized embryos to TNF- , did not inhibit development to the blastocyst stage, TNF- , increased the percentage of blastomeres undergoing apoptosis when exposure occurred for embryos ,9-cells. Increased blastomere apoptosis could conceivably compromise subsequent embryo survival. [source] Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleedingARTHRITIS & RHEUMATISM, Issue 6 2010Elvira L. Massó González Objective Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. Methods We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. Results The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82,5.31) for traditional NSAIDs and 1.88 (95% CI 0.96,3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17,3.33]), rofecoxib (2.12 [95% CI 1.59,2.84]), aceclofenac (1.44 [95% CI 0.65,3.2]), and celecoxib (1.42 [95% CI 0.85,2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87,36.04]) and piroxicam (9.94 [95% CI 5.99,16.50). Estimated RRs were 5.63 (95% CI 3.83,8.28) for naproxen, 5.57 (95% CI 3.94,7.87) for ketoprofen, 5.40 (95% CI 4.16,7.00) for indomethacin, 4.15 (95% CI 2.59,6.64) for meloxicam, and 3.98 (95% CI 3.36,4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r2 = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. Conclusion The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation. [source] Glucagon is absorbed from the rectum but does not hasten recovery from hypoglycaemia in patients with type 1 diabetesBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008David R. Parker WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Patients with type 1 diabetes experience recurrent hypoglycaemia and have abnormal glucose counter regulatory responses with a failure to secrete glucagon. It is unknown if rectal glucagon is absorbed and what effect this may have on counter regulation from hypoglycaemia. WHAT THIS STUDY ADDS , A rectal suppository of glucagon results in a rise in plasma glucagon with metabolic effects in normal subjects. Similarly rectal glucagon results in a rise in plasma glucagon in patients with type 1 diabetes, but 1 mg does not improve recovery rates from experimental hypoglycaemia when compared with placebo. , Larger doses of glucagon per rectum may provide pharmacological circulating concentrations with resulting therapeutic benefit during recovery from hypoglycaemia and deserves further study. AIMS A failure to secrete glucagon during hypoglycaemia is near universal in patients with type 1 diabetes 5 years after disease onset and may contribute to delayed counter-regulation during hypoglycaemia. Rectal glucagon delivery may assist glucose recovery following insulin-induced hypoglycaemia in such patients and has not been previously studied. METHODS Six male patients (age 21,38 years) with type 1 diabetes (median duration 10 years) without microvascular complications, were studied supine after an overnight fast on two separate occasions at least 14 days apart. After omission of their usual morning insulin and 45 min rest, hypoglycaemia was induced by an intravenous insulin infusion which was terminated when capillary glucose concentration reached 2.5 mmol l,1. Subjects were randomized to insert a rectal suppository containing 100 mg indomethacin alone (placebo) or 100 mg indomethacin plus 1 mg glucagon at the hypoglycaemic reaction. Serial measurements were made for 120 min. RESULTS In the two groups, mean (SD) plasma glucose concentrations fell to a similar nadir of 1.8 (0.7) mmol l,1 (placebo) and 2.1 (1.2) mmol l,1 (glucagon). Peak plasma glucagon following hypoglycaemia was higher in the glucagon group; 176 (32) ng l,1vs. 99 (22) ng l,1 after placebo (P = 0.006). However, the glucose recovery rate over 120 min after hypoglycaemia did not differ significantly. CONCLUSIONS Our results provide evidence for the absorption of glucagon from the rectum. They also indicate that 1 mg does not constitute a useful mode of therapy to hasten recovery from hypoglycaemia in patients with type 1 diabetes. [source] Non-lipooligosaccharide-mediated signalling via Toll-like receptor 4 causes fatal meningococcal sepsis in a mouse modelCELLULAR MICROBIOLOGY, Issue 3 2007Laura Plant Summary Meningococcal lipooligosaccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis with disease severity correlating with circulating concentrations of LOS and proinflammatory cytokines. In this study we show that the proinflammatory response to live meningococci in a mouse model of sepsis involves TLR4, but can develop independently of the expression of LOS. This is supported by data showing that in vivo an isogenic LOS-deficient strain, lpxA, induced equivalent disease severity and similar proinflammatory responses as the serogroup C wild-type parent strain FAM20. This response was abolished in TLR4,/, mice, and neither the wild-type strain of meningococci nor the LOS-deficient mutant was able to cause fatal sepsis in these mice. Mouse survival correlated with low levels of cytokines and chemokines, the chemotactic complement factor C5a and neutrophil levels in blood at 24 h post infection. These data suggest that during meningococcal sepsis the recognition of one or more unidentified non-LOS component(s) by TLR4 is important in stimulating proinflammatory responses, and that fatality associated with meningococcal sepsis in mice is induced by the proinflammatory host response. [source] |