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Abnormal rectal motor physiology and visceral hypersensitivity are implicated in the pathogenesis of irritable bowel syndrome. Endogenous opioids are involved in both the regulation of gut motility and the processing of sensory information. Our aim was to study the effect of suppression of endogenous opioid function by naloxone on rectal sensorimotor function in health. Eighteen healthy subjects participated in a rectal barostat study. Sensorimotor function was evaluated during two consecutive stepwise distensions separated by 30 min of basal tone recording, and with perception scoring on a 0-6 graded scale. Naloxone was administered, after 15 min of basal tone measurements, as an intravenous bolus (0.4 mg), followed by continuous infusion (20 microg kg(-1) h(-1)) in a placebo-controlled, single-blinded and randomized fashion. Naloxone did not alter rectal sensitivity. Comparison of visual analogue scale scores between naloxone and saline did not reveal altered intensities of pain or discomfort. Compared to the baseline distension, a significant adaptive increase in compliance occurred during the second distension after saline (7.8 +/- 0.7 vs 11.0 +/- 0.6 mL mmHg(-1), P = 0.0016). This dynamic change in rectal compliance did not occur after naloxone administration (8.8 +/- 0.7 vs 10.1 +/- 0.8 mL mmHg(-1), ns). Low intensity tonic distension induced a rectal adaptive relaxation, which was absent after naloxone. Naloxone does not alter rectal sensitivity but abolishes rectal adaptation in response to repeated balloon distention. These observations suggest that the endogenous opioid system is involved in control of rectal tone rather than rectal sensitivity.

Contains fulltext : 80319.pdf (Publisher’s version ) (Closed access) Residents report that they received inadequate teaching in palliative care and low levels of comfort and skills when taking care of dying patients. This study describes the effects of a problem-based palliative care course on perceived competence and knowledge in a representative Dutch cohort of residents in internal medicine. Before and after the course, we carried out a questionnaire survey and knowledge test in 91 residents. The results show that many residents felt they had limited competence or were incompetent when taking care of patients in the palliative care phase. This was particularly true with respect to communication concerning euthanasia and physician-assisted suicide or hastened death (86% and 85% respectively reported limited competence or incompetence). Participants reported that they received inadequate training in palliative care and believed that specific education would make them feel more competent. The number of times that residents were engaged in palliative care situations and the years of clinical experience had a positive influence on perceived competence. Participating in the course improved perceived competence and knowledge in palliative care. No correlation was found between perceived competence and knowledge of palliative care.

To the Editor: Excess levels of TNF-α have been associated with certain autoimmune diseases. Prolonged administration of TNF-α antibody is used to effectively treat chronic inflammatory diseases such as rheumatic diseases and Crohn’s disease [1]. Anti-TNF-α drugs have clearly been shown to suppress disease activity in rheumatoid arthritis, and are a candidate therapy for immune intervention in type 1 diabetes. We report a case of a patient with juvenile idiopathic arthritis, who developed type 1 diabetes while receiving anti-TNF-α therapy.

Contains fulltext : 80053.pdf (Publisher’s version ) (Closed access) Ischaemia, like muscle contraction, has been reported to induce skeletal muscle glucose uptake in in vitro models. This stimulating effect appears independent of insulin and is probably mediated by activation of AMPK (AMP-activated protein kinase). In the present study, we hypothesized that in vivo in humans ischaemia- and insulin-induced glucose uptake are additive, and that the combined impact of ischaemia and contraction on glucose uptake is of a similar magnitude when each is applied separately. We assessed the effects of ischaemia with and without euglycaemic-hyperinsulinaemia (clamp; protocol 1) and with and without muscle contraction (protocol 2) on muscle FGU (forearm glucose uptake) in healthy subjects. Furthermore, we assessed the impact of ischaemia on FBF (forearm blood flow; plethysmography). In protocol 1, ischaemia increased FGU from 0.6+/-0.1 at baseline to 5.5+/-1.9 micromol x min(-1) x dl(-1), and insulin increased FGU to 1.6+/-0.3 micromol x min(-1) x dl(-1) (P

In animal models, administration of the adenosine analog AICA-riboside has shown beneficial effects on ischemia-reperfusion injury and glucose homeostasis. The vascular and/or metabolic effects of AICA-riboside administration in humans remain to be established. AICA-riboside was infused intra-arterially in four different dosages up to 8 mg·min−1·dl−1 in 24 healthy subjects. Forearm blood flow (FBF) and glucose uptake and plasma glucose, free fatty acid, and AICA-riboside concentrations were assessed. We also combined AICA-riboside infusion (2 mg·min−1·dl−1) with the intra-arterial administration of the adenosine receptor antagonist caffeine (90 μg·min−1·dl−1; n = 6) and with the endothelial NO synthase inhibitor l-NMMA (0.4 mg·min−1·dl−1; n = 6). Additional in vitro experiments were performed to explain our in vivo effects of AICA-riboside in humans. AICA-riboside increased FBF dose dependently from 2.0 ± 0.2 to 13.2 ± 1.9 ml·min−1·dl−1 maximally ( P < 0.05 for all dosages). The latter was not reduced by caffeine administration but was significantly attenuated by l-NMMA infusion. Despite high plasma AICA-riboside concentrations, forearm glucose uptake did not change. In vitro experiments showed rapid uptake of AICA-riboside by the equilibrative nucleoside transporter in erythrocytes and subsequent phosphorylation to AICA-ribotide. We conclude that AICA-riboside induces a potent vasodilator response in humans that is mediated by NO. Despite high local plasma concentrations, AICA-riboside does not increase skeletal muscle glucose uptake.

Contains fulltext : 81471.pdf (Publisher’s version ) (Closed access) Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune disorders which have commonalities in their pathogenesis. We aimed to replicate known RA loci in a Dutch RA population, and to investigate whether the effect of known RA and CD risk factors generalize across the two diseases. We selected all loci associated to either RA or CD in a GWAS and confirmed in an independent cohort, with a combined P-value cut-off P < 5 x 10(-6). We genotyped 11 RA and 11 CD loci in 1368 RA patients, 795 CD patients and 1683 Dutch controls. We combined our results in a meta-analysis with UK GWAS on RA (1860 cases; 2938 controls) and CD (767 cases; 1422 controls). In the Dutch RA cohort, the PTPN22 and IL2/IL21 variants showed convincing association (P = 3.4 x 10(-12) and P = 2.8 x 10(-4), respectively). Association of RA with the known CD risk variant in the SH2B3 was also observed, predominantly in the subgroup of rheumatoid factor-positive RA patients (P = 0.0055). In a meta-analysis of Dutch and UK data sets, shared association with six loci (TNFAIP3, IL2/IL21, SH2B3, LPP, MMEL1/TNFRSF14 and PFKFB3/PRKCQ) was observed in both RA and CD cohorts. We confirmed two known loci and identified four novel ones for shared CD-RA genetic risk. Most of the shared loci further emphasize a role for adaptive and innate immunity in these diseases.

Purpose: To explore the effect of the nutritional state on the solubilizing properties of human intestinal fluids (HIF) on a time-after-food administration basis. Methods: HIF were collected in fractions of 30 min from five volunteers in the fasted, fed and fat-enriched fed state. In vitro solubility of five BCS class II drugs (danazol, diazepam, nifedipine, ketoconazole, indomethacin) was assessed in the intestinal fractions and simulated intestinal fluids. Results: Solubilities in intestinal fractions were characterized by high time- and subject-dependent variability. For the non-ionized drugs, solubility in early intestinal fractions was higher in both fed states compared to the fasted state, and in the fat-enriched fed state compared to the fed state. Solubility in simulated intestinal fluids did not sufficiently predict the solubilizing capacity of the early postprandial phase. Solubility in HIF was shown to be determined by a complex interplay of various intraluminal parameters. For the ionized drugs, pH played a significant role for indomethacin (R 2∈=∈0.86); for the partly ionized ketoconazole other intraluminal parameters were also important. Conclusions: Solubilizing capacity of HIF in the fed state is strongly time-dependent. Intraluminal dissolution may, therefore, vary with drug arrival time in the small intestine and constitute a source of variability in intestinal drug absorption. © 2009 Springer Science+Business Media, LLC.

Background: Catheter-related bloodstream infection (CRBSI) causes substantial morbidity and mortality, but few randomized, controlled studies have been conducted to guide therapeutic interventions. Methods: To determine whether linezolid would be noninferior to vancomycin in patients with CRBSI, we conducted an open-label, multicenter, comparative study. Patients with suspected CRBSI were randomized to receive linezolid or vancomycin (control group). The primary end point was microbiologic outcome at test of cure 1-2 weeks after treatment, as assessed by step-down procedure. The first analysis population was complicated skin and skin structure infection (cSSSI) in patients with suspected CRBSI; patients with CRBSI were analyzed if noninferiority criteria (lower bound of the 95% confidence interval [CI] not outside -15%) were met. Results: Noninferiority criteria were met for cSSSI (microbiologic success rate for linezolid recipients, 89.6% [146 for 163 patients]; for the control group, 89.9% [134 of 149]; 95% CI, -7.1 to 6.4) and CRBSI (for linezolid recipients, 86.3% [82 of 95]; for the control group, 90.5% [67 of 74]; 95% CI, -13.8 to 5.4). The frequency and severity of adverse events were similar between groups. Mortality rates were 10.4% for linezolid recipients (28 of 269 patients) and 10.1% for control subjects (26 of 257) in the modified intent-to-treat population (i.e., all patients with gram-positive baseline culture) through test of cure, and they were 21.5% for linezolid recipients (78 of 363) and 16.0% for the control group (58 of 363; 95% CI, -0.2 to 11.2) for all treated patients through poststudy treatment day 84. Conclusions: Linezolid demonstrated microbiologic success rates noninferior to those for vancomycin in patients with cSSSIs and CRBSIs caused by gram-positive organisms. Patients with catheter-related infections must be carefully investigated for the heterogeneous underlying causes of high morbidity and mortality, particularly for infections with gram-negative organisms.

Background In hypertension, a state of increased (central) sympathetic activity exists. This high sympathetic activity is associated with worse prognosis and refractoriness to pharmacological interventions. Animal experimental data suggest that HMG CoA reductase inhibitors (statins) can reduce sympathetic activity at a central level. We hypothesized that atorvastatin 80 mg/day could reduce sympathetic activity in human patients with hypertension. Methods Using a prospective, randomized, placebo-controlled, double-blind, cross-over design, patients were randomly assigned to atorvastatin 80 mg/day or placebo, for 3 weeks. Sympathetic nervous system activity was measured at the end of each treatment period, in 13 patients with mild to moderate hypertension by microneurography for direct muscle sympathetic nerve recording (MSNA) and plasma norepinephrine concentrations. Effects on blood pressure were assessed by 24 hour ambulatory blood pressure measurement. Results Atorvastatin significantly reduced MSNA (atorvastatin: 58.5±2.0 vs. placebo: 64.7±3.0 bursts/100 beats, P=0.02). Although MSNA values and plasma cholesterol levels were correlated, reduction in MSNA was independent of the degree of reduction in plasma cholesterol. Atorvastatin had no effect on plasma norepinephrine levels nor on daytime and night time blood pressure. Conclusion: In patients with mild to moderate hypertension, atorvastatin treatment reduces central sympathetic nervous outflow. This finding supports the concept that HMG CoA reductase regulates sympathetic nervous system activity at the central level and indicates a sympathoinhibitory role for atorvastatin in human hypertensive patients.

Contains fulltext : 69672.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Interleukin-18 (IL-18) has been recently demonstrated to improve experimental hyperphagia and insulin resistance. Paradoxically, concentrations of circulating IL-18 in obese subjects and in patients with type 2 diabetes are increased. The objective of this study is to provide an explanation for this paradox. DESIGN: We have hypothesized that cells from obese individuals or from patients with type 2 diabetes mellitus have a diminished response to stimulation with IL-18. IL-18 responsiveness was tested by stimulating blood monocytes of obese or diabetes patients with rIL-18 or microbial components. RESULTS: Obese individuals and patients with type 2 diabetes mellitus exhibit increased circulating concentrations of IL-18. More importantly, leukocytes isolated from obese or type 2 diabetes patients respond poorly after stimulation with IL-18, as reflected by defective interferon-gamma (IFN gamma) production. The defective response to IL-18 stimulation was accompanied by a 50% reduction in the expression of IL-18R alpha and beta chains. In addition, cells of patients with obesity and diabetes displayed an impaired release of IFN gamma after challenge with bacterial or fungal pathogens, which was due to defective IL-18-mediated signaling. CONCLUSION: Patients with obesity or type 2 diabetes mellitus are characterized by lower responses after stimulation with IL-18. This IL-18 resistance explains the association of obesity and diabetes with high IL-18 circulating concentrations, similar to hyperinsulinemia and hyperleptinemia. IL-18 resistance may represent an important mechanism of the increased susceptibility of these patients to a number of infections.

Contains fulltext : 70835.pdf (Publisher’s version ) (Closed access) Hypoglycemia unawareness has been linked to desensitization of the beta2-adrenergic receptor. Desensitization of the beta2-adrenergic receptor (ADRB2) is genetically determined by the Arg16Gly variant of this receptor. We tested the hypothesis that hypoglycemia unawareness is more common among patients homozygous for the Gly16 variant. We performed genotyping of the A265G (Arg16Gly) polymorphism in the ADRB2 gene in 85 patients with type 1 diabetes and classified them according to hypoglycemia awareness status. A total of 45 patients (53%) were homozygous for Gly16, 32 patients (38%) were heterozygous and eight patients (9%) were homozygous for Arg16. Hypoglycemia unawareness was 3.4-fold more common among patients homozygous for Gly16 than among patients with other variants of the Arg16Gly polymorphism (P=0.014). We conclude that patients with type 1 diabetes who carry two alleles of the Gly16 variant of ADRB2 are at increased risk of developing hypoglycemia unawareness. Future studies are required to confirm these results in larger, independent populations.

Contains fulltext : 71261.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Muscle capillary perfusion can be measured by contrast-enhanced ultrasound. We examined whether a less time-consuming ultrasound technique, called "real-time imaging," could be used to measure capillary recruitment in human forearm skeletal muscle. METHODS: We measured microvascular blood volume and microvascular flow velocity using bolus injections of contrast microbubbles after forearm muscle exercise and a two-hour infusion of insulin into the brachial artery (both associated with capillary recruitment) and after sodium nitroprusside infusion (no changes in flow distribution). RESULTS: After an intravenous bolus injection of the contrast agent, the steady-state concentration of contrast agent in forearm muscle lasted long enough (approximately 190 seconds) for the duration of the measurements (which take 70-80 seconds), rendering the continuous infusion of microbubbles unnecessary. Microvascular blood-volume measurements showed a good short-time reproducibility and a good reproducibility after repositioning of the forearm. Reproducibility of microvascular flow velocity was too low. Exercise and insulin infusion both increased microvascular blood volume, consistent with capillary recruitment. Sodium nitroprusside had no effect. CONCLUSION: Real-time contrast imaging, after bolus injections of an ultrasound contrast agent, provides reliable information about capillary recruitment in human forearm skeletal muscle, and may offer a valuable tool in studying human (patho)physiology.

Contains fulltext : 69622.pdf (Publisher’s version ) (Closed access) AIMS/HYPOTHESIS: The 5'-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients. METHODS: Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg(-1) min(-1)) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 +/- 2 years; BMI 28 +/- 1 kg/m(2)). RESULTS: Plasma glucose rate of appearance (R (a)) was reduced following AICAR administration, while plasma glucose rate of disappearance (R (d)) was similar in the AICAR and control test. Consequently, blood glucose disposal (R (d) expressed as a percentage of R (a)) was increased following AICAR infusion (p < 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p < 0.001). Plasma NEFA R (a) and R (d) were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p < 0.001). CONCLUSIONS/INTERPRETATION: The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.

Fifty-eight males and 34 females with nongonococcal urethritis and/or cervicitis were treated to compare the efficacy and safety of 7-day regimens of oral ofloxacin 300 mg twice daily and doxycycline hyclate 100 mg twice daily. Forty-seven patients were randomized to receive ofloxacin and 45 patients to receive doxycycline. The microbiologic response rate was 97% (32/33) for both ofloxacin and doxycycline; the combined microbiologic and clinical cure rates were 98% for both treatment groups (ofloxacin 46/47, doxycycline 44/45). Ofloxacin was as effective as doxycycline in the treatment of chlamydial infections (96% vs. 100%). In patients with Ureaplasma urealyticum, the initial response was complete with either drug, but recurrence of infection was observed with both treatment groups (1 of 4 patients in the ofloxacin group and 2 of 11 patients in the doxycycline group). In the treatment of mixed Chlamydia trachomatis and U. urealyticum infections, all 5 patients treated with ofloxacin and 3 of 4 patients treated with doxycycline were cured. In symptomatic patients whose initial cultures were negative, clinical cures were complete with both drugs, but Ureaplasma was isolated at 3 or more weeks post-treatment in 2 patients treated with ofloxacin. In a study of single-dose ofloxacin treatment of uncomplicated gonorrhea, Neisseria gonorrhoeae was eradicated in all subjects, but C. trachomatis was not reliably eradicated. Both drugs were well tolerated with only minimal adverse effects reported in either treatment group. A multiple-dose regimen of ofloxacin appears to be a highly effective and well-tolerated alternative to doxycycline in nongonococcal sexually transmitted disease.

Gastro-oesophageal reflux disease (GERD) is associated with a variety of typical and atypical symptoms. Patients often present in the first instance to a pharmacist or primary care physician and are subsequently referred to secondary care if initial management fails. Guidelines usually do not provide a clear guidance for all healthcare professionals with whom the patient may consult.To update a 2002-treatment algorithm for GERD, making it more applicable to pharmacists as well as doctors.A panel of international experts met to discuss the principles and practice of treating GERD.The updated algorithm for the management of GERD can be followed by pharmacists, for over-the-counter medications, primary care physicians, or secondary care gastroenterologists. The algorithm emphasizes the importance of life style changes to help control the triggers for heartburn and adjuvant therapies for rapid and adequate symptom relief. Proton pump inhibitors will remain a prominent treatment for GERD; however, the use of antacids and alginate-antacids (either alone or in combination with acid suppressants) is likely to increase.The newly developed algorithm takes into account latest clinical practice experience, offering healthcare professionals clear and effective treatment options for the management of GERD.

Uncontrolled studies suggest benefit of intrapyloric injection of botulinum toxin (botox) for the treatment of gastroparesis, but controlled data are lacking.To perform a controlled study of botox injection in gastroparesis.Twenty-three gastroparesis patients (five men, age 45 +/- 3, 19 idiopathic) underwent two upper endoscopies with 4-week interval, with injection of saline or botox 4 x 25 U in a randomized double-blind-controlled crossover fashion. Before the start of the study and 4 weeks after each treatment, they underwent a solid and liquid gastric emptying breath test with measurement of meal-related symptom scores, and filled out the Gastroparesis Cardinal Symptom Index. Results (mean S.E.M.) were compared using Student's t-test.Twelve patients received botox and 11 saline as the first injection. Significant improvement in emptying and Gastroparesis Cardinal Symptom Index was seen after initial injection of saline or botox. No further improvement occurred after the second injection (respectively, botox and saline). Pooled data for both treatment groups showed no significant difference in improvements of solid t(1/2) (3.4 +/- 7.4 vs. 16.3 +/- 8.3, N.S.) and liquid t(1/2) (8.2 +/- 13.7 vs. 22.5 +/- 7.7, N.S.), meal-related symptom scores or Gastroparesis Cardinal Symptoms Index (GCSI; 6.1 +/- 1.5 vs. 3.8 +/- 1.5, N.S.).In a cohort of predominantly idiopathic gastroparesis patients, botox is not superior to placebo in improving either symptoms or the rate of gastric emptying.

Objectives: To compare the efficacy and safety of linezolid and vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in Japan. Methods: Patients with nosocomial pneumonia, complicated skin and soft-tissue infections or sepsis caused by MRSA were randomized to receive linezolid (600 mg every 12 h) or vancomycin (1 g every 12 h). Results: One hundred patients received linezolid and 51 received vancomycin with outcomes evaluated at the end of therapy (EOT) and at the follow-up (FU), 7-14 days later. At EOT, clinical success rates in the MRSA microbiologically evaluable population were 62.9% and 50.0% for the linezolid and vancomycin groups, respectively; and microbiological eradication rates were 79.0% and 30.0% in the two groups, respectively (P< 0.0001). At FU, the clinical success rates were 36.7% for both groups and the microbiological eradication rates were 46.8% and 36.7%, respectively. Reversible anaemia (13%) and thrombocytopenia (19%) were reported more frequently in linezolid patients; laboratory analysis showed mild decrease in platelet counts with full recovery by FU. The mean platelet count in linezolid patients with thrombocytopenia was 101 000/mm 3 . Significantly low platelet counts (

In the evaluation of several endoscopic antireflux procedures, a discrepancy in the degree of improvement between symptoms and objective reflux parameters as measured by pH-metry has been reported.To assess the additional value of impedance monitoring in the evaluation of endoscopic gastroplication for gastro-oesophageal reflux disease.Eighteen patients with gastro-oesophageal reflux disease were treated with three endoscopic gastroplications, and underwent 24 h pH-impedance monitoring before and 3 months after treatment.Total reflux exposure time as assessed by pH-metry and impedance monitoring was significantly decreased after treatment (P = 0.047 and0.001, respectively). When assessed with impedance monitoring, the mean number of reflux episodes was significantly decreased after the procedure (82 vs. 56, pre vs. post, P0.001). Furthermore, the mean numbers of liquid and acid reflux episodes in patients with symptomatic improvement were significantly reduced after treatment (P = 0.04 and 0.02, respectively). After treatment, mean volume clearance time (s) and mean number of proximal reflux episodes were significantly decreased (P0.001 and 0.002, respectively).Impedance monitoring can identify the specific effect of endoscopic gastroplication on the different types of reflux episodes with regard to gas-liquid composition and pH, as well as on volume clearance and the proximal extent of the refluxate.

A number of mechanisms, other than acid reflux, may be responsible for the symptoms of gastro-oesophageal reflux disease.To assess the importance of non-acid reflux mechanisms.This review is based on presentations and discussion at a workshop, where specialists in the field analysed data relating to these mechanisms.Weakly acidic reflux, pH (4-7), detected with impedance-pHmetry is associated with regurgitation and atypical gastro-oesophageal reflux disease symptoms. It is not clear whether pepsin and trypsin can elicit symptoms, but bile can elicit heartburn. The magnitude of reflux-induced oesophageal distension can be determined by high frequency ultrasonography and is not reduced by proton pump inhibition, suggesting that persisting symptoms 'on' a proton pump inhibitor may still be due to oesophageal distension by non-acidic reflux. Exaggerated longitudinal muscle contraction can induce non-acid-related heartburn. Preliminary studies showed a positive effect of baclofen, surgery or endoscopic procedures to reduce weakly acidic reflux.Mechanisms other than acid reflux are involved in some of the symptoms of gastro-oesophageal reflux disease. Controlled outcome studies are needed to clarify their roles and the indications for antireflux procedures in patients with persistent symptoms whilst 'on' a proton pump inhibitor.

Symptoms, oesophageal pHmetry and proton pump inhibitor treatment are used for diagnosing gastro-oesophageal reflux-related cough. Weakly acidic reflux is now increasingly associated with reflux symptoms such as regurgitation or chest pain.To study the association between weakly acidic reflux and cough in a selected, large group of patients with unexplained chronic cough.A total of 100 patients with chronic cough (77 'off' and 23 'on' a proton pump inhibitor) were studied using impedance-pHmetry for reflux detection and manometry for objective cough monitoring. Symptom Association Probability (SAP) Analysis characterized the reflux-cough association.Acid reflux could be a potential mechanism for cough in 45 patients (with either heartburn, high acid exposure or +SAP for acid reflux). Weakly acidic reflux could be a potential mechanism for cough in 24 patients (with either increased oesophageal volume exposure, increased number of weakly acidic reflux or +SAP for weakly acidic reflux). Reflux could not be identified as a potential mechanism for cough in 31 patients.A positive association between cough and weakly acidic reflux was found in a significant subgroup of patients with unexplained chronic cough. Impedance-pH-manometry identified patients in whom cough can be related to reflux that would have been disregarded using the standard diagnostic criteria for acid reflux.

Recent studies indicate that impaired meal accommodation or hypersensitivity to distention are highly prevalent in adult functional dyspepsia (FD). Our aim was to investigate whether similar abnormalities also occur in paediatric FD. Sixteen FD patients (15 girls, 10–16 years) were studied. The severity (0–3; 0, absent; 3, severe) of eight dyspeptic symptoms (epigastric pain, fullness, bloating, early satiety, nausea, vomiting, belching and epigastric burning) and the amount of weight loss were determined by questionnaire. All children underwent a gastric barostat study after an overnight fast to determine sensitivity to distention and meal-induced accommodation, which were compared with normal values in young adults (18–22 years). On a separate day, all patients underwent a gastric emptying breath test. A mean weight loss of 4.8 ± 0.9 kg was present in 14 children. Compared with controls, patients had lower discomfort thresholds to gastric distention (8.8 ± 1.0 mmHg vs 13.9 ± 1.9 mmHg, P

Contains fulltext : 53156.pdf (Publisher’s version ) (Closed access) Plasma NEFA (non-esterified fatty acid) concentrations are elevated in patients with obesity. In the present study we first aimed to provide an integral haemodynamic profile of elevated plasma NEFAs by the simultaneous assessment of blood pressure, pulse wave velocity, FBF (forearm blood flow) and sympathetic nervous system activity during acute elevation of NEFAs. Secondly, we hypothesized that NEFA-induced vasodilation is mediated by adenosine receptor stimulation. In a randomized cross-over trial in healthy subjects, Intralipid was infused for 2 h to elevate plasma NEFAs. Glycerol was administered as the Control infusion. We assessed blood pressure, pulse wave velocity, FBF (using venous occlusion plethysmography) and sympathetic nervous system activity by measurement of noradrenaline and adrenaline. During the last 15 min of Intralipid/Control infusion, the adenosine receptor antagonist caffeine (90 microg x min(-1) x dl(-1)) was administered into the brachial artery of the non-dominant arm. Compared with Control infusion, Intralipid increased pulse wave velocity, SBP (systolic blood pressure) and pulse pressure, as well as FBF (from 1.8+/-0.2 to 2.7+/-0.6 and from 2.3+/-0.2 to 2.7+/-0.6 ml x min(-1) x dl(-1) for Intralipid compared with Control infusion; P

Contains fulltext : 53138.pdf (Publisher’s version ) (Closed access) AIMS: According to the 'haemodynamic hypothesis', chronic hyperglycaemia induces an increase in tissue perfusion that predisposes to microangiopathy. We hypothesized that patients with longstanding diabetes mellitus (DM), who have not developed microvascular complications, would have normal tissue perfusion. METHODS: In six Type 1 diabetic patients (age 43.4 +/- 1.1 years; DM duration 25.3 +/- 2.6 years.; HbA(1c) 8.5 +/- 0.7%), who had no evidence of microvascular complications, and six age- and gender-matched healthy volunteers (Control) we measured haemodynamic parameters including forearm blood flow (FBF; plethysmography) and sympathetic tone, an important regulator of blood flow, by the combination of plasma sampling (catecholamine levels), microneurography and power spectral analysis of blood pressure and heart rate. RESULTS: FBF was increased in the diabetic compared with control subjects (4.8 +/- 1.2 vs. 2.2 +/- 0.3 ml/dl per min, P < 0.05) and forearm vascular resistance (FVR) was decreased (25 +/- 6 and 43 +/- 3 arbitrary units, P < 0.05). Heart rate was higher in diabetic subjects (77 +/- 10 vs. 57 +/- 2 beats/min, P < 0.05). All parameters of sympathetic tone were similar in diabetic and control subjects. CONCLUSIONS: In patients with Type 1 diabetes, without signs of microvascular complications and with diabetes duration of > 20 years, skeletal muscle blood flow was increased while sympathetic tone was normal. These results suggest that increased blood flow does not inevitably lead to microvascular complications and challenge the hypothesis that it has a causative role in the pathophysiology of complications.

Functional dyspepsia (FD) in pediatrics is defined as the presence of upper abdominal symptoms for at least 2 months in the absence of organic or metabolic disease likely to explain the symptoms. The main proposed pathophysiological mechanisms are visceral hypersensitivity,impaired gastric accommodation (GA) and delayed gastric emptying. At present, the gastric barostat is the gold standard to measure GA. However, this procedure is perceived as very invasive and it might alter the normal gastric physiology. Recently, we proposed the intragastric pressure (IGP) measurement during nutrient intake as a potential alternative for assessing GA in adults. This technique uses a thin manometry catheter that measures the IGP over the entire length of the stomach. By means of this study we aim to introduce the HRM as new minimally invasive technique to measure GA and nutrient tolerance in children.After the manometry probe and a second infusion catheter were positioned through the nose into the stomach, the IGP was measured 30 minutes before and during intragastric infusion of nutrient drink (300 Kcal, 60 ml per minute). The patients were asked to score hunger and satiation and 6 epigastric symptoms (fullness, nausea, belching of air, cramps in the abdomen, bloating and pain) at 5-minute intervals. The experiment ended when the volunteers scored maximal satiation at 1-minute intervals by using a graphic rating scale that combines verbal descriptors on a scale graded from 0-5 (1, threshold; 5, maximum satiety).For this study 13 FD pediatric patients (92% female, 14.8 ± 0.8 years old, BMI: 19.5 ± 0.8) and 12 young adult volunteers (100% female, 22.2 ± 0.4 years old, BMI: 21.2 ± 0.3) were recruited. The Rome III questionnaire showed that FD patients suffered mainly from postprandial fullness (75%), epigastric pain (58%), bloating (50%), nausea (50%) and early satiation (42%). In both groups, intragastric infusion of nutrient drink induced a rapid drop in proximal stomach IGP. The average AUC change from baseline was -44.7 ± 11.0 mmHg in patients and -48.4 ± 25.2 mmHg in healthy subjects. Patients tended to score maximal satiation at lower volumes compared healthy subjects (433.8 ± 64.2 ml and 600.0 ± 67.6 mL respectively, p = 0.1). All FD patients and healthy subjects tolerated the catheters and could finalize the study.The IGP measurement during intragastric nutrient drink infusion is a promising minimally invasive alternative to the gastric barostat method to assess GA and nutrient tolerance. Future studies need to increase the patient numbers and compare the measurements in different subsets of pediatric FD (e.g. weight loss vs. no weight loss, present or absent early satiation, etc.).

Introduction This is the first study to assess the burden of IBS-C in 6 European countries (France, Germany, Italy, Spain, Sweden, UK). Here we present the results for the UK. Method Observational, retrospective-prospective (6 months each) study in patients (pts) diagnosed with IBS-C in the last five years (Rome-III criteria) and moderate-to-severe symptoms at baseline: IBS-Symptom Severity Score (IBS-SSS) ≥175. Health resource utilisation was retrospectively and prospectively assessed. Symptom evolution was assessed in the prospective period, and quality-of-life (QoL) was assessed at baseline with EuroQoL-5D (EQ-5D) and IBS-QoL. Work productivity was prospectively assessed using the Work Productivity and Activity Impairment (WPAI): IBS-C questionnaire. Results 104 pts were included (79% severe, mean age [± SD] 45.5 ± 14.6 yrs, 93% female). At baseline, symptom severity (IBS-SSS; severe >300) was 373.1 ± 82.5; presenteeism (WPAI:IBS-C; mean ± SD): 47.9% ± 28.7%; absenteeism: 8.4% ± 24.2%; work productivity loss: 51.5% ± 27.2%; daily activity impairment: 56.8% ± 29.6%. Mean IBS-QoL was 57.2 ± 24.2, (scale: 0–100 [best-to-worst]) and mean EQ-5D was 54.0 ± 23.3 (scale: 0–100 [worst-to-best]. 87.5% and 64.4% of pts reported moderate-to-severe problems in pain/discomfort, anxiety/depression respectively. Most prevalent symptoms were abdominal pain (92%) and bloating (91%). 70% pts consulted a GP, and 100% a gastroenterologist; mean: 6.2 and 2.7 visits, respectively. 24% pts required emergency department visits or hospitalisation (mean stay [95% CI]: 12 [2.5–21.1] days). 52% had a diagnostic test (mean [95% CI]: 3.6 [2.9–4.4]). 90% pts took prescription drugs for IBS-C. Mean (95% CI) annual direct cost for the NHS: £ 1753 (1251–2308); the mean pt cost: £ 315 (184–482). 51% of pts took sick leave (mean: 5.2 times; mean duration: 26 days) and 82% had productivity losses (mean: 162 h). Mean indirect costs were £ 3407 (2078–4977). Total costs amounted to £ 5443 (3970–7252)/year. Conclusion Moderate-to-severe IBS-C has a major impact on patient QoL, productivity, and healthcare resource utilisation. Disclosure of interest Y. Yiannakou Conflict with: Grants: Shire; Medtronic. Speaker fees: Almirall; Shire; Sucampo, M. Eugenicos Conflict with: Consultant/Advisory Board Member: Almirall; Astellas; Dr Falk Pharma; NAPP; and Shire, D. Sanders Consultant for: Almirall, A. Emmanuel Conflict with: Advisory Board and Educational Talk honoraria: Almirall., P. Whorwell Conflict with: Consultant/research grant support: Almirall; Chr. Hansen; Danone Research; Ironwood; Salix; Shire; Sucampo, F. Butt: None Declared, S. Bridger: None Declared, N. Arebi: None Declared, A. Millar Conflict with: The hospital received payment from Almirall for the conduct of the study, V. Kaushik Conflict with: Advisory Board and Educational Talk honoraria: Almirall. Meeting support: Cooks; Tillotts; AbbVie., M. Rance Employee of: Almirall, J. Mackinnon Employee of: TFS Develop S. L., contracted by Almirall S. A to conduct the study, J. Bertsch Employee of: TFS Develop S. L, contracted by Almirall S. A. to conduct the study, J. Fortea Employee of: Almirall, J. Tack Conflict with: Grants/research support: Abbott; Novartis; Shire. Honoraria/consultancy fees: Almirall; AstraZeneca; Danone; GI Dyamics; GlaxoSmithKline; Ironwood; Janssen; Menarini; Novartis; Rhythm; Shire; Takeda; Theravance; Tsumura; Will Pharma; Zeria. Speaker fees: Abbott; Almirall; AstraZeneca; Janssen; Menarini; Novartis; Shire; Takeda; Zeria.

Introduction The IBIS-C study assessed the burden of IBS-C in 6 European countries (France, Germany, Italy, Spain, Sweden, and UK). Here we present the diagnosis and management results for the UK. Method Observational study in patients (pts) diagnosed with moderate-to-severe IBS-C in the last five years (Rome-III criteria) with a 12-month follow-up (6 months retrospective and 6 months prospective, in order to assess health resource utilisation [HRU] prior to and after an active phase of the disease). Moderate-to-severe IBS-C was defined as an IBS-Symptom Severity Score (IBS-SSS) ≥175. Results 104 pts were included (79% severe, mean age [±SD] 45.5 ± 14.6 years old, 93% female). Mean time since diagnosis: 2.6 ± 4.0 years; mean symptom duration: 15.3 ± 14.9 yrs. Diagnostic procedures were highly variable; the most common were blood tests (72%), colonoscopy (69%), and abdominal ultrasound (55%). At inclusion the most prevalent symptoms were abdominal pain (92%) and bloating (91%). Main ongoing comorbidities were anxiety (50%), chronic pain (44%), headache (40%), insomnia (33%), or dyspepsia (31%). 52% of pts had an average of 3.6 ± 2.7 diagnostic tests during follow-up, the most common were haematology (29%) and clinical chemistry (29%) blood tests, and colonoscopy (13%). 93% of pts took prescription drugs (90% took prescription drugs for their IBS-C). The most common medication groups were: laxatives (81%), prokinetics (32%), antispasmodics (20%), and analgesics (18%) alone or in combination. Overall, 63% of pts took OTC medication for their IBS-C; the most common were laxatives (37%), prebiotics/probiotics (14%), and peppermint oil (14%). In addition, 36% of pts received complementary therapies. Overall, marginal improvement was noted in symptom severity (IBS-SSS total score) between baseline (373 ± 83) and the 6-month visit (324 ± 113). Conclusion Moderate-to-severe IBS-C symptoms often remain undiagnosed for many years and degree of control does not improve over time even though there is a high degree of prescription medication use. Consequently, moderate-to-severe IBS-C continues to be a burden despite the availability of therapeutic interventions. Disclosure of interest Y. Yiannakou Conflict with: Grants: Shire; Medtronic. Speaker fees: Almirall; Shire; Sucampo, M. Eugenicos Conflict with: Consultant/Advisory Board Member: Almirall; Astellas; Dr Falk Pharma; NAPP; and Shire., D. Sanders Consultant for: Almirall, A. Emmanuel Conflict with: Advisory Board and Educational Talk honoraria: Almirall., P. Whorwell Conflict with: Consultant/research grant support: Almirall; Chr. Hansen; Danone Research; Ironwood; Salix; Shire; Sucampo., F. Butt: None Declared, S. Bridger: None Declared, N. Arebi: None Declared, A. Millar Conflict with: The hospital received payment from Almirall for the conduct of the study, V. Kaushik Conflict with: Advisory Board and Educational Talk honoraria: Almirall. Meeting support: Cooks; Tillotts; AbbVie, M. Rance Employee of: Almirall, J. Mackinnon Employee of: TFS Develop S. L, contracted by Almirall S. A to conduct the study, J. Bertsch Employee of: TFS Develop S. L, contracted by Almirall S. A to conduct the study, J. Fortea Employee of: Almirall, J. Tack Conflict with: Grants/research support: Abbott; Novartis; Shire. Honoraria/consultancy fees: Almirall; AstraZeneca; Danone; GI Dyamics; GlaxoSmithKline; Ironwood; Janssen; Menarini; Novartis; Rhythm; Shire; Takeda; Theravance; Tsumura; Will Pharma; Zeria. Speaker fees: Abbott; Almirall; AstraZeneca; Janssen; Menarini; Novartis; Shire; Takeda; Zeria.

A multicenter, randomized, controlled, investigator-blind study was performed to evaluate the safety and efficacy of oral cefdinir versus oral penicillin V for the treatment of pharyngitis due to group A beta-hemolytic streptococci (GABHS). Patients 13 years of age and older were randomized to receive either oral cefdinir (300 mg twice a day) for 5 days followed by placebo for 5 days or oral penicillin V (250 mg four times a day) for 10 days. Throat cultures were obtained, and signs and symptoms of pharyngitis were recorded at study admission and follow-up visits on study days 11 to 15, 16 to 20, and 25 to 31. Patients kept a diary to record medication intake and their assessment of throat pain at admission and at each day of study treatment. Five hundred fifty-eight patients were enrolled, of whom 432 (77.4%) were clinically and microbiologically evaluable. The GABHS eradication rates 5 to 10 days after completion of therapy were 193 of 218 (88.5%) in the cefdinir group and 176 of 214 (82.2%) in the penicillin group ( P = 0.053). Clinical cure rates were 89.0 and 84.6%, respectively ( P = 0.80). By the time of the long-term follow-up visit, 2 to 3 weeks after completion of treatment, 156 of 191 (81.7%) of the assessable cefdinir patients and 152 of 195 (77.9%) of the penicillin patients remained free of GABHS. Both treatments were well tolerated, with adverse reaction rates of 18.3% in the cefdinir study arm and 15.0% in the penicillin study arm ( P = 0.278). Five-day treatment with cefdinir is safe and effective therapy for GABHS pharyngitis. Based on its twice-a-day dosage and shorter course of therapy, leading to potentially greater patient compliance, cefdinir may be considered for use in the treatment of pharyngitis caused by GABHS.

Sumatriptan, a 5-hydroxytryptamine(1D) (5-HT(1D))-receptor agonist used in the treatment in migraine, inhibits gastric motility via the enteric nervous system. As no studies have reported enteric neuronal 5-HT(1D) receptors, we used conventional intracellular recordings to characterize the actions of sumatriptan on 145 guinea-pig antral myenteric neurones. In 24 of 29 neurones with a 5-HT(1P) receptor-mediated depolarizing response to 5-HT, application of sumatriptan caused a dose-dependent depolarization, accompanied by increased membrane resistance and enhanced excitability. Depolarizing responses to sumatriptan occurred both in cholinergic and in nitrergic neurones. Sumatriptan did not mimic the 5-HT(3) receptor-mediated fast-depolarizing responses or 5-HT(1A) receptor-mediated inhibitory responses to 5-HT. Sumatriptan had no effect on neurones not responding to 5-HT. The depolarizing response to sumatriptan was inhibited by renzapride, but not by 5-HT(1-7) receptor antagonists. We conclude that sumatriptan behaves as an agonist at the 5-HT(1P) receptor on myenteric neurones in the guinea-pig gastric antrum. The actions of sumatriptan on gastric motility seem to be attributable to a direct action on enteric neurones.

Many patients with diabetes mellitus view subcutaneous injections of insulin as a daily burden. Pulmonary delivery of insulin offers an alternative route of administration and may as such improve diabetes treatment. Inhaled insulin provides a rapid absorption of insulin, but with low bioavailability. Phase III clinical trials in type 1 and type 2 diabetes have disclosed clinical equivalence between three inhaled insulin products (Exubera, AErx idMs, and hIIp) and regular human insulin, both in terms of glycaemic control and hypoglycaemic risk. Inhaled insulin cannot be used to replace basal insulin requirements. The most commonly reported adverse effects of inhaled insulin are cough and insulin antibody formation, the clinical significance of which is uncertain. No or minimal deterioration in pulmonary function parameters have been recorded, although studies were typically of short duration. Patients participating in inhaled insulin trials generally expressed satisfaction with the product and chose to remain on it. The availability of inhaled insulin may increase willingness in type 2 diabetic patients to consider insulin therapy. More studies of longer duration are required to determine (pulmonary) safety and cost-effectiveness of inhaled insulin, and to disclose which patients may benefit the most.

Iatrogenic hypoglycaemia is a well-known complication of insulin therapy in patients with diabetes mellitus and a limiting factor for glycaemic control. In a setting of endogenous insulin deficiency (type 1 and advanced type 2 diabetes), one episode of hypoglycaemia reduces both counterregulatory hormone responses to and subjective awareness of subsequent hypoglycaemia, thus impairing physiological defences against hypoglycaemia. This phenomenon may lead to a vicious cycle of recurrent hypoglycaemia and glucose counterregulatory failure, of which hypoglycaemia unawareness (i.e. the inability to perceive symptoms of hypoglycaemia) is the clinical representative. The underlying mechanism of hypoglycaemia-induced counterregulatory failure has not yet been disclosed. Patients with clinical hypoglycaemia unawareness are at high risk of severe hypoglycaemia that requires third-party assistance. Management options include avoidance of hypoglycaemic events and optimisation of insulin therapy to limit deterioration of glycaemic control associated with hypoglycaemia avoidance. Several counterregulatory-stimulating agents have been found to improve hypoglycaemic awareness in small clinical trials, but none have been tested in sufficiently large randomised studies to justify their use in daily practice. More research is required to elucidate the pathogenesis of counterregulatory failure and to develop adequate treatment strategies.

Contains fulltext : 50283.pdf (Publisher’s version ) (Closed access) BACKGROUND: According to the 'haemodynamic hypothesis', increased tissue perfusion predisposes to microangiopathy in diabetic patients. We hypothesized that the typical haemodynamic changes underlying the increased tissue perfusion can be explained by a decreased sympathetic nerve activity caused by chronic hyperglycaemia. In this study we investigated sympathetic activity in patients with uncomplicated type 1 diabetes mellitus (DM). MATERIALS AND METHODS: In 15 DM patients (DM duration 6.3 +/- 3.8 year; HbA1c 7.9 +/- 1.3%) and 16 age- and sex-matched healthy volunteers (Control), sympathetic nervous system activity was measured at rest (baseline) and during sympathoneural stimulation (lower body negative pressure (LBNP)) by means of interstitial and plasma noradrenaline (NA) sampling and power spectral analysis. Muscle sympathetic nerve activity (MSNA) was measured before (baseline) and during a cold pressure test. Forearm blood flow was measured during forearm vascular alpha- and beta-adrenergic receptor blockade. RESULTS: At baseline, forearm vascular resistance (FVR), plasma NA concentrations, MSNA and heart rate variability were similar in both groups. LBNP-induced vasoconstriction was significantly attenuated in the DM group compared with the Control group (DeltaFVR: 12 +/- 4 vs. 19 +/- 3 arbitrary units, P < 0.05). The responses of plasma NA and heart rate variability did not differ. CONCLUSIONS: Baseline FVR and sympathetic nerve activity are normal in patients with uncomplicated type 1 diabetes. However, the forearm vasoconstrictor response to sympathetic stimulation is attenuated, which cannot be attributed to an impaired sympathetic responsiveness.

Gastro-oesophageal reflux disease is a multifaceted and multifactorial disorder which results from the reflux of gastric contents into the oesophagus. Animal studies suggest that synergism between acid and pepsin and conjugated bile acids have the greatest damaging potential for oesophageal mucosa, although unconjugated bile acids may be caustic at more neutral pH. Human studies are compatible with a synergistic action between acid and duodenogastric reflux in inducing lesions. During prolonged monitoring studies, typical gastro-oesophageal reflux symptoms are more related to acid reflux events than to non-acid reflux events. However, symptoms that persist during acid suppressive therapy are often related to non-acid reflux events. The therapeutic options for the non-acid component of the refluxate, including acid suppression, prokinetics, baclofen, surgery and mucosal protective agents like alginates, are discussed.

Diazinon and cypermethrin are pesticides extensively used in sheep dipping. Diazinon is a known anti-cholinesterase, but there is limited information regarding its molecular mechanism of action. This paper describes the effects of diazinon and cypermethrin at a morphological and molecular level on differentiating mouse N2a neuroblastoma and rat C6 glioma cell lines. Concentrations up to 10 microM of both compounds and their mixture had no effect on the viability of either cell line, as determined by methyl blue tetrazolium reduction and total protein assays. Microscopic analysis revealed that 1 microM and 10 microM diazinon but not cypermethrin inhibited the outgrowth of axon-like processes in N2a cells after a 24-h exposure but neither compound affected process outgrowth by differentiating C6 cells at these concentrations. Under these conditions, 10 microM diazinon inhibited AChE slightly compared to the control after a 4-h exposure but not after 24 h. Western blotting analysis showed that morphological changes were associated with reduced cross-reactivity with antibodies that recognize the neurofilament heavy chain (NFH), microtubule associated protein MAP 1B and HSP-70 compared to control cell extracts, whereas reactivity with anti-alpha-tubulin antibodies was unchanged. Aggregation of NFH was observed in cell bodies of diazinon-treated N2a cells, as determined by indirect immunofluorescence staining. These data demonstrate that diazinon specifically targets neurite outgrowth in neuronal cells and that this effect is associated with disruption of axonal cytoskeleton proteins, whereas cypermethrin has no effect on the same parameters.

Frequency of atypical symptoms in patients suffering from gastro-oesophageal reflux disease (GORD) is not well known, and the optimal management of such symptoms has not been well established. Our aims were to set up an observatory of these atypical symptoms of GORD in Belgium and to study the efficacy of one month treatment with esomeprazole 40 mg.Gastroenterologists participating in this observational survey were asked to register every new outpatient with symptoms of GORD during a period of 20 consecutive working days. All patients who reported predominant presence of atypical manifestations of GORD were documented and characterized more in detail. In patients with dominant chest pain or ENT symptoms, a treatment with esomeprazole 40 mg daily during 4 weeks was proposed.90 gastroenterologists included 2864 patients consulting for symptoms suggestive of GORD, including 776 (27.1%) with dominant atypical symptoms. Endoscopy (performed in 2800 patients) showed significantly less oesophagitis in atypical than in typical GORD patients (68% vs. 81.1%; P0.0001). Management of atypical GORD patients appeared to be very heterogeneous. Overall 516/776 patients were included in the open phase of treatment with esomeprazole 40 mg, but data for analysis are only available in 228 patients. After one month, symptoms had disappeared in 57.1% and significantly improved in 26.6%.Atypical GORD represents a large number of consultations in gastroenterology in Belgium. It is associated with less endoscopic lesions than typical GORD. Its management is heterogeneous reflecting the lack of guidelines on this topic. Response rate after esomeprazole 40 mg for one month in this open uncontrolled trial was high. This result warrants confirmation in a placebo-controlled trial.

In Europe, the thiazolidinedione derivatives pioglitazone and rosiglitazone have been approved for the treatment of type 2 diabetes mellitus either as monotherapy for patients with intolerance or contraindications to metformin or in combination therapy. This class of drugs seems particularly suited for obese patients, but is currently not considered as a first choice for monotherapy. The efficacy with respect to blood glucose lowering is comparable with sulphonylurea (SU) derivatives and with metformin. Long-term data with respect to efficacy and side effects are still limited.

Good glycaemic control of diabetes mellitus is still hampered by the fear of insulin injections. Particularly in patients with type 2 diabetes, inhaled insulin as a novel therapeutic option for glycaemic control could be an alternative to subcutaneous insulin. Phase III clinical studies have shown glycaemic equivalence between inhaled insulin and conventional subcutaneous insulin. However, no study comparing inhaled insulin with short-acting insulin analogues has yet been published. Thus, methodological problems preclude conclusive remarks concerning quality-of-life issues. Inhaled insulin should be reserved for selected patient groups only. Lengthier studies to evaluate the long-term (pulmonary) safety of inhaled insulin and a cost-effectiveness study are needed.

Previously, we demonstrated that intestinal inflammation leads to a postinflammatory loss of nitric oxide synthase (NOS)-expressing myenteric neurones and motility disturbances. Here, we investigated whether high NO concentrations could be responsible for the decrease in NOS neurones. Myenteric neurone cultures, prepared from guinea-pig small intestine, were incubated with NO donors [sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1)]. After fixation, NOS neurones were identified by NADPH diaphorase staining and neurone-specific enolase (NSE)-positive neuronal content was assessed with an enzyme-linked immunosorbent assay (ELISA)-based method. Twenty-four hours incubation with SIN-1 (10(-3) mol L(-1)) or SNP (10(-4) mol L(-1) or higher) reduced the number of NADPH diaphorase-positive neurones. SNP incubation did not affect the NSE-positive neuronal content. Shorter incubations (SNP: 4 and 12 h) had no significant effect. The SNP-induced reduction was reversed by glutathione (GSH), but not by NO- or O-scavengers, whereas GSH depletion enhanced the decrease. The NO-dependent guanylate cyclase-blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) did not affect the SNP effect. This reduction can be explained by either specific apoptosis of NOS neurones or downregulation of NOS activity. However, TdT-mediated X-dUTP nick end labelling (TUNEL stainings argue in favour of the latter. In conclusion, the NO donor SNP decreases the number of NOS-expressing myenteric neurones time and concentration dependently, without affecting the amount of neuronal material. Glutathione plays an important protective role.

Contains fulltext : 50274.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N-monomethyl-L-arginine-acetate (L-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemic-euglycemic clamp (120 min, 120 mU/m(2) per min). RESULTS: As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or L-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35-6.87, P = 0.0005) and increased plasma volume by 255 ml/1.73 m(2) (80-430, P = 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R(2) = 0.53, P = 0.001). CONCLUSIONS: Rosiglitazone improved insulin sensitivity but had no effect on NO-dependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation.

It is generally accepted that enteropathy-type intestinal lymphoma (EATL) arises against a background of gluten enteropathy. We investigate whether patients with this diagnosis had celiac disease or pre-existing celiac disease, based on gliadin and endomysium antibodies, as well as duodenal biopsies, HLA typing and response to gluten-free diet.Retrospective study of patients with the diagnosis of peripheral T cell lymphoma of the intestine between January 1990 and January 2002 at the university hospital Gasthuisberg Leuven (n = 14). Patients in whom serologic testing was performed or patients known with pre-existing celiac disease (CD) were included (n = 9). Six of these nine patients were tested for endomysium antibodies (AEM), none of them were positive. Of the six patients with biopsies of mucosa uninvolved by lymphoma, all of them had villous atrophy; five had increased intraepithelial lymphocytes (IEL). In the four patients were HLA typing was performed, the results were compatible with CD. The three patients with initially diagnosed celiac disease all improved on gluten free diet (control biopsies improved as well, but failed to normalise). Of the six other patients, one patient never started GFD, two didn't get better, one initially went better after GFD, and one went better with the concomitantly started chemotherapy.There are two possible explanations: Either these patients with EATL have indeed gluten intolerance but the sensitivity of AEM is overestimated in this patient population; or these patients don't have gluten intolerance and EATL itself can mimic CD or other factors mimicking CD are at risk for developing EATL.

Contains fulltext : 49829.pdf (Publisher’s version ) (Closed access) Microdialysis is a sampling method that permits measurement of hormones, drugs, and other lower molecular weight compounds present in interstitial fluid. We developed a straightforward mathematical model that predicts a linear relationship between the reciprocal dialysate concentration of the analyte from the interstitium and perfusion rate, permitting estimation of the interstitial concentration by extrapolation to zero perfusion rate. Conversely, linearity between the reciprocal dialysate concentration of internal standard added to the perfusion medium (retrodialysis), and the reciprocal perfusion rate, is predicted. In nine healthy volunteers, interstitial norepinephrine (NE) was estimated by NE measurements in microdialysates obtained from skeletal muscle and adipose subcutaneous tissue, using sodium salicylate (Sal) in the perfusion buffer as internal standard, at perfusion rates of 2 and 5 mul/min. Comparison with microdialysis in vitro by immersing the probe in a large volume of buffer containing NE showed that the in vivo (retro)recovery of NE and Sal is almost exclusively determined by transport of NE through the interstitial space toward and Sal from the membrane and that membrane permeability itself plays a negligible role. This was supported by the observation that applying lower body negative pressure, a measure that is unlikely to affect membrane permeability, resulted in a significant (p < 0.05) decrease of Sal retrorecovery from muscle interstitium. This validated new model significantly adds insight into the factors determining recovery of substances from the interstitium in microdialysis and provides a simpler alternative to previous approaches for estimation of interstitial concentrations.

Background. Gram-positive pathogens can cause serious infections in neutropenic patients with cancer, and vancomycin therapy is often initiated empirically. Linezolid may offer an option for these patients.Methods. To compare the safety and efficacy of linezolid and vancomycin in febrile, neutropenic patients with cancer, we conducted a double-blind, multicenter equivalence study. Eligible patients with proven or suspected infection due to a gram-positive pathogen were randomized to receive linezolid or vancomycin.Results. Clinical success rates 7 days after completion of therapy (primary end point) were equivalent between groups in the intent-to-treat (ITT) analysis (linezolid, 219 [87.3%] of 251 patients; vancomycin, 202 [85.2%] of 237 patients; 95% CI, -4.1 to 8.1; P = .52), modified ITT analysis, clinically evaluable analysis, and microbiologically evaluable analysis, as well as between subsets analyzed by malignancy and infection type. Mean time to defervescence was shorter for linezolid than vancomycin in the modified ITT (6.6 vs. 8.5 days; P = .04) and microbiologically evaluable subsets (5.9 vs. 9.1 days; P = .01), although post hoc analyses revealed delayed recovery of absolute neutrophil counts for linezolid in these subsets (P < .05). There were no between-group differences in microbiologic success rates in the modified ITT subset (41 [57.7%] of 71 patients vs. 29 [50.0%] of 58 patients; P = .38) and microbiologically evaluable subsets, as well as in mortality rates in the ITT subset (17 [5.6%] of 304 patients vs. 23 [7.6%] of 301 patients; P = .31) and all subsets. Distribution of adverse events, including reported hematologic events, was similar between groups, except that linezolid was associated with fewer drug-related adverse events (52 [17.2%] of 303 patients vs. 72 [24.0%] of 300 patients; P = .04) and fewer cases of drug-related renal failure (1 [0.3%] of 303 patients vs. 7 [2.3%] of patients; P = .04).Conclusions. Linezolid demonstrated efficacy and similar safety outcomes equivalent to those for vancomycin in febrile neutropenic patients with cancer.

Contains fulltext : 51057.pdf (Publisher’s version ) (Closed access) Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.

Contains fulltext : 51401.pdf (Publisher’s version ) (Closed access) It was recently suggested that HIV-associated adipose redistribution syndrome (HARS) results from an autonomic dysbalance. We investigated the local and global sympathetic nervous system function of patients with HIV-1 infection and HARS. Interstitial noradrenaline concentrations in skeletal muscle and subcutaneous adipose tissue were increased in the absence of changes in global sympathetic nerve activity, consistent with locally increased sympathetic activity. This could promote localized lipolysis in subcutaneous adipose tissue and contribute to the development of HARS.

The aim of this study is to use anamnesis and laryngeal examination to investigate the occurrence of the gastroesophageal reflux disease GERD (with symptoms of regurgitation and heartburn, signs of oesophagitis, and pathological pH monitoring) among patients with suspected laryngopharyngeal reflux.One hundred and sixty-nine patients with laryngopharyngeal reflux indicated by anamnesis and laryngeal examination were evaluated retrospectively with endoscopy and 24-hour double-probe pH monitoring.Combining endoscopy and pH monitoring made possible a diagnosis of GERD in 130 patients (77%). Of these patients, 58% had erosive oesophagitis and 84% had pathological oesophageal acid exposure. Of the patients with suspected laryngopharyngeal reflux and with established GERD, 49% reported gastrointestinal symptoms like heartburn or acid regurgitation. Erosive oesophagitis was confirmed in 45% of patients: grade 1 in 60 (35%), grade 2 in 10 patients (6%), and grades 3 and 4 in 3 patients each (2%). Distal oesophageal pH monitoring was pathological in 65% of patients. Of these, 93% had upright pathological acid exposure. Proximal oesophageal acid exposure was pathological in 39% of patients.Reflux can be suspected when a patient presents typical laryngeal symptoms and signs. The majority of these patients will not have typical GERD symptoms like heartburn, and endoscopic oesophagitis, mostly grade 1, is present in only a subset of patients with LPR. Oesophageal pH monitoring is the most appropriate test to demonstrate pathological oesophageal acid exposure.

Obesity is characterised by insulin resistance and by elevated levels of proinflammatory markers. We investigated whether, in the absence of changes in glucose, thiazolidinediones (TZDs) have anti-inflammatory effects and whether improvement of insulin sensitivity correlates with suppression of inflammatory markers.We performed a randomised double-blind placebo-controlled crossover study with troglitazone (400 mg daily for eight weeks) in 15 normoglycaemic obese subjects. We measured plasma high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and tumour necrosis factor-alpha (TNF-alpha) after each of the two treatment periods and in 13 age- and sex-matched lean individuals.Obese subjects were insulin resistant (decreased glucose infusion rate (GIR) during euglycaemic hyperinsulinaemic clamp) and had higher plasma levels of hsCRP, IL-6, leptin, tPA, and PAI-1 compared with lean subjects. TNF-alpha also tended to be higher. Troglitazone improved insulin sensitivity (mean increase in whole body glucose uptake 23.1 +/- 10.5% (p = 0.047)) and normalised plasma concentrations of hsCRP, tPA and TNF-alpha, whereas it did not significantly change IL-6, leptin and PAI-1. Changes in GIR did not correlate with changes in inflammatory markers.Troglitazone induces suppression of some of the inflammatory markers that are elevated in normoglycaemic obese subjects. The suppression of inflammatory markers, however, does not correlate with improvement in insulin sensitivity, suggesting involvement of partially differential mechanisms in these effects of TZDs.

Contains fulltext : 48014.pdf (Publisher’s version ) (Closed access) BACKGROUND: By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity. METHODS: In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 +/- 7 years) were randomized to rosuvastatin 40 mg day(-1) or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic-hyperinsulinaemic clamp after 12 weeks of both treatment periods. RESULTS: Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides -28%; LDL-c -50%; VLDL-c -56%, VLDL-TG -39%) and both parameters of low-grade inflammation (as measured by hsCRP, -16%) and oxidative stress (as measured by plasma-oxLDL, -55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41.7 +/- 17.4 vs. 40.6 +/- 11.1 L kg(-1) min(-1), placebo vs. rosuvastatin, P = 0.71). CONCLUSION: Despite marked improvements in lipid and lipoprotein values, low-grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH.

Various tests exist to quantify beta cell (BC) function, but do not necessarily provide information on BC mass (BCM), while BCM seems an important predictor of future BC failure. A method for reliable BCM quantification would be a tremendous asset to better elucidate the pathophysiology of type 1 and type 2 diabetes (T1D and T2D), and to determine effects of therapeutic interventions.