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This multicenter, randomized, controlled, investigator-masked study was performed to assess the efficacy and tolerability of cefdinir for the treatment of streptococcal pharyngitis. Children aged 1 through 12 years with signs and symptoms of pharyngitis and a positive result on a rapid screening test for Streptococcus pyogenes were randomly assigned to receive cefdinir 14 mg/kg QD, cefdinir 7 mg/kg BID, or penicillin V 10 mg/kg 4 times daily for 10 days. Seven hundred ninety-two patients were enrolled, and 682 were clinically and microbiologically assessable. All treatment groups had similar demographic characteristics (-50.0% male, predominantly white, median age 7 years). The eradication rates of S pyogenes, determined 4 to 9 days after completion of therapy, were 94.3% in the cefdinir QD group, 94.3% in the cefdinir BID group, and 70.0% in the penicillin V group (95% confidence interval [CI] 17.6%-30.9%, P < 0.001 for cefdinir QD vs penicillin; CI 17.5%-30.9%, P < 0.001 for cefdinir BID vs penicillin). Clinical cure rates were 97.4%, 96.0%, and 86.3% for the cefdinir QD, cefdinir BID, and penicillin groups, respectively (CI 6.1%-15.9%, P = 0.001 for cefdinir QD vs penicillin; CI 4.6%-14.8%, P = 0.001 for cefdinir BID vs penicillin). Adverse reactions occurred in 8.3%, 8.7%, and 7.6% of cefdinir QD, cefdinir BID, and penicillin patients, respectively (P = NS). Treatment with cefdinir, either QD or BID, was associated with higher eradication rates of S pyogenes and higher clinical cure rates. Both cefdinir and penicillin were well tolerated. Three patients, 1 receiving cefdinir BID and 2 receiving penicillin, discontinued the study drug because of adverse reactions.

It was previously shown that systemic hyperinsulinemia induces vasodilation in human skeletal muscle. The mechanism mediating this vasodilation is not yet completely clarified. Based on data from animal experiments, we hypothesized that stimulation of the adenosine receptor is involved in insulin-induced vasodilation. To test this hypothesis, a 105-min hyperinsulinemic euglycemic clamp was performed in three groups of eight healthy volunteers. In group 1, placebo was infused into the left brachial artery (experimental forearm). In the second and third group, respectively, draflazine (an adenosine-uptake blocker) and theophylline (an adenosine-receptor antagonist) were administered by intrabrachial infusion. Forearm blood flow (FBF) was measured by venous-occlusion plethysmography, both at the experimental and the control forearms. The percentage decrease in flow ratio (FBF experimental arm/control arm) in the draflazine group was significantly less pronounced than that in the placebo group, whereas the percentage decrease in flow ratio was larger in the theophylline group. These results demonstrate that the insulin-induced increase in blood flow in the experimental arm was more pronounced at the site of adenosine-uptake blockade by draflazine, whereas this was reduced during adenosine-receptor antagonism by theophylline. Our observations are compatible with the hypothesis that insulin-induced vasodilation is mediated by the release of adenosine.

Because of increasing resistance to older antimicrobial agents, newer drugs need to be evaluated for the treatment of skin and skin-structure infections (SSSIs). This double-masked, randomized, comparative, multicenter study enrolled patients aged 13 years or older with SSSIs to receive either cefdinir 300 mg BID or cephalexin 500 mg QID for 10 days. Nine hundred fifty-two patients (474 in the cefdinir group and 478 in the cephalexin group) took part, primarily white males between 18 and 65 years of age. There were two follow-up visits, with efficacy determined at the test-of-cure visit, 7 to 16 days posttherapy. Many patients were not microbiologically assessable, primarily because of negative cultures at study admission. Patients who required surgical intervention (e.g., incision and drainage) at the site of infection more than 24 hours after the initiation of drug therapy were defined as treatment failures. Significantly more isolated pathogens were resistant to cephalexin than to cefdinir. In the 178 efficacy-assessable cefdinir-treated patients, the rate of pathogen eradication was 93% (200/215), and the rate of successful clinical response was 88% (157/178), compared with 89% (221/247) and 87% (177/204), respectively, in the 204 efficacy-assessable cephalexin-treated patients. Using confidence-interval analysis, the microbiologic and clinical response rates of the cefdinir-treated patients were statistically equivalent to those of the cephalexin-treated patients. At the follow-up visits, patients were questioned about any adverse events occurring since their previous visit. Any untoward symptom occurring during or within 2 days after completion of drug treatment was considered an adverse reaction if the investigator judged it to be definitely, probably, or possibly related to the study drug. One hundred twenty-three (26%) cefdinir-treated patients and 77 (16%) cephalexin-treated patients experienced at least one adverse reaction, a statistically significant difference. Study drug was discontinued for adverse reactions in 20 (4%) cefdinir-treated patients and 13 (3%) cephalexin-treated patients; in the two groups, 10 and 7 patients, respectively, were discontinued for diarrhea. Cefdinir taken BID was as effective as cephalexin taken QID in the treatment of mild-to-moderate SSSIs and was well tolerated by most patients. The increased antibacterial activity of cefdinir must be balanced against the higher rate of diarrhea seen in patients treated with this drug.

Several lines of evidence indicate a significant association between insulin and cardiovascular disease. This association might be explained by direct (cardio) vascular effects of insulin. Two hemodynamic actions of insulin are discussed in this review; it induces direct vasodilation in skeletal muscle and stimulation of the sympathetic nervous system. These closely linked effects normally offset each other. Although more insight has been obtained into responses in insulin-resistant individuals and possible mechanisms, direct evidence to support a causative role for insulin is not yet available.

Visceral hypersensitivity is now recognised as a major pathophysiological mechanism in functional gastrointestinal disorders of the upper gastrointestinal tract. In patients with non-cardiac chest pain and functional dyspepsia, a high prevalence of visceral hypersensitivity has been indeed observed. In these patients, luminal physiological stimuli can be perceived as unpleasant or even painful. Although the fine mechanisms underlying such “aberrant perceptions” are yet not fully clarified, it is thought that an altered activation of the gut-wall receptors, an altered conduction of sensory inputs at the level of neural pathways, or an impaired processing of the sensations at the level of brain, may occur along the brain–gut axis. So far, drugs able to reduce hypersensitivity, that target each of the constituents of the stimuli–perception chain, have the therapeutic potential to reduce visceral hypersensitivity and, thus, to improve the symptoms. In this context, the availability of new agonists/antagonists to neurotransmitters offers a new exciting tool for the treatment of functional disorders of the upper gastrointestinal tract.

Six hundred ninety patients were enrolled in a multicenter, randomized, double-blind trial comparing the efficacy and safety of cefdinir with those of cefaclor in the treatment of community-acquired pneumonia. Patients received either 10 days of treatment with cefdinir (n = 347) at 300 mg twice daily or 10 days of treatment with cefaclor (n = 343) at 500 mg three times daily. Microbiological assessments were performed on sputum specimens obtained at admission and at the two posttherapy visits, if available. Respiratory tract pathogens were isolated from 538 (78%) of 690 patient admission sputum specimens, with the predominant pathogens being Haemophilus parainfluenzae, Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus. The microbiological eradication rates at the test-of-cure visit were 92% (238 of 260 pathogens) and 93% (245 of 264 pathogens) for the evaluable patients treated with cefdinir and cefaclor, respectively. A satisfactory clinical response (cure plus improvement) was achieved in 89% (166 of 187) and 86% (160 of 186) of the evaluable patients treated with cefdinir and cefaclor, respectively. Except for the incidence of diarrhea, adverse event rates while on treatment were equivalent between the two treatment groups. Diarrhea incidence during therapy was higher for patients treated with cefdinir (13.7%) than for patients treated with cefaclor (5.3%). These results indicate that cefdinir is effective and safe in the treatment of patients with pneumonia.

Familial combined hyperlipidemia (FCH) is a heterogeneous lipid disorder, caused by overproduction of VLDL and characterized by the occurrence of small, dense LDL particles, all features that are also associated with insulin resistance. Therefore, insulin sensitivity was examined directly by means of the euglycemic hyperinsulinemic clamp technique in male nonobese, normotensive FCH patients and compared with that of their nonaffected relatives, matched for age and body mass index (BMI). In addition, an oral 75-g glucose tolerance test (OGTT) was performed and lipid values, including the LDL subfraction profile, were determined. During the clamp, forearm blood flow (FBF) was measured by venous occlusion plethysmography. All participants had a normal glucose response after the glucose load, whereas FCH patients showed hyperinsulinemia after OGTT and higher fasting C-peptide levels. During the clamp, insulin concentrations increased equally in both groups. Mean whole-body glucose uptake (M) (120 to 180 minutes) was lower in FCH patients than in nonaffected relatives (6.89±0.31 versus 8.94±0.76 mg • kg -1 • min -1 ; P =.01). In addition, the glucose uptake per unit insulin (I) was lower in FCH patients (insulin sensitivity index [M/I], 7.46±0.50 versus 9.51±0.53; P =.009). M significantly correlated with BMI, plasma cholesterol and triglyceride concentrations, and the individual LDL density. The FBF correlated with insulin sensitivity and increased significantly in nonaffected relatives (1.9±0.12 to 2.5±0.4 mL • min -1 • dL -1 ; P =.025) but not in patients. Thus, FCH patients characterized by a predominance of small, dense LDL are insulin resistant compared with their nonaffected relatives. This insulin resistance may partly be explained by a decreased insulin-induced vasodilation in skeletal muscle. ( Arterioscler Thromb Vase Biol. 1997;17:1465-1471.)

Three hundred ninety-four patients, aged 6 months to 12 years, entered a multicenter, randomized, controlled, investigator-blind study comparing cefdinir, 7 mg/kg of body weight twice a day, with cephalexin, 10 mg/kg four times a day, each given for 10 days. The most common infections treated were impetigo and secondary infection of preexisting dermatitis. The most common pathogens isolated were Staphylococcus aureus and Streptococcus pyogenes. Two hundred thirty-one patients were microbiologically evaluable. Microbiologic eradication rates were 164 of 165 pathogens (99.4%) in the cefdinir group and 152 of 156 pathogens (97.4%) in the cephalexin group (P = 0.14). Clinical cure rates were 116 of 118 patients (98.3%) in the cefdinir group and 106 of 113 patients (93.8%) in the cephalexin group (P = 0.056). Sixteen percent of cefdinir patients and 11% of cephalexin patients experienced adverse events (P = 0.11), the most common being diarrhea, which affected 8% of the cefdinir group and 4% of the cephalexin group. Cefdinir appears to be an effective and well-tolerated agent for the treatment of uncomplicated skin and skin structure infections in pediatric patients.

Summary: in this; study we examined the effects of long-term treatment of 19 patients with primary hypertension with the sr adrenoceptor antagonist atenolol on norepinephrine and epi­ nephrine kinetics, at rest and during sympathoadrenal stimula­ tion by lower body negative pressure. Norepinephrine and epinephrine kinetics were measured by using the radioisotopedi luti on technique by steady-state infusion of tritiated norepi­ nephrine and epinephrine. The patients were studied before and at the end of 3 months of treatment with atenolol (50 or 100 mg daily). A control group of four normotensive subjects was stud­ ied before and after 3 months without any drug treatment. In this group, only arterial blood samples were collected without infu­ sion of the tritiated catecholamines. Atenolol decreased blood pressure and heart rate, but forearm vascular resistance was not affected by atenolol. During atenolol, baseline arterial plasma epinephrine decreased from 0.23 ± O.02 to U.17 ± O.Oi nM (p < 0,05), and this was accompanied by a decrease in total body ep­ inephrine spillover from 0,50 ± 0.05 to 0.35 ± 0.04 nmol/min (p < 0.05), In the control group, arterial plasma epinephrine had not decreased after 3 months. In addition, the increment of arterial plasma epinephrine during lower body negative pressure at-40 mm Hg was attenuated during atenolol. Atenolol had no effect on total body and forearm norepinephrine spillover rates, either at rest or during lower body negative pressure. Clearance ivtes of epinephrine and norepinephrine were not significantly ef­ fected by atenolol. These results suggest that treatment of pa­ tients with primary hypertension with the s j-adrenoceptor blocker atenolol inhibits the adrenomedullary secretion of epi­ nephrine, but it does not affect the biochemical indices of sympathoneural activity, It remains speculative whether this selec­ tive effect of atenolol on epinephrine secretion contributes to its hypotensive action and to its cardioprotective effects in the long term. KeyWords: s (-Adrenergic— Sympathoadrenal activity— Hypertension— Catecholamines.

A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagon-like peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals.The targeting of (111)In-labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq (111)In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq (111)In-labelled exendin in five patients with type 1 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images.In rats, (111)In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes.These studies indicate that (111)In-labelled exendin may be suitable for non-invasive quantification of BCM.ClinicalTrials.gov NCT01825148, EudraCT: 2012-000619-10.

A 74-year-old woman went to the gastroenterologist because of an altered defaecation pattern. Colonoscopy could not be completed due to sigmoid angulation. A CT-scan of the colon showed that the colon was located in the left side of the abdomen, as a result of embryonic non-rotation of the intestine. In adults this is generally asymptomatic. Non-specific abdominal complaints or volvulus seldom occur. Surgical intervention is rarely necessary.

Diabetic gastroparesis (DGP) is a gastric complication of diabetes mellitus that causes nausea, vomiting, early satiety, bloating and abdominal pain, in addition to significant morbidity.Original and review articles were reviewed through PubMed, including relevant guidelines from the European and American Neurogastroenterology Societies.Diagnosis of DGP requires endoscopy and measurement of gastric emptying. Management requires prokinetic therapy, usually in addition to antinausea or other medications.The pathogenesis of DGP is poorly understood. Management strategies are highly variable. Growing points Prokinetic and neuromodulatory medications are in human clinical trials specifically for gastroparesis.Further understanding of the molecular pathology leading to DGP is required to potentially arrest the development of this serious diabetic complication. Evaluation of novel agents for use in DGP is sorely needed.

The intimate association between glial cells and neurons within the enteric nervous system has confounded careful examination of the direct responsiveness of enteric glia to different neuroligands. Therefore, we aimed to investigate whether neurotransmitters known to elicit fast excitatory potentials in enteric nerves also activate enteric glia directly.We studied the effect of acetylcholine (ACh), serotonin (5-HT), and adenosine triphosphate (ATP) on intracellular Ca(2+) signaling using aequorin-expressing and Fluo-4 AM-loaded CRL-2690 rat and human enteric glial cell cultures devoid of neurons. The influence of these neurotransmitters on the proliferation of glia was measured and their effect on the expression of c-Fos as well as glial fibrillary acidic protein (GFAP), Sox10, and S100 was examined by immunohistochemistry and quantitative RT-PCR.Apart from ATP, also ACh and 5-HT induced a dose-dependent increase in intracellular Ca(2+) concentration in CRL-2690 cells. Similarly, these neurotransmitters also evoked Ca(2+) transients in human primary enteric glial cells obtained from mucosal biopsies. In contrast with ATP, stimulation with ACh and 5-HT induced early gene expression in CRL-2690 cells. The proliferation of enteric glia and their expression of GFAP, Sox10, and S100 were not affected following stimulation with these neurotransmitters.We provide evidence that enteric glial cells respond to fast excitatory neurotransmitters by changes in intracellular Ca(2+). On the basis of our experimental in vitro setting, we show that enteric glia are not only directly responsive to purinergic but also to serotonergic and cholinergic signaling mechanisms.

Item does not contain fulltext Obesity-induced inflammation is associated with insulin resistance and morphologically characterized by macrophage influx into the adipose tissue. Recently, various other immune cells, including B- and T-cells, have been shown to participate in modulating adipose tissue inflammation during the development of obesity. We show that HFD-feeding modulates the influx of B and T-cells into adipose tissue of obese animals, suggestive of a role of the adaptive immune system in the development of adipose tissue inflammation. Despite a lower bodyweight after HFD-feeding, gene expression levels of CD68, F4/80 and MCP-1 in white adipose tissue were enhanced in SCID animals that lack B- and T-cells. Moreover, conditioned medium from adipose tissue explants of HFD-fed SCID mice revealed increased release of IL-6 and CXCL1 compared to WT animals. Compared to WT mice, glucose tolerance was impaired in B- and T-cell deficient mice after HFD-feeding. Thus, complete B- and T-cell deficiency does not protect against HFD-induced adipose tissue inflammation and glucose intolerance. In contrast, SCID mice showed an increased pro-inflammatory status at the level of the adipose tissue in some cytokines. Our findings suggest that a delicate balance between various B- and T-cell populations controls adipose tissue inflammation.

Caspase-1 is known to activate the proinflammatory cytokines IL-1 beta and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-deficient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-deficient and wild-type mice. Caspase-1 deficiency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [H-3] TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [H-3] TG-containing olive oil revealed that caspase-1 deficiency reduced TG absorption and subsequent uptake of TG-derived FA in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic TG content, caspase-1 deficiency reduced hepatic VLDL-TG production. Intestinal and hepatic gene expression analysis revealed that caspase-1 deficiency did not affect FA oxidation or FA uptake but rather reduced intracellular FA transport, thereby limiting lipid availability for the assembly and secretion of TG-rich lipoproteins.(jlr) The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion.-van Diepen, J. A., R. Stienstra, I. O. C. M. Vroegrijk, S. A. A. van den Berg, D. Salvatori, G. J. Hooiveld, S. Kersten, C. J. Tack, M. G. Netea, J. W. A. Smit, L. A. B. Joosten, L. M. Havekes, K. W. van Dijk, and P. C. N. Rensen. Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion. J. Lipid Res. 2013. 54: 448-456.

Contains fulltext : 118937.pdf (Publisher’s version ) (Open Access) Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-13C]glucose infusion to increase plasma 13C enrichment. In vivo brain 13C magnetic resonance spectroscopy was used to measure the time course of 13C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (VTCA) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the VTCA, was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the VTCA was inversely related to the HbA1C and was, under hypoglycemic conditions, approximately 45\% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes.

Contains fulltext : 126268.pdf (Publisher’s version ) (Open Access) AIMS/HYPOTHESIS: Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin-associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive. METHODS: We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy. RESULTS: As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-alpha and IL-1beta after 6 months of insulin therapy compared with those who had not gained weight. CONCLUSIONS/INTERPRETATION: We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00781495. FUNDING: The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation.

Item does not contain fulltext OBJECTIVE: The 5-item World Health Organization well-being index is a commonly used measure of emotional well-being, but research on psychometric properties in outpatients with diabetes is scarce. We examined psychometric and screening properties for depression of this index in a large sample of Dutch outpatients with diabetes. METHODS: Patients with Type 1 (n = 384) and Type 2 (n = 549) diabetes from three outpatient clinics completed the WHO-5 index, the nine-item Patient Health Questionnaire, the Problem Areas in Diabetes survey and the Short Form-12 health survey. Internal consistency of the WHO-5 index was determined by Cronbach's alpha. The factor structure was tested by confirmatory factor analysis. Concurrent validity was assessed by correlations with the Patient Health Questionnaire, Problem Areas in Diabetes and the Short Form-12 mental component scores. Sensitivity and specificity of the WHO-5 index as depression screener were tested against two existing Patient Health Questionnaire cut-off scores for depression using receiver operating characteristic curves. RESULTS: A one-factor structure of the WHO-5 index was verified by confirmatory factor analysis for patients with Type 1 and Type 2 diabetes. Moderate to strong correlations were observed between the WHO-5 index and the Patient Health Questionnaire scores, the Problem Areas in Diabetes scores and the Short Form-12 mental component scores (r = 0.55-0.69, P < 0.001). Receiver operating characteristic curves showed that a WHO-5 index cut-off of < 50 performed best as an indication for likely depression, with sensitivity compared with a Patient Health Questionnaire score >/= 10 and >/= 12 of 79% and 88%, respectively, and specificity of 88% and 76%, respectively. CONCLUSIONS: The WHO-5 index is a short, psychometrically sound measure of emotional well-being that appears suitable for use as screening test for likely depression in outpatients with Type 1 and Type 2 diabetes.

Item does not contain fulltext PURPOSE: Insulin degludec coformulated with insulin aspart (as IDegAsp) can cover 24 h basal insulin and postprandial insulin requirements after a main meal with one injection. We compared glycemic stability following IDegAsp or insulin glargine (IGlar) given before the evening meal in patients with type 2 diabetes. METHODS: A subset of 112 insulin-naive type 2 diabetes patients from a randomized, parallel-group trial (IDegAsp versus IGlar, each added to metformin) underwent 72 h continuous interstitial glucose (IG) monitoring after 16 weeks of treatment. End points included mean IG concentrations, 2 h postprandial IG increments and postprandial peak, IG fluctuation (summed area above and below mean IG), within-subject coefficient of variation (day-to-day variation) in mean nocturnal IG, and episodes of low (10 mmol/liter) IG. Values were derived for the entire 72 h, with the nocturnal interval (0001-0559 h) also assessed. RESULTS: The postdinner IG increment observed with IGlar did not occur with IDegAsp [IDegAsp - IGlar, -1.42 (-2.15, -0.70) mmol/liter]. Nocturnal IG fluctuation was 21% lower with IDegAsp [IDegAsp/IGlar, 0.79 (0.66, 0.96) mmol/liter], with 48% fewer nocturnal high IG episodes [ratio IDegAsp/IGlar, 0.52 (0.32, 0.87)]. CONCLUSIONS: IDegAsp given with the evening meal reduces postdinner glucose excursion and provides more stable nocturnal glycemia as compared with IGlar.

Systemic hyperinsulinemia induces vasodilation in human skeletal muscle. This vasodilation contributes to insulin-stimulated glucose uptake and has been found to be reduced in various insulin-resistant states. The mechanism of the effect of insulin on vascular tone is not completely understood. We hypothesized that activation of the sodium-potassium pump (Na + ,K + -ATPase) located in endothelial or smooth muscle cells would be involved in the insulin-mediated vasodilation. Therefore, in 24 healthy, nonsmoking, nonobese, normotensive volunteers, we infused ouabain, a specific inhibitor of Na + ,K + -ATPase, into the brachial artery before and during euglycemic hyperinsulinemia. As expected, insulin (systemic concentrations, approximately 700 [low] and 1400 [high] pmol·L −1 ) induced vasodilation in the control arm (forearm blood flow [FBF, plethysmography] from 1.6±0.2 to 2.1±0.4 mL·dL −1 ·min −1 [low insulin] and from 1.6±0.2 to 2.1±0.2 [high insulin], P −1 ·min −1 [low] and from 1.3±0.1 to 1.3±0.1 [high], P =NS). Ouabain-induced increases in forearm potassium release were partly reversed by insulin. To investigate whether the mechanism of action could be at the endothelial level, we infused N G -monomethyl- l -arginine (L-NMMA), an inhibitor of endothelial nitric oxide synthase (0.05, 0.1, and 0.2 mg·dL −1 ·min −1 ) intra-arterially in 12 subjects and induced a clear dose-dependent decrease of FBF from 1.7±0.2 to 1.2±0.1 mL·dL −1 ·min −1 ( P −1 ·min −1 , n=6, P =.66). These results demonstrate that insulin induces vasodilation by stimulation of Na + ,K + -ATPase. This activation of Na + ,K + -ATPase could occur at the level of the endothelium rather than that of vascular smooth muscle and contributes to the endothelium-dependent vasodilator response to insulin.

Summary: The relation betw een insulin resistance/ hyperinsulinemia and cardiovascular disease may be re­ lated to one of the cardiovascular effects of insulin. In acute experiments in humans, systemic euglycemic hy- perinsulinemia induced vasodilation in skeletal muscle. Furthermore, the sympathetic nervous system is acti­ vated, although this does not lead to increase in blood pressure (BP). We hypothesized that insulin could induce vasodilation either by reduction of a- or by augmentation of p-adrenergic responsiveness. The effect of insulin in­ fusion into the brachial artery (regional forearm hyperin­ sulinemia; venous insulin concentration —500 pM) on forearm blood flow (FBF: plethysmography) was studied. Responses to the a-adrenoceptor-mediated vasoconstric­ tor norepinephrine (NE: once with and once without the p- adrenoceptor antagonist propranolol, 2 x n = 12; 9 par­ ticipated in both), and to the p-adrenoceptor-mediated vasodilator isoproterenol (n = 12 ) were measured before and during local hyperinsulinemia. Time/control studies (n = 6) were performed. Insulin alone induced vasodila­ tion, as indicated by an increase in FBF'ratio (infused/ control arm) from 1 .2 ± 0 .1 to 1 .6 ± 0 .2 , p = 0.009. Increasing dosages of N E (1.25 to 240 ng * d l ' 1 • m l ' 1) induced vasoconstriction that was more pronounced dur­ ing concomitant propranolol infusion (p < 0 .0 0 1 ), indicat­ ing a dose-dependent vasodilatory component in the ef­ fect of NE. Isoproterenol (ISO 0.03 to 10 ng * dl~* ' ini'"1), a pure p-adrenoceptor agonist, induced vasodilation. The percentage changes of FBF-ratio during NE + propran­ olol were similar and not significantly different before and during hyperinsulinemia. The same was true of the re­ sponse to N E alone and the response to ISO. Neither was the intrinsic p-agonist component of N E influenced by insulin. Repeated NE infusion showed no time- or vehicle effect. We conclude that regional hyperinsulinemia in the physiological range induces local vasodilation in the skel­ etal muscle vascular bed, but this vasodilation is not me­ diated through modulation of a- or p-adrenergic respon­ siven ess. Key Words: Insulin— a-A d ren ocep tor— p- Adrenoceptor— V as odilation.

This paper aims to measure upper esophageal sphincter (UES) distensibility and extent and duration of UES opening during swallowing in healthy subjects using EndoFLIP(®).Fourteen healthy subjects (20-50 years) were recruited. An EndoFLIP(®) probe was passed trans-orally and the probe balloon was positioned across the UES. Two 20-mL ramp distensions were completed and UES cross-sectional area (CSA) and intra-balloon pressure (IBP) were evaluated. At 12-mL balloon volume, subjects completed dry, 5- and 10-mL liquid swallows and extent (mm) and duration (s) of UES opening and minimum IBP (mmHg) were analyzed across swallows.Thirteen subjects completed the study protocol. A significant change in UES CSA (P.001) and IBP (P.000) was observed during 20-mL distension. UES CSA increased up to 10-mL distension (P.001), from which point IBP raised significantly (P = 0.004). There were significant changes in UES diameter (mm) (P.000) and minimum IBP (mmHg) (P.000) during swallowing events. Resting UES diameter (4.9 mm; IQR 0.02) and minimum IBP (18.8 mmHg; IQR 2.64) changed significantly during dry (9.6 mm; IQR 1.3: P.001) (3.6 mmHg; IQR 4.1: P = 0.002); 5 mL (8.61 mm; IQR 2.7: P.001) (4.8 mmHg; IQR 5.7: P.001) and 10-mL swallows (8.3 mm; IQR 1.6: P0.001) (3 mmHg; 4.6: P.001). Median duration of UES opening was 0.5 s across dry and liquid swallows (P = 0.91). Color contour plots of EndoFLIP(®) data capture novel information regarding pharyngo-esophageal events during swallowing.Authors obtained three different types of quantitative data (CSA, IBP, and timing) regarding UES distensibility and UES opening patterns during swallowing in healthy adults using only one device (EndoFLIP(®)). This new measure of swallowing offers fresh information regarding UES dynamics which may ultimately improve patient care.

The fourth branchial cleft fistula, which can be the origin of a recurrent left neck abscess, is a rare congenital malformation. Its diagnosis can be difficult. A ten-year-old girl presented with a left painful swelling of the neck. At ultrasonography and tomodensitometry, the diagnosis of thyroglossal cyst was suspected. Antibiotics were prescribed before surgical resection. The intervention was successful and the peroperative macroscopic aspect of the lesion suggested a dermoid cyst. Four months later, the same symptoms reappeared with fever. An intravenous antibiotic therapy was started while a magnetic resonance imaging demonstrated a possible aero-digestive tract fistula. Two days later, the patient developed an aero-cutaneous fistula. Oral antibiotics were started. Five months later, the girl came back for a second recurrence. A few days after her admission, she developed again an aero-cutaneous fistula. The diagnosis of surinfected fourth cleft fistula was made. An antibiotic therapy was started until the second intervention. After discussion about embryology, we describe the physiopathology, the differential diagnosis and the management of a fourth branchial cleft fistula causing recurrent left neck abscess.

Background Type 2 diabetes is associated with considerable comorbidity and severe complications, which reduce quality of life of the patients and require high levels of healthcare. The Diabetes Pearl is a large cohort of patients diagnosed with type 2 diabetes, covering different geographical areas in the Netherlands. The aim of the study is to create a research infrastructure that will allow the study of risk factors, including biomarkers and genetic determinants for severe diabetes complications. Methods/design Baseline examinations began November 2009 and will continue through 2012. By the end of 2012, it is expected that 7000 patients with type 2 diabetes will be included in the Diabetes Pearl cohort. To ensure quality of the data collected, standard operation procedures were developed and used in all 8 recruitment centers. From all patients who provide informed consent, the following information is collected: personal information, medication use, physical examination (antropometry, blood pressure, electrocardiography (ECG), retina photographs, ankle-brachial index, peripheral vibration perception), self-report questionnaire (socio-economic status, lifestyle, (family) history of disease, and psychosocial well-being), laboratory measurements (glucose, A1c, lipid profile, kidney function), biobank material (storage of urine and blood samples and isolated DNA). All gathered clinical data and biobank information is uploaded to a database for storage on a national level. Biobanks are maintained locally at all recruitment centers. Discussion The Diabetes Pearl is large-scale cohort of type 2 diabetes patients in the Netherlands aiming to study risk factors, including biomarkers and genetic markers, for disease deterioration and the development of severe diabetes complications. As a result of the well-designed research design and the national coverage, the Diabetes Pearl data can be of great value to national and international researchers with an interest in diabetes related research.

OBJECTIVE Limited information is available regarding the metabolic effects of high altitude trekking in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Thirteen individuals with type 2 diabetes took part in a 12-day expedition to the summit of Mount Toubkal (altitude, 4,167 m), Morocco, after 6 months of exercise training. Energy expenditure, body weight, blood glucose, fasting insulin, lipids, and HbA1c were assessed. RESULTS Training reduced fasting glucose (−0.7 ± 0.9 mmol/L, P = 0.026) and increased exercise capacity (+0.3 ± 0.3 W/kg, P = 0.005). High altitude trekking decreased fasting insulin concentrations (−3.8 ± 3.2 μU/L, P = 0.04), total cholesterol (−0.7 ± 0.8 mmol/L, P = 0.008), and LDL cholesterol (−0.5 ± 0.6 mmol/L, P = 0.007). CONCLUSIONS High altitude trekking preceded by exercise training is feasible for patients with type 2 diabetes. It improves blood glucose, lipids, and fasting insulin concentrations, while glucose control is maintained.

Background In patients with type 1 diabetes mellitus (T1DM), cardiovascular events are more common, and the outcome following a myocardial infarction is worse than in nondiabetic subjects. Ischemic or pharmacological preconditioning are powerful interventions to reduce ischemia reperfusion (IR)-injury. However, animal studies have shown that the presence of T1DM can limit these protective effects. Therefore, we aimed to study the protective effect of ischemic preconditioning in patients with T1DM, and to explore the role of plasma insulin and glucose on this effect. Methods 99mTechnetium-annexin A5 scintigraphy was used to detect IR-injury. IR-injury was induced by unilateral forearm ischemic exercise. At reperfusion, Tc-annexin A5 was administered, and IR-injury was expressed as the percentage difference in radioactivity in the thenar muscle between the experimental and control arm 4 hours after reperfusion. 15 patients with T1DM were compared to 21 nondiabetic controls. The patients were studied twice, with or without ischemic preconditioning (10 minutes of forearm ischemia and reperfusion). Patients were studied in either normoglycemic hyperinsulinemic conditions (n = 8) or during hyperglycemic normoinsulinemia (n = 7). The controls were studied once either with (n = 8) or without (n = 13) ischemic preconditioning. Results Patients with diabetes were less vulnerable to IR-injury than nondiabetic healthy controls (12.8 ± 2.4 and 11.0 ± 5.1% versus 27.5 ± 4.5% in controls; p Conclusions Patients with T1DM are more tolerant to forearm IR than healthy controls in our experimental model. The efficacy of ischemic preconditioning to limit IR-injury, however, is reduced by acute hyperglycemia. Trial Registration The study is registered at www.clinicaltrials.gov (NCT00184821)

Previous work indicated that psychosocial factors (depression and somatization) are more strongly associated with symptom severity and weight loss in functional dyspepsia (FD) than gastric sensorimotor function. However, there is conflicting evidence regarding the association of these etiopathogenetic factors with Rome III symptom-based subgroups in FD [epigastric pain syndrome (EPS), postprandial distress syndrome (PDS)]. We aimed to test whether gastric sensitivity and emptying, depression, and somatization are differentially associated with empirically derived functional gastroduodenal disorders (FGD) symptom factors in one comprehensive model.In 259 tertiary care FD patients, we studied gastric sensorimotor function with barostat and gastric emptying breath test. Depression, somatization, and FGD symptoms were measured using self-report questionnaires. Confirmatory factor analysis (CFA) on 7 FGD symptoms was used to determine the fit of a latent variable structure based on Rome III symptom-based subgroups. Structural equation modeling (SEM) was used to test the putative relationships of the symptom factors with gastric sensorimotor function, depression, and somatization.The results of the CFA show a good fit [C(min) /DF = 1.54, CFI(comparative fit index) = 0.97] for the three-factor solution based on Rome III subgroups. The SEM also fitted the data well (C(min) /DF = 1.24, CFI = 0.98) and demonstrated that gastric sensitivity and depression are associated with PDS and nausea and vomiting. Gastric emptying is uniquely associated with EPS and somatization is strongly associated with all three symptom factors.Confirmatory factor analysis confirms the existence of three FGD symptom factors, corresponding to Rome III symptom-based subgroups. The SEM results suggest that different psychobiological mechanisms may play a role in these subgroups.

Postswallow residue is indicative of impaired pharyngeal bolus clearance. The integrated nadir impedance to impedance ratio (iZn/Z) is a novel functional variable that can be derived using automated impedance manometry (AIM). In this study, the postswallow pharyngeal iZn/Z was evaluated as a potential correlated postswallow residue and therefore predictor of ineffective swallowing.Optimal iZn/Z criteria were determine using a database of 50 randomly selected bolus swallows recorded with impedance, manometry, and videofluoroscopy. The iZn/Z was derived for a region of interest (ROI), spanning the mid-point of the pharyngeal stripping wave to the upper esophageal sphincter proximal margin, and from 0.25 to 1.25 s after the peak of the pharyngeal stripping wave. Videofluorscopy was scored by four experts using a six-point bolus residue scale (BRS) score. Optimized criteria for iZn/Z were then applied to a much larger database of 225 swallows scored for residue by one expert observer.Among individual database, swallows iZn/Z was significantly correlated with average expert BRS score (r = 0.748, P0.0001). An iZn/Z of ≥ 500 was optimally predictive of swallows with residue defined by a BRS score of 4 or more. Within the larger cohort, iZn/Z was higher in dysphagia patient swallows compared with controls [2 (1, 4) vs 1 (1, 3), P0.005] and swallows with an iZn/Z ≥ 500 had higher bolus residue scores [4 (1, 6) vs 2 (1, 4), P0.001].The AIM derived iZn/Z is an easily determined objective non-radiological marker of clinically relevant postswallow residue and therefore has potential diagnostic relevance as a predictor of ineffective swallowing.

We recently showed in a euglycaemic glucose clamp study among 18 healthy volunteers that using jet injectors rather than conventional pens significantly improved the time-action profiles of rapid-acting insulin analogs. Here, we investigated whether such profiles were modified by body mass index (BMI) and related weight parameters by comparing insulin administration by jet injection to that by conventional pen in subgroups defined by BMI, waist-to-hip ratio, waist circumference and insulin dose. After conventional administration, times to peak insulin levels (T-INS(max)) occurred 31.1 [95% confidence interval (CI) 13.7-48.5] min later and time to maximum glucose requirement (T-GIR(max)) 56.9 (95%CI 26.6-87.3) min later in more obese (BMI23.6 kg/m(2)) than in lean subjects (BMI23.6 kg/m(2)). In contrast, T-INS(max) and T-GIR(max) were similar in subjects with high and low BMI, when insulin was administered by jet injection. We conclude that using jet injection for insulin administration may especially benefit subjects with higher body weight.

Different studies indicated a correlation between intragastric pressure (IGP) and satiation. Our aim was to investigate this correlation while artificially increasing the IGP.In 12 fasted healthy volunteers an infusion catheter and a manometry probe were positioned intragastrically. Intragastric pressure was increased using a custom-made belt before or progressively during intragastric nutrient infusion. Nutrient drink (1.5 kcal mL(-1)) was intragastrically infused at 60 mL min(-1) . The subjects scored satiation using a 6-point Likert scale until maximum, when the infusion ended and the belt was released. Results are presented as mean ± S.E.M. and compared using a paired t-test.When the belt was tightened before the nutrient infusion, fasting IGP was significantly increased (13.6 ± 1.3 vs 9.6 ± 0.9 mmHg; P0.05) but no differences in satiation could be observed. When progressively tightening the belt during nutrient infusion the IGP increased with 0.43 ± 0.04 mmHg per minute while in control experiments this was 0.28 ± 0.05 mmHg per minute (P0.01). During the latter experiment satiation linearly increased with 0.35 ± 0.03 and 0.29 ± 0.02 units per minute until maximal satiation (P0.01) while maximum volume consumed was 926 ± 66 and 1095 ± 82 mL when progressively increasing the IGP vs control respectively (P0.01).These findings indicate that IGP per se does not affect satiation but that a gradual IGP increase during food intake is associated with decreased food intake, indicating that gastric accommodation is an important determinant of food intake.

Improvement in subjective symptoms has been reported in functional dyspepsia (FD) patients administered with acotiamide. Improvement was confirmed in meal-related symptoms, such as postprandial fullness, upper abdominal bloating, and early satiety. We examined the mechanism underlying the effects of acotiamide on gastric accommodation reflex (GAR) and gastroduodenal motility in FD patients.Thirty-four FD patients (mean age, 40.4 years) were examined ultrasonographically before and after 14-18 days of acotiamide (100 mg t.i.d.) or placebo administration. To assess GAR, expansion rate in cross-sectional area of the proximal stomach was measured after every 100-mL ingestion, using a straw, of up to 400 mL of a liquid meal (consommé soup, 13.1 kcal; 400 mL) in a supine position. Next, we measured gastric emptying rate (GER), motility index (MI, antral contractions), and reflux index (RI, duodenogastric reflux) to assess gastroduodenal motility. Patients also completed a survey based on the seven-point Likert scale both before and after drug administration.Of the 37 cases, 19 and 18 were administered with acotiamide and placebo A respectively, significant difference was observed in GAR between the acotiamide and placebo groups (21.7%vs 4.4%) after 400 mL ingestion. GER significantly accelerated after treatment in the acotiamide group (P = 0.012), no significant differences were observed in MI and RI between the two groups. Improvement rates were 35.3 and 11.8% for the acotiamide and placebo groups.Acotiamide significantly enhances GAR and GER in FD patients. Acotiamide may have therapeutic potential for FD patients.

Autophagy, an evolutionary conserved process aimed at recycling damaged organelles and protein aggregates in the cell, also modulates proinflammatory cytokine production in peripheral blood mononuclear cells. Because adipose tissue inflammation accompanied by elevated levels of proinflammatory cytokines is characteristic for the development of obesity, we hypothesized that modulation of autophagy alters adipose tissue inflammatory gene expression and secretion. We tested our hypothesis using ex vivo and in vivo studies of human and mouse adipose tissue. Levels of the autophagy marker LC3 were elevated in sc adipose tissue of obese vs. lean human subjects and positively correlated to both systemic insulin resistance and morphological characteristics of adipose tissue inflammation. Similarly, autophagic activity levels were increased in adipose tissue of obese and insulin resistant animals as compared with lean mice. Inhibition of autophagy by 3-methylalanine in human and mouse adipose tissue explants led to a significant increase in IL-1β, IL-6, and IL-8 mRNA expression and protein secretion. Noticeably, the enhancement in IL-1β, IL-6, and keratinocyte-derived chemoattractant (KC) by inhibition of autophagy was more robust in the presence of obesity. Similar results were obtained by blocking autophagy using small interfering RNA targeted to ATG7 in human Simpson-Golabi-Behmel syndrome adipocytes. Our results demonstrate that autophagy activity is up-regulated in the adipose tissue of obese individuals and inhibition of autophagy enhances proinflammatory gene expression both in adipocytes and adipose tissue explants. Autophagy may function to dampen inflammatory gene expression and thereby limit excessive inflammation in adipose tissue during obesity.

Item does not contain fulltext Obesity-induced inflammation is an important contributor to the induction of insulin resistance. Recently, the cytokine interleukin-1beta (IL-1beta) has emerged as a prominent instigator of the proinflammatory response in obesity. Several studies over the last year have subsequently deciphered the molecular mechanisms responsible for IL-1beta activation in adipose tissue, liver, and macrophages and demonstrated a central role of the processing enzyme caspase-1 and of the protein complex leading to its activation called the inflammasome. These data suggest that activation of the inflammasome represents a crucial step in the road from obesity to insulin resistance and type 2 diabetes.

Background Invasive techniques are still required to distinguish between uncomplicated and complicated forms of CD. Methods We set out to investigate the potential use of novel serum parameters, including IL-6, IL-8, IL-17, IL-22, sCD25, sCD27, granzyme-B, sMICA and sCTLA-4 in patients diagnosed with active CD, CD on a GFD, Refractory coeliac disease (RCD) type I and II, and enteropathy associated T-cell lymphoma (EATL). Results In both active CD and RCDI-II elevated levels of the proinflammatory IL-8, IL-17 and sCD25 were observed. In addition, RCDII patients displayed higher serum levels of soluble granzyme-B and IL-6 in comparison to active CD patients. In contrast, no differences between RCDI and active CD or RCDII were observed. Furthermore, EATL patients displayed higher levels of IL-6 as compared to all other groups. Conclusions A series of novel serum parameters reveal distinctive immunological characteristics of RCDII and EATL in comparison to uncomplicated CD and RCDI.

The objective of this study was to investigate the relationship between plasma and brain glucose levels during euglycemia and hypoglycemia in healthy subjects and patients with type 1 diabetes mellitus (T1DM). Hyperinsulinemic euglycemic (5 mmol/L) and hypoglycemic (3 mmol/L) [1-13C]glucose clamps were performed in eight healthy subjects and nine patients with uncomplicated T1DM (HbA1c 7.7 ± 1.4%). Brain glucose levels were measured by 13C magnetic resonance spectroscopy. Linear regression analysis was used to fit the relationship between plasma and brain glucose levels and calculate reversible Michaelis-Menten (MM) kinetic parameters. Brain glucose values during euglycemia (1.1 ± 0.4 μmol/g vs. 1.1 ± 0.3 μmol/g; P = 0.95) and hypoglycemia (0.5 ± 0.2 μmol/g vs. 0.6 ± 0.3 μmol/g; P = 0.52) were comparable between healthy subjects and T1DM patients. MM kinetic parameters of combined data were calculated to be maximum transport rate/cerebral metabolic rate of glucose (Tmax/CMRglc) = 2.25 ± 0.32 and substrate concentration at half maximal transport (Kt) = 1.53 ± 0.88 mmol/L, which is in line with previously published data obtained under hyperglycemic conditions. In conclusion, the linear MM relationship between plasma and brain glucose can be extended to low plasma glucose levels. We found no evidence that the plasma to brain glucose relationship or the kinetics describing glucose transport over the blood–brain barrier differ between healthy subjects and patients with uncomplicated, reasonably well-controlled T1DM.

Nunes PM, van de Weijer T, Veltien A, Arnts H, Hesselink MK, Glatz JF, Schrauwen P, Tack CJ, Heerschap A. Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice. Am J Physiol Endocrinol Metab 303: E71-E81, 2012. First published April 10, 2012; doi: 10.1152/ajpendo.00597.2011.-Adipose triglyceride lipase (ATGL) is a lipolytic enzyme that is highly specific for triglyceride hydrolysis. The ATGL-knockout mouse (ATGL(-/-)) accumulates lipid droplets in various tissues, including skeletal muscle, and has poor maximal running velocity and endurance capacity. In this study, we tested whether abnormal lipid accumulation in skeletal muscle impairs mitochondrial oxidative phosphorylation, and hence, explains the poor muscle performance of ATGL(-/-) mice. In vivo H-1 magnetic resonance spectroscopy of the tibialis anterior of ATGL(-/-) mice revealed that its intramyocellular lipid pool is approximately sixfold higher than in WT controls (P = 0.0007). In skeletal muscle of ATGL(-/-) mice, glycogen content was decreased by 30% (P

ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects (6 active and 2 placebo) who received 15 mg/kg for 5 days. Safety was assessed from adverse event (AE) reporting, standard clinical laboratory procedures, and testing for renal, cochlear, and vestibular function. ACHN-490 exhibited linear and dose-proportional PK, with agreement between the studies for PK parameters assessed. The 15-mg/kg dose did not accumulate with repeated dosing over 5 days. Mean steady-state (±standard deviation) area under the concentration-time curve from 0 to 24 h (AUC 0-24 ), maximum concentration of drug in serum ( C max ), half-life ( t 1/2 ), clearance, and volume of distribution at steady state ( V ss ) for the 15-mg/kg, day 5 dose were 239 ± 45 h·mg/liter, 113 ± 17 mg/liter, 3 ± 0.3 h, 1.1 ± 0.1 ml/min/kg, and 0.24 ± 0.04 liters/kg, respectively. AEs were mild to moderate and rapidly resolved. No evidence of nephrotoxicity or ototoxicity was observed.

The aim was to compare gastric emptying rate and nutrient tolerance during a satiety drinking test in children with functional dyspepsia (FD) and obesity and to study the relationship between daily caloric intake and the satiety drinking test.A total of 28 dyspeptic children (22 girls, mean age 12.5 ± 3.1 years) and 15 obese children (five girls, 13.3 ± 1.8 years) were studied. The patients underwent an octanoic acid gastric emptying breath test and a satiety drinking test. Prior to both tests, a dyspepsia questionnaire was filled out to calculate the mean calorie intake.The most prevalent dyspeptic symptoms were early satiety (96.4%), postprandial fullness (89.2%), and epigastric pain (78.6%), followed by nausea (50%). All dyspeptic and obese children (n = 43) started the satiety drinking test and 41 children completed the test until a score of 5 was reached. The maximum ingested volume in FD was significantly lower than in obesity or in age-matched healthy controls (252 ± 85 vs 479 ± 199 and 359 ± 29 mL respectively, both P0.05). As a group, dyspeptic children had significantly slower gastric emptying than obese children (89.7 ± 54.8 min vs 72.5 ± 26.0 min, P = 0.05). Daily calorie intake was significantly higher in obese children than that in dyspeptic children (2325 ± 469 vs 1503 ± 272 cal, P0.0001). The endpoint of the satiety drinking test was significantly correlated with body weight or BMI (both R = 0.41, P = 0.04), but not with daily calorie intake, gastric emptying rate or age.The satiety drinking test is a potentially useful non-invasive tool in the investigation of children with FD and obesity.

There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P0.05) and duration (6.1 vs. 4.2 seconds, P0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.

The increased central sympathetic activity typically associated with chronic heart failure (CHF) is probably mediated by formation of reactive oxygen species (ROS) in the brain. Our objective was to undertake a trial to test our hypothesis that administration of the well-known antioxidant and ROS scavenger ascorbic acid, would reverse or reduce the sympathetic overactivity in CHF patients.In a prospective, randomized, placebo-controlled, double-blind, cross-over trial, 11 CHF patients were treated with ascorbic acid 2 g/day or placebo for 3 days. At the end of each treatment period, sympathetic nervous system activity was measured by microneurography for direct muscle sympathetic nerve activity (MSNA) recording, analysis of heart rate variability (HRV) and measurement of plasma norepinephrine concentrations.During ascorbic acid administration, plasma vitamin C levels were higher than during placebo (74·9 ± 6·0 μmol/L vs. 54·8 ± 4·6 μmol/L, P = 0·03). Ascorbic acid had no effect on sympathetic activity: MSNA (ascorbic acid: 66·8 ± 3·3 vs. placebo 66·9 ± 3·2 bursts/100 beats, P = 0·98). In addition, HRV and plasma norepinephrine levels did not differ. Short-term administration of the antioxidant ascorbic acid in CHF patients does not reverse the increased sympathetic activity as measured by microneurography, HRV and plasma norepinephrine levels. The use of higher oral dosages seems not feasible due to accompanying side effects.

Increased body weight is associated with higher intragastric pressure. Proximal extent of reflux is a determinant of symptoms in patients with gastro-esophageal reflux disease (GERD). We aimed to investigate the association between body mass index (BMI) and abdominal circumference on the incidence and proximal extent of reflux.A total of 95 patients [37 men, age 51(16-82) years] with typical and/or atypical GERD symptoms underwent 24 h impedance-pH monitoring. Forty-nine patients were studied 'off' and 46 'on' proton pump inhibitors (PPI) treatment. Reflux was classified as acid (pH 4) or weakly acidic (pH 4-7). Proximal extent was defined as the number of reflux events reaching ≥15 cm above the lower esophageal sphincter. Body mass index and abdominal circumference (cm) were assessed.In patients 'off' PPI, there was a correlation between BMI and esophageal acid exposure (ρ = 0.53, P 0.001), volume exposure (ρ = 0.48, P 0.001), total number of reflux events (ρ = 0.47, P 0.001) and number of acid reflux events (ρ = 0.49, P 0.001). In patients 'on' PPI there was a correlation between BMI and esophageal acid exposure (ρ = 0.32, P = 0.03), volume exposure (ρ = 0.46, P 0.01) and total number of reflux events (ρ = 0.33, P = 0.03). Similar correlations were found between abdominal circumference and reflux. A correlation between BMI and proximal extent of reflux was present in patients 'off' PPI (ρ = 0.32, P = 0.03). In patients 'on' PPI, we found a correlation between abdominal circumference and proximal extent (ρ = 0.31, P = 0.03).Body mass index and abdominal circumference may contribute to GER and its proximal extent, in patients 'on and 'off' PPI. Further studies investigating the role of weight reduction in the control of GERD symptoms are warranted.

In refractory celiac disease (RCD), intestinal epithelial damage persists despite a gluten-free diet. Characteristic for RCD type II (RCD II) is the presence of aberrant surface TCR-CD3− intraepithelial lymphocytes (IELs) that can progressively replace normal IELs and eventually give rise to overt lymphoma. Therefore, RCD II is considered a malignant condition that forms an intermediate stage between celiac disease (CD) and overt lymphoma. We demonstrate in this study that surface TCR-CD3− IEL lines isolated from three RCD II patients preferentially lyse epithelial cell lines. FACS analysis revealed that DNAM-1 was strongly expressed on the three RCD cell lines, whereas other activating NK cell receptors were not expressed on all three RCD cell lines. Consistent with this finding, cytotoxicity of the RCD cell lines was mediated mainly by DNAM-1 with only a minor role for other activating NK cell receptors. Furthermore, enterocytes isolated from duodenal biopsies expressed DNAM-1 ligands and were lysed by the RCD cell lines ex vivo. Although DNAM-1 on CD8+ T cells and NK cells is known to mediate lysis of tumor cells, this study provides, to our knowledge, the first evidence that (pre)malignant cells themselves can acquire the ability to lyse epithelial cells via DNAM-1. This study confirms previous work on epithelial lysis by RCD cell lines and identifies a novel mechanism that potentially contributes to the gluten-independent tissue damage in RCD II and RCD-associated lymphoma.

Previous studies have established the presence of a postprandial acid pocket at the gastro-oesophageal junction.To investigate whether altering gastric motility would affect the location and the extent of postprandial acid pockets in healthy volunteers and also to study the presence of bile in this pocket.A total of 16 healthy volunteers underwent pH and Bilitec probe stepwise pull-through to measure regional differences in pH and bile absorbance before and 10, 30 and 50 min after a liquid meal. At the start of the meal, saline, erythromycin or sumatriptan was administered.After saline, ingestion of a meal induced an acid pocket, with a mean pH drop of 2.26 (compared to 0.25 before the meal, P0.05) and a nadir pH of 2.71. The acid pocket persisted 30 and 50 min postprandially (pH drops 1.59 and 1.68 and nadir pH 3.17 and 2.52 respectively). Compared with saline, erythromycin significantly suppressed the pH drop and nadir pH (on average 0.66 and 3.4 at 10 min; comparable patterns at 30 and 50 min). After sumatriptan a significantly lower nadir pH was observed at 30 and 50 min (respectively 2.02 and 1.74, P0.05 compared with saline). A postprandial bile pocket was noted in 50% of pull-throughs after saline, compared to 78% after erythromycin and 31% after sumatriptan.The presence of a bile pocket in a subset of the subjects confirms the heterogeneity of postprandial intragastric contents. Erythromycin disrupts the acid pocket but increases the presence of bile, while sumatriptan has opposite effects.