Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis.

BACKGROUND: Psoriasis is a chronic, recurrent skin disease that affects approximately 2-3% of the world's population, and can significantly impair patients' wellbeing and their physical and mental functioning. AIM: To systematically evaluate the efficacy and safety of ustekinumab versus placebo for psoriasis. METHODS: We performed a systematic review of all the relevant published literature relating to randomized controlled trials (RCTs) of ustekinumab from 1990 to August 2013. Relative ratios (RRs) and 95% confidence intervals (CIs) were calculated, and meta-analysis was conducted with Revman5.2.6 software, while GRADE Profile 3.6 was used to evaluate the quality of the evidence. RESULTS: In total, 9 RCTs involving 11 381 patients were included. The meta-analysis results were as follows. (i) At the end of 12 weeks, the ustekinumab group had a larger number of patients with improvement in Psoriasis Area and Severity Index (PASI) of at least 50% (PASI50), at least 75% (PASI75) and at least 90% (PASI90); a larger number with improvement in Physician's Global Assessment (PGA), and a larger number with improvement in Dermatology Life Quality Index (DLQI) to a score of 0 or 1 (no effect at all on patient's life). (ii) There was no significant difference in efficacy between 45 mg and 90 mg ustekinumab at the end of 12 weeks. (iii) There was no obvious difference between the ustekinumab and placebo groups in the incidence of adverse events over 5 years. There was also no obvious difference between the two doses of ustekinumab after 5 years. CONCLUSION: Our results indicate that ustekinumab is safe for patients with moderate to severe plaque psoriasis over a period of 5 years, and it is effective after 12 weeks. There was no significant superiority in efficacy between the 45 mg and 90 mg doses for short-term therapy. Results of the long-term safety evaluation are consistent with short-term reports of ustekinumab safety. More long-term studies and RCTs are needed to validate these results.

The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells.

AIMS/HYPOTHESIS: We have previously found that the mass of perivascular adipose tissue (PVAT) correlates negatively with insulin sensitivity and post-ischaemic increase in blood flow. To understand how PVAT communicates with vascular vessels, interactions between perivascular, subcutaneous and visceral fat cells with endothelial cells (ECs) were examined with regard to inflammatory, metabolic and angiogenic proteins. To test for possible in vivo relevance of these findings, circulating levels of the predominant secretion product, hepatocyte growth factor (HGF), was measured in individuals carefully phenotyped for fat distribution patterns. METHODS: Mono- and co-cultures of human primary fat cells with ECs were performed. mRNA expression and protein production were studied using Luminex, cytokine array, RealTime Ready and ELISA systems. Effects of HGF on vascular cells were determined by WST assays. In patients, HGF levels were measured by ELISA, and the mass of different fat compartments was determined by whole-body MRI. RESULTS: In contrast with other fat cell types, PVAT cells released higher amounts of angiogenic factors, e.g. HGF, acidic fibroblast growth factor, thrombospondin-1, serpin-E1, monocyte chemotactic protein-1 and insulin-like growth factor-binding protein -3. Cocultures showed different expression profiles from monocultures, and mature adipocytes differed from pre-adipocytes. HGF was preferentially released by PVAT cells and stimulated EC growth and smooth muscle cell cytokine release. Finally, in 95 patients, only PVAT, not visceral or subcutaneous mass, correlated independently with serum HGF levels (p = 0.03; r = 0.225). CONCLUSIONS: Perivascular (pre-)adipocytes differ substantially from other fat cells with regard to mRNA expression and protein production of angiogenic factors. This may contribute to fat tissue growth and atherosclerotic plaque complications. Higher levels of angiogenic factors, such as HGF, in patients with increased perivascular fat mass may have pathological relevance.

Effects of neurotrophin 3 on gastric and colonic motility in awake rats.

Neurotrophin 3 (NT3) and its receptors are expressed throughout the gastrointestinal tract, especially in the enteric nervous system. However, little is known about the effects of NT3 on gastrointestinal motility. To investigate the effects of NT3 on gastric or colonic motility under baseline conditions, after subdiaphragmatic vagotomy and in a model of postoperative ileus. Sprague-Dawley rats were equipped with strain gauge transducers on the gastric or colonic wall. Motility was recorded for 30 min, followed by i.v. administration of NT3 and motility-recording for another 60 min. Experiments were performed on three consecutive days and separately in a postoperative ileus model. To evaluate a vagal pathway, experiments were also performed on vagotomized rats. NT3 inhibited gastric motility. This inhibitory effect was reduced by subdiaphragmatic vagotomy. Preoperative treatment with NT3 prolonged the postoperative gastric ileus compared to vehicle treatment. Colonic motility in the intact animal was unchanged by NT3, but was increased postoperatively. NT3 treatment inhibited gastric but not colonic motility. This inhibition of gastric motility seems to be partly mediated by the vagus nerve. NT3 aggravates gastric postoperative ileus but attenuates colonic postoperative ileus, which corresponds to the observed positive effects of NT3 on constipated patients.

Risk of fecal diversion in complicated perianal Crohn's disease.

The purpose of the study was to determine the overall risk of a permanent stoma in patients with complicated perianal Crohn's disease, and to identify risk factors predicting stoma carriage. A total of 102 consecutive patients presented with the first manifestation of complicated perianal Crohn's disease in our outpatient department between 1992 and 1995. Ninety-seven patients (95%) could be followed up at a median of 16 years after first diagnosis of Crohn's disease. Patients were sent a standardized questionnaire and patient charts were reviewed with respect to the recurrence of perianal abscesses or fistulas and surgical treatment, including fecal diversion. Factors predictive of permanent stoma carriage were determined by univariate and multivariate analysis. Thirty of 97 patients (31%) with complicated perianal Crohn's disease eventually required a permanent stoma. The median time from first diagnosis of Crohn's disease to permanent fecal diversion was 8.5 years (range 0-23 years). Temporary fecal diversion became necessary in 51 of 97 patients (53%), but could be successfully removed in 24 of 51 patients (47%). Increased rates of permanent fecal diversion were observed in 54% of patients with complex perianal fistulas and in 54% of patients with rectovaginal fistulas, as well as in patients that had undergone subtotal colon resection (60%), left-sided colon resection (83%), or rectal resection (92%). An increased risk for permanent stoma carriage was identified by multivariate analysis for complex perianal fistulas (odds ratio [OR] 5; 95% confidence interval [CI] 2-18), temporary fecal diversion (OR 8; 95% CI 2-35), fecal incontinence (OR 21, 95% CI 3-165), or rectal resection (OR 30; 95% CI 3-179). Local drainage, setons, and temporary stoma for deep and complicated fistulas in Crohn's disease, followed by a rectal advancement flap, may result in closing of the stoma in 47% of the time. The risk of permanent fecal diversion was substantial in patients with complicated perianal Crohn's disease, with patients requiring a colorectal resection or suffering from fecal incontinence carrying a particularly high risk for permanent fecal diversion. In contrast, patients with perianal Crohn's disease who required surgery for small bowel disease or a segmental colon resection carried no risk of a permanent stoma.

Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity.

BACKGROUND: Gastrointestinal hormone release and the regulation of appetite and body weight are thought to be dysbalanced in obesity. However, human data investigating the expression of gastrointestinal hormones in the obese are rare. We studied the expression of ghrelin, leptin, and the serotonergic system in stomach tissue and serum of obese and non-obese individuals. METHODS: Gastric tissue and serum were collected from 29 adult obese (BMI 48.7 ± 10.6 kg/m(2) ; mean ± SD) who underwent laparoscopic sleeve gastrectomy. Gastric biopsies, surgery specimen or serum was obtained from 35 adult non-obese humans (BMI 22.7 ± 1.9 kg/m(2) ). Ghrelin, ghrelin O-acyl transferase (GOAT), leptin, leptin receptor, and tryptophan hydroxylase 1 (TPH1) mRNA expression were measured by qRT-PCR. Serotonin (5HT) and leptin protein concentration were quantified in tissue extracts and serum; GOAT and ghrelin-positive cells were immunohistologically quantified in tissue. Additionally, 21 blood immune markers were analyzed. KEY RESULTS: In gastric tissue, GOAT-positive cells were reduced (p < 0.01), but ghrelin-positive cells and mRNA were increased (both p < 0.05) in obese compared with non-obese individuals. Gastric leptin (p < 0.001) and leptin receptor (p < 0.001) mRNA expression, as well as leptin concentrations in serum (p < 0.001), were increased in obese compared with non-obese individuals. Serum 5HT was reduced (p < 0.05), while tissue 5HT and TPH1 mRNA were reduced only by trend. Interleukin 1 receptor a (IL1Ra), IL-8, IL-12, and monocyte chemoattractant protein 1 (IL1Ra) were increased and IL1Ra correlated negatively with serum leptin. CONCLUSIONS & INFERENCES: Our data indicate that obesity causes a dysregulation of gastrointestinal hormones at the tissue level and serum, including a negative correlation with an increased marker of subclinical inflammation.

Preoperative intraluminal application of capsaicin increases postoperative gastric and colonic motility in rats.

In a model to investigate postoperative gastrointestinal motility with strain gauge transducers in awake rats, we tested the effects of intraluminal capsaicin infusion into the cecum 2 days or 14 days prior to abdominal surgery. Acute infusion of capsaicin into the cecum for 30 minutes increased the gastric, small intestinal, and colonic motility index by up to 115%, 34%, and 59%, respectively, compared to vehicle infusion. Intraluminal capsaicin infusion 2 days prior to abdominal surgery significantly increased the intraoperative gastric and colonic motility index by 166% and 100%, respectively, compared to vehicle, but had no effect on small intestinal motility. The postoperative decrease in gastric or colonic motility was completely prevented by capsaicin pretreatment, representing a 73% and a 72% increase in the motility index during the first postoperative hour and a 40% and a 29% increase in the motility index during the second postoperative hour compared to vehicle, whereas the postoperative decrease in small intestinal motility was not altered by capsaicin pretreatment. In contrast, intraluminal capsaicin infusion 14 days prior to abdominal surgery had no effect on postoperative inhibition of gastrointestinal motility. Our results suggest that capsaicin-sensitive visceral afferent C-fibers, presumably of the submucosa, play an important role in mediating postoperative ileus. Intraluminal capsaicin does probably ablate these nerve fibers temporarily, with no systemic side effects observed with the use of the tail flick test as a measure of skin nociception.

Nitric oxide synthase inhibition results in immediate postoperative recovery of gastric, small intestinal and colonic motility in awake rats.

BACKGROUND: Nitric oxide (NO) is known to inhibit gastrointestinal motility. However, no detailed analysis of gastric, small intestinal and colonic motor effects, including effects on contraction frequency, has, as yet, been reported after NO inhibition in awake rats. We therefore investigated the effects of NO synthase inhibition on gastric, small intestinal and colonic motility in awake rats under baseline conditions and in a postoperative ileus model. METHODS: In Sprague-Dawley rats, strain gauge transducers were sutured either to the gastric corpus, the small intestine or the colon. After 3 days, L-NMMA (NO synthase inhibitor), D-NMMA or vehicle was given i.v., while the motility was recorded continuously. In addition, postoperative gastric, small intestinal or colonic motility was investigated after L-NMMA or vehicle treatment prior to abdominal surgery. The motility index, the contraction amplitude, the area under the contraction amplitude and the contraction frequency were analysed. RESULTS: L-NMMA decreased gastric motility to 60+/-8% for about 15 min, but continuously increased small intestinal motility to 221+/-22% and colonic motility to 125+/-7% compared to baseline (baseline=100%; p<0.01 for all comparisons). L-NMMA increased the contraction frequency throughout the gastrointestinal tract (stomach, 13+/-2%; small intestine, 8+/-1%; colon, 16+/-5%; p<0.01 vs. baseline for all comparisons). L-NMMA injection prior to surgery did not prohibit intraoperative inhibition of gastrointestinal motility, but did result in immediate recovery of gastric, small intestinal and colonic motility postoperatively (L-NMMA vs. vehicle, 0-60 min postoperatively; stomach, 90+/-9% vs. 53+/-3%; small intestine, 101+/-5% vs. 57+/-3%; colon, 134+/-6% vs. 60+/-5%; p<0.01 for all comparisons; no significant difference between preoperative baseline motility and L-NMMA treated rats postoperatively). CONCLUSIONS: Under baseline conditions, endogenous NO inhibits small intestinal and colonic motility and gastric, small intestinal and colonic contraction frequency in awake rats. In the early postoperative period, endogenous NO is a major inhibitory component that seems to constitute the common final pathway of mediators and the neural pathways inhibiting gastrointestinal motility in rats.

Prevalence of vertebral alterations and the effects of calcium and vitamin D supplementation on calcium metabolism and bone mineral density after gastrectomy.

BACKGROUND: Bone disease is common after gastrectomy, resulting in decreased bone mass and an increased risk of fracture. No proven therapy is currently available. METHODS: Serum markers of calcium metabolism in 98 patients after partial or total gastrectomy were compared with those in 30 age- and sex-matched healthy controls. Patients with disorders of calcium metabolism were investigated by conventional radiography and single-energy computed tomography of the spine. Forty patients participated in a 1-year follow-up study to investigate the effects of vitamin D and calcium supplementation on calcium metabolism and bone mineral density. RESULTS: Altered serum markers of calcium and phosphate metabolism were observed in 77 (79 per cent) of 98 patients. Sixty (79 per cent) of these had vertebral alterations. Vertebral fractures were detected in 22 patients, grade I vertebral deformities in 50 patients, grade II deformities in 22 patients and osteopenia (Z-score less than - 1) in 30 patients. Calcium and vitamin D supplementation resulted in an increase in 25-hydroxy-vitamin D (P < 0.001), 1,25-dihydroxy-vitamin D (P = 0.048) and osteocalcin (P = 0.045), whereas levels of parathyroid hormone were decreased (P = 0.007). Bone mineral density did not change over time. CONCLUSION: Disturbances of calcium and bone metabolism are common after gastrectomy. Calcium and vitamin D supplementation normalized levels of markers of calcium metabolism and might have prevented age-related bone mass loss, although it did not increase bone mineral density after 1 year.

Telemetric small intestinal motility recording in awake rats: a novel approach.

INTRODUCTION: Ideally, gastrointestinal motility recording should be done in freely moving, stress-free animals. However, no such method is currently available for rats. METHODS: Two NiCr electrodes were sutured to the jejunum and connected to an implantable electromyographic (EMG) transmitter in rats. EMG signals were radio-transmitted to a receiver placed at the bottom of the rats' home cages. RESULTS: Fasting and postprandial jejunal EMG signals could be detected by telemetry. Phase III contractions of the MMC were easy to identify visually and occurred at a rate of about 4.8 per hour. Feeding disrupted the phasic contraction pattern 15 min after the start of food intake and lasted for 2 h. The motility index (MI, area under the curve) was calculated and increased postprandially. CONCLUSION: Telemetric transmission of rat gastrointestinal EMG signals is feasible and results are comparable to those given in the literature.

Extrinsic neural innervation mediates absorption of water and electrolytes in canine proximal colon in vivo.

INTRODUCTION: Extrinsic innervation mediates a proabsorptive effect in small intestine. Our aim was to determine whether extrinsic neural input modulates similar effects in the proximal colon in vivo. METHODS: Ten adult dogs underwent enteric isolation of a 50-cm proximal colon loop; five each were randomized to undergo extrinsic denervation (Ext Den) of the isolated colonic segment or to serve as neurally innervated controls. After recovery, a 38 degrees C electrolyte solution (Na(+) 125 meq/L, K(+) 9 meq/L, Cl(-) 75 meq/L, HC03(-) 65 meq/L) was infused at 4 ml/min into the segment. Effluent was collected in 30-min intervals for 2 h after achieving steady state (determined by 14C nonabsorbable marker recovery); four studies were conducted at 1 and 12 weeks postoperatively. Net flux of H20, Na(+), K(+), and Cl(-) was determined. Colon morphometry was evaluated at 0 and 14 weeks. Data are presented as mean +/- SEM. Unpaired t test was applied for comparisons. RESULTS: Net absorptive flux of H20 (microL/min/cm) was decreased in Ext Den vs controls at 1 week (4.40 +/- 0.63 vs 7.92 +/- 0.92, P = 0.03) but was not different at 12 weeks (4.70 +/- 1.20 vs 5.97 +/- 0.69; P > 0.05). Na(+) and Cl(-) followed the trends in H20 absorption (P < or = 0.05). Crypt depth (microm) decreased in controls at 14 weeks vs 0 week (915 +/- 20 vs 740 +/- 07, P = 0.01) but remained unchanged in Ext Den. CONCLUSIONS: Loss of extrinsic neural input decreases colonic absorption. This observation suggests that extrinsic neural innervation provides net proabsorptive mechanisms for absorption of water and electrolytes in the proximal canine colon.

Intraperitoneal capsaicin treatment reduces postoperative gastric ileus in awake rats.

INTRODUCTION: Postoperative gastric ileus interferes with postoperative recovery of the patients. Previous studies suggest that capsaicin-sensitive afferent neurons are involved in the mediation of postoperative gastric ileus. METHODS: A group of rats were equipped with a strain gauge transducer sutured to the gastric wall. Gastric motility was recorded after intraperitoneal injection of capsaicin (0.1 micromol/kg and 1 micromol/kg) or vehicle. The rats were given 2 days of recovery before gastric motility was investigated in a postoperative ileus model. RESULTS: Pretreatment with capsaicin 2 days prior to abdominal surgery significantly increased postoperative gastric motility, with complete recovery of gastric motility at 30 min postoperatively (with the baseline motility index set at 100+/-4%, the gastric motility index 30-45 min postoperatively was 64+/-4% for the vehicle, 138+/-20% for capsaicin 0.1 micromol/kg, and 110+/-12% for capsaicin 1 micromol/kg: P=0.0008 vehicle vs capsaicin). In contrast, capsaicin treatment 2 h prior to abdominal surgery did not increase postoperative gastric motility (gastric motility index 30-45 min postoperatively was 64+/-4% for the vehicle and 51+/-8% for capsaicin 0.1 micromol/kg). The acute intraperitoneal injection of capsaicin decreased gastric motility by about 50-60%, the response lasting for 15-30 min. CONCLUSIONS: Intraperitoneal capsaicin treatment 2 days prior to abdominal surgery resulted in immediate recovery of postoperative gastric motility, indicating an important role for serosal visceral afferent nerve fibers in the mediation of postoperative gastric ileus. Possibly, capsaicin or vanilloid (capsaicin) receptor agonists can be used to treat postoperative ileus in the future.

Vagal innervation modulates motor pattern but not initiation of canine gastric migrating motor complex.

To determine the role of vagal nerves in initiation and modulation of the gastric migrating motor complex (MMC), motor activity was recorded in four dogs before and after total abdominal vagotomy during fasting, after exogenous intravenous motilin and insulin, and after feeding. After vagotomy, a temporally coordinated cyclic gastric and small bowel MMC persisted with an unchanged period. During gastric phase III, vagotomy decreased number of contractions (42 +/- 4 vs. 16 +/- 2), number of groupings of contractions (14 +/- 1 vs. 7 +/- 1), and motility index (12 +/- 1 vs. 10 +/- 1) and increased the duration between groupings (1 +/- 1 vs. 3 +/- 1 min) (P < 0.05 in each). Before and after vagotomy, motilin and insulin induced a premature MMC with minor changes in contractile pattern. A 200-g liver meal but not a 50-g liver meal inhibited the gastric MMC after vagotomy. A cyclic MMC persisted after vagotomy, but the contractile pattern during gastric phase III was altered. After a short recovery period, vagal innervation to the stomach modulates the pattern but not the presence of gastric interdigestive motility during phase III.