A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene.

Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the α2δ family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (α2δ3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, α2δ3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in α2δ3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in α2δ3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.

Sedation during endoscopic procedures: a Hellenic Society of Gastroenterology Position Statement.

Administration of sedation by non-anesthesiologists during gastrointestinal endoscopy remains highly controversial in Greece. The aim of this set of 16 position statements prepared by experts in the field on behalf of the Hellenic Society of Gastroenterology is to aid gastroenterologists in their everyday clinical practice and provide evidence for the best use of drugs for the sedation of patients who undergo an endoscopy. The statements address issues such as the level of sedation required, the best drugs used, their mode of action, their side-effects and possible ways to counter their action, and were adopted if at least 80% of all participants agreed upon them.

Capsule endoscopy in the investigation of patients with portal hypertension and anemia.

INTRODUCTION: Data on small bowel abnormalities in patients with portal hypertension (PHT) are limited. Bleeding from the gastrointestinal tract and anemia are common complications in these patients. Capsule endoscopy (CE) was used to evaluate small bowel (SB) pathology in patients with PHT and anemia, and possible associations with various parameters were examined. METHODS: Thirty-five patients with PHT referred for CE investigation of the SB for anemia were prospectively enrolled in the study, as well as 70 age- and sex-matched control patients with anemia, normal liver function and no evidence of PHT who underwent CE. RESULTS: Findings compatible with portal hypertensive enteropathy (PHE) were detected in 65.7% of the patients and in 15.7% of the controls chi2=26.641, P=0.000). Abnormalities in PHT patients included varices in 25.7%, diffuse changes of mucosa with inflammatory-like appearance in 42.9%, and angiodysplasias and/or spider angiomas in 22.9% of cases. The presence of PHE was significantly associated only with the presence of severe portal hypertensive gastropathy, while the presence of SB varices alone was significantly associated with the presence of severe portal hypertensive gastropathy, larger esophageal varices and the presence of colonic varices. CONCLUSIONS: Varices, diffuse changes of mucosa with inflammatory-like appearance, and angiodysplasias and/or spider angiomas are detected more often in patients with PHT than in controls, and probably constitute the endoscopic characteristics of PHE. CE of the SB added a significant number of likely important findings to those detected by conventional endoscopic techniques for the clinical management of patients with PHT and anemia.

Oral Ingestion of Collagen Hydrolysate Leads to the Transportation of Highly Concentrated Gly-Pro-Hyp and Its Hydrolyzed Form of Pro-Hyp into the Bloodstream and Skin.

Collagen hydrolysate is a well-known dietary supplement for the treatment of skin aging; however, its mode of action remains unknown. Previous studies have shown that the oral ingestion of collagen hydrolysate leads to elevated levels of collagen-derived peptides in the blood, but whether these peptides reach the skin remains unclear. Here, we analyzed the plasma concentration of collagen-derived peptides after ingestion of high tripeptide containing collagen hydrolysate in humans. We identified 17 types of collagen-derived peptides transiently, with a particular enrichment in Gly-Pro-Hyp. This was also observed using an in vivo mouse model in the plasma and skin, albeit with a higher enrichment of Pro-Hyp in the skin. Interestingly, this Pro-Hyp enrichment in the skin was derived from Gly-Pro-Hyp hydrolysis, as the administration of pure Gly-Pro-Hyp peptide led to similar results. Therefore, we propose that functional peptides can be transferred to the skin by dietary supplements of collagen.

Wireless capsule endoscopy in the investigation of patients with chronic renal failure and obscure gastrointestinal bleeding (preliminary data).

AIM: To investigate the role of wireless capsule endoscopy (WCE) in detection of small bowel (SB) pathology in patients with chronic renal failure (CRF) and obscure bleeding. METHODS: Consecutive CRF patients with obscure bleeding were prospectively studied. Patients with normal renal function and obscure bleeding, investigated during the same period with WCE, were used for the interpretation of results. RESULTS: Seventeen CRF patients (11 overt, 6 occult bleeding) and 51 patients (33 overt, 18 occult bleeding) with normal renal function were enrolled in this study. Positive SB findings were detected in 70.6% of CRF patients and in 41.2% of non-CRF patients (P < 0.05). SB angiodysplasia was identified in 47% of CRF patients and in 17.6% of non-CRF patients. Univariate logistic regression revealed CRF as a significant predictive factor for angiodysplasia (P < 0.05). Therapeutic measures were undertaken in 66% of the patients with the positive findings. CONCLUSION: According to our preliminary results, SB angiodysplasia was found in an increased prevalence among CRF patients with obscure bleeding. WCE is useful in diagnosis of gastrointestinal pathologies and in planning appropriate therapeutic intervention and, therefore, should be included in the work-up of this group of patients.

Endoscopic variceal ligation vs. propranolol for prevention of first variceal bleeding: a randomized controlled trial.

OBJECTIVES: Data in the literature regarding the role of endoscopic variceal ligation for the prevention of first variceal bleeding in cirrhotic patients are controversial. To further explore this issue we have compared ligation and propranolol treatment in a prospective randomized study. METHODS: Sixty patients with cirrhosis and oesophageal varices with no history but at high risk of bleeding were randomized to ligation treatment (30 patients) or propranolol (30 patients). Patients were followed for approximately 27.5 months. RESULTS: Variceal obliteration was achieved in 28 patients (93.3%) after 3+/-1 sessions. The mean daily dose of propranolol was 60.3+/-13.3 mg. Two patients (6.7%) in the ligation group and nine patients (30%) in the propranolol group developed variceal bleeding (P = 0.043). The actuarial risks of variceal bleeding at 2 years were 6.7% and 25%, respectively. On multivariate analysis, propranolol treatment and grade III varices turned out to be predictive factors for the risk of variceal bleeding. Mortality was not different between the two groups. There were no serious complications due to ligation. Propranolol treatment was discontinued in four patients because of side effects. CONCLUSIONS: Variceal ligation is a safe and more effective method than propranolol treatment for the prevention of first variceal bleeding in cirrhotic patients with high-risk varices.

The Par complex and integrins direct asymmetric cell division in adult intestinal stem cells.

The adult Drosophila midgut is maintained by intestinal stem cells (ISCs) that generate both self-renewing and differentiating daughter cells. How this asymmetry is generated is currently unclear. Here, we demonstrate that asymmetric ISC division is established by a unique combination of extracellular and intracellular polarity mechanisms. We show that Integrin-dependent adhesion to the basement membrane induces cell-intrinsic polarity and results in the asymmetric segregation of the Par proteins Par-3, Par-6, and aPKC into the apical daughter cell. Cell-specific knockdown and overexpression experiments suggest that increased activity of aPKC enhances Delta/Notch signaling in one of the two daughter cells to induce terminal differentiation. Perturbing this mechanism or altering the orientation of ISC division results in the formation of intestinal tumors. Our data indicate that mechanisms for intrinsically asymmetric cell division can be adapted to allow for the flexibility in lineage decisions that is required in adult stem cells.

Convergent solid-phase synthesis of hirudin.

Hirudin variant 1 (HV1), a small protein consisting of 65 amino acids and three disulfide bonds, was synthesized by using Fmoc-based convergent methods on 2-chlorotrityl resin (CLTR). The linear sequence was assembled by the sequential condensation of 7 protected fragments, on the resin-bound 55-65 fragment. The conditions of fragment assembly were carefully studied to determine the most efficient synthetic protocol. Crude reduced [Cys(16, 28)(Acm)]-HV1 thus obtained was easily purified to homogeneity by RP-HPLC. Disulfide bridges were successfully formed by a two-step procedure, involving an oxidative folding step to form Cys(6)-Cys(14) and Cys(22)-Cys(39) linkages, followed by iodine oxidation to form the Cys(16)-Cys(28) bond. The correct disulfide bond alignment was established by peptide mapping using Staphylococcus aureus V8 protease at pH 4.5.

Safety of extension of a previous endoscopic sphincterotomy: a prospective study.

OBJECTIVES: Data in the literature regarding complication risks after the extension of a previous endoscopic biliary sphincterotomy (repeat endoscopic biliary sphincterotomy) are limited and controversial. To explore this issue, we prospectively studied complications after repeat sphincterotomy and compared them with those of biliary endoscopic sphincterotomy in consecutive patients with choledocholithiasis. METHODS: A total of 250 patients underwent endoscopic biliary sphincterotomy and 81 underwent extension of a previous one. All patients had choledocholithiasis and were enrolled using specific criteria, excluding parameters predisposing to increased postsphincterotomy complications. RESULTS: The overall complication rate was 2.46% in the repeat sphincterotomy and 8.4% in the sphincterotomy group (p > 0.05). Complications for the repeat sphincterotomy and initial sphincterotomy groups, respectively, were as follows: bleeding, 2.46% and 2.8%; pancreatitis, 0% and 4.8% (p < 0.05); cholangitis, 0% and 0.4%; perforation, 0% and 0.4%; and hyperamylasemia, 3.7% and 12.8% (p < 0.05). There were no deaths. Bleeding episodes in the former group occurred when repeat sphincterotomy was performed early after the primary one. CONCLUSIONS: Repeat sphincterotomy is a safe technique for the treatment of patients with choledocholithiasis and seems to be as safe as initial sphincterotomy. It is not associated with increased hemorrhage risk. There is a trend toward a higher risk of hemorrhage when repeat sphincterotomy is performed early. Repeat sphincterotomy is safer than the initial sphincterotomy with respect to pancreatic complications.