Treatment of eosinophilic esophagitis by dilation.

Treatment options for eosinophilic esophagitis (EoE) include drugs, diets and esophageal dilation. Esophageal dilation can be performed using either through-the-scope balloons or wire-guided bougies. Dilation can lead to long-lasting symptom improvement in EoE patients presenting with esophageal strictures. Esophageal strictures are most often diagnosed when the 8- to 9-mm outer diameter adult gastroscope cannot be passed any further or only against resistance. A defined esophageal diameter to be targeted by dilation is missing, but the majority of patients have considerable symptomatic improvement when a diameter of 16-18 mm has been reached. A high complication rate, especially regarding esophageal perforations, has been reported in small case series until 2006. Several large series were published in 2007 and later that demonstrated that the complication risk (especially esophageal perforation) was much lower than what was reported in earlier series. The procedure can therefore be regarded as safe when some simple precautions are followed. It is noteworthy that esophageal dilation does not influence the underlying eosinophil-predominant inflammation. Patients should be informed before the procedure that postprocedural retrosternal pain may occur for some days, but that it usually responds well to over-the-counter analgesics such as paracetamol. Dilation-related superficial lacerations of the mucosa should not be regarded and reported as complications, but instead represent a desired effect of the therapy. Patient tolerance and acceptance for esophageal dilation have been reported to be good.

The Macklin effect: a frequent etiology for pneumomediastinum in severe blunt chest trauma.

STUDY OBJECTIVES: To review the etiology and pathophysiology of pneumomediastinum in severe blunt trauma, with a special interest in one of its possible origins, the Macklin effect. The Macklin effect relates to a three-step pathophysiologic process: blunt traumatic alveolar ruptures, air dissection along bronchovascular sheaths, and spreading of this blunt pulmonary interstitial emphysema into the mediastinum. The clinical relevance of the Macklin effect was also evaluated. SETTING: A university hospital serving as a reference trauma center. PATIENTS: A selection of 51 patients with severe blunt trauma between 1995 and 2000. Inclusion criteria: Severe trauma or high-speed deceleration justifying chest CT; if chest CT demonstrated a pneumomediastinum, bronchoscopy and esophagoscopy were performed to rule out tracheobronchial or esophageal injury. DESIGN: Retrospective analysis of patients' clinical files, chest CT, and bronchoscopy and esophagoscopy reports. The Macklin effect was diagnosed when an air collection adjacent to a bronchus and a pulmonary vessel could be clearly identified on the chest CT. Clinical relevance of the Macklin effect was statistically evaluated regarding its repercussions on the pulmonary gas exchange function, the respective durations of intensive care and total hospital stay, and the associated injuries. RESULTS: Twenty (39%) Macklin effects and 5 tracheobronchial injuries (10%) were identified. One tracheobronchial injury occurred simultaneously with the Macklin effect. The presence of the Macklin effect affected neither the clinical profile nor the result of pulmonary gas analysis on hospital admission, but was associated with a significant (p < 0.001) lengthening of the intensive care stay. CONCLUSIONS: The Macklin effect is present in 39% of severe blunt traumatic pneumomediastinum detected by CT. Its identification does not rule out a tracheobronchial injury. The Macklin effect reflects severe trauma, since it is associated with significantly prolonged intensive care stay.

Citrus fruit and cancer risk in a network of case-control studies.

BACKGROUND: Citrus fruit has shown a favorable effect against various cancers. To better understand their role in cancer risk, we analyzed data from a series of case-control studies conducted in Italy and Switzerland. PATIENTS AND METHODS: The studies included 955 patients with oral and pharyngeal cancer, 395 with esophageal, 999 with stomach, 3,634 with large bowel, 527 with laryngeal, 2,900 with breast, 454 with endometrial, 1,031 with ovarian, 1,294 with prostate, and 767 with renal cell cancer. All cancers were incident and histologically confirmed. Controls were admitted to the same network of hospitals for acute, nonneoplastic conditions. Odds ratios (OR) were estimated by multiple logistic regression models, including terms for major identified confounding factors for each cancer site, and energy intake. RESULTS: The ORs for the highest versus lowest category of citrus fruit consumption were 0.47 (95% confidence interval, CI, 0.36-0.61) for oral and pharyngeal, 0.42 (95% CI, 0.25-0.70) for esophageal, 0.69 (95% CI, 0.52-0.92) for stomach, 0.82 (95% CI, 0.72-0.93) for colorectal, and 0.55 (95% CI, 0.37-0.83) for laryngeal cancer. No consistent association was found with breast, endometrial, ovarian, prostate, and renal cell cancer. CONCLUSIONS: Our findings indicate that citrus fruit has a protective role against cancers of the digestive and upper respiratory tract.

Electrical colonic stimulation reduces mean transit time in a porcine model.

Abstract Electrical stimulation is a new way to treat digestive disorders such as constipation. Colonic propulsive activity can be triggered by battery operated devices. This study aimed to demonstrate the effect of direct electrical colonic stimulation on mean transit time in a chronic porcine model. The impact of stimulation and implanted material on the colonic wall was also assessed. Three pairs of electrodes were implanted into the caecal wall of 12 anaesthetized pigs. Reference colonic transit time was determined by radiopaque markers for each pig before implantation. It was repeated 4 weeks after implantation with sham stimulation and 5 weeks after implantation with electrical stimulation. Aboral sequential trains of 1-ms pulse width (10 V; 120 Hz) were applied twice daily for 6 days, using an external battery operated stimulator. For each course of markers, a mean value was computed from transit times obtained from individual pig. Microscopic examination of the caecum was routinely performed after animal sacrifice. A reduction of mean transit time was observed after electrical stimulation (19 +/- 13 h; mean +/- SD) when compared to reference (34 +/- 7 h; P = 0.045) and mean transit time after sham stimulation (36 +/- 9 h; P = 0.035). Histological examination revealed minimal chronic inflammation around the electrodes. Colonic transit time measured in a chronic porcine model is reduced by direct sequential electrical stimulation. Minimal tissue lesion is elicited by stimulation or implanted material. Electrical colonic stimulation could be a promising approach to treat specific disorders of the large bowel.

Einfluss von L-Carnitin-supplementierter total parenteraler Ernährung (TPE) auf die postoperative Fett- und Stickstoff-Utilisation [Effect of L-carnitine supplemented total parenteral nutrition on postoperative lipid and nitrogen utilization].

During episodes of trauma carnitine-free total parenteral nutrition (TPN) may result in a reduction of the total body carnitine pool, leading to a diminished rate of fat oxidation. Sixteen patients undergoing esophagectomy were equally and randomly divided and received isonitrogenous (0.2 gN/kg.day) and isocaloric (35 kcal/kg.day TPN over 11 days without and with L-carnitine supplementation (12 mg/kg.day). Compared with healthy controls, the total body carnitine pool was significantly reduced in both groups prior to the operation. Without supplementation carnitine concentrations were maintained, while daily provision of carnitine resulted in an elevation of total carnitine mainly due to an increase of the free fraction. Without supplementation the cumulative urinary carnitine losses were 11.5 +/- 6.3 mmol corresponding to 15.5% +/- 8.5% of the estimated total body carnitine pool. Patients receiving carnitine revealed a positive carnitine balance in the immediate postoperative phase, 11.1% +/- 19.0% of the infused carnitine being retained. After 11 days of treatment comparable values for respiratory quotient, plasma triglycerides, free fatty acids, ketone bodies, and cumulative nitrogen balance were observed. It is concluded that in the patient population studied here carnitine supplementation during postoperative TPN did not improve fat oxidation or nitrogen balance.

Exposure to solute stress affects genome-wide expression but not the polycyclic aromatic hydrocarbon-degrading activity of Sphingomonas sp. strain LH128 in biofilms.

Members of the genus Sphingomonas are important catalysts for removal of polycyclic aromatic hydrocarbons (PAHs) in soil, but their activity can be affected by various stress factors. This study examines the physiological and genome-wide transcription response of the phenanthrene-degrading Sphingomonas sp. strain LH128 in biofilms to solute stress (invoked by 450 mM NaCl solution), either as an acute (4-h) or a chronic (3-day) exposure. The degree of membrane fatty acid saturation was increased as a response to chronic stress. Oxygen consumption in the biofilms and phenanthrene mineralization activities of biofilm cells were, however, not significantly affected after imposing either acute or chronic stress. This finding was in agreement with the transcriptomic data, since genes involved in PAH degradation were not differentially expressed in stressed conditions compared to nonstressed conditions. The transcriptomic data suggest that LH128 adapts to NaCl stress by (i) increasing the expression of genes coping with osmolytic and ionic stress such as biosynthesis of compatible solutes and regulation of ion homeostasis, (ii) increasing the expression of genes involved in general stress response, (iii) changing the expression of general and specific regulatory functions, and (iv) decreasing the expression of protein synthesis such as proteins involved in motility. Differences in gene expression between cells under acute and chronic stress suggest that LH128 goes through changes in genome-wide expression to fully adapt to NaCl stress, without significantly changing phenanthrene degrading activity.

Eosinophile Ösophagitis : Die Sicht des Gastroenterologen [Eosinophilic esophagitis : The gastroenterologist's perspective].

Eosinophilic esophagitis is characterized by symptoms of esophageal dysfunction and eosinophil-predominant esophageal inflammation. Eosinophilic inflammation in other parts of the gastrointestinal tract is absent and several differential diagnoses for esophageal eosinophilia have to be excluded before diagnosing eosinophilic esophagitis. Most patients are male and have concomitant atopic disorders. Therapeutic options are based on drugs, diet and dilation.

Stricture prevention after extended circumferential endoscopic mucosal resection by injecting autologous keratinocytes in the sheep esophagus.

BACKGROUND: During the past decades, endoscopic mucosal resection (EMR) has been developed to treat early intramucosal esophageal cancers and dysplastic Barrett's esophagus. The primary drawback of this method is severe postsurgical esophageal stricture formation. The purpose of this preclinical study was to assess strategies for prevention of this major complication by injecting autologous keratinocytes in the EMR mucosal defect in the sheep model. METHODS: Circumferential, 6-cm-long EMRs were performed in the esophagus of nine sheep. Autologous keratinocytes were harvested 2 weeks before EMR and cultured. Circumferential resection consisted of two opposite hemicircumferential mucosectomies allowing a widespread resection of 24 cm(2). Immediately after EMR, autologous keratinocytes were endoscopically injected in the mucosal defect. Animals were sacrificed after 6 months. RESULTS: Circumferential EMRs were successfully performed in all animals. There were no intra- or postoperative complications. None of the animals developed strictures. All animals were sacrificed at 6 months as planned. Histological examinations showed fibrotic changes in 10 % (range 0-25 %) of the circumferential muscularis propria interna layer and 7.2 % (range 0-25 %) in the muscularis propria externa layer at the midportion of the EMR. No circumferential transmural fibrosis was identified. CONCLUSIONS: Prevention of stricture formation after extensive (6-cm long) circumferential EMR of the sheep esophagus can be achieved by injecting autologous keratinocytes into the wound of the resected mucosal segment.

High amplitude contractions in the middle third of the esophagus: a manometric marker of chronic alcoholism?

BACKGROUND--Oesophageal motor abnormalities have been reported in alcoholism. AIM--To investigate the effects of chronic alcoholism and its withdrawal on oesophageal disease. PATIENTS--23 chronic alcoholic patients (20 men and three women; mean age 43, range 23 to 54). METHODS--Endoscopy, manometry, and 24 hour pH monitoring 7-10 days and six months after ethanol withdrawal. Tests for autonomic and peripheral neuropathy were also performed. Motility and pH tracings were compared with those of age and sex matched control groups: healthy volunteers, nutcracker oesophagus, and gastro-oesophageal reflux disease. RESULTS--14 (61%) alcoholic patients had reflux symptoms, and endoscopy with biopsy showed oesophageal inflammation in 10 patients. One patient had an asymptomatic squamous cell carcinoma. Oesophageal motility studies in the alcoholic patients showed that peristaltic amplitude in the middle third was > 150 mm Hg (95th percentile (P95) of healthy controls) in 13 (57%), the ratio lower/ middle amplitude was < 0.9 in 15 (65%) (> 0.9 in all control groups), and the lower oesophageal sphincter was hypertensive (> 23.4 mm Hg, P95 of healthy controls) in 13 (57%). All three abnormalities were present in five (22%). Abnormal reflux (per cent reflux time > 2.9, P95 of healthy controls) was shown in 12 (52%) alcoholic patients, and was unrelated to peristaltic dysfunction. Subclinical neuropathy in 10 patients did not effect oesophageal abnormalities. Oesophageal motility abnormalities persisted at six months in six patients with ongoing alcoholism, whereas they reverted towards normal in 13 who remained abstinent; reflux, however, was unaffected. CONCLUSIONS--Oesophageal peristaltic dysfunction and reflux are frequent in alcoholism. High amplitude contractions in the middle third of the oesophagus seem to be a marker of excessive alcohol consumption, and tend to improve with abstinence.

Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.

BACKGROUND & AIMS: Development of strictures is a major concern for patients with eosinophilic esophagitis (EoE). At diagnosis, EoE can present with an inflammatory phenotype (characterized by whitish exudates, furrows, and edema), a stricturing phenotype (characterized by rings and stenosis), or a combination of these. Little is known about progression of stricture formation; we evaluated stricture development over time in the absence of treatment and investigated risk factors for stricture formation. METHODS: We performed a retrospective study using the Swiss EoE Database, collecting data on 200 patients with symptomatic EoE (153 men; mean age at diagnosis, 39 ± 15 years old). Stricture severity was graded based on the degree of difficulty associated with passing of the standard adult endoscope. RESULTS: The median delay in diagnosis of EoE was 6 years (interquartile range, 2-12 years). With increasing duration of delay in diagnosis, the prevalence of fibrotic features of EoE, based on endoscopy, increased from 46.5% (diagnostic delay, 0-2 years) to 87.5% (diagnostic delay, >20 years; P = .020). Similarly, the prevalence of esophageal strictures increased with duration of diagnostic delay, from 17.2% (diagnostic delay, 0-2 years) to 70.8% (diagnostic delay, >20 years; P < .001). Diagnostic delay was the only risk factor for strictures at the time of EoE diagnosis (odds ratio = 1.08; 95% confidence interval: 1.040-1.122; P < .001). CONCLUSIONS: The prevalence of esophageal strictures correlates with the duration of untreated disease. These findings indicate the need to minimize delay in diagnosis of EoE.

Dynamic modulation of CCR7 expression and function on naive T lymphocytes in vivo.

The chemokine receptor CCR7 is critical for the recirculation of naive T cells. It is required for T cell entry into secondary lymphoid organs (SLO) and for T cell motility and retention within these organs. How CCR7 activity is regulated during these processes in vivo is poorly understood. Here we show strong modulation of CCR7 surface expression and occupancy by the two CCR7 ligands, both in vitro and in vivo. In contrast to blood, T cells in SLO had most surface CCR7 occupied with CCL19, presumably leading to continuous signaling and cell motility. Both ligands triggered CCR7 internalization in vivo as shown in Ccl19(-/-) and plt/plt mice. Importantly, CCR7 occupancy and down-regulation led to strongly impaired chemotactic responses, an effect reversible by CCR7 resensitization. Therefore, during their recirculation, T cells cycle between states of free CCR7 with high ligand sensitivity in blood and occupied CCR7 associated with continual signaling and reduced ligand sensitivity within SLO. We propose that these two states of CCR7 are important to allow the various functions CCR7 plays in T cell recirculation.

The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses.

Despite advances in surgery, radio- and chemotherapy, therapeutic approaches for patients with head and neck squamous carcinoma (HNSCC) need to be improved. Immunotherapies eliciting tumor specific immune responses might constitute novel treatment options. We therefore investigated the expression and immunogenicity of two tumor-associated antigens (TAA) the receptor for hyaluronic acid mediated motility (RHAMM) and carboanhydrase IX (G250/CAIX) in HNSCC patients. Twenty-two HNSCC samples were examined for the expression of RHAMM and G250 by Western blotting and immunohistochemistry, 14/22 samples were tested for HLA-A2 expression by flow cytometry. For 8/22 samples single tumor-cell suspensions were generated, and mixed lymphocyte peptide cultures (MLPC) were performed to evaluate the frequencies of cytotoxic T cells specifically recognizing RHAMM and G250 using Tetramer staining/multi-color flow cytometry and enzyme linked immunosorbent spot (ELISPOT) assays. RHAMM and G250 were expressed in 73 and 80% of the HNSCC samples at the protein level. A co-expression of both TAAs could be detected in 60% of the patients. In 4/8 HLA-A2+ patients, 0.06-0.13% of CD8+ effector T cells recognized Tetramers for RHAMM or G250 and secreted IFNgamma and granzyme B in ELISPOT assays. RHAMM and G250 are expressed at high frequency and high protein level in HNSCCs and are recognized by cytotoxic CD8+ effector T cells. Therefore both TAAs constitute interesting targets for T cell based immunotherapies for HNSCC.

The puzzles of the prokineticin 2 pathway in human reproduction.

Prokineticin, 1 (PROK1) and prokineticin 2 (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. MIT-1 was initially identified as a non-toxic constituent in the venom of the black mamba snake (Dendroaspis polylepis) (Joubert and Strydom, 1980) while Bv8 was identified in the skin secretion of the toad, Bombina variegate (Mollay et al., 1999). All three homologs stimulate gastrointestinal motility thus accounting for their family name "prokineticins" (Schweitz et al., 1990, 1999). However, since its initial description, both PROK1 and PROK2 have been found to regulate a dazzling array of biological functions throughout the body. In particular, PROK1 acts as a potent angiogenic mitogen on endocrine vascular epithelium, thus earning its other name, Endocrine gland-vascular endothelial factor (EG-VEGF) (LeCouter et al., 2002). In contrast, the PROK2 signaling pathway is a critical regulator of olfactory bulb morphogenesis and sexual maturation in mammals and this function is the focus of this review.

mTORC2 regulates PGE(2)-mediated endothelial cell survival and migration

Prostaglandin E-2 (PGE(2)) promotes angiogenesis by in part inducing endothelial cell survival and migration. The present study examined the role of mTOR and its two complexes, mTORC1 and mTORC2, in PGE(2)-mediated endothelial cell responses. We used small interfering RNA (siRNA) to raptor or rictor to block mTORC1 or mTORC2, respectively. We observed that down-regulation of mTORC2 but not mTORC1 reduced baseline and PGE(2)-induced endothelial cell survival and migration. At the molecular level, we found that knockdown of mTORC2 inhibited PGE2-mediated Rac and Akt activation two important signaling intermediaries in endothelial cell migration and survival, respectively. In addition, inhibition of mTORC2 by prolonged exposure of endothelial cells to rapamycin also prevented PGE2-mediated endothelial cell survival and migration confirming the results obtained with the siRNA approach. Taken together these results show that mTORC2 but not mTORC1 is an important signaling intermediary in PGE2-mediated endothelial cell responses.

Les complications de la cirrhose hépatique: varices oesophagiennes, ascite et carcinome hépato-cellulaire [Complications of liver cirrhosis: oesophageal varices, ascites and hepato-cellular carcinoma]

The principal treatment for bleeding oesophageal varices is endoscopic ligation. Non-cardioselective beta-blockers are the gold-standard of primary prophylaxis. The principal treatment for ascites is a salt-free diet and diuretics, mainly spironolactone, if necessary associated with a loop diuretic. In refractory ascites, paracentesis or installation of a transjugular intrahepatic portosystemic shunt (TIPS) are two possible treatment options. Cirrhosis patients are at higher risk of developing hepato-cellular carcinoma. Surgery is only possible in a small number of cases. Percutaneous destruction techniques have nearly the same survival rate as that obtained by surgery and should be proposed to patients where surgery is not an option.