Impact of genetic polymorphisms on the pathogenesis of idiopathic achalasia: Association with IL33 gene variant.

AIM: To investigate the association of single nucleotide polymorphisms (SNPs) of genes involved in the regulation of immune responses, IL33, IL1RL1, IL23R, and IL10, with idiopathic achalasia in an Italian cohort of patients. MATERIALS AND METHODS: A panel of eleven polymorphisms were genotyped in 116 unrelated idiopathic achalasic patients and 371 healthy subjects, by using TaqMan genotyping assays. RESULTS: Significant differences of allele (P=0.0065, OR=1.59, CI=1.14-2.22) and genotype (P=0.0097, OR=1.74, CI=1.14-2.65) frequencies of the IL33 rs3939286 variant were found between achalasic patients and controls. No association of the other investigated SNPs was detected. No differences in genotype and allele distribution were found with respect to clinical characteristics of patients. CONCLUSION: We provide for the first time an association between the risk of developing idiopathic achalasia and IL-33 variant, underling the role of cytokines and inflammatory mediators on the pathogenesis of the disease.

Erythrocytes-mediated delivery of dexamethasone 21-phosphate in steroid-dependent ulcerative colitis: a randomized, double-blind Sham-controlled study.

BACKGROUND: Efficacy of erythrocyte-mediated delivery of dexamethasone 21-phosphate in patients with steroid-dependent ulcerative colitis. METHODS: Thirty-seven patients with steroid-dependent ulcerative colitis were randomized to infusions of dexamethasone 21-phosphate encapsulated into autologous erythrocytes (n = 19) or to sham infusions (n = 18). Each infusion was given monthly for 6 months. The primary endpoint was the proportion of patients able to discontinue oral corticosteroids during treatment while maintaining clinical remission or stable disease. Secondary endpoint was the proportion of patients with disappearance of steroid-related adverse events. RESULTS: At each infusion, a mean of 9.8 ± 4.6 mg dexamethasone 21-phosphate was administered at each infusion, which allowed steady-state plasma levels of 8 ng/mL for the following 28 days. Thirteen patients in the dexamethasone 21-phosphate group and 4 sham-treated patients attained the primary outcome of the study, i.e., maintaining a stable condition despite oral steroids withdrawal (P = 0.008). In the remaining patients (6 and 15 in the 2 experimental groups, respectively), the treatment was prematurely withdrawn because of clinical deterioration while tapering oral steroids. At endoscopy, mucosal healing was ascertained in 4 patients and 1 patient of the 2 experimental groups, respectively (P = 0.339). At inclusion, 14 and 13 patients in the 2 experimental groups complained of steroid-related adverse events; at end of the treatment, events were still present in 5 and 13 patients, respectively (P = 0.008). CONCLUSIONS: In patients with steroid-dependent ulcerative colitis, 6-month therapy with low dose of dexamethasone 21-phosphate allowed the withdrawal of oral steroids and the reversal of steroid-related adverse events in most patients while maintaining clinical remission (ClinicalTrials.gov number, NCT01171807).

Fundoplication after heller myotomy: a retrospective comparison between nissen and dor.

OBJECTIVE: A retrospective comparison between Nissen and Dor fundoplication after laparoscopic Heller myotomy for achalasia. MATERIALS AND METHODS: From 1998 to 2004 a first group of 48 patients underwent Heller myotomy and Nissen fundoplication for idiopathic achalasia (H+N group). From 2004 to 2010 a second group of 40 patients underwent Heller myotomy followed by Dor fundoplication (H+D group). Some patients received a previous endoscopic treatment with pneumatic dilatation or endoscopic injection of botulinum toxin that provided them only a temporary clinical benefit. Changes in clinical and instrumental examinations from before to after surgery were evaluated in all patients. Clinical evaluation was carried out using a modified DeMeester symptom score system. RESULTS: Dor fundoplication treatment reduced both dysphagia and regurgitation severity scores significantly more than Nissen fundoplication (p<0.0001). Indeed, the incidence of dysphagia was significantly higher in patients treated with floppy-Nissen than in those treated with Dor fundoplication: by defining dysphagia as a DeMeester score equal to 3 (arbitrary cut-off), at the end of follow-up dysphagia occurred in 17.65% and 0% (p=0.037) of patients belonging to the H+N and H+D groups, respectively. CONCLUSION: Heller myotomy followed by Dor fundoplication is a safe and valuable treatment. The procedure showed a lower incidence of postoperative dysphagia versus Nissen fundoplication and a negligible incidence of postoperative GERD in a long-term postoperative follow-up.

An immunohistochemical study of the myenteric plexus in idiopathic achalasia.

BACKGROUND: Achalasia is a primary esophageal motor disorder characterized by degenerative changes of the myenteric plexus. The pathophysiologic abnormalities may be the final result of several intermeshing mechanisms, and more than one single factor may cause the motor abnormalities. AIMS: To report our experience in investigating the myenteric plexus of achalasia patients undergoing esophagomyotomy. PATIENTS AND METHODS: Tissue samples from 12 patients undergoing Heller myotomy for achalasia were evaluated and compared with esophageal tissue specimens from 7 controls. Enteric neurons and interstitial cells of Cajal (ICC) were assessed by immunohistochemical methods, and the presence of vasoactive intestinal polypeptide ergic fibers and of CD3 lymphocytes. The possible presence of herpesvirus was also assessed by immunohistochemistry, whereas that of papillomavirus was assessed by in-situ hybridization. RESULTS: Compared with controls, achalasia patients displayed a significant decrease of both enteric neurons and ICC. Immunoreactivity for vasoactive intestinal polypeptide was completely absent in each patient. CD3 staining disclosed myenteric plexitis in 5 (42%) patients; no control patient had plexitis. All patients were completely negative for the presence of both herpes simplex virus and human papillomavirus. CONCLUSIONS: The enteric nervous system of the lower esophageal sphincter area is impaired in patients with "idiopathic achalasia," and the abnormalities involve ICC and neurons in many patients. The triggering factors for these abnormalities are, however, still unknown.

Erythrocyte-mediated delivery of dexamethasone in patients with mild-to-moderate ulcerative colitis, refractory to mesalamine: a randomized, controlled study.

BACKGROUND AND AIM: Nearly 25% of patients with ulcerative colitis (UC) requiring steroids therapy become steroid-dependent after 1 yr, and virtually all develop steroid-related adverse events. We planned a controlled study to investigate the efficacy and safety of dexamethasone 21-P (Dex 21-P) encapsulated into erythrocytes (DEE). MATERIALS AND METHODS: Forty patients with mild-to-moderate UC, refractory to mesalamine, were randomly assigned to one of the following three treatments: two DEE infusions 14 days apart (group A, N = 20), oral prednisolone (0.5 mg/kg for 14 days followed by a 6 mg/weekly tapering (group B, N = 10), and sham infusions (group C, N = 10). The clinical, biochemical, and endoscopic parameters were monitored at inclusion and after 8 wk. RESULTS: In group A, a mean dose of 9.9 +/- 4.1 mg Dex 21-P was loaded into autologous erythrocytes at each infusion. At 8 wk, 15 patients in group A (75%), 8 in group B (80%), and 1 in group C (10%, P < 0.001 vs A and B) were in clinical and endoscopic remission. When compared with the baseline values, C-reactive protein (CRP) dropped in groups A (1.6 mg/dL vs 0.4 mg/dL, P= 0.006) and B (1.0 vs 0.5, P= 0.02), but not in group C. No steroid-related adverse events were apparent in the patient treated with DEE, compared with 8 out of 10 patients on oral steroids (P< or = 0.01). CONCLUSION: Low doses of Dex (mean total dose +/- 20 mg) loaded into autologous erythrocytes were significantly more effective than sham infusions in terms of symptoms relief, endoscopic, and biochemical improvements in UC patients refractory to mesalamine. In addition, in contrast to oral prednisolone (mean total dose +/- 1 g), no steroid-related adverse events were induced.