Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity.

BACKGROUND: Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). AIM: To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility. METHODS: Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods. RESULTS: Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (n = 37) or placebo (n = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008-1 µg/mL] and rifampin (MIC range 0.004-0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC50 range ≤0.06-32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested. CONCLUSIONS: In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. CLINICALTRIALS. GOV IDENTIFIER: NCT01543178.

Severity in irritable bowel syndrome: a Rome Foundation Working Team report.

OBJECTIVES: The concept of severity in irritable bowel syndrome (IBS) is clinically recognized and operative in diagnostic decision making and treatment planning. Yet, there is no consensus on its definition, and there are limited data on the prevalence of severity subgroups, its medical and psychosocial determinants, and its association with other health status measures. The aims of the Rome Foundation Working Team Committee were to summarize current research, to develop a consensus of understanding on this concept, and to make recommendations for its use in research and clinical care. METHODS: In 2006, a multinational committee of clinical investigators with expertise in IBS and/or psychometric research methods undertook a systematic review of the literature relating to severity in IBS. Owing to limited data, the Foundation commissioned three clinical studies to better characterize the concept of severity in IBS, and summary information and recommendations for future research and clinical care were developed. RESULTS: The main findings were: (i) severity in IBS is defined as a biopsychosocial composite of patient-reported gastrointestinal and extraintestinal symptoms, degree of disability, and illness-related perceptions and behaviors; (ii) both visceral and central nervous system physiological factors affect severity; as severity increases, the central nervous system provides a greater contribution; (iii) severity is related to and influences health-related quality of life and health behaviors and also guides diagnostic and therapeutic clinical decision making; (iv) severity can be subcategorized into clinically meaningful subgroups as mild (∼40%), moderate (∼35%), and severe (∼25%), and this provides a working model for use in future research and clinical care. CONCLUSIONS: Future work is required to understand more precisely the factors contributing to severity and to develop a valid patient-reported instrument to measure severity in IBS.

Modeling of spatially referenced environmental and meteorological factors influencing the probability of Listeria species isolation from natural environments.

Many pathogens have the ability to survive and multiply in abiotic environments, representing a possible reservoir and source of human and animal exposure. Our objective was to develop a methodological framework to study spatially explicit environmental and meteorological factors affecting the probability of pathogen isolation from a location. Isolation of Listeria spp. from the natural environment was used as a model system. Logistic regression and classification tree methods were applied, and their predictive performances were compared. Analyses revealed that precipitation and occurrence of alternating freezing and thawing temperatures prior to sample collection, loam soil, water storage to a soil depth of 50 cm, slope gradient, and cardinal direction to the north are key predictors for isolation of Listeria spp. from a spatial location. Different combinations of factors affected the probability of isolation of Listeria spp. from the soil, vegetation, and water layers of a location, indicating that the three layers represent different ecological niches for Listeria spp. The predictive power of classification trees was comparable to that of logistic regression. However, the former were easier to interpret, making them more appealing for field applications. Our study demonstrates how the analysis of a pathogen's spatial distribution improves understanding of the predictors of the pathogen's presence in a particular location and could be used to propose novel control strategies to reduce human and animal environmental exposure.

Acute technical feasibility of an endoscopic duodenal-jejunal bypass sleeve in a porcine model: a potentially novel treatment for obesity and type 2 diabetes.

BACKGROUND: The concept of endoluminal therapy for various disease states has gained significant attention. This report describes the authors' initial animal experience with a novel endoscopic duodenal-jejunal bypass sleeve (DJBS) in a porcine model. The DJBS consists of an implant delivered endoscopically, anchored in the proximal duodenum, and extended into the jejunum. This device aims to mimic the intestinal bypass effects of Roux-en-y gastric bypass without the need for stapling or anastomosis and may offer novel therapeutic benefit for patients with obesity, type 2 diabetes, or both. METHODS: Five DJBS devices were delivered in five domestic, female Yorkshire pigs. The devices were delivered and retrieved the same day and left in situ for less than 1 h. The animals were kept alive for 4 days after explantation for evaluation of their general health after the procedure. After they were killed, gastric, duodenal, and jejunal tissues were examined and harvested for histologic assessment of any acute device or procedure-related effects. RESULTS: Delivery of the implant took an average of 18 min (range, 10-38 min) and required an average fluoroscopy time of 8.1 min (range, 3.8-16.6 min). Retrievals were performed in an average of 7.4 min (range, 5-9 min) using fluoroscopy for an average of 2.3 min (range, 1.3-4.5 min). Followed for 4 days after explantation, the animals were normal and healthy. There were no pathologic findings in the explanted tissue. CONCLUSIONS: The DJBS can be safely deployed and retrieved endoscopically. Future long-term survival studies are warranted to help define the role of promising technology.

Chronic in-vivo experience with an endoscopically delivered and retrieved duodenal-jejunal bypass sleeve in a porcine model.

BACKGROUND: The role of duodenal bypass as an underlying mechanism of action in gastric bypass surgery has received considerable attention. We report the initial feasibility study of a totally endoscopically delivered and retrieved duodenal-jejunal bypass sleeve in a chronic porcine model. METHODS: The implant consists of a 60-cm fluoropolymer sleeve that is endoscopically deployed via a coaxial catheter system into the jejunum and fixed in the proximal duodenum with a Nitinol anchor. The system creates a proximal biliopancreatic diversion. Six female Yorkshire pigs were endoscopically implanted; all survived. Four animals (group 1) were slated to survive 90 days, two animals (group 2) for 120 days, and three animals (group 3) underwent sham endoscopy and were survived 120 days. Animals were fed standard dry pig chow 0.5 kg three times daily. Data points included daily general health, weekly weight, serum blood tests (complete blood count, amylase, lipase, liver function tests), and monthly evaluation of anchor/sleeve position/patency by fluoroscopy and endoscopy. Following the in-vivo period, the devices were endoscopically removed and the animals were sacrificed. Duodenal and jejunal tissue samples were assessed histologically. RESULTS: All six test animals were implanted and explanted without significant adverse events. In group 1, the first animal had no device-related issues. The second animal had a pivoted anchor requiring repositioning at day 63. That animal had no further difficulties. The third animal had an incidental partial rotation of the anchor noted at the 90 day explantation. The fourth animal was incidentally implanted with a crossover of the anchor struts, which was endoscopically corrected on day 14. However, on day 20 the animal had persistent vomiting, and the device was explanted. Both group 2 animals survived 120 days. One animal had a partially rotated anchor but was asymptomatic. The average weight gain between test and sham groups was 0.23 kg/day and 0.42 kg/day, respectively (p = 0.01). CONCLUSIONS: A totally endoscopic and reversible bypass of the duodenum and proximal jejunum has been achieved for 90-120 days. Initial experience suggests patency of the sleeve and acceptable tissue response. Reduced weight gain in the test animals suggests device efficacy. Further investigation is warranted.

Reduction in pain: Is it worth the gain? The effect of opioids on the GI tract.

The use of opioid medications for acute and chronic pain has increased significantly in the past 20 years in the United States. Given the high density of opioid receptors in the gastrointestinal tract, side effects are common in these patients including constipation, dysphagia, bloating, nausea, and vomiting. These side effects, which are experienced by most patients who take opioids, can lead to significant impairment in quality of life. Unlike other side effects from opioids, gastrointestinal side effects do not diminish with continued use, often leading patients to reduce or discontinue their opioid treatment to relieve these side effects. Therefore, physicians must be aware and anticipate potential side effects in patients receiving opioids to ensure appropriate pain management.

Emergency department utilisation for inflammatory bowel disease in the United States from 2006 to 2014.

BACKGROUND: Despite advances in treatment, patients with inflammatory bowel disease (IBD) frequently require emergency department (ED) visits and hospitalisations. AIMS: To analyse trends in ED visits and subsequent hospitalisations for IBD in the United States (US). METHODS: Data were analysed from the Nationwide Emergency Department Sample (NEDS) years 2006-2014. The NEDS is the largest all-payer ED database in the US, weighted to represent 135 million visits/year. IBD was identified using ICD-9 codes for Crohn's disease (CD) or ulcerative colitis (UC). Surgeries were identified using procedure codes. RESULTS: The frequency of IBD-ED visits increased 51.8%, from 90 846 visits in 2006 to 137 946 in 2014, which was statistically significant in linear regression. For comparison, all-case ED use between 2006 and 2014 increased 14.8%. In-patient hospitalisations from the ED decreased 12.1% for IBD (from 64.7% rate of hospitalisation from the ED in 2006 to 52.6% in 2014), with a UC:CD ratio of 1.2:1 in 2006 and 1.3:1 in 2014. Chi-square analysis revealed that this was a significant decrease. Surgery rates also showed a statistically significant decrease. The mean ED charge per patient rose 102.5% and the aggregate national cost of IBD-ED visits increased 207.5%. CD accounted for over twice as many visits as UC in both years. UC, age, male gender, highest income quartile, private insurance, Medicaid/Medicare, and tobacco use were associated with in-patient admissions. CONCLUSIONS: The number of ED visits due to IBD and associated charges have continued to rise, while the rates of in-patient hospitalisations referred from the ED and surgeries have decreased.

Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study.

BACKGROUND: A genetic contribution has been proposed for irritable bowel syndrome (IBS) and gastro-oesophageal reflux disease (GERD), but is controversial. No twin data exist for dyspepsia. AIM: To determine the relative contribution of genetic factors in GERD, dyspepsia (upper abdominal pain) and IBS. METHODS: A total of 986 twin pairs (from initial mail-out response 51%). Both members completed validated symptom and psychological questionnaires; 481 monozygotic pairs [mean (s.d.) age 53 +/- 5.8 years] and 505 dizygotic pairs (mean age 54 +/- 5.6 years). RESULTS: Prevalence of IBS, dyspepsia and GERD was 12%, 10% and 20%, respectively. Polychoric correlation for monozygotic twins for IBS (0.47) and GERD (0.44) were both substantially larger than those for dizygotic twins (0.17 and -0.37, respectively). Polychoric correlation was slightly lower in monozygotic than dizygotic twins for dyspepsia. Genetic modelling confirmed the independent additive genetic effects in GERD and IBS but not dyspepsia. Estimates of genetic variance were 22% for IBS, 13% for GERD and 0% for dyspepsia, but adjusting for anxiety and depression removed the statistical significance for IBS and GERD. CONCLUSIONS: There is a genetic contribution to GERD and IBS but not dyspepsia; this may be mediated by the hereditability of anxiety and depression.

A meta-analysis of the placebo response in complementary and alternative medicine trials of irritable bowel syndrome.

Among patients with irritable bowel syndrome (IBS) enrolled in clinical trials of conventional medical therapy, the placebo response rate is high. IBS patients also frequently use complementary and alternative medicine (CAM), which may act through an 'enhanced placebo effect'. The purpose of this study was to estimate the magnitude of the placebo response rate in CAM trials for IBS and to identify factors that influence this response. We performed a systematic review and meta-analysis of randomized, placebo-controlled clinical trials of CAM therapies for IBS identified from MEDLINE/EMBASE/PsychLIT databases from 1970 to 2006. Placebo and active treatment response rates for global symptom improvement were assessed. Nineteen studies met the inclusion criteria. The pooled estimate of the placebo response rate was 42.6% (95% confidence interval, 38.0-46.5%). Significant heterogeneity existed across trials (range 15.0-72.2%, P < 0.00001). Higher placebo response rates correlated with a longer duration of treatment (r = 0.455, P = 0.05) and a greater number of office visits (r = 0.633, P = 0.03). Among IBS patients in CAM trials, the placebo response rate is high. That this rate is similar in magnitude to that seen in conventional medicine trials suggests that the placebo response is independent of the type of therapy used and that it is not particularly 'enhanced' in CAM trials.

Endoscopic full-thickness plication for the treatment of GERD: long-term multicenter results.

BACKGROUND: The purpose of the present study was to assess the long-term safety and durability of effect for endoscopic full-thickness plication for the treatment of symptomatic gastroesophageal reflux disease (GERD). The Plicator (NDO Surgical, Inc., Mansfield, MA) used delivers a transmural suture through the gastric cardia to restructure the antireflux barrier. Published reports have shown the Plicator procedure to be effective in reducing GERD symptoms and medication use at 1 year post-plication. METHODS: Twenty-nine patients with chronic heartburn requiring maintenance daily anti-secretory therapy were treated at five sites. Patients received a single full-thickness plication in the gastric cardia 1cm below the gastroesophageal junction (GE) junction. Re-treatments were not permitted. Patients were evaluated at baseline for GERD symptoms and medication use. Intermediate (12 month) and long-term subject follow-up (median follow-up: 36.4 months; range, 31.2-43.9 months) were completed to evaluate procedure safety and durability of effect. RESULTS: Twenty-nine patients completed the 12-month and 36-month follow-up. All procedure-related adverse events occurred acutely, and no new events were observed during extended follow-up. At 36-months post-procedure, 57% (16/28) of baseline proton pump inhibitor (PPI)-dependent patients remained off daily PPI therapy. Treatment effect remained stable from 12- to 36-months, with 21/29 patients off daily PPI at 12 months compared to 17/29 patients at 36-months. Median GERD- Health Related Quality of Life (HRQL) scores remained significantly improved at 36 months versus baseline off-meds scores (8 versus 19, p < 0.001). In addition, the proportion of patients achieving > or = 50% improvement in GERD-HRQL score was consistent from 12 months (59%) to 36 months (55%). CONCLUSIONS: Endoscopic full-thickness plication can reduce GERD symptoms and medication use for at least 3-years post-procedure. Treatment effect is stable from 1 to 3 years, and there are no long-term procedural adverse effects.

Gender differences in chronic constipation on anorectal motility.

BACKGROUND: The epidemiology of chronic constipation (CC) skews toward female predominance, yet men make up an important component of those suffering from CC. We sought to determine whether there are sex-specific differences in symptoms and physiologic parameters on anorectal manometry (ARM). METHODS: We performed a case-control analysis of sequential men and age-matched women (2:1 ratio) presenting for ARM as part of the evaluation of CC. We collected physiologic parameters derived from 3D high-resolution ARM in addition to the ROME III constipation module and the Pelvic Floor Distress Inventory 20 (PFDI-20) questionnaires. We analyzed univariate, sex-specific differences in ARM physiologic parameters and PFDI-20 parameters and adjusted for putative confounders using multivariate logistic regression. KEY RESULTS: Our study enrolled 80 men and 165 age-matched women. Men had a higher median sphincter resting pressure (81.2 vs 75.2 mm Hg, P=.01) and mean squeeze pressure (257.0 vs 170.5 mm Hg, P<.0001) than women. Although men reported significantly less severe straining and incomplete evacuation, they had greater mean rectoanal pressure differential (-106.7 vs -71.1 mm Hg, P<.0001), smaller mean defecation index (0.17 vs 0.27, P=.03) and higher volume threshold for urgency (115.2 v. 103.4 mL, P=.03). However, women were more likely to have abnormal balloon expulsion time (BET) than men (52.7% vs 35.0%, P=.01). After multivariate analysis, male gender was the only independent predictor of a normal BET (OR: 0.48, 95% CI: 0.27-0.86, P=.01). CONCLUSIONS & INFERENCES: Men and women with CC differ with regard to symptom severity and physiologic parameters derived from ARM suggesting differences in their pathophysiology.

Dexamethasone implant in diabetic macular edema in real-life situations.

PURPOSE: To report outcome of eyes with recalcitrant and naive eyes with diabetic macular edema (DME) treated with intravitreal dexamethasone implants (Ozurdex) injection. METHODS: Retrospective multicenter data analysis of eyes with DME treated with Ozurdex implant and with minimum follow-up of at least one year after the first implant. Data collected included demographic details, history of presenting illness, past treatment history, clinical examination details including visual acuity at presentation, and follow-up with imaging and treatment details. Paired sample t-test was used to measure mean differences between pre- and post-implant values obtained at baseline and last follow-up. RESULTS: A total of 79 eyes (62 subjects) were included. Sixty-four eyes had been previously treated; 15 eyes were naive. Among the previously treated eyes, mean interval between first Ozurdex injection and any previous treatment was 7.69±8.2 months. In naive eyes, the visual acuity improved from baseline 0.58±0.25 to 0.44±0.33 logMAR at last follow-up (P=0.05). In eyes that had been previously treated, the improvement was from 0.65±0.34 at baseline to 0.48±0.35 logMAR (P=0.01). Mean treatment-free interval was 6.5±4.5 months. Nine eyes were steroid responder with controlled intraocular pressure (IOP), none showed any spike in IOP during the follow-up period. CONCLUSIONS: Ozurdex implant could be a good alternative for recalcitrant as well as naive eyes with DME. The visual gain after initial implant injection was fairly maintained, with additional treatment usually after 6 months in naive eyes. Ozurdex appeared safe even in steroid responders with good control of IOP with antiglaucoma medications.

The placebo effect in irritable bowel syndrome trials: a meta-analysis.

BACKGROUND: Despite the apparent high placebo response rate in randomized placebo-controlled trials (RCT) of patients with irritable bowel syndrome (IBS), little is known about the variability and predictors of this response. OBJECTIVES: To describe the magnitude of response in placebo arms of IBS clinical trials and to identify which factors predict the variability of the placebo response. METHODS: We performed a meta-analysis of published, English language, RCT with 20 or more IBS patients who were treated for at least 2 weeks. This analysis is limited to studies that assessed global response (improvement in overall symptoms). The variables considered as potential placebo modifiers were study design, study duration, use of a run-in phase, Jadad score, entry criteria, number of office visits, number of office visits/study duration, use of diagnostic testing, gender, age and type of medication studied. FINDINGS: Forty-five placebo-controlled RCTs met the inclusion criteria. The placebo response ranged from 16.0 to 71.4% with a population-weighted average of 40.2%, 95% CI (35.9-44.4). Significant associations with lower placebo response rates were fulfillment of the Rome criteria for study entry (P=0.049) and an increased number of office visits (P=0.026). CONCLUSIONS: Placebo effects in IBS clinical trials measuring a global outcome are highly variable. Entry criteria and number of office visits are significant predictors of the placebo response. More stringent entry criteria and an increased number of office visits appear to independently decrease the placebo response.

The clinical predictors of aetiology and complications among 173 patients presenting to the Emergency Department with oesophageal food bolus impaction from 2004-2014.

BACKGROUND: Oesophageal food bolus impaction (OFBI) is a common gastrointestinal emergency. AIM: To describe contemporary aetiologies of OFBI, and variables that may predict eosinophilic esophagitis (EoE) related OFBI as well as complications. METHODS: Patients presenting to the Emergency Department between 2004 and 2014 with OFBI who underwent oesophagogastroduodenoscopy (EGD) were included. Clinical and endoscopic variables, as well as complications, were recorded. Aetiology of OFBI was determined by reviewing endoscopy reports. A diagnosis of EoE was confirmed via pathology (>15 eosinophils/high-powered field) at the index or follow-up EGD. Logistic regression was used to report associations of variables and complications. RESULTS: Of the 173 patients with OFBI, 139 (80%) had an aetiology recognised, the most frequent being EoE (27%, n = 47), Schatzki's ring (20%, n = 34) and oesophageal stricture (13%, n = 22). Six patients (3%) had oesophageal cancer. Patients with EoE-related OFBI tended to be younger (42 vs. 69 years, P < 0.001), male (81% vs. 52%, P = 0.001), have a prior history of OFBI (45% vs. 18%, P = 0.001), and present during spring or summer (62% vs. 44%, P = 0.04). Eighteen patients (10%) had a complication associated with OFBI, with 3 (2%) perforations. On multivariate regression, patients with EoE-related OFBI were not more likely to have a complication (OR 1.07, P = 0.92), although hypoxia at presentation (OR 59.7, P = 0.006) was associated with complications. CONCLUSIONS: Eosinophilic esophagitis accounts for over a quarter of patients with oesophageal food bolus impaction. Overall complication rate was 10%, with a 2% perforation rate. Clinical characteristics of patients with eosinophilic esophagitis differ from other patients with oesophageal food bolus impaction.

Inpatient burden of childhood functional GI disorders in the USA: an analysis of national trends in the USA from 1997 to 2009.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are among the most common outpatient diagnoses in pediatric primary care and gastroenterology. There is limited data on the inpatient burden of childhood FGIDs in the USA. The aim of this study was to evaluate the inpatient admission rate, length of stay (LoS), and associated costs related to FGIDs from 1997 to 2009. METHODS: We analyzed the Kids' Inpatient Sample Database (KID) for all subjects in which constipation (ICD-9 codes: 564.0-564.09), abdominal pain (ICD-9 codes: 789.0-789.09), irritable bowel syndrome (IBS) (ICD-9 code: 564.1), abdominal migraine (ICD-9 code: 346.80 and 346.81) dyspepsia (ICD-9 code: 536.8), or fecal incontinence (ICD-codes: 787.6-787.63) was the primary discharge diagnosis from 1997 to 2009. The KID is the largest publicly available all-payer inpatient database in the USA, containing data from 2 to 3 million pediatric hospital stays yearly. KEY RESULTS: From 1997 to 2009, the number of discharges with a FGID primary diagnosis increased slightly from 6,348,537 to 6,393,803. The total mean cost per discharge increased significantly from $6115 to $18,058 despite the LoS remaining relatively stable. Constipation and abdominal pain were the most common FGID discharge diagnoses. Abdominal pain and abdominal migraine discharges were most frequent in the 10-14 year age group. Constipation and fecal incontinence discharges were most frequent in the 5-9 year age group. IBS discharge was most common for the 15-17 year age group. CONCLUSIONS & INFERENCES: Hospitalizations and associated costs in childhood FGIDs have increased in number and cost in the USA from 1997 to 2009. Further studies to determine optimal methods to avoid unnecessary hospitalizations and potentially harmful diagnostic testing are indicated.

The role of the liver in the response to LPS: experimental and clinical findings.

The liver plays an important physiological role in lipopolysaccharide (LPS) detoxification and, in particular, hepatocytes are involved in the clearance of endotoxin of intestinal derivation. In experimental shock models, tumor necrosis factor (TNF)-alpha induces hepatocyte apoptosis and lethal effects are due to secreted TNF-alpha and not to cell-associated TNF-alpha. An exaggerated production of TNF-alpha has been reported in murine viral infections, in which mice become sensitized to low amounts of LPS and both interferon (IFN)-gamma and IFN-alpha/beta are involved in the macrophage-induced release of TNF-alpha. The prominent role of LPS and TNF-alpha in liver injury is also supported by studies of ethanol-induced hepatic damage. In humans, evidence of LPS-induced hepatic injury has been reported in cirrhosis, autoimmune hepatitis, and primary biliary cirrhosis and a decreased phagocytic activity of the reticulo-endothelial system has been found in these diseases. The origin of endotoxemia in hepatitis C virus (HCV) infected patients seems to be multifactorial and LPS may be of exogenous or endogenous derivation. In endotoxemic HCV-positive patients responsive to a combined treatment with IFN-alpha/ribavirin (RIB), endotoxemia was no longer detected at the end of the therapeutic regimen. By contrast, 48% of the non-responders to this treatment were still endotoxemic and their monocytes displayed higher intracellular TNF-alpha and interleukin (IL)-1beta levels than responders. Moreover, in responders, an equilibrium between IFN-gamma and IL-10 serum levels was attained. In the non-responders, serum levels of IL-10 did not increase following treatment. This may imply that an imbalance between T helper (Th)1 and Th2 derived cytokines could be envisaged in the non-responders.

Autosomal recessive form of whistling face syndrome in sibs.

Two sibs with the whistling face syndrome, born to unaffected parents, are presented. They had the full facial and limb manifestations typical of this disorder, for which there is evidence of autosomal dominant inheritance. The existence of an autosomal recessive form of this syndrome has been suspected previously on the basis of a limited number of observations. Our study substantiates genetic heterogeneity of this condition and suggests that the autosomal recessive form could be even less rare than is generally considered.

Decreased myelotoxicity of gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC) with cisplatin infusion on day 15.

In a multicenter phase II Italian trial that used a 28-day dosing schedule of gemcitabine on days 1, 8, and 15 and cisplatin on day 2, thrombocytopenia and neutropenia were the main dose-limiting toxicities observed. The aim of the present study was to determine whether using 15-day cisplatin in lieu of the standard 2-day schedule in combination with weekly gemcitabine would decrease expected myelotoxicities, particularly thrombocytopenia. Fifty-one patients with advanced non-small cell lung cancer (NSCLC), a median age of 62 years (range 31-76) and baseline Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1, were enrolled. Twenty-four patients had stage IIIA-B disease and 27 had stage IV. Patients received gemcitabine 1000 mg/m(2) on days 1, 8, 15, and cisplatin 100 mg/m(2) on day-15, every 28 days for a total of 151 cycles. All patients were evaluable for toxicity. Grades 3 and 4 thrombocytopenia was observed in 16% of patients, grades 3 and 4 neutropenia in 35% of patients, and grade 3 anemia in 4% of patients (no grade 4 anemia). Nonhematologic toxicity was mild. Two patients had grade 3 vomiting, and another had grade 4 hepatic toxicity only after gemcitabine administration. The dose intensity of gemcitabine and cisplatin was well maintained. Of the 45 patients evaluable for response, there were 22 (49%) partial responders, 7 (15.5%) minimal responders, 9 (20%) with stable disease, and 7 (15.5%) progressions. Compared with the schedule used in a multicenter phase II Italian trial (day 2 cisplatin), day-15 cisplatin decreases incidences of thrombocytopenia (16 vs. 52%) and anemia (4 vs. 25%); the occurrence of neutropenia is similar (35 vs. 36%). Response rates are also similar (49 vs. 54%).

Helicobacter pylori infection, immune response and vaccination.

It is well known that abnormal immune responses may play a pathogenic role in the H. pylori-related gastropathy. Indeed, as far as humoral immune response is concerned, it is still debated whether specific anti-H. pylori antibodies have a protective or noxious effect in infected hosts. Besides proinflammatory cytokines released from macrophages, such as tumor-necrosis factor-a and interleukin-1beta, and IFN-gamma derived from T-helper 1 lymphocytes, also interleukin-10, a product of T-helper 2 lymphocytes with antiinflammatory properties, seems to be surprisingly involved in the pathogenesis of H. pylori-induced gastritis. In addition, lipopolysaccharide derived from the outher membrane of H. pylori acts as a chemoattractant for monocytes and induces release of free radicals, interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha. On the other hand, H. pylori lipopolysaccharide could be responsible for the increased polyamine concentrations in the gastric mucosa and polyamines, such as putrescine, spermidine and spermine, could be involved in the increased cell proliferation and consequent possible neoplastic transformation of the gastric mucosa. Incubation of peripheral blood mononuclear cells with H. pylori increases significantly the surface expression of CD95 receptor (Fas), thus suggesting that these bacteria are able to induce apoptosis. In animal models, different types of vaccination have been investigated, including stimulation of nasal and rectal lymphoid tissue, as well as adoptive transfer of T cell from donors immunized with H. pylori. However, results obtained are frequently disappointing. In humans, urease of H. pylori was safely used as oral vaccine in the absence or presence of adjuvants with encouraging results. Finally, DNA vaccines could offer in the future advantages for prophylactic H. pylori eradication, especially where population is infected by this microorganism since childhood.