A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS.

BACKGROUND: Micro-inflammation is considered an element in the pathogenesis of irritable bowel syndrome (IBS). High-sensitivity C reactive protein (hs-CRP) was previously shown to be higher in IBS compared to healthy controls, albeit within the normal range. Since probiotics may suppress micro-inflammation in the gut, we tested if they reduce symptoms and inflammatory markers (hs-CRP and fecal calprotectin (FC) in diarrhea-predominant IBS (IBS-D). The aim of this study was to assess the clinical and laboratory effects of BIO-25, a multispecies probiotic, in women with IBS-D. METHODS: A double-blind, placebo-controlled study. Following a 2-week run-in, eligible women were assigned at random to a probiotic capsule or an indistinguishable placebo, twice daily for 8 weeks. IBS symptoms and stool consistency were rated daily by Visual Analogue Scales (VAS) and the Bristol Stool Scale (BSS). High-sensitivity C reactive protein was tested at baseline, 4 and 8 weeks. FC was tested at baseline and 8 weeks. KEY RESULTS: One hundred and seventy-two IBS-D patients were recruited and 107 eligible patients were allocated to the intervention (n=54) or placebo (n=53) group. All symptoms improved in both groups with no significant difference between them in symptom improvement, hs-CRP or FC levels. CONCLUSIONS & INFERENCES: An 8-week treatment with BIO-25 improved symptoms in women with IBS-D, but was not superior to placebo. This rigorously designed and executed study supports the findings of other studies that did not demonstrate superiority of probiotics over placebo in IBS. High quality clinical studies are necessary to examine the efficacy of other specific probiotics in IBS-D patients since data are still conflicting.

Safety and efficacy of the vibrating capsule, an innovative non-pharmacological treatment modality for chronic constipation.

BACKGROUND: Constipation is a common disorder. Because the prevalence is high and the satisfaction level with currently available treatment is low, there is an unmet need for innovative treatment. We assessed the safety and efficacy of the Vibrant Capsule, a non-pharmacological device that is assumed to induce a normal peristaltic wave in the large intestine to alleviate constipation. METHODS: Two animal safety studies and a safety study on healthy volunteers were conducted, followed by a prospective, non-randomized, open-label, single group assignment, safety and efficacy study. The latter was conducted among 26 patients who ingested the capsule twice weekly for a study period of 7.5 weeks, after a run-in period of 2 weeks without usual treatment for constipation. KEY RESULTS: In the studies on animals and healthy volunteers, there were no adverse events. Twenty-eight patients began the clinical trial and 26 completed it (25 women). The mean age was 47.0 ± 12.6 years (range: 19-65). The two dropouts, who completed the safety phase, and the 26 who completed the entire study expelled the capsule without difficulty. Twelve participants reported 27 adverse events, none serious, and all transient. There was a significant increase of 1.60 ± 1.09 in the mean number of bowel movements/week from 2.19 ± 0.67 to 3.79 ± 1.31 (p < 0.001). This increase was seen in 23 of the 26 patients (88.5%). The mean number of spontaneous bowel movements for the study group increased in each treatment week compared to baseline. CONCLUSIONS & INFERENCES: The Vibrant Capsule is safe and potentially effective in the treatment of constipation, justifying randomized controlled studies.

The contribution of personal and exposure characteristics to the adjustment of adolescents following war.

The study examined the unique contribution of both personal characteristics and several types of exposure variables to the adjustment of Israeli adolescents following the Second Lebanon War. Two thousand three hundred and fourteen adolescents, who lived in areas that were the target of multiple missile attacks, completed self-report questionnaires assessing personal characteristics of gender and early traumatic events, subjective exposure (i.e., measures of fear and shortage of basic necessities during the war), objective exposure (i.e., exposure to missile attacks, knowing someone who was wounded or killed) and media exposure. Fifteen percent of the adolescents reported moderate or severe post-traumatic symptoms. Girls and adolescents who experienced earlier traumatic events were at higher risk for distress. While the level of direct exposure contributed to greater distress, the contribution of subjective exposure was significantly stronger. The discussion deals with the unique contribution of both subjective and objective characteristics to post-war adjustment.

Assessment of high-sensitivity CRP as a marker of micro-inflammation in irritable bowel syndrome.

BACKGROUND: The diagnosis of irritable bowel syndrome (IBS) is symptom-based. Although considered a functional disease, accumulating evidence supports a low-grade gut inflammation as an element of its pathophysiology. Thus, high-sensitivity C-reactive protein (hs-CRP), a marker of micro inflammation, may be elevated in IBS. Our aim was to assess whether hs-CRP is higher in IBS patients compared to healthy controls (HC) and does it differ among the IBS clinical subgroups and correlate with disease severity. METHODS: A diagnostic case control study was conducted in two gastroenterology departments. Eighty-eight IBS patients who were recruited prospectively answered the Rome III diagnostic questionnaire. They all completed the Functional Bowel Disorder Severity Index (FBDSI), dietary, and general health questionnaires. All patients underwent blood sampling for hs-CRP levels. Each IBS patient was matched to four HC by age, gender, and BMI. Blood samples were obtained from the HC at a periodic health survey. KEY RESULTS: The mean hs-CRP level in the IBS group was significantly higher than in HC (1.17±1.26mg L(-1) vs 0.72±0.91mg L(-1) respectively, P=0.001). Hs-CRP levels were highest in patients with diarrhea-predominant IBS and in patients with greater disease severity. A cut-off value of 1.08mg L(-1) had a sensitivity of 60.2% and a specificity of 68% for differentiating IBS from HC. CONCLUSIONS & INFERENCES: Hs-CRP levels are higher in IBS patients than HC, but still in the normal laboratory range. This may reflect the low-grade gut inflammation believed to occur in IBS and support its existence.

Complex trauma of war captivity: a prospective study of attachment and post-traumatic stress disorder.

BACKGROUND: Victims of war captivity sometimes suffer from complex post-traumatic stress disorder (PTSD), a unique form of PTSD that entails various alterations in personality. These alterations may involve changes in attachment orientation. METHOD: The sample comprised two groups of veterans from the 1973 Yom Kippur War: 103 ex-prisoners of war (ex-POWs) and 106 comparable control veterans. They were assessed at two points in time, 18 years and 30 years after the war. RESULTS: Ex-POWs suffered from more post-traumatic symptoms than controls at both measurements points and these symptoms increased only among ex-POWs from Time 1 to Time 2. In addition, both attachment anxiety and attachment avoidance increased with time among ex-POWs, whereas they decreased slightly or remained stable among controls. Finally, the increases in attachment anxiety and avoidance were positively associated with the increase in post-traumatic symptoms among both study groups. Further analyses indicated that early PTSD symptoms predicted later attachment better than early attachment predicted later PTSD symptoms. CONCLUSIONS: The results suggest that: (1) complex traumas are implicated in attachment orientations and PTSD symptoms even many years after captivity; (2) there is an increase in attachment insecurities (anxiety, avoidance) and an increase in PTSD symptoms decades after the captivity; (3) and post-traumatic stress symptoms predict attachment orientations better than attachment orientations predict an increase in PTSD symptoms.

The impact of resource loss on Holocaust survivors facing war and terrorism in Israel.

We examined the distress level of 102 Holocaust survivors in Israel during a recent period of continuous exposure of the Israeli population to terror and the threat of missile attack. Based on the Conservation of Resources (COR) theory, we explored the contribution of losses suffered during the Holocaust and of current loss of resources due to terror attacks on their distress level. Twenty one percent of the sample had probable PTSD and high psychological distress levels in general. Current loss of psychosocial resources contributed significantly to survivors' current PTSD symptomatology and general psychological distress, above the contribution of the previous Holocaust-related loss. Our findings support COR theory, which states that traumatic events are associated with ongoing and often rapid loss of resources. Resource loss, in turn, is associated with higher distress levels. Moreover, current loss of resources compounds the impact of earlier resource losses incurred during the Holocaust.

Assessment of dietary nutrients that influence perception of intra-oesophageal acid reflux events in patients with gastro-oesophageal reflux disease.

BACKGROUND: Gastro-oesophageal reflux disease symptoms are most commonly reported postprandially, suggesting that some diet components are likely to induce symptoms more than others. AIMS: To determine which of the various dietary nutrients is a strong predictive factor for symptom generation in association with an acid reflux event. METHODS: Subjects with typical heartburn symptoms were evaluated by the gastro-oesophageal reflux disease Symptom Checklist, demographics questionnaire, upper endoscopy and pH testing. During the pH study, patients completed a detailed 24-h dietary intake record. This included time of meals, description of food components and the amount and type of food preparation. RESULTS: Fifty gastro-oesophageal reflux disease patients completed all stages of the study. A total of 112 (78%) symptoms were considered as sensed reflux event. Body mass index did not correlate with having perceived reflux. Patients who consumed more cholesterol, saturated fatty acids and had more percentage calories from fat were significantly more likely to experience a perceived reflux event. Regression analysis and beta-coefficient were specifically significant for cholesterol. CONCLUSION: Of all dietary nutrients, cholesterol enhances the most the perception of intra-oesophageal acid reflux events in patients with gastro-oesophageal reflux disease.

Esophageal acid exposure at pH < or = 2 is more common in Barrett's esophagus patients and is associated with oxidative stress.

Barrett's esophagus (BE) patients demonstrate a higher distal esophageal acid exposure profile than other gastroesophageal reflux disease patients. Cellular oxidative stress has been proposed to contribute to the development of BE and esophageal adenocarcinoma. However, a relationship between low esophageal pH and oxidative stress has yet to be elucidated. The aim of this study was to determine the duration of low pH exposure in the esophagus of BE patients compared to those with erosive esophagitis (EE) and to test if brief exposure to low pH leads to the induction of reactive oxygen species (ROS). Seventy-three patients with BE or EE were evaluated by 24-hour esophageal pH monitoring and the percentage of time during which there was exposure to pH < or = 4 and pH < or = 2 was recorded. In vitro, Seg-1 and Het-1A cells were evaluated after brief exposure to pH4 or pH2 by flow cytometry and fluorescent microscopy for the production of ROS. BE patients demonstrated a significantly higher exposure to low pH values (pH < or = 2) than EE patients. The mean percent total time, duration and mean number of reflux episodes at pH < or = 2 were 2.8 +/- 0.53%, 28.8 +/- 3.6 seconds and 79 +/- 11.4 episodes in BE patients, whereas in EE patients they were significantly less, 1.16 +/- 0.3%, 15.6 +/- 1.2 seconds and 48.3 +/- 8.8 episodes, respectively (P < 0.05). In vitro experiments indicate that esophageal cells, when exposed to pH 2, produce ROS. In vitro studies using brief pH 2 exposure are biologically relevant to the clinical situation. Our studies indicate that such exposure induces oxidative stress. This stress may cause DNA damage, mutations and progression to cancer.

Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease--where next?

Proton-pump inhibitor failure has become a common clinical dilemma in gastrointestinal clinics and has been increasingly encountered at the primary care level as well. Underlying mechanisms are diverse and may overlap. Most patients who have proton-pump inhibitor failure are likely to originate from the non-erosive reflux disease phenotype. Currently, available diagnostic modalities provide limited clues to the exact underlying cause. Treatment relies primarily on escalating dosing of proton-pump inhibitors. However, new insights into the pathophysiology of proton-pump inhibitor failure are likely to provide alternative therapeutic options.

Feasibility and tolerability of transnasal/per-oral placement of the wireless pH capsule vs. traditional 24-h oesophageal pH monitoring--a randomized trial.

BACKGROUND: The wireless pH is a new technique to monitor oesophageal acid exposure. AIM: To compare the feasibility and tolerability of the wireless pH capsule vs. the traditional pH probe. METHODS: Consecutive patients referred for a pH test were enrolled into the study. Patients were randomized to traditional pH probe, or wireless pH capsule. Patients recorded their activities, food consumption, symptoms, satisfaction with the test and completed a quality of life questionnaire. RESULTS: Of the 50 patients recruited, 25 patients underwent placement of the traditional pH probe, and 25 the wireless pH capsule. Patients with the wireless pH capsule had less nose pain, runny nose, throat pain, throat discomfort and headache as compared with those with the traditional pH probe (P = 0.047, P = 0.001, P = 0.032, P = 0.001, P = 0.009, respectively). Patients in the wireless pH capsule group had more chest discomfort during the pH test (P = 0.037). Patients in the wireless pH capsule group perceived the test as interfering less with their overall daily activities, eating and sleep (P =0.001, P = 0.003, P = 0.025, respectively), and had overall satisfaction with the test (P = 0.023). CONCLUSIONS: Transnasal/per-oral placement of the wireless pH capsule is significantly better tolerated then the traditional pH probe.

Assessment of oesophageal motor function in patients with dysphagia or chest pain - the Clinical Outcomes Research Initiative experience.

BACKGROUND: Available prospectively acquired data on the distribution of oesophageal motor abnormalities in patients being evaluated for non-cardiac chest pain and/or dysphagia are relatively scarce. AIM: To evaluate the distribution of oesophageal motor abnormalities in patients with dysphagia, non-cardiac chest pain or both using the national Clinical Outcomes Research Initiative (CORI) database. METHODS: The CORI oesophageal motility database originates from 19 community, university and VA medical centres. Data were collected using a computerized motility report-generating program, combined with the CORI module. Data from each site were encrypted and sent to the CORI National Repository for analysis. The database includes the assessment of the lower and upper oesophageal sphincter function and the motor activity of the oesophageal body. RESULTS: Five hundred and eighty-seven consecutive patients who underwent motility studies between 1998 and 2001 were included in the CORI database and analysed for this report. Four hundred and three patients (69%) had dysphagia as their primary indicator for the examination, 140 patients (24%) had non-cardiac chest pain and 44 patients (7%) had both dysphagia and non-cardiac chest pain. In all three groups, a normal motility study was the most frequent finding (dysphagia, 53%; chest pain, 70%; both, 55%). The most common motility abnormality in the group with non-cardiac chest pain was a hypotensive lower oesophageal sphincter (61%). Nutcracker oesophagus and non-specific oesophageal motility disorders were each diagnosed in only 10% of patients with non-cardiac chest pain. In patients with dysphagia, ineffective peristalsis was the most common oesophageal dysmotility (27%), followed by achalasia and non-specific oesophageal motility disorders (18% and 14%, respectively). Achalasia and non-specific oesophageal motility disorders were the most common oesophageal motility abnormalities in patients with both chest pain and dysphagia (35% and 25%, respectively). CONCLUSIONS: The most common oesophageal motility abnormality in patients with non-cardiac chest pain is a hypotensive lower oesophageal sphincter; nutcracker oesophagus and non-specific oesophageal motility disorders are relatively uncommon; the most common oesophageal motility abnormality in patients with dysphagia is ineffective peristalsis and, for those with both dysphagia and non-cardiac chest pain, it is achalasia.

New horizons in the medical treatment of gastro-oesophageal reflux disease.

Proton pump inhibitors (PPIs) have revolutionized the treatment of gastro-oesophageal reflux disease (GERD). However, nearly 30% of all GERD patients are still symptomatic despite standard dose PPI treatment. Consequently, better treatment options are needed particularly in nonerosive reflux disease (NERD), which provides the largest number of patients that fail PPI. Transient lower esophageal relaxation (TLESR) is the underlying mechanism for most acid reflux events. Therefore, reducing the rate of TLESRs pharmacologically is an attractive therapeutic approach. Some compounds that were evaluated include: anticholinergics, opioids, cholecystokinin antagonists, nitric oxide antagonists, somatostatin, and GABA-B agonists. Currently, the GABA-B agonist baclofen generated the most promising results. Although data regarding GERD is lacking, visceral pain modulation, either pharmacologically or via mind-body interventions, was found to be efficacious in a variety of functional bowel disorders, including functional chest pain of presumed esophageal origin. Finally, intensive research is currently undergoing to develop newer acid suppressive agents. The acid pump inhibitors are reversible competitive inhibitors of the proton pump. These agents are potent suppressors of gastric acid secretion, and their effect is unrelated to food intake. Moreover, they demonstrate a faster onset of action and a predictable dose response effect as compared to the current PPIs. Although some of the preliminary clinical data is promising, thus far none of these agents is commercially available.

Secondary traumatization among wives of PTSD and post-concussion casualties: distress, caregiver burden and psychological separation.

This study has two aims. First, it assesses the implication of husbands' post-traumatic stress disorder (PTSD) and post-concussion syndrome (PC) on their wives' sense of burden and emotional distress. The second aim was to examine the implication of the women's separation-individuation on their adjustment. Sixty women participated in study: 20 women married to war veterans diagnosed as suffering to PTSD, 20 women married to war veterans suffering from PC, and 20 women married to healthy controls. Data was collected using self report questionnaires assessing psychiatric symptomatology, caregiver burden and psychological separation-individuation. Results indicate that women from both research groups suffer from higher levels of burden and distress than controls. The level of separation-individuation was found to be correlated to levels of burden and distress. The complex implications of living with a traumatized spouse are discussed.

Posttraumatic residues of captivity: a follow-up of Israeli ex-prisoners of war.

BACKGROUND: This article examines the long-term impact of wartime captivity. METHOD: One hundred sixty-four prisoners of war (POWs) and 189 matched combatants of the 1973 Yom Kippur War filled out a series of questionnaires that assessed posttraumatic stress disorder (PTSD), general psychiatric symptomatology, and social functioning according to DSM-III-R criteria. RESULTS: Almost 2 decades after the war, ex-POWs exhibited higher rates and greater intensity of posttraumatic stress reactions, more general psychiatric symptomatology, and more severe problems in functioning at home, at work, and in the military than did the control group (Israeli veterans who were not POWs). They were also more likely to obtain official disability recognition and to seek psychological help. Their recovery was slower and professional help less effective. In addition, the veterans with PTSD in both groups had high rates of comorbid general psychiatric symptomatology. CONCLUSION: These findings point to the depth, range, and persistence of the stress residuals of wartime captivity.

An eighteen-year follow-up study of Israeli prisoners of war and combat veterans.

The current study assesses the psychological and psychiatric aftermath of war captivity; 164 Israeli ex-POWs and 189 comparable controls were assessed for posttraumatic stress disorder, intrusion and avoidance tendencies, and generalized psychiatric symptomatology 18 years after the war. Findings indicated that trauma-related psychopathology and general psychiatric symptomatology were more prevalent among POWs than among their matched controls. In addition, captivity experience, social support at homecoming, and, above all, sociodemographic and military factors were found to be strongly correlated with the outcome measures. Theoretical and clinical implications of the aftermath of captivity are discussed.

Galectin-8. A new rat lectin, related to galectin-4.

A protein of 35 kDa which has the characteristic properties of galectins (S-type lectins) was cloned from rat liver cDNA expression library. Since names for galectins 1-7 were already assigned, this new protein was named galectin-8. Three lines of evidence demonstrate that galectin-8 is indeed a novel galectin: (i) its deduced amino acid sequence contains two domains with conserved motifs that are implicated in the carbohydrate binding of galectins, (ii) in vitro translation products of galectin-8 cDNA or bacterially expressed recombinant galectin-8 are biologically active and possess sugar binding and hemagglutination activity, and (iii) a protein of the expected size (34 kDa) that binds to lactosyl-Sepharose and reacts with galectin-8-specific antibodies is present in rat liver and comprises approximately 0.025% of the total Triton X-100-soluble hepatic proteins. Overall, galectin-8 is structurally related (34% identity) to galectin-4, a soluble rat galectin with two carbohydrate-binding domains in the same polypeptide chain, joined by a link peptide. Nonetheless, several important features distinguish these two galectins: (i) Northern blot analysis revealed that, unlike galectin-4 that is confined to the intestine and stomach, galectin-8 is expressed in liver, kidney, cardiac muscle, lung, and brain; (ii) unlike galectin-4, but similar to galectins-1 and -2, galectin-8 contains 4 Cys residues; (iii) the link peptide of galectin-8 is unique and bears no similarity to any known protein; (iv) the N-terminal carbohydrate-binding region of galectin-8 contains a unique WG-E-I motif instead of the consensus WG-E-R/K motif implicated as playing an essential role in sugar-binding of all galectins. Together with galectin-4, galectin-8 therefore represents a subfamily of galectins consisting of a tandem repeat of structurally different carbohydrate recognition domains within a single polypeptide chain.

Cytokine-induced resistance to microbial infections in normal, immunosuppressed and bone marrow transplanted mice.

We studied the efficacy of in vivo and in vitro treatments with IL-1, IL-2, IL-3, and GM-CSF in the protection against bacterial (Salmonella typhimurium), fungal (Candida albicans) and viral (influenza virus A/PR8) infections, of normal, sublethally irradiated and lethally irradiated, bone marrow (BM) reconstituted mice. In parallel, the cytokines were tested for their ability to potentiate hematopoietic activity in vitro and in vivo. We demonstrate that, under the experimental conditions employed, IL-1 had the best protective activity against the three micro-organisms in both normal and immunocompromised mice when administered in vivo. Administration of IL-2 led to increased resistance in normal but not in immunodeficient mice, whereas GM-CSF had no beneficial effects. In contrast, preincubation of BM cells in these cytokines, singly or combined, prior to transplantation to lethally irradiated mice, did not confer protection against subsequent infection, although it increased the number of BM derived CFU-GM in culture (except in the case of IL-2). Administration of IL-1 or GM-CSF to BM transplanted mice facilitated WBC recovery, whereas IL-2 delayed it. Collectively, the data suggest that IL-1, alone or combined with other cytokines, may be beneficial in the prevention or treatment of microbial infections in immunocompromised and BM transplanted patients. It can also be concluded that enhanced hematopoietic recovery may not always coincide with the development of resistance to micro-organisms.