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Background Ageing can result in major changes in the composition and metabolic activities of bacterial populations in the large gut and an impaired immune system. Aim To investigate the effects of synbiotic consumption on the colonic microbiota, immune function and health status in older people. Methods A randomised, double-blind placebo-controlled, 4-week crossover study was carried out, involving 43 older volunteers, using a synbiotic comprising the probiotic Bifidobacterium longum and an inulin-based prebiotic Synergy 1 (SudZucker, Mannheim, Germany). Faecal and blood samples were collected, and clinical status scored at the start, and at 2- and 4-week intervals, with a 4-week washout between each feeding period. Faecal bacteria were determined by fluorescent in situ hybridisation. Short-chain fatty acid concentrations, cytokine production, bowel habit and a range of clinical parameters were measured. Results The synbiotic increased bifidobacterial numbers by 1.4 log units ( P < 0.0001) and also increased members of the phyla Actinobacteria and Firmicutes ( P = 0.0004, P < 0.0001). Proteobacteria were reduced by 1.0 log units ( P < 0.0001). Synbiotic feeding was associated with increased butyrate production ( P = 0.0399). The pro-inflammatory response was modified by the synbiotic, with significantly reduced pro-inflammatory cytokine TNF-α in peripheral blood after 2 and 4 weeks of synbiotic consumption ( P = 0.02, P = 0.0406). The synbiotic had no effect on bowel habit or any clinical parameters. Conclusion Short-term synbiotic use can be effective in improving the composition and metabolic activities of colonic bacterial communities and immune parameters in older people. This study was registered at clinicaltrials.gov as NCT01226212. [ABSTRACT FROM AUTHOR]

Summary Barrett's oesophagus ( BO) and gastro-oesophageal reflux disease ( GERD) are precursors of oesophageal adenocarcinoma ( OAC). There is an oesophageal biofilm, which changes in disease, but its role in aetiopathogenesis remains unclear. Aim To define the oesophageal microbiota of patients with GERD, BO and OAC compared with controls and to investigate mucosal responses related to the microbiota. Methods Cultural analysis identified the dominant bacterial species from a subset of each disease group. Based on this, molecular techniques were used to define the cohort. Host responses were analysed in tissues and co-culture experiments. Results A total of 111 species belonging to 26 genera were isolated. There was a significant decrease in bacterial counts in the GERD and BO groups for all genera except Campylobacter, which colonised GERD and Barrett's patients in increasing numbers. Campylobacter concisus was the dominant species. This relationship was not seen in the cancer group. Significant increases in IL-18 were seen in GERD and BO colonised by Campylobacter. Conclusions This study defines differences in the oesophageal biofilm in disease states, revealing the emergence of C. concisus as the dominant new colonist in the refluxed oesophagus. We also associate the presence of these bacteria with increased expression of cytokines related to carcinogenesis. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to determine if genetic variation in the pain-modulating gene DREAM and its pathway genes influence susceptibility to reporting musculoskeletal pain in the population. Methods Pairwise tag single nucleotide polymorphisms ( SNPs) in DREAM, PDYN and OPRK1 were genotyped in a UK population-based discovery cohort in whom pain was assessed using blank body manikins at three time points. Depression and anxiety symptoms were assessed at the first time point. Zero-inflated negative binomial regression was used to test for association between SNPs and the maximum number of pain sites reported (0-29) across the three time points. Significantly associated SNPs ( p < 0.05) were subsequently genotyped for validation in a cohort of European men with pain assessed at two time points. Results Thirty-five SNPs were genotyped in 1055 subjects, of whom 83% reported pain, in the discovery cohort. SNPs in each gene were associated with the maximum number of pain sites reported, were independent of symptoms of anxiety and depression and had a significant cumulative effect ( p = 7.0 × 10−5). Significantly associated SNPs were successfully genotyped in 1733 men, 76% of whom reported pain, in the validation cohort, but did not show significant association with the number of pain sites. Conclusions Genetic variation in the DREAM pathway genes was associated with the extent of pain reporting in a population-based cohort. These findings were not replicated in a single independent cohort; however, given the potential of this pathway as a therapeutic target, further investigation in additional cohorts is warranted. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2010; 32: 872–883 Background Crohn’s disease is an inflammatory illness in which the immune response against gut microorganisms is believed to drive an abnormal immune response. Consequently, modification of mucosal bacterial communities, and the immune effects they elicit, might be used to modify the disease state. Aim To investigate the effects of synbiotic consumption on disease processes in patients with Crohn's disease. Methods A randomized, double-blind placebo-controlled trial was conducted involving 35 patients with active Crohn's disease, using a synbiotic comprising Bifidobacterium longum and Synergy 1. Clinical status was scored and rectal biopsies were collected at the start, and at 3- and 6-month intervals. Transcription levels of immune markers and mucosal bacterial 16S rRNA gene copy numbers were quantified using real-time PCR. Results Significant improvements in clinical outcomes occurred with synbiotic consumption, with reductions in both Crohn's disease activity indices ( P = 0.020) and histological scores ( P = 0.018). The synbiotic had little effect on mucosal IL-18, INF-γ and IL-1β; however, significant reductions occurred in TNF-α expression in synbiotic patients at 3 months ( P = 0.041), although not at 6 months. Mucosal bifidobacteria proliferated in synbiotic patients. Conclusion Synbiotic consumption was effective in improving clinical symptoms in patients with active Crohn's disease. [ABSTRACT FROM AUTHOR]

Background Prebiotics are short-chain carbohydrates that alter the composition, or metabolism, of the gut microbiota in a beneficial manner. It is therefore expected that prebiotics will improve health in a way similar to probiotics, whilst at the same time being cheaper, and carrying less risk and being easier to incorporate into the diet than probiotics. Aim To review published evidence for prebiotic effects on gut function and human health. Methods We searched the Science Citation Index with the terms prebiotic, microbiota, gut bacteria, large intestine, mucosa, bowel habit, constipation, diarrhoea, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pouchitis, calcium and cancer, focussing principally on studies in humans and reports in the English language. Search of the Cochrane Library did not identify any clinical study or meta-analysis on this topic. Results Three prebiotics, oligofructose, galacto-oligosaccharides and lactulose, clearly alter the balance of the large bowel microbiota by increasing bifidobacteria and Lactobacillus numbers. These carbohydrates are fermented and give rise to short-chain fatty acid and intestinal gas; however, effects on bowel habit are relatively small. Randomized-controlled trials of their effect in a clinical context are few, although animal studies show anti-inflammatory effects in inflammatory bowel disease, while calcium absorption is increased. Conclusions It is still early days for prebiotics, but they offer the potential to modify the gut microbial balance in such a way as to bring direct health benefits cheaply and safely. [ABSTRACT FROM AUTHOR]

The relationship between the dose of tacrolimus, trough tacrolimus blood concentration, and selected clinical endpoints (acute rejection, nephrotoxicity, and other toxicities) were examined in a prospective, multicenter clinical trial to validate the use of an enzyme-linked immunosorbent assay (ELISA) for monitoring whole-blood concentrations of tacrolimus in liver transplant patients. A total of 111 subjects from six transplant centers were evaluated over 12 weeks posttransplantation. In addition to trough tacrolimus blood concentrations, hematocrit, ALT, AST, GGTP, alkaline phosphatase, total bilirubin, serum creatinine, BUN, serum potassium, serum magnesium, blood glucose, and serum albumin were also measured. The relationship between trough tacrolimus blood concentrations and clinical endpoints was analyzed using both a logistic regression model and a Cox proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between increasing trough tacrolimus blood concentrations and decreasing risk of acute rejection was demonstrated over a 7-day time window. Nephrotoxicity and other toxicities also demonstrated statistically significant relationships with trough tacrolimus blood concentrations. The results of the Cox analysis were consistent with the logistic regression analysis. Using receiver operator characteristic curves, trough tacrolimus concentrations as measured by the ELISA method were able to differentiate the occurrence of nephrotoxicity and toxicity from nonevents. To minimize nephrotoxicity of tacrolimus, it is necessary to maintain trough blood concentrations below 15 ng/ml. This study demonstrates that the ELISA method used to measure tacrolimus blood concentrations in this study provides information of predictive value for managing the risk of nephrotoxicity, other toxicity, and rejection in liver transplant patients. [ABSTRACT FROM AUTHOR]

Certain strains of viridans streptococci bind platelets, which release ATP from dense granules and then aggregate. By hydrolyzing the released ATP to the platelet agonist, ADP, cell wall-associated ATPase activity of Streptococcus sanguis may amplify the aggregation of platelets. To identify and characterize this ecto-ATPase activity, whole cells were incubated with [14C]-ATP. The cell-free nucleotides were separated by thin-layer chromatography and quantified by liquid scintillation counting. Whole-cell activity showed temperature and pH optima in the physiological range. To isolate a soluble fraction with ATPase activity from the cell wall, whole cells were digested under osmotically stable conditions to produce protoplasts. Protoplasts and cells were separated from soluble cell wall materials by centrifugation. ATPase activity in cell fractions was identified by zymograms of native 8% polycrylamide gels after electrophoresis. The ecto-ATPase preparation, membrane and cytoplasmic ATPase in lysed protoplasts showed different zymograms and sensitivity to inhibition by DCCD, ouabain vanadate, azide and NEM. In electron micrographs of ultrathin sections of cells of S. sanguis, ATPase activity was localized to the cell wall. Since the pattern of localization to the wall changed with the phase of growth, the ecto-ATPase of S. sanguis may be associated with the development and maintenance of the cell wall. [ABSTRACT FROM AUTHOR]

Incidence and mortality rates for oral and pharyngeal cancers have been reported to be increasing in Europe and the United States, with particularly large increases in mortality in central and eastern Europe. Such increases have been noted to be birth cohort-based, primarily affecting young and middle-aged men. In this report oral and pharyngeal cancer incidence data from New South Wales, Australia has been analysed for the period 1972-90. Although an increase in the incidence of oral and pharyngeal cancer occurred during the mid-1970s and early 1980s, it did not continue. This pattern is consistent with Australian trends in per capita consumption of tobacco, alcohol, fruit and vegetables. Individual regions within metropolitan Sydney showed substantial geographical variation with age-specific rates of oral and pharyngeal cancers (combined) in middle-aged men being at least three times higher in the city of Sydney than in New South Wales as a whole. Given the preventable nature of the disease, such high rates need not occur. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that abnormalities in the hypothalamic-pituitary-adrenal (HPA) stress-response system would act as an effect moderator between HPA function and the onset of chronic widespread pain (CWP)., Methods: We conducted a population-based prospective cohort study. Current pain and psychosocial status were ascertained in 11,000 subjects. Of the 768 eligible subjects free of CWP but at future risk based on their psychosocial profile, 463 were randomly selected, and 267 (57.7%) consented to assessment of their HPA axis function. Diurnal function was measured by assessing levels of salivary cortisol in the morning (9:00 AM) and evening (10:00 PM). Serum cortisol levels were measured after an overnight low-dose (0.25 mg) dexamethasone suppression test and a potentially stressful clinical examination. All subjects were followed up 15 months later to identify cases of new-onset CWP., Results: A total of 241 subjects (94.9%) completed the followup study, and 28 (11.6%) reported the new onset of CWP. High levels of cortisol post-dexamethasone (odds ratio [OR] 3.53, 95% confidence interval [95% CI] 1.17-10.65), low levels in morning saliva (OR 1.43, 95% CI 0.52-3.94), and high levels in evening saliva (OR 2.32, 95% CI 0.64-8.42) were all associated with CWP. These 3 factors were found to be independent and additive predictors of CWP (OR for all 3 factors 8.5, 95% CI 1.5-47.9) in analyses controlling for age, sex, depression, sleep disturbance, recent traumatic life events, and pain status. One or more of these 3 HPA factors identified 26 (92.9%) cases of new-onset CWP., Conclusion: Among a group of psychologically at-risk subjects, dysfunction of the HPA axis helps to distinguish those who will and will not develop new-onset CWP.

Objective: Chronic widespread pain, the clinical hallmark of the fibromyalgia syndrome, is associated with other physical and psychological symptoms both in patients studied in a clinical setting and in those identified in the community. The present study was undertaken to examine the hypothesis that psychological and physical indicators of the process of somatization predict the development of new chronic widespread pain., Methods: In this population-based prospective study, 1,658 adults ages 18-65 years completed a detailed pain questionnaire, which included a pain drawing. They also completed the following psychosocial instruments: General Health Questionnaire, Somatic Symptom Checklist, Fatigue Questionnaire, and Illness Attitude Scales. Individuals were followed up at 12 months, at which time 1,480 (93% of subjects still living at their baseline address) provided data on pain status, using the same instruments., Results: At baseline, 825 subjects were classified as pain free and 833 as having pain not satisfying criteria for chronic widespread pain. Of those, 18 (2%) and 63 (8%), respectively, were classified as having chronic widespread pain at followup. After adjustment for age and sex, there were strong relationships between baseline test scores and subsequent risk of chronic widespread pain (odds ratio for the Somatic Symptom Checklist 3.3; odds ratio for the Illness Behavior subscale of the Illness Attitude Scales 9.0). All 95% confidence intervals excluded unity. These associations were independent of baseline pain status., Conclusion: Subjects who are free of chronic widespread pain are at increased future risk of its development if they display other aspects of the process of somatization. Data from this population-based prospective study lend powerful support to the hypothesis that chronic widespread pain can be one manifestation of the somatization of distress.

Objective: Patients with chronic widespread pain (CWP) have been reported to have a greater prevalence of mental disorders and somatization than that found in the general population, but the true association between CWP and mental disorders is unknown. In this study, we investigated whether there is an increased prevalence of mental disorder in people with CWP from the general population. We also describe the psychiatric diagnoses associated with CWP., Methods: In a population-based case-control study, 1,953 subjects (75% of a random sample of individuals age 18-65 years) completed a questionnaire that included a pain assessment and the 12-item General Health Questionnaire (GHQ-12). Of 710 subjects scoring >1 on the GHQ-12, 301 were assessed further using a structured psychiatric interview and detailed assessment of medical records to identify cases of mental disorder, in accordance with criteria of the 10th edition of the International Classification of Diseases. The association between CWP and mental disorder was modeled using logistic regression, adjusting for possible confounders including age, sex, and nonresponders., Results: We estimated the overall population prevalence of mental illness to be 11.9%. The odds of having a mental disorder for subjects with versus those without CWP were 3.18 (95% confidence interval 1.97-5.11). Most subjects with mental disorders were diagnosed as having mood and anxiety disorders. Only 3 cases of somatoform disorders were identified, and all were associated with pain., Conclusion: This study, although unable to demonstrate a cause-and-effect relationship, showed that 16.9% of those with CWP were estimated to have a psychiatric diagnosis, suggesting that these disorders should be identified and treated.

Objective: To examine the hypothesis that characteristics of somatization and illness behavior, and their childhood antecedents, are associated with the presence of multiple tender points., Methods: Two hundred eighty-nine subjects who had demonstrated psychological distress (General Health Questionnaire score > or =2) had a tender point examination and in-depth psychological evaluation. In addition, subjects were interviewed about a number of adverse childhood experiences. The 99 subjects with 5 or more tender points were compared with the remaining 190 subjects., Results: A high tender point count (> or =5) was associated with low levels of self-care (odds ratio [OR] 2.4, 95% confidence interval [95% CI] 1.1-5.0), reports of a greater number of somatic symptoms (OR 2.2, 95% CI 1.0-4.9), high levels of fatigue (OR 3.3, 95% CI 1.7-6.3), and a pattern of illness behavior characterized by increased medical care usage (OR 4.2, 95% CI 2.1-8.4). Those with high tender point counts were substantially more likely to report adverse childhood experiences, including loss of parents (OR 2.1, 95% CI 1.1-3.9) and abuse (OR 6.9, 95% CI 2.0-24.6). These results were not explained by the presence of chronic pain., Conclusion: These data add further weight to the hypothesis that tender points, as part of the fibromyalgia syndrome, are strongly associated with specific components of psychological distress as well as characteristics of somatization and its antecedents. It is possible that these features contribute to the development of the syndrome of fibromyalgia.