[The improvement of the transfer into daily life of progressive relaxation after an inpatient psychosomatic rehabilitation]. / Verbesserung des Transfers von Progressiver Relaxation in den Alltag der Patienten nach stationärer psychosomatischer Rehabilitation.

AIM OF THE STUDY: The aim of the current study was the identification of predictors for a successful transfer of progressive relaxation (PR) into clinical and daily life. Furthermore the development of tension-related symptoms dependening of the frequency of continuous practise was detected. METHODS: 411 patients of a psychosomatic rehabilitation clinic attended a 6-h-course of progressive relaxation and were interviewed at 3 different times by a modified version of the "diagnostisches und evaluatives Instrumentarium für Entspannungstraining und Entspannungstherapie (ET-EVA)": at the beginning of therapy (T1), at discharge (T2) and 3 months after discharge by postal service (T3). After 3 months 274 patients (78.3%) sent the completed questionnaires back. The frequency of exercising by at least once a week was defined as successful. To detect the extent of symptom improvement, difference values between the different measuring times and effect sizes were calculated. To identify predictors of the frequency of daily practise, bivariate correlations and linear regression were used. RESULTS: 69.4% of the patients continued the exercises successfully beyond the course. The improved experience of relaxation directly after the program (r=-0.184; p<0.01) had a positive influence on the frequency of practising during hospital stay. 3 months after discharge 50.4% of the participants were practising at least once a week. The frequency of practise during hospital stay (r=0.558; p<0.01) and the experience of relaxation at T3 (r=-0.356; p<0.01) could be identified as predictors of a successful transfer into daily life of progressive relaxation. In the context of the linear regression the effect of the frequency of practise during hospital stay (Beta=0.506; p<0.01) and the experience of relaxation after 3 months (Beta=-0.275; p<0.01) remained significant predictors and explaines 40.9% of the variance. The items of all 6 symptom scales decreased significantly from T1 to T2 (p<0.01) and the feeling of discomfort after 3 months was significantly below the base level of T1 (p<0.01). The patients who practised at least once a week - compared to the not-practising patients - declared significantly less tension-related symptoms at T3 (p<0.01) and could achieve a significantly stronger change of wellbeing and relaxation experience at T2 and T3 (p<0.01). CONCLUSION: 50.4% of the patient implemented the relaxation training in their daily routine. The experienced alteration in terms of self-efficacy plays a meaningful role concerning the frequency of practise in hospital stay and daily routine. In future courses attention should be paid to the initial experience of relaxation. The frequency of practise once a week turned out to be the most effective.

A vegan or vegetarian diet substantially alters the human colonic faecal microbiota.

BACKGROUND/OBJECTIVES: Consisting of ≈10(14) microbial cells, the intestinal microbiota represents the largest and the most complex microbial community inhabiting the human body. However, the influence of regular diets on the microbiota is widely unknown. SUBJECTS/METHODS: We examined faecal samples of vegetarians (n=144), vegans (n=105) and an equal number of control subjects consuming ordinary omnivorous diet who were matched for age and gender. We used classical bacteriological isolation, identification and enumeration of the main anaerobic and aerobic bacterial genera and computed absolute and relative numbers that were compared between groups. RESULTS: Total counts of Bacteroides spp., Bifidobacterium spp., Escherichia coli and Enterobacteriaceae spp. were significantly lower (P=0.001, P=0.002, P=0.006 and P=0.008, respectively) in vegan samples than in controls, whereas others (E. coli biovars, Klebsiella spp., Enterobacter spp., other Enterobacteriaceae, Enterococcus spp., Lactobacillus spp., Citrobacter spp. and Clostridium spp.) were not. Subjects on a vegetarian diet ranked between vegans and controls. The total microbial count did not differ between the groups. In addition, subjects on a vegan or vegetarian diet showed significantly (P=0.0001) lower stool pH than did controls, and stool pH and counts of E. coli and Enterobacteriaceae were significantly correlated across all subgroups. CONCLUSIONS: Maintaining a strict vegan or vegetarian diet results in a significant shift in the microbiota while total cell numbers remain unaltered.

Postinfectious irritable bowel syndrome: follow-up of a patient cohort of confirmed cases of bacterial infection with Salmonella or Campylobacter.

BACKGROUND: Gastrointestinal infections have been proposed to predict subsequent irritable bowel syndrome (IBS) but large-scale infectious events are rare and long-term data are missing. METHODS: We identified 576 individuals with a Salmonella or Campylobacter infection between 2000 and 2009 that were followed by a short postal questionnaire asking for the presence of current symptoms in 2010. In case of agreement (n = 90), an extended postinfectious (PI)-IBS questionnaire was mailed including the Hospital Anxiety Depression Scale and the Patient Health Questionnaire. KEY RESULTS: A total of 189 patients reported back (36%); 98 had a Salmonella and 91 had a Campylobacter infection, of which 56 reported persistent symptoms (9.7% of the initial sample). Fifty-one patients returned the PI-IBS questionnaire. Of 48 patients with complete data, 15 reported no or mild symptoms of abdominal pain or discomfort while 17 had moderate and 16 severe symptoms. Twenty-two met Rome IBS criteria, 14 (29%) reported GI symptoms before the infection. Patients with moderate and/or severe PI-IBS symptoms were significantly more often females, were more often infected by Salmonella than by Campylobacter, had more severe symptoms during the initial infection, and had more often GI symptoms prior to the infection. They reported higher anxiety, depression, and somatisation scores, but were not different with respect to acute stool habits. CONCLUSIONS & INFERENCES: Nearly 10% of patients with an intestinal bacterial infection report postinfectious symptoms up to 10 years after the infectious event. They represent a clinically important population with high psychiatric comorbidity and somatic symptom burden.

[Placebo response: in studies on pain and under other clinical conditions]. / Placeboresponse: In Studien zum Schmerz und anderen klinischen Bedingungen.

This contribution compares unexplained essential questions regarding the placebo response with current empirical evidence: (1) Are the placebo response rates equivalent in the groups treated with medication or placebo? Very little evidence has been gathered to support this generally accepted additivity while some findings negate its validity. (2) Is the placebo response a function of the probability of receiving medication or placebo? There are indications that the number of study groups included in a trial determines the level of placebo and medication response. (3) How great is the placebo response in trials that directly compare a (new) medication with one that for example is already on the market? There are indications that such comparative studies produce higher placebo response rates. (4) How high is the placebo response rate in everyday clinical practice--or does the response to a medication in trials substantiate the effect of the medication in everyday clinical practice?

[Probiotic therapy of the irritable bowel syndrome]. / Probiotische Behandlung des Reizdarmsyndroms.

The irritable bowel syndrome (IBS) is among the most common disorders in gastroenterological practice with a prevalence of approx. 12 % in Germany, and it is characterized by abdominal pain or discomfort, altered stool frequency and consistency, and meteorism and bloating. There is currently no agreement between those seeing patients with IBS (general practitioner, gastroenterologist, psychosomatics) on the criteria for clinical diagnosis. Metaanalyses of treatment studies in IBS have shown that probiotics have a high clinical efficacy in IBS, especially since development of novel pharmaceutical compounds have not reached the market or have been withdrawn. In addition to the actual status of probiotic efficacy in IBS studies conducted worldwide, we present 3 German clinical studies with probiotic E.COLI preparations that have proven their efficacy in IBS in adults and in children.

Acute tryptophan depletion increases experimental nausea but also induces hunger in healthy female subjects.

BACKGROUND: Acute tryptophan depletion (ATD) is an experimental model to reduce central serotonin levels. METHODS: Thirty-eight healthy female subjects were randomly assigned to two groups (ATD and control) in a randomized, double-blinded parallel-group design. Following a standardized and balanced amino acid diet (including 1.21 g tryptophan) on the first day, they received either a protein drink without tryptophan (but substituted by other amino acids) (ATD condition) or the balanced protein drink with tryptophan (control condition) 24 h later. Four hours after its consumption, they were exposed to a standard rotation procedure. Symptom ratings (SR), ratings of hunger and mood scores were taken prior to rotation, at each break, and 15 and 30 min thereafter, together with saliva cortisol samples. KEY RESULTS: Five subjects could not tolerate the entire rotation procedure and were excluded from analysis. For the remaining n = 33, SR and hunger ratings were higher during ATD than during control conditions, but mood was unaffected. Cortisol levels rose significantly with rotation but were unaffected by ATD. High baseline cortisol levels were associated with lower SR during rotation. The protective effects of morning cortisol were pronounced during the menstrual and follicular phase of the cycle and not present during ovulation and the luteal phase. CONCLUSIONS & INFERENCES: Acute tryptophan depletion is associated with increased symptoms of nausea in healthy female subjects when exposed to body rotation. Acute tryptophan depletion also increases hunger rating. These opposite effects may indicate independent actions of the serotonin on central and peripheral functions.

The effects of maturation on the colonic microflora in infancy and childhood.

The composition of colonic mircoflora and its changes with maturation have rarely been investigated in large samples. Methods. We used conventional microbiological testing to analyse the colonic flora (Kyberstatus, Institut forMicroecology, Herborn, Germany) of stool samples from 12 484 children with different intestinal and nonintestinal diagnoses. Stool samples were analysed for total colony forming units (CFU) (per g stool) and the abundance of Bifidobacteria, Bacteroides sp., Escherichia coli, Enterococcus sp., and Lactobacillus sp. with respect to age, gender. A subset of 1089 infants was analysed for monthly changes within the first year of life. Results. Total CFU and individual microbial species were highest during the first year of life, decreased within the first 2 years, and then stabilized for the remaining childhood. In infants, the total CFU rose until month 5, declined with weaning, and peaked at 9-10 months. Significant effects of age, but not of gender, were found in Bacteroides sp. and Lactobacilli. However Bacterioids sp. and Lactobacilli increased with age, while Enterococci and E. coli decreased, and Bifidobacteria remained stable. Conclusion. Colonic microflora show both a bacteria-specific and general pattern of maturation which is most profound within the first year.

Biofeedback therapy in fecal incontinence and constipation.

We examine the collected evidence for efficacy of biofeedback therapy (BFT) in incontinence and constipation by means of meta-analysis of randomized controlled trials. PubMed search was performed to identify treatment trials that match quality criteria (adequate control groups, randomization). They were entered into meta-analyses using fixed effect models and computing odds ratio (OR) and 95% confidence interval (CI) of treatment effects. For constipation, eight BFT trials were identified. In four trials, electromyographic (EMG) BFT was compared to non-BFT treatments (laxatives, placebo, sham training and botox injection), while in the remaining four studies EMG BFT was compared to other BFT (balloon pressure, verbal feedback) modes. Meta-analyses revealed superiority of BFT to non-BFT (OR: 3.657; 95% CI: 2.127-6.290, P < 0.001) but equal efficacy of EMG BFT to other BF applications (OR: 1.436; CI: 0.692-3.089; P = 0.319). For fecal incontinence, a total of 11 trials were identified, of which six compared BFT to other treatment options (sensory training, pelvic floor exercise and electrical stimulation) and five compared one BFT option to other modalities of BFT. BFT was equal effective than non-BFT therapy (OR: 1.189, CI: 0.689-2.051, P = 0.535). No difference was found when various modes BFT were compared (OR: 1.278, CI: 0.736-2.220, P = 0.384). Included trials showed a substantial lack of quality and harmonization, e.g. variable endpoints and missing psychological assessment across studies. BFT for pelvic floor dyssynergia shows substantial specific therapeutic effect while BFT for incontinence is still lacking evidence for efficacy. However, in both conditions the mode of BFT seems to play a minor role.

The effects of ageing on the colonic bacterial microflora in adults.

BACKGROUND: The composition of the fecal mircoflora and its changes on ageing have rarely been investigated in large samples of both patients and volunteers. METHODS: We analysed the fecal flora by conventional microbiological testing (Kyberstatus, Institute of Microecology, Herborn, Germany) of stool samples from 35 292 adults (age: 46.3 +/- 0.08 [18 to 96] years, 9564 males, 24 784 females; remaining = missing data) with different intestinal and non-intestinal diagnoses for total colony-forming units (CFU) (per g stool) as well as relative abundance of Bifidobacteria, Bacteroides spp., Escherichia coli, Enterococcus spp., and Lactobacillus spp. with respect to age, gender, and clinical data available (e. g., stool consistency and pH). RESULTS: The total CFU was stable and showed no age- or gender-related changes. Individual bacterial species constantly and significantly increased with age (E. coli, Enterococci spp.), or decreased at higher age (Bacteroides spp.), or were stable throughout the life span (Lactobacilli, Bifidobacteria). Gastrointestinal diagnoses (Crohn's disease, n = 198; ulcerative colitis, n = 515; irritable bowel syndrome, n = 7765; other GI diagnoses, n = 10 478) tended to exhibit some specificity of the bacterial profile, and when GI diagnoses were excluded, the age-related bacterial profile of the remaining group (n = 15 619, m:f = 4197:11 422) was not different. CONCLUSION: Conventional microbiological investigations of the fecal microbiota showed both bacteria-specific as well as a general pattern of ageing of the colonic microbiota, with the last decades (more than 60 years) demonstrating the most profound changes. It remains to be shown whether these changes reflect direct changes of the gut microbiota, the mucosal innate immunity, or indirect consequences of age-related altered nutrition.

Cortisol levels predict motion sickness tolerance in women but not in men.

A variety of intrinsic and extrinsic factors contribute to motion sickness severity in a stressful motion environment. The interplay of all these factors may partially explain the high inter-subject variability of motion sickness susceptibility found in many studies as well as some of the contradictory findings between studies regarding the modulating influence of single factors. We investigated the role of endogenous cortisol levels, gender and repetitive experience for motion sickness susceptibility. Motion sickness was induced in 32 healthy, but motion-sickness susceptible volunteers (16:16 males:females), by means of a vection drum. Subjects were investigated between 8:00 am (high cortisol) and 11:00 am (low cortisol), and on five consecutive days. Tolerance to rotation (RT) of the drum, motion sickness symptom ratings (SR) and salivary cortisol levels were assessed. Baseline cortisol levels correlated positively with RT in women, but not in men. RT showed a gender-specific time course across days, with higher values in males than in females on day 1, and sensitization on day 3 only in men. SR and cortisol levels following rotation did not differ between males and females, or between testing days. Gender differences in motion sickness susceptibility appear to be linked to a different role of basal cortisol levels for motion sickness tolerance. Results clearly indicate the need to control for gender, day time and cortisol levels in studies of motion sickness.

[The placebo effect in medicine]. / Der Placeboeffekt in der Medizin.

Placebos are medication surrogates that are able to improve symptoms in patients when prescribed by a doctor and for a patient, and that cannot be explained by a drug. In clinical testing and presumably also in clinical routine, placebo effects contribute substantially to the efficacy of medicines, at least with every-day diseases and complaints. Placebos on the one hand, and the mechanisms the response on the other, have not interfered with the development on novel drugs in past years, but have also brought about research that investigates its mechanisms and public interest in its clinical use in everyday medicine. Current knowledge grows by about 10.000 publications per year on placebo-controlled studies, and by nearly 100 papers on the placebo effect itself. This review will focus on the history of placebo use in medicine, on ethical issues related to the use of placebos, on methodological problems in placebo-controlled trials and their alternatives, and on mechanisms of the placebo response in clinical and experimental research, e.g. on type, size, dynamics, determinants, and predictors of the placebo response in the literature.

The story of O--is oxytocin the mediator of the placebo response?

While the placebo responses in various medical conditions have been shown to follow a few basic principles such as expectancies, reward learning and Pavlovian conditioning, the underlying neurobiology and the mediating hormonal and/or neuromodulating processing have remained obscure. We here report the collected evidence that oxytocin (OXT), a 389-amino acid polypeptide located on chromosome 3p25 that is released in the brain (hypothalamus) and in peripheral tissue, is the central mediator of the placebo response: we hypothesize that exogenous OXT via an OXT agonist will enhance the placebo response, while exogenous OXT blockade by an antagonist will reduce the placebo response in placebo analgesia and other placebo models. It is furthermore proposed that the placebo response in trials may be predicted by circulating plasma OXT levels, the OXT receptor density in the brain and/or the presence of one or more of the single nucleotide polymorphisms of the OXT promoter gene.

Randomized controlled treatment trial of irritable bowel syndrome with a probiotic E.-coli preparation (DSM17252) compared to placebo.

BACKGROUND: Therapy trials with bacterial compounds in irritable bowel syndrome (IBS) have produced conflicting results and, so far, an E.-coli preparation has not been used. METHODS: Two hundred and ninety-eight patients with lower abdominal symptoms diagnosed as IBS were treated for 8 weeks by the compound Symbioflor-2 (Symbiopharm GmbH, Herborn, Germany), an Escherichia coli product (N = 148), or placebo (n = 150) in a double-blinded, randomized fashion. Patients were seen weekly by the physician, who assessed the presence of core IBS symptoms. Both an abdominal pain score (APS) as well as a general symptom score (GSS) were used as primary endpoints. Responders had to have complete absence of IBS core symptoms at > or = 1 visit during treatment. RESULTS: The responder rate in GSS to the drug was 27 / 148 (18.2 %) in comparison to placebo with 7 / 150 (4.67 %) (p = 0.000397). The improvement in APS was 28 / 148 (18.9 %) and 10 / 150 (6.67 %) for placebo (p = 0.001649). The response was reached from visit 3 onwards with both medication and placebo. Post-hoc analysis revealed no significant differences in efficacy of the drug between the gender and different age groups. CONCLUSION: Treatment of IBS with the probiotic Symbioflor-2 is effective and superior to placebo in reducing typical symptoms of IBS patients seen by general practitioners and by gastroenterologists.

The placebo response in functional dyspepsia--reanalysis of trial data.

Clinical trial data rarely identify factors contributing to the placebo response. We reanalysed the data from the placebo arm (n = 157) of a functional dyspepsia (FD) trial to determine predictors of placebo response including total GIS score, change in GIS score during run-in, type of FD symptoms, duration of illness, age, gender, body mass index (BMI), family occurrence of FD-like symptoms, smoking and alcohol consumption. The same response criteria were applied to the drug arm (n = 158) of the study. Based on the initial 40% response criterion of the study, 35 (22.2%) were classified as placebo responders (PR), whilst 122 (78.8%) were placebo non-responders (PnR). Response rates for the drug arm were 41.1 and 56.9% respectively. PR had significantly lower GIS scores compared to PnR at visit 1 (10.6 +/- 0.6 and 12.3 +/- 0.4, respectively, P = 0.035), but not at visit 2 with study medication dispensing (10.9 +/- 0.5 and 11.3 +/- 0.4). Hence, PR symptoms increased during run-in by 4.2% whilst PnR symptoms decreased by 6.3% (P < 0.005). Gender, age and duration and type of FD symptoms were not different between PR and PnR. Smoking was less prevalent in PR (3%) compared to PnR (21%) (P < 0.025). Increasing the criteria for the placebo response resulted in higher BMI for PR than for PnR (P = 0.035). None of the predictors for placebo response were able to distinguish responders from non-responders to the drug. Variables predicting the PR point towards behavioural and biological mechanism of the PR, operating simultaneously and independently.

Circadian variation of rectal sensitivity and gastrointestinal peptides in healthy volunteers.

The aim of our study was to identify diurnal variation of perception of rectal distension and the release of gastroenteropancreatic hormones. In 12 healthy male volunteers (25 years, range 22-32), a rectal balloon distension was performed. Rectal perception thresholds (minimal, urge and pain) and rectal compliance were double-measured with a computer-controlled barostat at seven standardized time points during the day (from 16.00 to 14.00 hours the following day). Blood samples were taken 30 min before and after each rectal distension procedure to determine plasma levels of cholecystokinin (CCK), pancreatic polypeptide (PP) and motilin. Sensory thresholds for urge and pain varied significantly with the time of day, with higher threshold levels in the evening than in the morning hours. Bowel wall compliance showed as well-significant variance at pain threshold and was higher during daytime than in the evening or at night. In contrast to motilin, release of CCK and PP also showed a significant variation depending on daytime. Perception of rectal distension stimuli as well as compliance was independent of intake of food and peptide hormone levels, but CCK and PP levels increased with food, and PP levels decreased with rectal distension. Significant differences in the perception of rectal distension stimuli for urge and pain depending on daytime were found, but the release of gastrointestinal peptides seemed not to be involved. This circadian variation needs to be taken into account in patients and volunteer studies.

A mixture of Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the irritable bowel syndrome--a randomized controlled trial with primary care physicians.

Therapy trials with bacterial compounds in irritable bowel syndrome (IBS) have produced conflicting results. This study was performed in 1988 and 1989, and was re-analysed according to current IBS standards. Two hundred ninety-seven patients with lower abdominal symptoms diagnosed as IBS were treated for 8 weeks by the compound ProSymbioflor((R)) (Symbiopharm GmbH, Herborn, Germany), an autolysate of cells and cell fragments of Enterococcus faecalis and Escherichia coli, or placebo in a double-blinded, randomized fashion. Patients were seen weekly by the physician, who assessed the presence of core IBS symptoms. Responders had at least a 50% decrease in global symptom score (GSS) and in abdominal pain score (APS) reports at >/=1 visit during treatment. The responder rate in GSS to the drug was 102/149 (68.5%) in comparison to placebo with 56/148 (37.8%) (P < 0.001), the improvement in APS was 108/149 (72.5%) and 66/148 (44.6%) respectively (P = 0.001). The number-needed-to-treat was 3.27 for GSS and 3.59 for the APS report. Kaplan-Meier analysis revealed a mean response time of 4-5 weeks for active treatment and more than 8 weeks for placebo (P < 0.0001). Treatment of IBS with the bacterial lysate ProSymbioflor is effective and superior to placebo in reducing typical symptoms of IBS patients seen by general practitioners.

[Placebo response in functional bowel disorders]. / Die Plazeboantwort bei funktionellen Magen-Darm-Störungen.

The placebo response in functional bowel disorders is incompletely understood, and is usually either mystified or down-played; a rational approach to the understanding of the placebo response, however, can be deduced from the scientific literature. We present 3 theories that may explain most of the placebo response in medical and psychological interventions. a) Regression to the Mean (RTM): This refers to "errors" in measuring the outcome of therapies that are due to small samples sizes, global assessment variables, spontaneous variability of symptoms, and other methodological reasons. b) Pavlovian Conditioning (PC): Here the placebo response occurs as the consequence of successful association of diagnostic and therapeutic procedures in the past (illness history) of the individual that resulted in symptom improvement. Stimuli in the context of a treatment can thus gain therapeutic potency (become conditioned stimuli), e. g., the procedure of an injection or the colour of a drug. c) Signal Detection theory (SDT): Manipulation of expectations and cognitions of the patient by suggestions and verbal instructions of the health-care system will change the willingness of the patient to perceive symptoms as improved/worsened, specifically if this happens under "noisy" circumstances, e. g., with high spontaneous variability of symptoms. All three models are illustrated with examples from the medical and psychological treatments or experiments, including recent findings of cortical correlates of the placebo response in functional brain imaging investigations. Potential biological mechanisms for the placebo response are discussed, including he possibility of the genetic predisposition to be a placebo responder.