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1.  Nucleotide supplementation: a randomised double-blind placebo controlled trial of IntestAidIB in people with Irritable Bowel Syndrome [ISRCTN67764449] 
Nutrition Journal  2006;5:16.
Background
Dietary nucleotide supplementation has been shown to have important effects on the growth and development of cells which have a rapid turnover such as those in the immune system and the gastrointestinal tract. Work with infants has shown that the incidence and duration of diarrhoea is lower when nucleotide supplementation is given, and animal work shows that villi height and crypt depth in the intestine is increased as a result of dietary nucleotides. Dietary nucleotides may be semi-essential under conditions of ill-health, poor diet or stress. Since people with Irritable Bowel Syndrome tend to fulfil these conditions, we tested the hypothesis that symptoms would be improved with dietary nucleotide supplementation.
Methods
Thirty-seven people with a diagnosis of Irritable Bowel gave daily symptom severity ratings for abdominal pain, diarrhoea, urgency to have a bowel movement, incomplete feeling of evacuation after a bowel movement, bloating, flatulence and constipation for 28 days (baseline). They were then assigned to either placebo (56 days) followed by experimental (56 days) or the reverse. There was a four week washout period before crossover. During the placebo and experimental conditions participants took one 500 mg capsule three times a day; in the experimental condition the capsule contained the nutroceutical substances. Symptom severity ratings and psychological measures (anxiety, depression, illness intrusiveness and general health) were obtained and analysed by repeated measures ANOVAs.
Results
Symptom severity for all symptoms (except constipation) were in the expected direction of baseline>placebo>experimental condition. Symptom improvement was in the range 4 – 6%. A feeling of incomplete evacuation and abdominal pain showed the most improvement. The differences between conditions for diarrhoea, bloating and flatulence were not significant at the p < .05 level. There were no significant differences between the conditions for any of the psychological measures.
Conclusion
Dietary nucleotide supplementation improves some of the symptoms of irritable bowel above baseline and placebo level. As expected, placebo effects were high. Apart from abdominal pain and urgency to have a bowel movement, the improvements, while consistent, are modest, and were not accompanied by improvements in any of the psychological measures. We suggest that the percentage improvement over and above the placebo effect is a physiological effect of the nucleotide supplement on the gut. The mechanisms by which these effects might improve symptoms are discussed.
doi:10.1186/1475-2891-5-16
PMCID: PMC1513247  PMID: 16762076
2.  Safety and Immunomodulatory Effects of Three Probiotic Strains Isolated from the Feces of Breast-Fed Infants in Healthy Adults: SETOPROB Study 
PLoS ONE  2013;8(10):e78111.
We previously described the isolation and characterization of three probiotic strains from the feces of exclusively breast-fed newborn infants: Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036. These strains were shown to adhere to intestinal mucus in vitro, to be sensitive to antibiotics and to resist biliary salts and low pH. In the present study, a multicenter, randomized, double-blind, placebo-controlled trial with 100 healthy volunteers in three Spanish cities was carried out to evaluate the tolerance, safety, gut colonization and immunomodulatory effects of these three probiotics. Volunteers underwent a 15-day washout period, after which they were randomly divided into 5 groups that received daily a placebo, a capsule containing one of the 3 strains or a capsule containing a mixture of two strains for 30 days. The intervention was followed by another 15-day washout period. Patients did not consume fermented milk for the entire duration of the study. Gastrointestinal symptoms, defecation frequency and stool consistency were not altered by probiotic intake. No relevant changes in blood and serum, as well as no adverse events occurred during or after treatment. Probiotic administration slightly modified bacterial populations in the volunteers’ feces. Intestinal persistence occurred in volunteers who received L. rhamnosus CNCM I-4036. Administration of B. breve CNCM I-4035 resulted in a significant increase in fecal secretory IgA content. IL-4 and IL-10 increased, whereas IL-12 decreased in the serum of volunteers treated with any of the three strains. These results demonstrate that the consumption of these three bacterial strains was safe and exerted varying degrees of immunomodulatory effects.
Trial Registration
ClinicalTrials.gov NCT01479543
doi:10.1371/journal.pone.0078111
PMCID: PMC3810271  PMID: 24205115
3.  A NON-DAIRY PROBIOTIC’S (POI) INFLUENCE ON CHANGING THE GASTROINTESTINAL TRACT’S MICROFLORA ENVIRONMENT 
Justification
Yogurt has been historically used to restore gut microflora adversely affected by antibiotic treatment. Certain fermented dairy products are probiotics; “live microorganisms which when administered in adequate amounts confer a health benefit to the host.” Microorganisms in foods may benefit certain health conditions such as diarrhea, gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, and cancer. A potential new probiotic from a Polynesian traditional food is poi; a starchy paste made from the corm of taro plants.
Objective
The purpose of this study was to determine if consumption of poi, a potential non-dairy probiotic, altered the microflora in the gastrointestinal tract of healthy adults.
Methods
A cross-over clinical study included 18 subjects (19–64 years of age) divided into a poi group (n=10) and control group (n=8). The study duration of 14 weeks consisted of a 2-week washout, 4-week treatment or control, a subsequent 2-week washout, cross-over of 4-week treatment or control, and a final 2-week washout. Subjects thus served as their own controls. While receiving the poi treatment, participants consumed fresh poi (1–2 days old) three times a day (130 g/meal or about _ cup/meal); the control group did not. Both groups filled out 3-day dietary records to ensure compliance. Measurable outcomes include pre-and post-treatment microbiological fecal culture analyses.
Results
We found no significant differences in total bacterial counts following a poi diet versus following a control diet, nor were significant differences found in counts of specific bacterial species. Lactococcus tends to be higher in poi when it is analyzed for specific bacteria, but the poi consumption in our study did not alter the mean concentration of individual bacterial species (log10 CFU/g wet feces) for Escherichia coli, Enterobacter, Klebsiella, Lactobacillus, Lactococcus, and Bifidobacterium. No significant differences in stool frequency or consistency were observed between the treatment and control group periods.
Conclusion
Poi consumption did not significantly alter total or individual bacterial counts in the human gastrointestinal tract. Further research might determine if “sour poi” (3–4 days old) has a greater affect than “fresh poi” (1–2 days old) as a potential probiotic, and a larger trial with longer diet durations may detect more subtle effects of poi consumption on bacterial counts.
PMCID: PMC1364477  PMID: 15712767
4.  Effects of probiotic Lactobacillus brevis KB290 on incidence of influenza infection among schoolchildren: an open-label pilot study 
Letters in Applied Microbiology  2014;59(6):565-571.
Abstract
We investigated the efficacy of dietary consumption of Lactobacillus brevis KB290 (KB290) against influenza in humans by a preliminary intervention study on elementary schoolchildren, using a commercially available probiotic drink. Subjects were divided into Groups A and B, and an open-label, parallel-group trial was conducted in two 8-week periods at a 1-month interval in winter 2013/2014. Group A was provided with a bottle of the test drink containing KB290 (about 6 billion colony-forming units) every school day in the first period and had no treatment in the second period, and vice versa for Group B. Epidemic influenza was not observed during the first period and only two of 1783 subjects were diagnosed. In the second period, the incidence of influenza in Groups A (no treatment) and B (provided the test drink) was 23·9 and 15·7%, respectively, and the difference was statistically significant (P < 0·001). The reduction in the incidence of influenza by KB290 consumption was especially remarkable in unvaccinated individuals. This is believed to be the first study to show a probiotic food reducing the incidence of influenza in schoolchildren, although further studies are needed to confirm the effectiveness of the probiotic strain KB290.
Significance and Impact of the Study
We demonstrated a reduction in the incidence of influenza in 1089 schoolchildren by continual intake of a probiotic drink containing Lactobacillus brevis KB290 (KB290), isolated from a traditional Japanese pickle ‘Suguki’. The effect was especially evident in subjects not inoculated with influenza vaccine. This is believed to be the first report to show reduced incidence of influenza in schoolchildren taking a probiotic food. Further studies are needed to confirm the effectiveness of the probiotic strain KB290, which may be useful in the development of potential anti-influenza agents derived from common foods.
doi:10.1111/lam.12340
PMCID: PMC4285317  PMID: 25294223
incidence; influenza; Lactobacillus brevis KB290; probiotics; schoolchildren
5.  Effects of Licorice on Relief and Recurrence of Menopausal Hot Flashes 
Vasomotor hot flash is the most common and distressful complication of menopausal women. Its treatment is the most frequent clinical challenge. As a result, an effective and harmless therapy is needed. This double-blind controlled clinical trial was conducted to determine the effects of licorice roots on the relief and recurrence of hot flash in menopausal women referring to the healthcare centers affiliated to Shahid Beheshti Medical University in 2010.
Ninety menopausal women complaining of hot flash were selected by reviewing their records in healthcare centers and randomly divided into 2 licorices (3 capsules daily containing 330 mg licorice abstract) and placebo (3 capsules daily containing 330 mg starch) groups over the 8 weeks of intervention and 4 weeks of follow-up. Two weeks prior to the intervention, the severity as well as frequency of hot flashes and the foods taken were asked and documented with questionnaires and data sheets. Data within and between the groups were analyzed by ANOVA with repeated measurements and t-test respectively.
Means of age and body mass index (BMI) of the subjects in licorice and placebo groups were 53 ± 3.2, 52.69 ± 2.8, 24.71 ± 3.2 and 23.61 ± 3.3, respectively. The groups were similar in terms of intervening variables. The frequency of hot flash decreased significantly in the experimental (than the placebo group) and this lasted for 2 weeks after the administration of the capsules. The severity of hot flash decreased in the licorice group as well. This decrease was also seen in the placebo group in the first week of the intervention. Decreased hot flash in the placebo group was only significant after the 1st week of intervention compared to the previous period. Recurrence of frequency and severity of hot flashes occurred 2 weeks after the termination of therapy.
The significant decrease in the placebo group after the 1st week of the intervention may be attributed to the psychological effects of placebo. Licorice roots decreased the frequency and severity of hot flashes. The administration of this harmless, inexpensive herb well accepted by the menopausal women together with the appropriate and continuous physical activities and consumption of dairy products are recommended for relieving this complication.
PMCID: PMC3832176  PMID: 24250477
Menopause; Menopausal women; Vasomotor hot flash; Post menopausal hot flash; Herbal medicine; Licorice
6.  I.31, a new combination of probiotics, improves irritable bowel syndrome-related quality of life 
AIM: To determine the dose-related effects of a novel probiotic combination, I.31, on irritable bowel syndrome (IBS)-related quality of life (IBS-QoL).
METHODS: A multicenter, randomized, double-blind, placebo-controlled intervention clinical trial with three parallel arms was designed. A total of 84 patients (53 female, 31 male; age range 20-70 years) with IBS and diarrhea according to Rome-III criteria were randomly allocated to receive one capsule a day for 6 wk containing: (1) I.31 high dose (n = 28); (2) I.31 low dose (n = 27); and (3) placebo (n = 29). At baseline, and 3 and 6 wk of treatment, patients filled the IBSQoL, Visceral Sensitivity Index (VSI), and global symptom relief questionnaires.
RESULTS: During treatment, IBS-QoL increased in all groups, but this increment was significantly larger in patients treated with I.31 than in those receiving placebo (P = 0.008). After 6 wk of treatment, IBS-QoL increased by 18 ± 3 and 22 ± 4 points in the high and the low dose groups, respectively (P = 0.041 and P = 0.023 vs placebo), but only 9 ± 3 in the placebo group. Gut-specific anxiety, as measured with VSI, also showed a significantly greater improvement after 6 wk of treatment in patients treated with probiotics (by 10 ± 2 and 14 ± 2 points, high and low dose respectively, P < 0.05 for both vs 7 ± 1 score increment in placebo). Symptom relief showed no significant changes between groups. No adverse drug reactions were reported following the consumption of probiotic or placebo capsules.
CONCLUSION: A new combination of three different probiotic bacteria was superior to placebo in improving IBS-related quality of life in patients with IBS and diarrhea.
doi:10.3748/wjg.v20.i26.8709
PMCID: PMC4093724  PMID: 25024629
Irritable bowel syndrome; Probiotic combination; Irritable bowel syndrome; Quality-of-life
7.  Effectiveness of artichoke extract in preventing alcohol-induced hangovers: a randomized controlled trial 
Background
Extract of globe artichoke (Cynara scolymus) is promoted as a possible preventive or cure for alcohol-induced hangover symptoms. However, few rigorous clinical trials have assessed the effects of artichoke extract, and none has examined the effects in relation to hangovers. We undertook this study to test whether artichoke extract is effective in preventing the signs and symptoms of alcohol-induced hangover.
Methods
We recruited healthy adult volunteers between 18 and 65 years of age to participate in a randomized double-blind crossover trial. Participants received either 3 capsules of commercially available standardized artichoke extract or indistinguishable, inert placebo capsules immediately before and after alcohol exposure. After a 1-week washout period the volunteers received the opposite treatment. Participants predefined the type and amount of alcoholic beverage that would give them a hangover and ate the same meal before commencing alcohol consumption on the 2 study days. The primary outcome measure was the difference in hangover severity scores between the artichoke extract and placebo interventions. Secondary outcome measures were differences between the interventions in scores using a mood profile questionnaire and cognitive performance tests administered 1 hour before and 10 hours after alcohol exposure.
Results
Fifteen volunteers participated in the study. The mean number (and standard deviation) of alcohol units (each unit being 7.9 g, or 10 mL, of ethanol) consumed during treatment with artichoke extract and placebo was 10.7 (3.1) and 10.5 (2.4) respectively, equivalent to 1.2 (0.3) and 1.2 (0.2) g of alcohol per kilogram body weight. The volume of nonalcoholic drink consumed and the duration of sleep were similar during the artichoke extract and placebo interventions. None of the outcome measures differed significantly between interventions. Adverse events were rare and were mild and transient.
Interpretation
Our results suggest that artichoke extract is not effective in preventing the signs and symptoms of alcohol-induced hangover. Larger studies are required to confirm these findings.
PMCID: PMC280580  PMID: 14662662
8.  A candidate probiotic with unfavourable effects in subjects with irritable bowel syndrome: a randomised controlled trial 
BMC Gastroenterology  2010;10:16.
Background
Some probiotics have shown efficacy for patients with irritable bowel syndrome (IBS). Lactobacillus (L.) plantarum MF1298 was found to have the best in vitro probiotic properties of 22 strains of lactobacilli. The aim of this study was to investigate the symptomatic effect of L. plantarum MF1298 in subjects with IBS. Primary outcome was treatment preference and secondary outcomes were number of weeks with satisfactory relief of symptoms and IBS sum score.
Methods
The design was a randomised double blind placebo-controlled crossover trial. 16 subjects with IBS underwent two three-week periods of daily intake of one capsule of 1010 CFU L. plantarum MF 1298 or placebo separated by a four-week washout period.
Results
Thirteen participants (81%; 95% CI 57% to 93%; P = 0.012) preferred placebo to L. plantarum MF1298 treatment. The mean (SD) number of weeks with satisfactory relief of symptoms in the periods with L. plantarum MF1298 and placebo were 0.50 (0.89) and 1.44 (1.26), respectively (P = 0.006). IBS sum score was 6.44 (1.81) in the period with L. plantarum MF1298 treatment compared with 5.35 (1.77) in the period with placebo (P = 0.010). With a clinically significant difference in the IBS sum score of 2 in disfavour of active treatment, the number needed to harm was 3.7, 95% CI 2.3 to 10.9.
Conclusions
This trial shows for the first time an unfavourable effect on symptoms in subjects with IBS after intake of a potential probiotic.
The trial registration number
Clinical trials NCT00355810.
doi:10.1186/1471-230X-10-16
PMCID: PMC2831047  PMID: 20144246
9.  A Randomized, Double-Blind, Placebo-Controlled Trial of Lessertia frutescens in Healthy Adults 
PLoS Clinical Trials  2007;2(4):e16.
Objectives:
Indigenous medicines are widely used throughout Africa, despite a lack of scientific evidence for their safety or efficacy. The aims of this study were: (a) to conduct a pilot study of the safety of a common indigenous South African phytotherapy, Lessertia frutescens (Sutherlandia), in healthy adults; and (b) to contribute to establishing procedures for ethical and scientifically rigorous clinical trials of African indigenous medicines.
Design:
A randomized, double-blind, placebo-controlled trial of Sutherlandia leaf powder in healthy adults.
Setting:
Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, South Africa.
Participants:
25 adults who provided informed consent and had no known significant diseases or allergic conditions nor clinically abnormal laboratory blood profiles during screening.
Intervention:
12 participants randomized to a treatment arm consumed 400 mg capsules of Sutherlandia leaf powder twice daily (800 mg/d). 13 individuals randomized to the control arm consumed a placebo capsule. Each participant received 180 capsules for the trial duration of 3 mo.
Outcome Measures:
The primary endpoint was frequency of adverse events; secondary endpoints were changes in physical, vital, blood, and biomarker indices.
Results:
There were no significant differences in general adverse events or physical, vital, blood, and biomarker indices between the treatment and placebo groups (p > 0.05). However, participants consuming Sutherlandia reported improved appetite compared to those in the placebo group (p = 0.01). Although the treatment group exhibited a lower respiration rate (p < 0.04) and higher platelet count (p = 0.03), MCH (p = 0.01), MCHC (p = 0.02), total protein (p = 0.03), and albumin (p = 0.03), than the placebo group, these differences remained within the normal physiological range, and were not clinically relevant. The Sutherlandia biomarker canavanine was undetectable in participant plasma.
Conclusion:
Consumption of 800 mg/d Sutherlandia leaf powder capsules for 3 mo was tolerated by healthy adults.
Editorial Commentary
Background: In Africa, traditional herbal medicines are given for many illnesses. In particular, one herbal medicine, Sutherlandia (Lessertia frutescens) is commonly given in the belief that this herb will treat some of the symptoms associated with HIV/AIDS, such as nausea and lack of appetite, amongst others. However, there is very little evidence relating to the safety and none to the efficacy of this herb. Generally, when new drugs are developed, the first stage of human testing involves a Phase 1 trial. This type of trial would typically involve small numbers of healthy individuals, who would receive progressively increasing doses of the drug under study, and would be closely monitored for any sign of side effects. Phase 1 trials would typically also collect data from blood samples to find out how the drug is handled in the body and broken down and eliminated. Therefore, the researchers here carried out a preliminary study to assess just the safety of Sutherlandia. 25 healthy adults were randomized to receive either tablets containing a fixed dose of Sutherlandia leaf powder daily for three months, or matched placebo tablets containing lettuce leaf powder, for the same period of time. The main aim of the trial was to assess safety, so the primary outcomes were adverse events experienced by the participants. The researchers also measured standard outcomes such as blood pressure, heart rate, body weight, urine glucose, protein, and many others, at one-month intervals over the three-month period.
What the trial shows: Adverse events experienced by trial participants over the three months of this trial included those that might be expected in a group of otherwise healthy individuals, such as headaches, insomnia, allergies, malaise, palpitations, nosebleeds, and so on. The researchers did not see statistically significant differences between treatment and placebo groups in any of the major categories of these events. Most physical and laboratory measurements also showed no statistically significant differences between the study groups. However, there were statistically significant, but small, differences between groups in respiratory rate and in various basic blood tests. The researchers did not think these differences were clinically important. Overall, this trial suggested that Sutherlandia use was not associated with side effects at this dosage and over this time scale.
Strengths and limitations: Strengths of this study include the use of randomization to distribute individuals to either the Sutherlandia or control groups, and in the use of a placebo control group, which therefore allowed the researchers to compare the frequencies of adverse events in the Sutherlandia group with what might be expected among healthy individuals over the course of three months. An important limitation is the small sample size of the trial. This size limits the sensitivity of the trial to detect rare adverse events to the herb under study, and therefore one cannot say conclusively that the herb is safe, based on this data. Additionally, the study looked only at the participants' response to one dosage level of Sutherlandia. A strategy using progressively increasing doses would have allowed the researchers to see if there was a maximum tolerated dose to this herb. A further limitation in this study is the lack of data relating to how the herb is broken down in the body; these data are normally an important part of Phase 1 trials and, combined with safety data, are crucial to finding out whether a compound is safe when given at a dosage that allows it to be available to the appropriate tissues.
Contribution to the evidence: Data from previous studies in nonhuman primates have shown that Sutherlandia is not associated with toxic or other side effects at approximately equivalent or higher doses than that normally taken by people with HIV/AIDS. This study adds safety data relating to Sutherlandia consumption in healthy humans, which confirm the primate data. However, it is crucial to collect more data relating to how the probable active ingredients of Sutherlandia are absorbed and broken down, and to assess safety at different dosages, before studies are even considered for the next stage, which is to see whether Sutherlandia has any efficacy in people with HIV/AIDS.
doi:10.1371/journal.pctr.0020016
PMCID: PMC1863514  PMID: 17476314
10.  A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation 
OBJECTIVES:
Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C).
METHODS:
This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration's (FDA's) primary end point for IBS-C (responder: improvement of ≥30% in average daily worst abdominal pain score and increase by ≥1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.
RESULTS:
The trial evaluated 800 patients (mean age=43.5 years, female=90.5%, white=76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P<0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of ≥30% in abdominal pain (50.1 vs. 37.5%, P=0.0003) and an increase of ≥1 CSBM from baseline (48.6 vs. 29.6%, P<0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P<0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P<0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients.
CONCLUSIONS:
Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.
doi:10.1038/ajg.2012.255
PMCID: PMC3504311  PMID: 22986440
11.  Effect of the consumption of a fermented dairy product containing Bifidobacterium lactis DN-173 010 on constipation in childhood: a multicentre randomised controlled trial (NTRTC: 1571) 
BMC Pediatrics  2009;9:22.
Background
Constipation is a frustrating symptom affecting 3% of children worldwide. Randomised controlled trials show that both polyethylene glycol and lactulose are effective in increasing defecation frequency in children with constipation. However, in 30–50%, these children reported abdominal pain, bloating, flatulence, diarrhoea, nausea and bad taste of the medication. Two recent studies have shown that the fermented dairy product containing Bifidobacterium lactis strain DN-173 010 is effective in increasing stool frequency in constipation-predominant irritable bowel syndrome patients with a defecation frequency < 3/week and in constipated women with a defecation frequency < 3/week. Goal of this study is to determine whether this fermented dairy product is effective in the treatment of constipated children with a defecation frequency < 3/week.
Methods/design
It is a two nation (The Netherlands and Poland) double-blind, placebo-controlled randomised multicentre trial in which 160 constipated children (age 3–16 years) with a defecation frequency <3/week will be randomly allocated to consume a fermented dairy product containing Bifidobacterium lactis DN-173 010 or a control product, twice a day, for 3 weeks. During the study all children are instructed to try to defecate on the toilet for 5–10 minutes after each meal (3 times a day) and daily complete a standardized bowel diary. Primary endpoint is stool frequency. Secondary endpoints are stool consistency, faecal incontinence frequency, pain during defecation, digestive symptoms (abdominal pain, flatulence), adverse effects (nausea, diarrhoea, bad taste) and intake of rescue medication (Bisacodyl). Rate of success and rate of responders are also evaluated, with success defined as ≥ 3 bowel movements per week and ≤1 faecal incontinence episode over the last 2 weeks of product consumption and responder defined as a subject reporting a stool frequency ≥ 3 on the last week of product consumption. To demonstrate that the success percentage in the intervention group will be 35% and the success percentage in the control group (acidified milk without ferments, toilet training, bowel diary) will be 15%, with alpha 0.05 and power 80%, a total sample size of 160 patients was calculated.
Conclusion
This study is aimed to show that the fermented dairy product containing Bifidobacterium lactis strain DN-173 010 is effective in increasing stool frequency after 3 weeks of product consumption in children with functional constipation and a defecation frequency < 3/week.
doi:10.1186/1471-2431-9-22
PMCID: PMC2662858  PMID: 19296845
12.  Lactobacillus gasseri SBT2055 reduces postprandial and fasting serum non-esterified fatty acid levels in Japanese hypertriacylglycerolemic subjects 
Background
Lactobacillus gasseri SBT2055 (LG2055) inhibits dietary fat absorption in rats and exerts preventive effects on abdominal adiposity in rats and humans. The present study aimed to evaluate the effects of LG2055 on postprandial serum lipid responses in Japanese subjects with hypertriacylglycerolemia after the intake of oral fat-loading test (OFLT) meals.
Methods
We conducted a single-blind, placebo-controlled, within-subject, repeated-measure intervention trial. Twenty subjects initially ingested the fermented milk (FM) without LG2055 for 4 weeks (control FM period), followed by a 4-week washout period, and then consumed FM containing LG2055 for 4 weeks (active FM period). The subjects were asked to consume FM at 200 g/day. At the end of each 4-week period, an 8-h OFLT was conducted. Blood samples were collected at fasting and every hour for 8 h after OFLT meal intake. Thereafter, postprandial serum non-esterified fatty acid (NEFA) and triacylglycerol (TAG) levels and fasting blood parameters were measured.
Results
The OFLT showed that the postprandial serum NEFA levels from 120 to 480 min and the postprandial serum TAG level at 120 min in the active FM period were significantly (P < 0.05) lower than those in the control FM period. The fasting serum NEFA level in the active FM period significantly (P < 0.001) decreased at week 4 from the initial period compared with the control FM period.
Conclusions
The consumption of probiotic LG2055 reduced postprandial and fasting serum NEFA levels, suggesting its possible contribution to the reduction of the risk for obesity and type 2 diabetes mellitus.
Trial registration
UMIN000011605
doi:10.1186/1476-511X-13-36
PMCID: PMC3944925  PMID: 24548293
Probiotics; Lactobacillus gasseri SBT2055; Oral fat-loading test; Postprandial lipid response; Fermented milk products; Non-esterified fatty acid; Triacylglycerol
13.  Effects of Chili Treatment on Gastrointestinal and Rectal Sensation in Diarrhea-predominant Irritable Bowel Syndrome: A Randomized, Double-blinded, Crossover Study 
Background/Aims
Whether, chronic chili ingestion can desensitize transient receptor potential vanilloid type 1 receptors in gastrointestinal (GI) tract leading to decrease GI symptoms and sensation in diarrhea-predominant irritable bowel syndrome (IBS-D) patients has not been well explored. The aim of this study was to determine the effects of 6-week chili treatment on postprandial GI symptoms and rectal sensation in response to balloon distention in IBS-D patients.
Methods
Sixteen IBS-D patients received placebo or chili capsules before meals 3 times/day for 6 weeks in a randomized, double-blinded, crossover fashion with 4-week washout period. Postprandial GI symptoms were evaluated. All patients underwent a rectal barostat study to evaluate rectal sensory threshold at the end of each treatment.
Results
The maximum postprandial abdominal burning scores were similar between both treatments at baseline (1.4 [0.0–2.0] vs. 1.1 [0.0–2.8], P > 0.05) but were significantly decreased after chili (0.0 [0.0–0.5] vs. 0.3 [0.0–1.6], P < 0.05) at the end of treatment. The chili treatment significantly increased sensory threshold for the first rectal sensation (median [interquartile range]:16 [12–16] mmHg vs. 8 [8–16] mmHg, P < 0.05) however, there was no significant effect on rectal compliance (7.3 ± 1.0 vs. 7.1 ± 1.8 mL/mmHg). Other postprandial GI symptoms did not vary significantly between both treatments at baseline and the end of treatment.
Conclusions
In IBS-D patients, 6-week chili ingestion significantly decreased postprandial abdominal burning and increased the rectal sensory threshold. These findings suggest a desensitization effect of chili ingestion on transient receptor potential vanilloid type 1 receptors in the proximal gut and rectum.
doi:10.5056/jnm14022
PMCID: PMC4102147  PMID: 24867591
Capsaicin; Gastrointestinal tract; Irritable bowel syndrome; Sensation
14.  Positive Effects of Soy Lecithin-Derived Phosphatidylserine plus Phosphatidic Acid on Memory, Cognition, Daily Functioning, and Mood in Elderly Patients with Alzheimer’s Disease and Dementia 
Advances in Therapy  2014;31:1247-1262.
Introduction
We report previously unpublished, early pilot studies performed with a brain-health food supplement containing a proprietary blend of 100 mg phosphatidylserine (PS) and 80 mg phosphatidic acid (PA) produced from soy lecithin.
Methods
Serum analysis after single PS+PA ingestion was performed in healthy volunteers. A 3-month double-blind, placebo-controlled study assessed the influence of three PS+PA capsules/day, (300 mg PS + 240 mg PA/day) or placebo on memory and mood in functioning, non-depressive elderly people with memory problems, using the Wechsler Memory Scale and the List of Depressive Symptoms. Furthermore, a 2-month randomized, double-blind, placebo-controlled trial assessed the effect of three PS+PA capsules/day (300 mg PS + 240 mg PA/day) or placebo on daily functioning, mental health, emotional state, and self-reported general condition in patients with Alzheimer’s disease (AD).
Results
Serum PS peaked 90 min after ingestion, returning to baseline after 180 min. In the elderly, PS+PA [per protocol (PP) n = 31], unlike placebo (PP n = 26), significantly improved memory and prevented “winter blues” in a pre–post comparison. In the patients with AD, daily functioning (i.e., 7 activities of daily living) under PS+PA (PP n = 53) remained unchanged, but declined from 5.62 to 4.90 under placebo (PP n = 39; P = 0.035), with significant group difference (P = 0.021). The PS+PA group had 3.8% deterioration and 90.6% stability in daily functioning, compared to 17.9% and 79.5% under placebo, respectively (P = 0.066). Forty-nine percent of the PS+PA patients reported an improved general condition, compared to 26.3% under placebo (P = 0.084). Approximately, 43% of the PS+PA patients, but none under placebo, continued post-trial supplementation (while double-blinded). No negative side effects were observed.
Conclusion
PS is efficiently absorbed after oral consumption. A positive influence of PS+PA on memory, mood, and cognition was demonstrated among elderly test subjects. Short-term supplementation with PS+PA in patients with AD showed a stabilizing effect on daily functioning, emotional state and self-reported general condition. The data encourage long-term studies with PS+PA in AD patients and other elderly with memory or cognition problems.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0165-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-014-0165-1
PMCID: PMC4271139  PMID: 25414047
Alzheimer’s disease; Cognition; Daily functioning; Dementia; Elderly; Memory; MemreePlus™; Mood; Phosphatidic acid; Soy lecithin-derived phosphatidylserine
15.  Mexiletine for Symptoms and Signs of Myotonia in Non-Dystrophic Myotonia: A Randomized Controlled Trial 
Context
Non-dystrophic myotonias (NDM) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally-limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in case studies and one single blind trial. As is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible.
Objective
To determine the effects of mexiletine for symptoms and signs of myotonia in NDM.
Design, Setting, and Participation
Fifty-nine patients with NDM participated in a randomized, double-blind, placebo-controlled two-period crossover study conducted between December 23, 2008 and March 30, 2011 at 7 neuromuscular referral centers in 4 countries, as part of the NIH-funded Rare Disease Clinical Research Network.
Intervention
Oral 200 mg mexiletine or placebo capsules three times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1 week wash-out between periods.
Main Outcome Measures
Patient-reported stiffness recorded on an interactive voice response diary (IVR) was the primary endpoint (1 ‘minimal’ to 9 ‘worst ever experienced’). Secondary endpoints included IVR-reported changes in pain, weakness, and tiredness, clinical myotonia assessment, quantitative grip myotonia, Individualized Neuromuscular Quality of Life (INQoL, percent of maximal detrimental impact), SF-36, electrophysiological exercise testing, and needle EMG.
Results
Mexiletine significantly improved patient-reported stiffness on the IVR. Because of a statistically significant interaction between treatment and period for this outcome, primary endpoint is presented by period (period 1 means were mexiletine 2.53 versus placebo 4.21, difference −1.68, 95% Confidence Interval [CI] −2.66, −0.706, P<0.001; period 2 means were mexiletine 1.60 versus placebo 5.27, difference −3.68, 95% CI −3.85, −0.139, P=0.04). Mexiletine improved the INQoL QOL score (mexiletine 14.0, placebo 16.7, difference −2.69, 95% CI −4.07, −1.30, P<0.001) and decreased handgrip myotonia on clinical exam (seconds: mexiletine 0.164, placebo 0.494, difference −0.330, 95% CI −0.633, −0.142, P<0.001). The most common adverse effect was gastrointestinal (9 mexiletine, 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 placebo, 1 mexiletine). One serious adverse event was determined to be not study-related.
Conclusion
In this preliminary study of patients with NDM, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding.
Trial Registration
Clinicaltrials.gov identifier: NCT 00832000
doi:10.1001/jama.2012.12607
PMCID: PMC3564227  PMID: 23032552
16.  Dark chocolate or tomato extract for prehypertension: a randomised controlled trial 
Background
Flavanol-rich chocolate and lycopene-rich tomato extract have attracted interest as potential alternative treatment options for hypertension, a known risk factor for cardiovascular morbidity and mortality. Treatment of prehypertension (SBP 120–139/DBP 80–89 mmHg) may forestall progression to hypertension. However, there has been only limited research into non-pharmacological treatment options for prehypertension. We investigated the effect of dark chocolate or tomato extract on blood pressure, and their acceptability as an ongoing treatment option in a prehypertensive population.
Methods
Our trial consisted of two phases: a randomised controlled three-group-parallel trial over 12 weeks (phase 1) followed by a crossover of the two active treatment arms over an additional 12-week period (phase 2). Group 1 received a 50 g daily dose of dark chocolate with 70% cocoa containing 750 mg polyphenols, group 2 were allocated one tomato extract capsule containing 15 mg lycopene per day, and group 3 received one placebo capsule daily over 8 weeks followed by a 4-week washout period. In phase 2 the active treatment groups were crossed over to receive the alternative treatment. Median blood pressure, weight, and abdominal circumference were measured 4-weekly, and other characteristics including physical activity, general health, energy, mood, and acceptability of treatment were assessed by questionnaire at 0, 8 and 20 weeks. We analysed changes over time using a linear mixed model, and one time point differences using Kruskal-Wallis, Fisher's-Exact, or t-tests.
Results
Thirty-six prehypertensive healthy adult volunteers completed the 6-month trial. Blood pressure changes over time within groups and between groups were not significant and independent of treatment. Weight and other characteristics did not change significantly during the trial. However, a marked difference in acceptability between the two treatment forms (chocolate or capsule) was revealed (p < 0.0001). Half of the participants allocated to the chocolate treatment found it hard to eat 50 g of dark chocolate every day and 20% considered it an unacceptable long-term treatment option, whereas all participants found it easy and acceptable to take a capsule each day for blood pressure.
Conclusion
Our study did not find a blood pressure lowering effect of dark chocolate or tomato extract in a prehypertensive population. Practicability of chocolate as a long-term treatment option may be limited.
Trial registration
Identifier: ACTRN12609000047291
doi:10.1186/1472-6882-9-22
PMCID: PMC2712451  PMID: 19583878
17.  The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials 
Alimentary Pharmacology & Therapeutics  2014;40(11-12):1302-1312.
Background
Few clinical trials in chronic idiopathic constipation (CIC) patients have evaluated abdominal symptom severity and whether CIC patients with abdominal symptoms respond similarly to patients with limited abdominal symptoms.
Aims
To examine abdominal symptom severity and relationships between symptoms and global measures at baseline; compare linaclotide's effect on symptoms in subpopulations with more or less abdominal pain; and assess relationships between symptom improvement and global measures in these two subpopulations.
Methods
In two phase 3 trials, patients meeting modified Rome II CIC criteria were assigned to linaclotide 145 μg, 290 μg, or placebo once daily. Patients rated abdominal and bowel symptoms daily during 2-week pre-treatment and 12-week treatment periods. Linaclotide's effect on symptoms and global measures [constipation severity, health-related quality of life (HRQOL), treatment satisfaction] and their inter-relationships were assessed in post hoc analyses of abdominal pain subpopulations.
Results
Of 1271 CIC patients, 23%, 32%, and 43% reported moderate-to-severe abdominal pain, discomfort, and bloating, respectively, during baseline. In more-severe abdominal pain patients, abdominal symptoms were more strongly correlated than bowel symptoms with global measures, but in less-severe abdominal pain patients, abdominal and bowel symptoms were similarly correlated with global measures, at baseline and post-treatment. Linaclotide significantly improved all symptoms and global measures in both subpopulations.
Conclusions
When abdominal pain is present in CIC, abdominal and not bowel symptoms may drive patient assessments of constipation severity, HRQOL, and treatment satisfaction. Linaclotide (145 μg and 290 μg) is an effective treatment for both abdominal and bowel symptoms, even in CIC patients with more severe abdominal pain at baseline. (Clinicaltrials.gov: NCT00765882, NCT00730015).
doi:10.1111/apt.12985
PMCID: PMC4278547  PMID: 25312449
18.  Effect of herbal extract granules combined with probiotic mixture on irritable bowel syndrome with diarrhea: study protocol for a randomized controlled trial 
Trials  2011;12:219.
Background
Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and change of bowel habits without organic disease. Many patients seek alternative IBS treatments because of the limitations of conventional treatments. Gwakhyangjeonggisan (GJS), a herbal formula, has long been used for alleviating diarrhea-predominant IBS (D-IBS) in traditional medicine. Duolac7S, which comprises 7 bacterial species as probiotics, has been frequently used for D-IBS. Although GJS and Duolac7S have been administered simultaneously in many D-IBS patients, no study has investigated the effects of GJS and Duolac7S combination therapy on D-IBS.
Methods/Design
The current trial is a randomized, double-blinded, placebo-controlled, 4-arm study. After a 2-week run-in period, 60 patients with D-IBS will be randomly assigned to one of the 4 combination groups consisting of GJS (water extract granules, 3 g/pack, 3 times a day) with Duolac7S (powder form, 1 capsule, 2 times a day) or their placebos and followed up for 2 weeks. The assigned treatments will last for 8 weeks. The primary outcomes are adequate relief of IBS pain and discomfort and the proportion of responders (on a weekly basis). The secondary outcomes are visual analog scale for IBS symptoms (on a daily basis), quality of life (at 0, 8, and 10 weeks), intestinal permeability, and composition of intestinal microbiota (at 0 and 8 weeks).
Discussion
The present study is designed to examine the safety and efficacy of GJS and Duolac7S combination therapy on D-IBS. Our study provides the clinical evidence of a new therapeutic strategy for D-IBS.
Trial registration
ClinicalTrials.gov NCT01342718 .
doi:10.1186/1745-6215-12-219
PMCID: PMC3198690  PMID: 21978382
19.  Long term efficacy, safety, and tolerabilitity of low daily doses of isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in the treatment of functional chronic constipation 
Gut  2000;46(4):522-526.
AIMS—To assess the long term therapeutic effectiveness, safety, and tolerability of low daily doses of isosmotic PEG electrolyte solutions (PMF-100) administered for a six month period for the treatment of functional constipation, in a double blind, placebo controlled, parallel group study.
METHODS—After an initial four week run in period with PMF-100 (250 ml twice daily; PEG 14.6 g twice daily), 70 patients suffering from chronic constipation (58 females, aged 42 (15) years) with normalised bowel frequency (>3 bowel movements (bm)/week) were randomly allocated to receive either PMF-100 or placebo, contained in sachets (one sachet in 250 ml of water twice daily) for 20 weeks. Patients were assessed at four week intervals, and reported frequency and modality of evacuation, laxative use, and relevant symptoms on a diary card. At weeks 1, 12, and 24, a physical examination and laboratory tests were performed.
RESULTS—Complete remission of constipation was reported by a significantly (p<0.01) higher number of patients treated with PMF-100 compared with placebo at each four week visit. At the end of the study, 77% of the PMF-100 group and 20% of the placebo group were asymptomatic. Compared with placebo, patients treated with PMF-100 reported hard/pellety stools and straining at defecation less frequently, a significantly higher bowel frequency (week 12: 7.4 (3.1) v 4.3 (2.5) bm/week, 95% CI 1.64, 4.42; week 24: 7.4 (3.2) v 5.4 (2.1) bm/week, 95% CI 0.13,3.93), reduced consumption of laxative/four weeks (week 12: 0.7 (2.7) v 2.2 (3.3), 95% CI −2.29, 0.03; week 24: 0.2 (0.8) v 1.4 (2), 95% CI −2.07, −0.023), reduced mean number of sachets used (week 12: 33 (13) v 43 (12), 95% CI −17.24, 4.56; week 24: 33 (13) v 44 (12), 95% CI −19.68, −2.24), and reduced number of drop outs for therapy failure (16 v 3; p<0.005). Adverse events, physical findings, laboratory values, palatability, and overall tolerance of the solutions did not differ between groups.
CONCLUSIONS—Administration of small daily doses of isosmotic PEG electrolyte balanced solutions was effective over a six month period for the treatment of functional constipation. A mean daily dose of approximately 300 ml of PEG solution (PEG 17.52 g) appeared to be safe, well tolerated, and devoid of significant side effects.


Keywords: constipation; polyethylene glycol; safety; tolerability
doi:10.1136/gut.46.4.522
PMCID: PMC1727881  PMID: 10716682
20.  Clinical trial: Lactobacillus plantarum 299v (DSM 9843) improves symptoms of irritable bowel syndrome 
AIM: To assess the symptomatic efficacy of Lactobacillus plantarum 299v (L. plantarum 299v) (DSM 9843) for the relief of abdominal symptoms in a large subset of irritable bowel syndrome (IBS) patients fulfilling the Rome III criteria.
METHODS: In this double blind, placebo-controlled, parallel-designed study, subjects were randomized to daily receive either one capsule of L. plantarum 299v (DSM 9843) or placebo for 4 wk. Frequency and intensity of abdominal pain, bloating and feeling of incomplete rectal emptying were assessed weekly on a visual analogue scale while stool frequency was calculated.
RESULTS: Two hundred and fourteen IBS patients were recruited. After 4 wk, both pain severity (0.68 + 0.53 vs 0.92 + 0.57, P < 0.05) and daily frequency (1.01 + 0.77 vs 1.71 + 0.93, P < 0.05) were lower with L. plantarum 299v (DSM 9843) than with placebo. Similar results were obtained for bloating. At week 4, 78.1 % of the patients scored the L. plantarum 299v (DSM 9843) symptomatic effect as excellent or good vs only 8.1 % for placebo (P < 0.01).
CONCLUSION: A 4-wk treatment with L. plantarum 299v (DSM 9843) provided effective symptom relief, particularly of abdominal pain and bloating, in IBS patients fulfilling the Rome III criteria.
doi:10.3748/wjg.v18.i30.4012
PMCID: PMC3419998  PMID: 22912552
Irritable bowel syndrome; Probiotics; Lactobacillus plantarum 299v; Clinical trial; Abdominal pain
21.  The consumption of seaweed as a protective factor in the etiology of breast cancer: proof of principle 
Journal of Applied Phycology  2012;25(3):771-779.
Daily consumption of seaweed has been proposed as a factor in explaining lower postmenopausal breast cancer (BC) incidence and mortality rates in Japan. This clinical trial assessed the impact of introducing seaweed- to non-seaweed-consuming American postmenopausal women. Fifteen healthy postmenopausal women were recruited for a 3-month single-blinded placebo controlled clinical trial; five had no history of BC (controls) and ten were BC survivors. Participants ingested ten capsules daily (5 g day−1) of placebo for 4 weeks, seaweed (Undaria) for 4 weeks, then placebo for another 4 weeks. Blood and urine samples were collected after each treatment period. Urinary human urokinase-type plasminogen activator receptor concentrations (uPAR) were analyzed by ELISA, and urine and serum were analyzed for protein expression using surface-enhanced laser desorption/ionization–time-of-flight mass spectrometry (SELDI-TOF-MS). Urinary creatinine standardized uPAR (in pg mL μg−1 creatinine) changed significantly between groups, decreasing by about half following seaweed supplementation (placebo 1, 1.5 (95 % CI, 0.9–2.1) and seaweed, 0.9 (95 % CI, 0.6–1.1) while placebo 2 returned to pre-seaweed concentration (1.7 (95 % CI, 1.2-2.2); p = 0.01, ANOVA). One SELDI-TOF-MS-identified urinary protein (m/z 9,776) showed a similar reversible decrease with seaweed and is reported to be associated with cell attachment. One serum protein (m/z 8,928) reversibly increased with seaweed and may be the immunostimulatory complement activation C3a des-arginine. uPAR is higher among postmenopausal women generally, and for BC patients, it is associated with unfavorable BC prognosis. By lowering uPAR, dietary seaweed may help explain lower BC incidence and mortality among postmenopausal women in Japan.
doi:10.1007/s10811-012-9931-0
PMCID: PMC3651528  PMID: 23678231
Breast cancer; Clinical trial; CM10 ProteinChip; Surface-enhanced laser desorption/ionization–time-of-flight mass spectrometry (SELDI-TOF-MS); Undaria pinnatifida; Human urokinase-type plasminogen activator receptor (uPAR)
22.  The Effectiveness of Community Action in Reducing Risky Alcohol Consumption and Harm: A Cluster Randomised Controlled Trial 
PLoS Medicine  2014;11(3):e1001617.
In a cluster randomized controlled trial, Anthony Shakeshaft and colleagues measure the effectiveness of a multi-component community-based intervention for reducing alcohol-related harm.
Background
The World Health Organization, governments, and communities agree that community action is likely to reduce risky alcohol consumption and harm. Despite this agreement, there is little rigorous evidence that community action is effective: of the six randomised trials of community action published to date, all were US-based and focused on young people (rather than the whole community), and their outcomes were limited to self-report or alcohol purchase attempts. The objective of this study was to conduct the first non-US randomised controlled trial (RCT) of community action to quantify the effectiveness of this approach in reducing risky alcohol consumption and harms measured using both self-report and routinely collected data.
Methods and Findings
We conducted a cluster RCT comprising 20 communities in Australia that had populations of 5,000–20,000, were at least 100 km from an urban centre (population ≥ 100,000), and were not involved in another community alcohol project. Communities were pair-matched, and one member of each pair was randomly allocated to the experimental group. Thirteen interventions were implemented in the experimental communities from 2005 to 2009: community engagement; general practitioner training in alcohol screening and brief intervention (SBI); feedback to key stakeholders; media campaign; workplace policies/practices training; school-based intervention; general practitioner feedback on their prescribing of alcohol medications; community pharmacy-based SBI; web-based SBI; Aboriginal Community Controlled Health Services support for SBI; Good Sports program for sports clubs; identifying and targeting high-risk weekends; and hospital emergency department–based SBI. Primary outcomes based on routinely collected data were alcohol-related crime, traffic crashes, and hospital inpatient admissions. Routinely collected data for the entire study period (2001–2009) were obtained in 2010. Secondary outcomes based on pre- and post-intervention surveys (n = 2,977 and 2,255, respectively) were the following: long-term risky drinking, short-term high-risk drinking, short-term risky drinking, weekly consumption, hazardous/harmful alcohol use, and experience of alcohol harm. At the 5% level of statistical significance, there was insufficient evidence to conclude that the interventions were effective in the experimental, relative to control, communities for alcohol-related crime, traffic crashes, and hospital inpatient admissions, and for rates of risky alcohol consumption and hazardous/harmful alcohol use. Although respondents in the experimental communities reported statistically significantly lower average weekly consumption (1.90 fewer standard drinks per week, 95% CI = −3.37 to −0.43, p = 0.01) and less alcohol-related verbal abuse (odds ratio = 0.58, 95% CI = 0.35 to 0.96, p = 0.04) post-intervention, the low survey response rates (40% and 24% for the pre- and post-intervention surveys, respectively) require conservative interpretation. The main limitations of this study are as follows: (1) that the study may have been under-powered to detect differences in routinely collected data outcomes as statistically significant, and (2) the low survey response rates.
Conclusions
This RCT provides little evidence that community action significantly reduces risky alcohol consumption and alcohol-related harms, other than potential reductions in self-reported average weekly consumption and experience of alcohol-related verbal abuse. Complementary legislative action may be required to more effectively reduce alcohol harms.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12607000123448
Please see later in the article for the Editors' Summary
Editors' Summary
Background
People have consumed alcoholic beverages throughout history, but alcohol use is now an increasing global public health problem. According to the World Health Organization's 2010 Global Burden of Disease Study, alcohol use is the fifth leading risk factor (after high blood pressure and smoking) for disease and is responsible for 3.9% of the global disease burden. Alcohol use contributes to heart disease, liver disease, depression, some cancers, and many other health conditions. Alcohol also affects the well-being and health of people around those who drink, through alcohol-related crimes and road traffic crashes. The impact of alcohol use on disease and injury depends on the amount of alcohol consumed and the pattern of drinking. Most guidelines define long-term risky drinking as more than four drinks per day on average for men or more than two drinks per day for women (a “drink” is, roughly speaking, a can of beer or a small glass of wine), and short-term risky drinking (also called binge drinking) as seven or more drinks on a single occasion for men or five or more drinks on a single occasion for women. However, recent changes to the Australian guidelines acknowledge that a lower level of alcohol consumption is considered risky (with lifetime risky drinking defined as more than two drinks a day and binge drinking defined as more than four drinks on one occasion).
Why Was This Study Done?
In 2010, the World Health Assembly endorsed a global strategy to reduce the harmful use of alcohol. This strategy emphasizes the importance of community action–a process in which a community defines its own needs and determines the actions that are required to meet these needs. Although community action is highly acceptable to community members, few studies have looked at the effectiveness of community action in reducing risky alcohol consumption and alcohol-related harm. Here, the researchers undertake a cluster randomized controlled trial (the Alcohol Action in Rural Communities [AARC] project) to quantify the effectiveness of community action in reducing risky alcohol consumption and harms in rural communities in Australia. A cluster randomized trial compares outcomes in clusters of people (here, communities) who receive alternative interventions assigned through the play of chance.
What Did the Researchers Do and Find?
The researchers pair-matched 20 rural Australian communities according to the proportion of their population that was Aboriginal (rates of alcohol-related harm are disproportionately higher among Aboriginal individuals than among non-Aboriginal individuals in Australia; they are also higher among young people and males, but the proportions of these two groups across communities was comparable). They randomly assigned one member of each pair to the experimental group and implemented 13 interventions in these communities by negotiating with key individuals in each community to define and implement each intervention. Examples of interventions included general practitioner training in screening for alcohol use disorders and in implementing a brief intervention, and a school-based interactive session designed to reduce alcohol harm among young people. The researchers quantified the effectiveness of the interventions using routinely collected data on alcohol-related crime and road traffic crashes, and on hospital inpatient admissions for alcohol dependence or abuse (which were expected to increase in the experimental group if the intervention was effective because of more people seeking or being referred for treatment). They also examined drinking habits and experiences of alcohol-related harm, such as verbal abuse, among community members using pre- and post-intervention surveys. After implementation of the interventions, the rates of alcohol-related crime, road traffic crashes, and hospital admissions, and of risky and hazardous/harmful alcohol consumption (measured using a validated tool called the Alcohol Use Disorders Identification Test) were not statistically significantly different in the experimental and control communities (a difference in outcomes that is not statistically significantly different can occur by chance). However, the reported average weekly consumption of alcohol was 20% lower in the experimental communities after the intervention than in the control communities (equivalent to 1.9 fewer standard drinks per week per respondent) and there was less alcohol-related verbal abuse post-intervention in the experimental communities than in the control communities.
What Do These Findings Mean?
These findings provide little evidence that community action reduced risky alcohol consumption and alcohol-related harms in rural Australian communities. Although there was some evidence of significant reductions in self-reported weekly alcohol consumption and in experiences of alcohol-related verbal abuse, these findings must be interpreted cautiously because they are based on surveys with very low response rates. A larger or differently designed study might provide statistically significant evidence for the effectiveness of community action in reducing risky alcohol consumption. However, given their findings, the researchers suggest that legislative approaches that are beyond the control of individual communities, such as alcohol taxation and restrictions on alcohol availability, may be required to effectively reduce alcohol harms. In other words, community action alone may not be the most effective way to reduce alcohol-related harm.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001617.
The World Health Organization provides detailed information about alcohol; its fact sheet on alcohol includes information about the global strategy to reduce the harmful use of alcohol; the Global Information System on Alcohol and Health provides further information about alcohol, including information on control policies around the world
The US National Institute on Alcohol Abuse and Alcoholism has information about alcohol and its effects on health
The US Centers for Disease Control and Prevention has a website on alcohol and public health that includes information on the health risks of excessive drinking
The UK National Health Service Choices website provides detailed information about drinking and alcohol, including information on the risks of drinking too much, tools for calculating alcohol consumption, and personal stories about alcohol use problems
MedlinePlus provides links to many other resources on alcohol
More information about the Alcohol Action in Rural Communities project is available
doi:10.1371/journal.pmed.1001617
PMCID: PMC3949675  PMID: 24618831
23.  Evaluation of the functional efficacy of an antioxidative probiotic in healthy volunteers 
Nutrition Journal  2005;4:22.
Background
In persons without clinical symptom it is difficult to assess an impact of probiotics regarding its effect on health. We evaluated the functional efficacy of the probiotic Lactobacillus fermentum ME-3 in healthy volunteers by measuring the influence of two different formulations on intestinal lactoflora, fecal recovery of the probiotic strain and oxidative stress markers of blood and urine after 3 weeks consumption.
Methods
Two 3-week healthy volunteer trials were performed. Open placebo controlled (OPC) study participants (n = 21) consumed either goat milk or by L. fermentum ME-3 fermented goat milk (daily dose 11.8 log CFU (Colony Forming Units). Double blind randomised placebo controlled (DBRP) study participants (n = 24) received either capsules with L. fermentum ME-3 (daily of dose 9.2 CFU) or placebo capsules.
The faecal lactoflora composition, faecal ME-3 recovery, effect of the consumption on intestinal lactoflora, and oxidative stress markers of blood (total antioxidative activity; total antioxidative status and glutathione red-ox ratio) was measured.
Results
ME-3 was well tolerated and a significant increase in total faecal lactobacilli yet no predominance of ME-3 was detected in all study groups. Faecal recovery of ME-3 was documented by molecular methods only in fermented milk group, however the significant improvement of blood TAA (Total Antioxidative Activity) and TAS (Total Antioxidative Status) indices was seen both in case of fermented goat milk and capsules", yet glutathione re-ox ratio values decreased only in case of fermented by ME-3 goat milk.
Conclusion
The functional efficacy of both consumed formulations of an antioxidative probiotic L. fermentum ME-3 is proved by the increase of the intestinal lactobacilli counts providing putative defence against enteric infections and by reduction of the oxidative stress indices of blood and urine of healthy volunteers. In non-diseased host the probiotic health claims can be assessed by improvement of some measurable laboratory indices of well-established physiological functions of host, e.g. markers of antioxidative defence system.
doi:10.1186/1475-2891-4-22
PMCID: PMC1198254  PMID: 16080791
24.  572 Effect of Enzymatically Modified Isoquercitrin, a Flavonoid, on Symptoms of Japanese Cedar Pollinosis 
Background
The prevalence of allergic diseases has increased all over the world during the last 2 decades. Dietary change is considered to be one of environmental factors that cause this increase and worsen allergic symptoms. If it is the case, an appropriate intake of foods and beverages with antiallergic activity is anticipated to prevent the onset of allergic diseases and ameliorate allergic symptoms. Flavonoids, ubiquitously present in vegetables, fruits or tea possess antiallergic and antioxidant effects, so that we examined the efficacy of a flavonoid on clinical symptoms of Japanese cedar pollinosis.
Methods
We investigated the efficacy of enzymatically modified isoquercitrin (EMIQ), a quercetin glycoside, to relieve symptoms of Japanese Cedar pollinosis by 3 different clinical trials. In either trial patients were randomly assigned to the EMIQ group or the placebo group and took one capsule containing EMIQ plus corn starch or corn starch only twice a day. The efficacy was evaluated with the total symptom, medication or QOL score. Study 1 (reference 1) and 2 (reference 2); EMIQ (100 mg/day) versus placebo, for 8 weeks, started after (study 1) and before (study 2) the onset of pollen release, Study 3; EMIQ (200 mg/day) versus placebo, for 4 weeks, started after the onset of pollen release.
Results
In study 1 and 2, during the entire study period, ocular + medication score for the EMIQ group was significantly lower (P < 0.05) than that of the placebo group. When limited to the period, total symptom + medication score for the EMIQ group was significantly lower than that for the placebo group in all 3 studies.
Conclusions
These results indicate that intake of EMIQ, a quercetin glycoside proved to be effective for the relief of symptoms caused by Japanese cedar pollinosis.
doi:10.1097/01.WOX.0000411687.36323.8b
PMCID: PMC3512685
25.  Reinforcing effects of caffeine in coffee and capsules. 
In a residential research ward the reinforcing and subjective effects of caffeine were studied under double-blind conditions in volunteer subjects with histories of heavy coffee drinking. In Experiment 1, 6 subjects had 13 opportunities each day to self-administer either a caffeine (100 mg) or a placebo capsule for periods of 14 to 61 days. All subjects developed a clear preference for caffeine, with intake of caffeine becoming relatively stable after preference had been attained. Preference for caffeine was demonstrated whether or not preference testing was preceded by a period of 10 to 37 days of caffeine abstinence, suggesting that a recent history of heavy caffeine intake (tolerance/dependence) was not a necessary condition for caffeine to function as a reinforcer. In Experiment 2, 6 subjects had 10 opportunities each day to self-administer a cup of coffee or (on different days) a capsule, dependent upon completing a work requirement that progressively increased and then decreased over days. Each day, one of four conditions was studied: caffeinated coffee (100 mg/cup), decaffeinated coffee, caffeine capsules (100 mg/capsule), or placebo capsules. Caffeinated coffee maintained the most self-administration, significantly higher than decaffeinated coffee and placebo capsules but not different from caffeine capsules. Both decaffeinated coffee and caffeine capsules were significantly higher than placebo capsules but not different from each other. In both experiments, subject ratings of "linking" of coffee or capsules covaried with the self-administration measures. These experiments provide the clearest demonstrations to date of the reinforcing effects of caffeine in capsules and in coffee.
doi:10.1901/jeab.1989.52-127
PMCID: PMC1338955  PMID: 2794839

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