BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes with symptomatic polyneuropathy.

INTRODUCTION: Diabetic sensorimotor polyneuropathy (DSPN) affects approximately 30% of people with diabetes, while around half of cases are symptomatic. Currently, there are only few pathogenetically oriented pharmacotherapies for DSPN, one of which is benfotiamine, a prodrug of thiamine with a high bioavailability and favourable safety profile. While benfotiamine has shown positive effects in preclinical and short-term clinical studies, no long-term clinical trials are available to demonstrate disease-modifying effects on DSPN using a comprehensive set of disease-related endpoints. METHODS AND ANALYSIS: The benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes trial is a randomised double-blind, placebo-controlled parallel group monocentric phase II clinical trial to assess the effects of treatment with benfotiamine compared with placebo in participants with type 2 diabetes and mild to moderate symptomatic DSPN. Sixty participants will be 1:1 randomised to treatment with benfotiamine 300 mg or placebo two times a day over 12 months. The primary endpoint will be the change in corneal nerve fibre length assessed by corneal confocal microscopy (CCM) after 12 months of benfotiamine treatment compared with placebo. Secondary endpoints will include other CCM measures, skin biopsy and function indices, variables from somatic and autonomic nerve function tests, clinical examination and questionnaires, general health, health-related quality of life, cost, safety and blood tests. ETHICS AND DISSEMINATION: The trial was approved by the competent authority and the local independent ethics committee. Trial results will be published in peer-reviewed journals, conference abstracts, and via online and print media. TRIAL REGISTRATION NUMBER: DRKS00014832.

Evaluation and Validation of a Joint Stress Test to Induce Activity-Related Knee Joint Discomfort - a Prospective Case-Control Study.

BACKGROUND: The assessment of improvement or maintenance of joint health in healthy subjects is a great challenge. The aim of the study was the evaluation of a joint stress test to assess joint discomfort in subjects with activity-related knee joint discomfort (ArJD). RESULTS: Forty-five subjects were recruited to perform the single-leg-step-down (SLSD) test (15 subjects per group). Subjects with ArJD of the knee (age 22-62 years) were compared to healthy subjects (age 24-59 years) with no knee joint discomfort during daily life sporting activity and to subjects with mild-to-moderate osteoarthritis of the knee joint (OA, Kellgren score 2-3, age 42-64 years). The subjects performed the SLSD test with two different protocols: (I) standardization for knee joint discomfort; (II) standardization for load on the knee joint. In addition, range of motion (ROM), reach test, acute pain at rest and after a single-leg squat and knee injury, and osteoarthritis outcome score (KOOS) were assessed. In OA and ArJD subjects, knee joint discomfort could be reproducibly induced in a short time interval of less than 10 min (200 steps). In healthy subjects, no pain was recorded. A clear differentiation between study groups was observed with the SLSD test (maximal step number) as well as KOOS questionnaire, ROM, and reach test. In addition, a moderate to good intra-class correlation was shown for the investigated outcomes. CONCLUSIONS: These results suggest the SLSD test is a reliable tool for the assessment of knee joint health function in ArJD and OA subjects to study the improvements in their activities. Further, this model can be used as a stress model in intervention studies to study the impact of stress on knee joint health function.

Effects of lemon verbena extract (Recoverben®) supplementation on muscle strength and recovery after exhaustive exercise: a randomized, placebo-controlled trial.

BACKGROUND: Exhaustive exercise causes muscle damage accompanied by oxidative stress and inflammation leading to muscle fatigue and muscle soreness. Lemon verbena leaves, commonly used as tea and refreshing beverage, demonstrated antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of a proprietary lemon verbena extract (Recoverben®) on muscle strength and recovery after exhaustive exercise in comparison to a placebo product. METHODS: The study was performed as a randomized, placebo-controlled, double-blind study with parallel design. Forty-four healthy males and females, which were 22-50 years old and active in sports, were randomized to 400 mg lemon verbena extract once daily or placebo. The 15 days intervention was divided into 10 days supplementation prior to the exhaustive exercise day (intensive jump-protocol), one day during the test and four days after. Muscle strength (MVC), muscle damage (CK), oxidative stress (GPx), inflammation (IL6) and volunteer-reported muscle soreness intensity were assessed pre and post exercise. RESULTS: Participants in the lemon verbena group benefited from less muscle damage as well as faster and full recovery. Compared to placebo, lemon verbena extract receiving participants had significantly less exercise-related loss of muscle strength (p = 0.0311) over all timepoints, improved glutathione peroxidase activity by trend (p = 0.0681) and less movement induced pain (p = 0.0788) by trend. Creatine kinase and IL-6 didn't show significant discrimmination between groups. CONCLUSION: Lemon verbena extract (Recoverben®) has been shown to be a safe and well-tolerated natural sports ingredient, by reducing muscle damage after exhaustive exercise. TRIAL REGISTRATION: The trial was registered in the clinical trials registry (clinical trial.gov NCT02923102). Registered 28 September 2016.

Identification of Shiga-Toxigenic Escherichia coli outbreak isolates by a novel data analysis tool after matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

The fast and reliable characterization of bacterial and fungal pathogens plays an important role in infectious disease control and tracking of outbreak agents. DNA based methods are the gold standard for epidemiological investigations, but they are still comparatively expensive and time-consuming. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a fast, reliable and cost-effective technique now routinely used to identify clinically relevant human pathogens. It has been used for subspecies differentiation and typing, but its use for epidemiological tasks, e. g. for outbreak investigations, is often hampered by the complexity of data analysis. We have analysed publicly available MALDI-TOF mass spectra from a large outbreak of Shiga-Toxigenic Escherichia coli in northern Germany using a general purpose software tool for the analysis of complex biological data. The software was challenged with depauperate spectra and reduced learning group sizes to mimic poor spectrum quality and scarcity of reference spectra at the onset of an outbreak. With high quality formic acid extraction spectra, the software's built in classifier accurately identified outbreak related strains using as few as 10 reference spectra (99.8% sensitivity, 98.0% specificity). Selective variation of processing parameters showed impaired marker peak detection and reduced classification accuracy in samples with high background noise or artificially reduced peak counts. However, the software consistently identified mass signals suitable for a highly reliable marker peak based classification approach (100% sensitivity, 99.5% specificity) even from low quality direct deposition spectra. The study demonstrates that general purpose data analysis tools can effectively be used for the analysis of bacterial mass spectra.

Effects of an L-arginine-based multi ingredient product on endothelial function in subjects with mild to moderate hypertension and hyperhomocysteinemia - a randomized, double-blind, placebo-controlled, cross-over trial.

BACKGROUND: Nutrition plays an important role in prevention and management of cardiovascular diseases (CVD) in early stages. Recent research demonstrated beneficial effects of various nutritional ingredients on vascular health. The aim of the current study was to evaluate the effects of an L-arginine-based multi ingredient product (AbMIP) on vascular function. METHODS: Twenty-five male and female subjects, aged between 45 and 65 years with elevated blood pressure and hyperhomocysteinemia were included in this cross-over trial. Subjects were randomly assigned to one of the two sequence groups (AbMIP -placebo or placebo - AbMIP). AbMIP and placebo were taken for 4 weeks, each. Endothelial function under fasting conditions, blood pressure, postprandial endothelial function after consumption of a high fat meal, homocysteine, asymmetric dimethyl arginine (ADMA) and Hba1c were determined. RESULTS: AbMIP significantly improved fasting endothelial function determined by EndoPAT™ when compared to placebo (p = 0.047). Similarly, homocysteine levels were significantly decreased after verum supplementation when compared to placebo (p < 0.0001). Systolic blood pressure decreased significantly under AbMIP (p = 0.002) and the reduction was more pronounced when compared to placebo. However, due to placebo-effects no significant difference could be found between groups (p = 0.586). The effects on postprandial endothelial function were stronger for AbMIP when compared with placebo but did not reach significance (p = 0.201). No significant effects of AbMIP were observed regarding HbA1c, ADMA and diastolic blood pressure. CONCLUSIONS: Due to improvement on endothelial function, decrease of elevated homocysteine levels and excellent tolerability, AbMIP was demonstrated to be a beneficial option for dietary treatment of endothelial dysfunction and hyperhomocysteinemia in early stages of CVD. TRIAL REGISTRATION: The clinical trials.gov identifier is NCT02392767 , November 14, 2014.

Effects of Mangifera indica (Careless) on Microcirculation and Glucose Metabolism in Healthy Volunteers.

A commercial Mangifera indica fruit powder (Careless) showed beneficial acute effects on microcirculation in a randomized, double-blind, crossover pilot study. Here, long-term effects on microcirculation and glucose metabolism were investigated in a double-blind, randomized, placebo-controlled, 3-arm parallel-design study in healthy individuals. A daily dose of 100 mg or 300 mg of the fruit powder was compared to placebo after supplementation for 4 weeks. Microcirculation and endothelial function were assessed by the Oxygen-to-see System and pulse amplitude tonometry, respectively. Glucose metabolism was assessed under fasting and postprandial conditions by capillary glucose and HbA1c values.Microcirculatory reactive hyperemia flow increased, especially in the 100 mg group (p = 0.025). The 300 mg of the M. indica fruit preparation reduced postprandial glucose levels by trend if compared to placebo (p = 0.0535) accompanied by significantly lower HbA1c values compared to baseline. Furthermore, 300 mg intake significantly improved postprandial endothelial function in individuals with decreased endothelial function after high-dose glucose intake (p = 0.0408; n = 11).In conclusion, the study suggests moderate beneficial effects of M. indica fruit preparation on microcirculation, endothelial function, and glucose metabolism.

In Vitro Activation of eNOS by Mangifera indica (Careless™) and Determination of an Effective Dosage in a Randomized, Double-Blind, Human Pilot Study on Microcirculation.

Mangifera indica fruit preparation (Careless™) activates the evolutionary conserved metabolic sensors sirtuin 1 and adenosine monophosphate-activated protein kinase, which have been identified as playing a key role in microcirculation and endothelial function. Here, an acute effect of a single dose of 100 mg or 300 mg Careless™ on microcirculation was investigated in a randomized, double-blind, crossover pilot study in ten healthy women to determine the effective dosage. Microcirculation and endothelial function were assessed by the Oxygen-to-see system and pulse amplitude tonometry (EndoPAT™), respectively. Cutaneous blood flow was increased over time by 100 mg (54% over pre-values, p = 0.0157) and 300 mg (35% over pre-value, p = 0.209) Careless™. The EndoPAT™ reactive hyperemia response was slightly improved 3 h after intake compared to pretesting with 300 mg Careless™. Furthermore, activation of endothelial nitric oxide synthase, as an important regulator for endothelial function, was tested in vitro in primary human umbilical vein endothelial cells. Careless™, after simulation of digestion, increased the activated form of endothelial nitric oxide synthase dose-dependently by 23% (300 µg/mL), 42% (1500 µg/mL), and 60% (3000 µg/mL) compared to the untreated control. In conclusion, the study suggests moderate beneficial effects of Careless™ on microcirculation, which is at least partly mediated by endothelial nitric oxide synthase activation.

Reduced muscular fatigue after a 12-week leucine-rich amino acid supplementation combined with moderate training in elderly: a randomised, placebo-controlled, double-blind trial.

BACKGROUND: Age-related muscle loss is characterised by a progressing decrease in muscle mass, strength and function. Besides resistance training and physical activity, appropriate nutrition that is rich in protein, especially branched-chain amino acids, is very important to support training effects and positively influence the protein synthesis to degradation ratio. AIM: The purpose of this study was to evaluate the effect of a 12-week leucine-rich amino acid supplementation in combination with moderate training. METHODS: Forty-eight healthy subjects exercised for 30 min three times per week and received either a leucine-rich amino acid supplementation or a placebo. Before and after supplementation, volunteers performed an exhaustive eccentric exercise protocol. Maximal concentric strength, muscle soreness, creatine kinase (CK), type II collagen collagenase cleavage neoepitope (C2C), C propeptide of type II procollagen (CP2) and safety assessments were performed before exercise and after 3, 24, 48 and 72 hours. RESULTS: The supplementation with leucine resulted in reduced loss of strength at 0 and 3 hours after downhill walking compared with the placebo (p=0.0439). The reduction of C2C/CP2 ratio deflection was significantly increased (p=0.038) due to leucine compared with the placebo. The same tendency could be observed for the recovery phase. No significant supplement effects for muscle soreness and CK could be observed. CONCLUSION: The principle findings show that leucine-rich amino acid supplementation can counteract the negative effects of eccentric exercise. The treatment resulted in a reduction of exercise-induced strength loss.

Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial.

BACKGROUND: Systemic enzyme therapy may improve symptoms of exhaustive eccentric exercise due to anti-inflammatory properties. METHODS: In a randomised, placebo-controlled, two-stage clinical trial, systemic enzyme therapy (Wobenzym) was administered for 72 hours before and 72 hours following a day on which subjects performed an exhaustive eccentric exercise (isokinetic loading of the quadriceps). Efficacy criteria (maximal strength and pain) and time points were selected to account for the multidimensional nature of exercise-induced muscle damage symptoms. Subjects were randomised in a crossover (stage I, n=28) and parallel group design (stage II, n=44). RESULTS: Analysis of stage I data demonstrated a significant superiority (Mann-Whitney=0.6153; p=0.0332; one sided) for systemic enzyme therapy compared with placebo. Stage II was designed as a randomised controlled parallel group comparison. Heterogeneity (I2>0.5) between stages led to separate analyses of stage I (endurance-trained subjects) and stage II (strength-trained subjects). Combined analysis resulted in no evidence for corresponding treatment effects. Analysis of pooled biomarker data, however, demonstrated significant favourable effects for systemic enzyme therapy in both stages. CONCLUSION: Systemic enzyme therapy before and after exhaustive eccentric exercise resulted in higher maximal concentric strength in the less strength-trained subjects (stage I) and in significant favourable effects on biomarkers (inflammatory, metabolic and immune) in all subjects. The application of these findings needs further evaluation.

Perilla extract improves gastrointestinal discomfort in a randomized placebo controlled double blind human pilot study.

BACKGROUND: Gastrointestinal (GI) discomfort, e.g. bloating or rumbling, is a common symptom in otherwise healthy adults. Approximately 20% of the population, particularly women suffer from gastrointestinal discomfort and this affects quality of life. Recent studies discovered a link between the body and mind, called the gut-brain axis. Psychosocial factors, such as e.g. daily stress may cause altered gut physiology leading to ileum contractions and consequently gastrointestinal symptoms. In vitro and ex vivo studies clearly showed that a Perilla frutescens extract combines prokinetic, antispasmodic and anti-inflammatory effects. The aim of the intervention was to investigate the effects of the proprietary Perilla extract on GI discomfort in healthy subjects with gastrointestinal discomfort and reduced bowel movements in comparison to a placebo product. METHODS: The pilot study was performed according to a double-blind, randomized, placebo-controlled parallel design. Fifty healthy subjects with gastrointestinal discomfort and reduced bowel movements, 30-70 years, documented their GI symptoms, stool frequency and consistency daily during a 2-week run-in phase and a 4-week intervention phase with Perilla frutescens extract or placebo. GI symptoms were assessed on a 5-point scale daily and average scores over 14 days intervals were calculated. RESULTS: All GI symptoms were significantly improved over time by Perilla frutescens extract during the intervention phase (bloating: -0.44±0.56, p=0.0003; passage of gas: -0.30±0.66, p=0.0264; GI rumbling: -0.55±0.87, p=0.0014; feeling of fullness: -0.36±0.72, p=0.0152; abdominal discomfort: -0.54±0.75, p=0.004), whereas in the placebo group only abdominal discomfort was significantly improved (-0.31±0.55, p=0.0345). In the subgroup of women results were strengthened and a subscore out of bloating and abdominal discomfort was significantly improved against placebo (95%CI 0.003 to 0.77; p=0.048). CONCLUSION: The demonstrated effects of Perilla frutescens extract to improve GI complaints offer very promising results, taking into consideration the challenging set up of a nutritional human study with healthy subjects and in the area of digestive health, which is known for high placebo effects. TRIAL REGISTRATION NUMBER: NCT01931930 at ClinicalTrials.gov, Registration date 23rd August 2013.

Spatial orientation of the subtalar joint axis is different in subjects with and without Achilles tendon disorders.

BACKGROUND: There are many possible predisposing factors for Achilles tendon disorders suggested in the literature but their pathogenetic relevance is not proven in most cases. The asymmetric mechanical load distribution within the Achilles tendon during locomotion is frequently addressed as a major risk factor for Achilles tendon disorders. The spatial orientation of the subtalar joint axis (STA) may influence the Achilles tendon loading possibly leading to overload injuries. Hypothesis There is a significant difference between the orientation of the STA in subjects with and without Achilles tendon pathologies. MATERIALS AND METHODS: 614 subtalar joint axes determined in 307 long-distance runners with and without Achilles tendon disorders were included. Achilles tendon disorders were defined as any Achilles tendon-related pain during or following running, existing for more than 2 weeks in the past. Motion analysis of the foot was performed using an ultrasonic pulse-echo-based measurement system. The orientation of the STA was expressed by two angles. RESULTS: The mean inclination angle was 42 ± 16° and the mean deviation angle was 11 ± 2 3°. There was a significant difference (p=0.002) between the mean deviation angle measured in subjects with Achilles tendon pathologies (18 ± 23°) and those without (10 ± 23°). CONCLUSIONS: The results demonstrate a wide interindividual variability of the spatial orientation of the STA. In addition, the mean deviation angle in people with Achilles tendon pathologies is significantly more oblique than in people without. This finding indicates that the spatial orientation of the STA is related to the incidence of overuse injuries of the Achilles tendon in the investigated sample.