Double-blind Crossover Study Research Articles

Protocol for a double-blind crossover randomised controlled trial to investigate inhalation CHallenge to assess Inducible Laryngeal Obstruction (CH-ILO)

Current ILO diagnosis is dependent on an individual being symptomatic. If results prove citric acid inhalation challenge agent provokes ILO it will provide new insights into neuronal mechanisms and support development of a standardised diagnostic test.IntroductionInducible laryngeal obstruction (ILO) remains a poorly understood condition in part due to lack of understanding about the underlying neuronal mechanisms. Many suffer delayed confirmed diagnosis as no standardised assessment exists. Based on previous work, we propose citric acid (CA) is the most appropriate inhalation agent for inducing upper airway reflex responses, with a view to developing an inhalation challenge test for ILO.Methods and analysisA single-centre, double-blind crossover study. The primary objective is to identify if CA inhalation challenge provokes laryngeal obstruction in patients with confirmed ILO. We will recruit: 10 participants with ILO, 10 with refractory chronic cough (RCC), 10 healthy controls. Each will undergo two inhalation challenges during laryngoscopy, with ascending concentrations of citric acid or saline control; participants will be randomised sequentially by a computer-generated schedule to determine order of delivery. Follow up is a telephone consultation. Randomisation and preparation of challenge agents will be by an unblinded study team member, not involved in data analysis. Challenge agents will only be unblinded on study completion. Log10concentration of CA evoking ILO will be compared between patient groups using a one-way ANOVA, comparing participants with ILO and participants with RCC to healthy controls.ConclusionThis will be the first randomised controlled trial to investigate the role of inhalation challenge as an assessment tool to evoke laryngeal obstruction in patients with confirmed ILO. If results prove citric acid inhalation challenge agent provokes ILO it will provide new insights into neuronal mechanisms and support development of a standardised diagnostic test.

The impact of exogenous ketone body suppletion on energy and pH balance in skeletal muscle during exercise in chronic heart failure patients: a prospective randomized double-blind cross-over study

Abstract Background Heart Failure (HF) is characterized by impediments in exercise capacity. Disruptions in the energy metabolism of skeletal muscle contribute to this condition. Pre-clinical and clinical evidence showed that reductions in carbohydrate and FA metabolism in HF may be partially overcome by a compensatory increase in ketone body oxidation and suggest that suppletion of ketone bodies (KB) may improve energy metabolism in HF. Purpose We tested the effect of exogenous KB suppletion on energy and pH balance during cycling exercise using 31P Magnetic Resonance (MR) Spectroscopy of the exercising quadriceps muscle in patients with HF. Methods In a randomized, double-blind, placebo-controlled cross-over study, 14 stable HF patients with reduced ejection fraction and diminished exercise capacity underwent maximal exercise testing in a MR scanner fitted with a cycling ergometer after KB or placebo treatment. Phosphocreatine (PCr) and inorganic phosphate (Pi) resonance amplitudes and frequencies were measured continuously in the quadriceps muscle during rest, exercise and recovery using in-vivo 31P MR spectroscopy (Figure 1). Results Patients had a median age of 66 [53 – 75] years, were 14% female, had a median LVEF of 37% [27 – 40] and circulating NT-pro BNP levels of 411 [182 – 946] pg/mL. Peak oxygen uptake (VO2) was 18.2 [15.2 – 20.3] ml/kg/min, which is 68% [62 – 78%] of predicted. After treatment, exercise performance in terms of cycling duration and workload were comparable between treatment arms (Figure 2). Quadriceps acidification during exercise was larger after KB suppletion compared to placebo (ΔpH: -0.2 [-0.3 - -0.1] vs -0.1 [-0.3 - -0.1] respectively; p=0.041) while quadriceps energy depletion during exercise was not altered by treatment (ΔPi/PCr 0.77 [0.55 – 2.51] vs 0.66 [0.46 – 0.81] respectively; p=0.087). Post-exercise mitochondrial oxidative function was similar between treatment arms (KB: PCr resynthesis rate 48 sec [25 – 59] versus placebo: 42 sec [36 – 63]; p=0.767). Conclusions Ketone body suppletion increased acidification and did not improve energy balance in skeletal muscle during exercise or mitochondrial function during recovery in patients with chronic HF. These results question the value of ketone bodies as treatment to boost muscular energy metabolism during exercise in HF.31P MRS Spectrum during exercise in HFExercise and energy parameters

Intensity-Dependent Effects of Low-Frequency Subthreshold rTMS on Primary Motor Cortex Excitability and Interhemispheric Inhibition in Elderly Participants: A Randomized Trial.

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) protocols targeting primary motor cortex (M1) are used in rehabilitation of neurological diseases for their therapeutic potential, safety, and tolerability. Although lower intensity LF-rTMS can modulate M1 neurophysiology, results are variable, and a systematic assessment of its dose effect is lacking. To determine the dose-response of LF-rTMS on stimulated and non-stimulated M1. In a sham-controlled randomized double-blind crossover study the effect of LF-TMS protocols were determined in 20 right-handed older healthy participants. In 3 sessions, 1 Hz rTMS at 80% (rTMS80), 90% (rTMS90) of motor threshold or sham stimulation were applied to left upper extremity M1. Outcome measures were curve parameters of the stimulus-response curve (maximum motor evoked potential [MEPMAX], slope and the intensity to evoke 50% MEPMAX), short-interval intracortical inhibition (SICI), and interhemispheric inhibition (IHI). Within LF-rTMS sessions, rTMS90, increased MEPMAX in the stimulated M1. Furthermore, rTMS90, increased the slope in the non-stimulated M1. LF-rTMS effects on SICI were dependent on the participants' baseline SICI, hemisphere, and intensity of conditioning pulse. Finally, rTMS90 increased whereas rTMS80 decreased IHI, for both IHI directions. These changes were dependent on baseline IHI and hemisphere and were no longer significant when baseline IHI was accounted for. Intensity of subthreshold LF-rTMS has differential effects on excitation and inhibition of stimulated and non-stimulated M1. The effects were small and were only demonstrated within the LF-rTMS sessions but were not different when compared to sham. rTMS related changes in SICI and IHI were dependent on baseline level. NCT02544503, NCT01726218.

Magnetic Garments Promote Parasympathetic Dominance and Improve Sleep Quality in Male Long-Distance Runners Following a 30 km Run

This study aimed to investigate the effects of high-intensity running on the autonomic nervous system and sleep quality of male long-distance runners and to examine the impact of wearing magnetic garments on these parameters. Fifteen highly trained male collegiate long-distance runners participated in a randomized, double-blind crossover study. Participants completed two 30 km runs (30k-RUN) during a 10-day training camp. After each run, they wore either magnetic (MAG) or non-magnetic control (CTRL) garments. Sleep quality and heart rate variability (HRV) were assessed using a wrist-worn device before and after each 30k-RUN. Wearing MAG garments post-30k-RUN resulted in significantly longer deep sleep duration compared to CTRL. HRV analysis revealed that the MAG condition led to a significantly higher root mean square of successive RR interval differences and high-frequency power, indicating enhanced parasympathetic activity. The low-frequency to high-frequency ratio was significantly lower in MAG than in CTRL. Perceived recovery scores were significantly higher in MAG than in CTRL. The findings of this study suggest that wearing magnetic garments following high-intensity endurance running may promote parasympathetic dominance and improve sleep quality in male long-distance runners. These findings indicate that magnetic garments may be a practical method for enhancing recovery in athletes following intense training.

Biofilm modulation and demineralization reduction after treatment with a new toothpaste formulation containing fluoride, casein phosphopeptide-amorphous calcium phosphate, and sodium trimetaphosphate: In situ study

ObjectiveThis in situ study aimed to evaluate a new toothpaste formulation containing fluoride (F), casein phosphopeptide amorphous calcium phosphate (CPP-ACP) and sodium trimetaphosphate (TMP) on the process of dental demineralization and biofilm composition. MethodsThis crossover double-blind study consisted of five phases, in which 10 volunteers wore intraoral appliances containing four bovine enamel specimens. The cariogenic challenge was performed using 30 % sucrose solution. Blocks were treated 3 ×/day with the following toothpastes: 1) Placebo (No F-TMP-CPP-ACP), 2) 1100 ppm F (1100F), 3) 1100F + 3 %TMP (1100F-TMP), 4) 1100F + 10 %CPP-ACP (1100F-CPP-ACP) and 5) 1100F-CPP-ACP-TMP. After 7 days, the percentage loss of surface hardness (%SH), integrated loss of subsurface hardness (ΔKHN), F, calcium (Ca) and phosphorus (P) concentration in the enamel was determined. The concentration of F, Ca, P and insoluble extracellular polysaccharide (EPS) in the biofilm were analyzed. ResultsThe addition of CPP-ACP-TMP to 1100F reduced %SH by 42 % and 39 % when compared to the 1100F and 1100F-CPP-ACP (p < 0.001); in addition, to a reduction in lesion body (ΔKHN) by 36 % for the same treatments. The treatment with 1100F-CPP-ACP-TMP led to a significant increase in the concentration of F, P and Ca in the enamel and biofilm, and reduced the concentration of EPS (p < 0.001). SignificanceToothpaste formulation containing 1100F-CPP-ACP-TMP prevented the reduction of enamel hardness and significantly influenced the ionic biochemical composition and insoluble extracellular polysaccharide (EPS) in biofilm formed in situ. These results are promising and provide valuable insights for the design of further clinical trials.

Evaluation of gabapentin administration on neurologic examination in 2 different age groups of healthy cats.

Gabapentin is often administered PO for preappointment or in-hospital anxiolysis in cats. A previous study reported mild changes on the neurologic examination after administration. Investigate the effects of gabapentin on anxiety, sedation, compliance, and neurologic examination in 2 age groups of cats. Thirty-one young cats and 12 geriatric cats perceived by their owners to be healthy and neurologically normal. Prospective double-blinded clinical crossover study. Assessment of baseline sedation and anxiety was performed before initial neurologic examinations and after gabapentin administration (100 mg/cat). Assessments were repeated 90 to 120 minutes after administration. Ease of handling pregabapentin and postgabapentin was assessed in the younger cats. All examinations were performed by a board-certified veterinary neurologist and scoring of examinations was performed by a different, masked board-certified neurologist. Sixteen cats (50%) in the younger cohort and 6 cats (50%) in the geriatric cohort exhibited an increase in their overall neurologic examination score postgabapentin administration, mainly through new or progressive postural reaction deficits and gait changes. Anxiety and sedation scores were significantly changed in the geriatric population (P < .01, P = .004, respectively); however, only sedation scores were significantly increased in the younger cats after gabapentin administration (P = .004). All study participants showed mild neurologic changes after gabapentin administration, most markedly noted in the geriatric population. Dose reduction of gabapentin for preappointment anxiolysis and neurologic examination in geriatric patients should be considered.

Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.

Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

Protein-based oral rehydration solutions for patients with an ileostomy: A randomised, double-blinded crossover study

Protein-based oral rehydration solutions for patients with an ileostomy: A randomised, double-blinded crossover study

Apparent Saturation of Branched-Chain Amino Acid Catabolism After High Dietary Milk Protein Intake in Healthy Adults

Abstract Context Milk protein contains high concentrations of branched-chain amino acids (BCAA) that play a critical role in anabolism and are implicated in the onset of obesity and chronic disease. Characterizing BCAA catabolism in the postprandial phase could elucidate the impact of protein intake on obesity risk established in the “early protein hypothesis.” Objective To examine the acute effects of protein content of young child formulas as test meals on BCAA catabolism, observing postprandial plasma concentrations of BCAA in relation to their degradation products. Methods The TOMI Add-On Study is a randomized, double-blind crossover study in which 27 healthy adults consumed 2 isocaloric young child formulas with alternating higher (HP) and lower (LP) protein and fat content as test meals during separate interventions, while 9 blood samples were obtained over 5 hours. BCAA, branched-chain α-keto acids (BCKA), and acylcarnitines were analyzed using a fully targeted HPLC-ESI-MS/MS approach. Results Mean concentrations of BCAA, BCKA, and acylcarnitines were significantly higher after HP than LP over the 5 postprandial hours, except for the BCKA α-ketoisovalerate (KIVA). The latter metabolite showed higher postprandial concentrations after LP. With increasing mean concentrations of BCAA, concentrations of corresponding BCKA, acylcarnitines, and urea increased until a breakpoint was reached, after which concentrations of degradation products decreased (for all metabolites except valine and KIVA and Carn C4:0-iso). Conclusion BCAA catabolism is markedly influenced by protein content of the test meal. We present novel evidence for the apparent saturation of the BCAA degradation pathway in the acute postprandial phase up to 5 hours after consumption.

Effects of fructan and gluten on gut microbiota in individuals with self-reported non-celiac gluten/wheat sensitivity—a randomised controlled crossover trial

BackgroundIndividuals with non-celiac gluten/wheat sensitivity (NCGWS) experience improvement in gastrointestinal symptoms following a gluten-free diet. Although previous results have indicated that fructo-oligosaccharides (FOS), a type of short-chain fructans, were more likely to induce symptoms than gluten in self-reported NCGWS patients, the underlying mechanisms are unresolved.MethodsOur main objective was therefore to investigate whether FOS-fructans and gluten affect the composition and diversity of the faecal microbiota (16S rRNA gene sequencing), faecal metabolites of microbial fermentation (short-chain fatty acids [SCFA]; gas chromatography with flame ionization detector), and a faecal biomarker of gut inflammation (neutrophil gelatinase-associated lipocalin, also known as lipocalin 2, NGAL/LCN2; ELISA). In the randomised double-blind placebo-controlled crossover study, 59 participants with self-reported NCGWS underwent three different 7-day diet challenges with gluten (5.7 g/day), FOS-fructans (2.1 g/day), and placebo separately (three periods, six challenge sequences).ResultsThe relative abundances of certain bacterial taxa were affected differently by the diet challenges. After the FOS-fructan challenge, Fusicatenibacter increased, while Eubacterium (E.) coprostanoligenes group, Anaerotruncus, and unknown Ruminococcaceae genera decreased. The gluten challenge was primarily characterized by increased abundance of Eubacterium xylanophilum group. However, no differences were found for bacterial diversity (α-diversity), overall bacterial community structure (β-diversity), faecal metabolites (SCFA), or NGAL/LCN2. Furthermore, gastrointestinal symptoms in response to FOS-fructans were generally not linked to substantial shifts in the gut bacterial community. However, the reduction in E. coprostanoligenes group following the FOS-fructan challenge was associated with increased gastrointestinal pain. Finally, correlation analysis revealed that changes in gastrointestinal symptoms following the FOS-fructan and gluten challenges were linked to varying bacterial abundances at baseline.ConclusionsIn conclusion, while FOS-fructans induced more gastrointestinal symptoms than gluten in the NCGWS patients, we did not find that substantial shifts in the composition nor function of the faecal microbiota could explain these differences in the current study. However, our results indicate that individual variations in baseline bacterial composition/function may influence the gastrointestinal symptom response to both FOS-fructans and gluten. Additionally, the change in E. coprostanoligenes group, which was associated with increased symptoms, implies that attention should be given to these bacteria in future trials investigating the impact of dietary treatments on gastrointestinal symptoms.Trial registrationClinicaltrials.gov as NCT02464150.

Clinical Evaluation of the Effect of Nanohydroxyapatite Lozenge on the pH of Dental Plaque.

This study investigated the influence of nanohydroxyapatite-containing (nanoHAP) lozenge on plaque pH following sucrose intake. Sixteen adult subjects were enrolled in this double-blind crossover study composed of four interventions: (1) 10% w/v sucrose solution, (2) 10% w/v sorbitol solution, (3) nanoHAP lozenge, and (4) 10% w/v sucrose solution challenge followed by nanoHAP lozenge. Following the determination of each subject's resting plaque pH, the pH was measured at different time intervals from 3 to 30 minutes from the start of intervention, with 7 days interval between the applications of different interventions. The data were analyzed using the analysis of variance and Tukey's test (α < 0.05). While sorbitol produces no change in plaque pH, nanoHAP-lozenge increased the plaque pH from a baseline of 7.0 ± 0.3 (mean ± sd) to 7.8 ± 0.2 (mean ± sd) within 30 minutes. Sucrose lowered the plaque pH from a baseline of 7.0 ± 0.4 (mean ± sd) to the lowest minimum of 5.1 ± 0.1 (mean ± sd) at the 7th minute, rising above the critical pH of enamel dissolution (5.5) at 12th minute and the baseline pH in more than 30 minutes. With lozenge intervention following sucrose challenge, plaque pH rose to 5.5 in 8 min, and to the baseline pH in 24 min. The cH area (Hydrogen ion concentration area) produced by sucrose (1.82 sq. units) was significantly (p < 0.05) greater than that produced when sucrose was challenged with lozenge (0.48 sq. units). Nanohydroxyapatite-containing lozenge increased plaque pH, reduced plaque pH drop in the presence of sucrose, and facilitated the rapid recovery of plaque pH after sucrose intake.

Sex-dependent responses to acute sodium bicarbonate different dose treatment: A randomized double-blind crossover study

ObjectivesThis study quantified blood bicarbonate (HCO3−) kinetics and gastrointestinal upset to determine the gender-related ergogenic potential of sodium bicarbonate (0.15-, 0.25- and 0.35 gSB·kgFat-free mass (FFM)–1) in high intensity functional training. DesignDouble-blind randomized placebo-controlled crossover. MethodsThirty female and male athletes performed two bouts of the Wingate Anaerobic Test (WAnTPRE-HIFT and WAnTPOST-HIFT) interspaced with two 3-min bouts of Wall Balls and Burpees 120min after ingestion of three sodium bicarbonate doses. Blood HCO3− was determined pre-ingestion, after supplementation and before/post exercise. Gastrointestinal upset was evaluated 120min post-ingestion. Control (CTRL) measurements were performed. ResultsThere were significant gender×treatment interactions for: changes in blood HCO3− at 60min post-ingestion (p=0.014; η2p=0.104; at 0.15gSB·kgFFM−1 males experienced higher increase than females); peak power (p=0.015; η2p=0.103) and average power (p=0.005; η2p=0.124) during WAnTPOST-HIFT, and changes in peak power between the Wingate Anaerobic Test bouts (p=0.049; η2p=0.081). Sodium bicarbonate compared to PLA had no significant impact on Wall Balls and Burpees performance. The dose of 0.35gSB·kgFFM−1 resulted in higher less severe gastrointestinal symptoms compared to CTRL and 0.15gSB·kgFFM−1 (p=0.001; W=0.178); and higher total gastrointestinal upset compared to CTRL, PLA and 0.15gSB·kgFFM−1 (p<0.001; W=0.323). ConclusionsThere were dose- and gender-related differences in extracellular buffering capacity and ergogenic potential of sodium bicarbonate. The study suggested a detrimental impact of gastrointestinal upset on performance.

Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Gaba-producing lactobacilli boost cognitive reactivity to negative mood without improving cognitive performance: A human Double-Blind Placebo-Controlled Cross-Over study

BackgroundPsychobiotic bacteria are probiotics able to influence stress-related behavior, sleep, and cognitive outcomes. Several in vitro and human studies were performed to assess their physiological potential, to find strains having psychotropic activity in humans, and to elucidate the metabolic pathways involved. In our previous in vitro study, we identified two strains Levilactobacillus brevis P30021 and Lactiplantibacillus plantarum P30025, able to produce GABA and acetylcholine, being promising candidates to provide an effect on mood and cognitive performance. AimTo investigate the effects of probiotics in the alleviation on the cognitive performance of moderately stressed healthy adults. Secondary outcomes were related to mood improvement, production of GABA, glutamate, acetylcholine, and choline and modification of the microbiota composition. MethodsA 12-week randomized, double-blind, placebo-controlled, cross-over study investigated the effects of a probiotic formulation (Levilactobacillus brevis P30021 and Lactiplantibacillus plantarum P30025) on psychological, memory, and cognition parameters in 44 (Probiotic = 44, Placebo = 43) adults with a mean age of 29 ± 5.7 years old by CogState Battery test. Subjects-inclusion criteria was a mild-moderate (18.7 ± 4.06) stress upon diagnosis using the DASS-42 questionnaire. ResultsProbiotic treatment had no effect on subjective stress measures. The probiotic formulation showed a significant beneficial effect on depressive symptoms by reducing cognitive reactivity to sad mood (p = 0.034). Rumination significantly improved after intake of the probiotic (p = 0.006), suggesting a potential benefit in reducing the negative cognitive effects associated with depression and improving overall mental health. When stratifying the treated subjects according to the response, we found an increase in the abundance of the probiotic genera in the gut microbiota of positive responders (p = 0.009 for Lactiplantibacillus and p = 0.004 for L.brevis). No relevant correlations were observed between the neurotransmitter concentration in the faecal sample, scores of LEIDS, DASS-42, and cognitive tests. ConclusionWe highlight the potential of this probiotic preparation to act as psycobiotics for the relief of negative mood feelings. The assessment of the psychotropic effects of dietary interventions in human participants has many challenges. Further interventional studies investigating the effect of these psychobiotic bacteria in populations with stressed-related disorders are required including longer period of intervention and larger sample size in order to verify the effects of the treatment on further stress-related indicators.

The Effect of Low-Dose Colchicine on the Phenotype and Function of Neutrophils and Monocytes in Patients with Chronic Coronary Artery Disease: A Double-Blind Randomized Placebo-Controlled Cross-Over Study.

Recent landmark trials showed that colchicine provides a substantial benefit in reducing major cardiovascular events in patients with coronary artery disease. Yet, its exact mechanism of action is still poorly understood. This study aimed to unravel the effect of colchicine on monocyte and neutrophil phenotype and function. A randomized double-blind placebo-controlled cross-over intervention study was executed in patients with a history of myocardial infarction. In neutrophils, colchicine treatment decreased CD62L expression and NGAL release upon ex vivo stimulation and increased PMA-induced ROS production. The effects of colchicine on monocytes were limited to a decrease in HLA-DR expression in the intermediate and nonclassical monocytes. Also, on the level of RNA expression, colchicine did not affect monocyte phenotype, while affecting various immunomodulating genes in neutrophils. Overall, our study suggests that treatment with colchicine affects neutrophil function, particularly by reducing neutrophil recruitment, lowering concentrations of NGAL, and changing the expression of various genes with immunomodulatory potential, whereas the effect on monocytes is limited.

Palmitoylethanolamide Does Not Affect Recovery from Exercise-Induced Muscle Damage in Healthy Males.

Strenuous eccentric exercise (EE) induces microstructural muscle damage, which decreases muscle performance. Palmitoylethanolamide (PEA) exerts analgesic and anti-inflammatory effects in clinical pain conditions and preclinical models of experimentally induced-inflammation. This might hold clues for improved recovery from EE. Therefore, the current study evaluates the effect of PEA supplementation on functional and molecular responses to a single EE bout. Eleven healthy male participants were included in a double-blind crossover study in which they received PEA (350 mg Levagen+) or placebo (maltodextrin) supplements, in a randomized order. In each experimental condition participants performed an acute bout of EE (24x10 eccentric contractions of the knee extensors on an isokinetic dynamometer). At baseline, 24 (D1), 48 (D2), 72 (D3) and 120 h (D5) following EE, maximal voluntary contraction and jump height were measured. Blood samples were collected at baseline and on D1-D5, and muscle biopsies were collected at baseline and on D2. Perceived muscle soreness, sleep quality and food intake were recorded daily. Muscle strength and jump height decreased following EE (up to ~40 and ~ 17% respectively; Ptime < 0.05) in both conditions. This drop was accompanied by an increase in plasma creatine kinase and perceived muscle soreness (Ptime < 0.05). Furthermore, EE, but not PEA, increased the expression of the myogenic marker Pax7 and of the catabolic markers p-FoxO1-3a, p62 and LC3BII/I (Ptime < 0.05). PEA supplementation does not improve muscle soreness, muscle strength and jump performance following a single EE bout. Additionally, PEA supplementation had no effect on local or systemic markers of muscle damage, catabolism or regeneration.

Combined effects of pharmacological interventions and intermittent theta-burst stimulation on motor sequence learning.

Drugs that modulate N-methyl-D-aspartate (NMDA) or γ-Aminobutyric acid type A (GABA A ) receptors can shed light on their role in synaptic plasticity mechanisms underlying the effects of non-invasive brain stimulation. However, research on the combined effects of these drugs and exogenous stimulation on motor learning is limited. This study aimed to investigate the effects of pharmacological interventions combined with intermittent theta-burst stimulation (iTBS) on human motor learning. Nine right-handed healthy subjects (mean age ± SD: 31.56 ± 12.96 years; 6 females) participated in this double-blind crossover study. All participants were assigned to four drug conditions in a randomized order: (1) D-cycloserine (partial NMDA receptor agonist), (2) D-cycloserine + dextromethorphan (NMDA receptor agonist + antagonist), (3) lorazepam (GABA A receptor agonist), and (4) placebo (identical microcrystalline cellulose capsule). After drug intake, participants practiced the 12-item keyboard sequential task as a baseline measure. Two hours after drug intake, iTBS was administered at the primary motor cortex. Following iTBS, the retention test was performed in the same manner as the baseline measure. Our findings revealed that lorazepam combined with iTBS impaired motor learning during the retention test. Future studies are still needed for a better understanding of the mechanisms through which TMS may influence human motor learning.

Identification of Sarmentosin as a Key Bioactive from Blackcurrants (Ribes nigrum) for Inhibiting Platelet Monoamine Oxidase in Humans.

Previous clinical studies indicate that monoamine oxidase-B (MAO-B) inhibition by blackcurrants must be predominantly attributed to bioactives other than anthocyanins. In this natural products discovery study, MAO-A/B inhibitory phytochemicals were isolated from blackcurrants, and a double-blind crossover study investigated the efficacy of freeze-dried whole-fruit blackcurrant powder in inhibiting MAO-B compared with blackcurrant juice in healthy adults. Platelet MAO-B inhibition was comparable between powder (89% ± 6) and juice (91% ± 4), and it was positively correlated with MAO-modulated plasma catecholamines, subjective alertness, and reduced mental fatigue, assessed using the Bond-Lader questionnaire. Sarmentosin, a nitrile glycoside, and its hydroxycinnamoyl esters were identified as novel MAO-A/B inhibitors from blackcurrant in vitro, and sarmentosin was demonstrated to inhibit platelet MAO-B activity in vivo. These findings confirm sarmentosin as the primary bioactive for MAO-A/B inhibition in blackcurrants, as well as its bioavailability and stability during freeze-drying, and suggest that consuming blackcurrant powder and juice may positively affect mood in healthy adults.

α- or β-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (β-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor β-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or β-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor β-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.

Short and long-term acceptability and efficacy of extended-release cornstarch in the hepatic glycogen storage diseases: results from the Glyde study

BackgroundHypoglycaemia is the primary manifestation of all the hepatic types of glycogen storage disease (GSD). In 2008, Glycosade®, an extended-release waxy maize cornstarch, was reported as an alternative to uncooked cornstarch (UCCS) which could prolong the duration of fasting in the GSD population. To date, there has been minimal published experience in (a) young children, (b) the ketotic forms of GSD, and (c) with daytime dosing. The Glyde study was created as a prospective, global initiative to test the efficacy and tolerance of Glycosade use across a broader and more diverse population.MethodsA randomised double-blind cross-over fasting study assessing the tolerance and efficacy of Glycosade compared with cornstarch was performed across disease types and ages. Participants and clinicians chose the product deemed superior, whilst still blinded. Participants were followed for 2 years to assess long-term metabolic control, growth, and quality of life.ResultsSixty-one participants (age 2–62 years; 59% female) were enrolled, and 58 participants completed the fasting studies (28 GSD I; 30 GSD III, VI, IX). Glycosade improved duration of fasting in GSD I and duration of fasting without ketosis in the ketotic forms. Chronic Glycosade use was chosen by 69% of participants. Those treated with Glycosade for the 2-year chronic phase used fewer doses of therapy while markers of metabolic control remained stable.ConclusionThe Glyde study is the first multi-centre international trial demonstrating the efficacy and tolerance of Glycosade in a large cohort of hepatic GSD patients across a diverse international population. The ability to use fewer doses of therapy per day and avoidance of overnight therapy may improve compliance, safety, and quality of life without sacrificing metabolic control.