Galactose Ingested with a High-Fat Beverage Increases Postprandial Lipemia Compared with Glucose but Not Fructose Ingestion in Healthy Men.

BACKGROUND: Fructose ingestion with a high-fat beverage increases postprandial lipemia when compared with glucose. It is unknown whether other sugars, such as galactose, also increase postprandial lipemia. OBJECTIVES: The objective was to assess whether galactose ingestion within a high-fat beverage increases postprandial lipemia relative to glucose or fructose. METHODS: Two experiments were conducted, which contrasted different test drinks under otherwise standardized conditions. In Experiment 1, 10 nonobese men (age: 22 ± 1 y; BMI, 23.5 ± 2.2 kg/2) ingested either galactose or glucose (0.75 g supplemented carbohydrate per⋅kilogram body mass) within a high-fat test drink (0.94 g fat per kilogram body mass). In Experiment 2, a separate group of 9 nonobese men (age: 26 ± 6 y; BMI: 23.5 ± 2.6 kg/m2) ingested either galactose or fructose (identical doses as those in Experiment 1) within the same high-fat test drink. Capillary blood was sampled before and at frequent intervals after ingestion of the test drinks for a 300-min period to determine plasma triacylglycerol, glucose, lactate, nonesterified fatty acid, and insulin concentrations. Paired t tests and 2-way, repeated-measures ANOVA were used to compare conditions within each experiment. RESULTS: The incremental AUC for triacylglycerol was greater following galactose ingestion compared with glucose (127 ± 59 compared with 80 ± 48 mmol⋅L-1 × 300 min, respectively; P = 0.04) but not compared with fructose (136 ± 74 compared with 133 ± 63 mmol⋅L-1 ×300 min, respectively; P = 0.91). Plasma lactate concentrations also increased to a greater extent with galactose compared with glucose ingestion (time-condition interaction: P < 0.001) but not fructose ingestion (time-condition interaction: P = 0.17). CONCLUSIONS: Galactose ingestion within a high-fat beverage exacerbates postprandial lipemia and plasma lactate concentrations compared with glucose but not fructose in nonobese men. These data suggest that galactose metabolism may be more similar to fructose than to glucose, providing a rationale to reassess the metabolic fate of galactose ingestion in humans. This trial was registered at clinicaltrials.gov as NCT03439878

The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion

Reliability of two goniometric methods of measuring active inversion and eversion range of motion at the ankle

BACKGROUND: Active inversion and eversion ankle range of motion (ROM) is widely used to evaluate treatment effect, however the error associated with the available measurement protocols is unknown. This study aimed to establish the reliability of goniometry as used in clinical practice. METHODS: 30 subjects (60 ankles) with a wide variety of ankle conditions participated in this study. Three observers, with different skill levels, measured active inversion and eversion ankle ROM three times on each of two days. Measurements were performed with subjects positioned (a) sitting and (b) prone. Intra-class correlation coefficients (ICC([2,1])) were calculated to determine intra- and inter-observer reliability. RESULTS: Within session intra-observer reliability ranged from ICC([2,1] )0.82 to 0.96 and between session intra-observer reliability ranged from ICC([2,1] )0.42 to 0.80. Reliability was similar for the sitting and the prone positions, however, between sessions, inversion measurements were more reliable than eversion measurements. Within session inter-observer measurements in sitting were more reliable than in prone and inversion measurements were more reliable than eversion measurements. CONCLUSION: Our findings show that ankle inversion and eversion ROM can be measured with high to very high reliability by the same observer within sessions and with low to moderate reliability by different observers within a session. The reliability of measures made by the same observer between sessions varies depending on the direction, being low to moderate for eversion measurements and moderate to high for inversion measurements in both positions

A shared MHC supertype motif emerges by convergent evolution in macaques and mice, but is totally absent in human MHC molecules

The SIV-infected rhesus macaque (Macaca mulatta) is the most established model of AIDS disease systems, providing insight into pathogenesis and a model system for testing novel vaccines. The understanding of cellular immune responses based on the identification and study of Major Histocompatibility Complex (MHC) molecules, including their MHC:peptide-binding motif, provides valuable information to decipher outcomes of infection and vaccine efficacy. Detailed characterization of Mamu-B*039:01, a common allele expressed in Chinese rhesus macaques, revealed a unique MHC:peptide-binding preference consisting of glycine at the second position. Peptides containing a glycine at the second position were shown to be antigenic from animals positive for Mamu-B*039:01. A similar motif was previously described for the Dd mouse MHC allele, but for none of the human HLA molecules for which a motif is known. Further investigation showed that one additional macaque allele, present in Indian rhesus macaques, Mamu-B*052:01, shares this same motif. These “G2” alleles were associated with the presence of specific residues in their B pocket. This pocket structure was found in 6% of macaque sequences but none of 950 human HLA class I alleles. Evolutionary studies using the “G2” alleles points to common ancestry for the macaque sequences, while convergent evolution is suggested when murine and macaque sequences are considered. This is the first detailed characterization of the pocket residues yielding this specific motif in nonhuman primates and mice, revealing a new supertype motif not present in humans

Lonely but avoidant—the unfortunate juxtaposition of loneliness and self-disgust

Loneliness is prevalent worldwide and is a known risk factor for numerous physical and mental health outcomes. The health consequences of chronic loneliness coupled with the cost on public health care has necessitated the development of interventions and campaigns to end loneliness globally. According to a recent meta-analysis, such interventions focus on improving social skills, increasing opportunities for social contact/support (i.e., reducing social isolation) or addressing maladaptive cognition (e.g., irrational thoughts, self-defeating, and self-blame thoughts). The results showed that changing maladaptive thoughts offer “the best chance” for alleviating feelings of loneliness. In accordance with the latter approach, this paper proposes a new paradigm in understanding and treating loneliness that takes into account self-disgust, an aversive self-conscious affective state that reflects disgust directed towards the self. Based on findings from published and unpublished data, it is argued that interventions against loneliness that focus exclusively on improving social skills and increasing opportunities for social contact may be ineffective because lonelier people experience more self-disgust, which makes them more socially inhibited and reluctant to connect with other people. Future interventions should consider self-disgust in the treatment of loneliness and explore ways to counter feelings of self-disgust

Caregiver delivered sensory electrical stimulation for post stroke upper limb spasticity: A single blind crossover randomized feasibility study

We developed a 64 channel sensory electrical stimulator which delivers a dynamic and variable ‘Sensory Barrage’ Stimulation (SBS). Our aim was to assess the feasibility of caregivers delivering the stimulation in the community for a clinical trial comparing single channel Transcutaneous Electrical Nerve Stimulation (TENS) with SBS for post stroke upper limb spasticity. We trained caregivers of 16 participants with post stroke upper limb spasticity to sequentially administer SBS and TENS for 60 min daily for four weeks each, with a washout period of two weeks in between. Outcome measures tested were recruitment and retention rates, compliance with interventions and daily recording of Participant -reported Numerical Rating Scale (NRS). We also collected results of Action Research Arm Test (ARAT), Leeds Arm Spasticity Impact Scale (LASIS) and Modified Ashworth Scale (MAS) for spasticity. Out of 21 potential participants, 16 consented and 15 completed the protocol. Ten participants received TENS for 80% (23/28) of the intended hours. Eleven participants completed NRS for at 80% (45/56) of the study days. All participants attended all visits. The MAS reduced by at least one in five participants after SBS and in three after TENS. Minimal Clinically Important Difference (MCID) of four points increase in ARAT was seen in five participants following TENS, and in four following SBS. A MCID of 18% decrease in NRS was reported by eight participants after TENS and three after SBS. This study demonstrated the feasibility of undertaking a trial of sensory electrical stimulation for post-stroke spasticity with caregivers delivering intervention in community. The study was not powered to detect efficacy of the interventions. Trial registration number: NCT02907775.Date 20-9-2016

Why are we not flooded by involuntary thoughts about the past and future? Testing the cognitive inhibition dependency hypothesis

© The Author(s) 2018In everyday life, involuntary thoughts about future plans and events occur as often as involuntary thoughts about the past. However, compared to involuntary autobiographical memories (IAMs), such episodic involuntary future thoughts (IFTs) have become a focus of study only recently. The aim of the present investigation was to examine why we are not constantly flooded by IFTs and IAMs given that they are often triggered by incidental cues while performing undemanding activities. One possibility is that activated thoughts are suppressed by the inhibitory control mechanism, and therefore depleting inhibitory control should enhance the frequency of both IFTs and IAMs. We report an experiment with a between-subjects design, in which participants in the depleted inhibition condition performed a 60-min high-conflict Stroop task before completing a laboratory vigilance task measuring the frequency of IFTs and IAMs. Participants in the intact inhibition condition performed a version of the Stroop task that did not deplete inhibitory control. To control for physical and mental fatigue resulting from performing the 60-min Stroop tasks in experimental conditions, participants in the control condition completed only the vigilance task. Contrary to predictions, the number of IFTs and IAMs reported during the vigilance task, using the probe-caught method, did not differ across conditions. However, manipulation checks showed that participants’ inhibitory resources were reduced in the depleted inhibition condition, and participants were more tired in the experimental than in the control conditions. These initial findings suggest that neither inhibitory control nor physical and mental fatigue affect the frequency of IFTs and IAMs.Peer reviewedFinal Published versio

The Effect of a Brief Mindfulness Intervention on Memory for Positively and Negatively Valenced Stimuli

A core component of mindfulness is non-judgmental observation of internal and external stimuli. The present study investigated the effect of mindfulness on memory for emotional stimuli. Participants were exposed to a brief mindfulness intervention and subsequently performed a verbal learning test consisting of positive, neutral, and negative words. Control participants received no intervention and directly performed the verbal learning test. After 20 min, participants recalled as many words as possible. Participants in the mindfulness condition remembered a significantly lower proportion of negative words compared to control participants. No differences between both groups were observed for the proportion of remembered positive words. These findings suggest that memory processes may be a potential mechanism underlying the link between mindfulness and subjective well-being

The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients – a multicenter randomized study

Background: Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects. Methods: Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT. Results: A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 [plus or minus] 45 IU/L and 55 [plus or minus] 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group. Conclusion: Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.Funding for this study was provided by McNeil Consumer Healthcare to the Denver Health Authority, Denver, Colorado

Challenges Predicting Ligand-Receptor Interactions of Promiscuous Proteins: The Nuclear Receptor PXR

Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5α-androstan-3β-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches