Anatomical bases of fast parietal grasp control in humans: A diffusion-MRI tractography study.

The dorso-posterior parietal cortex (DPPC) is a major node of the grasp/manipulation control network. It is assumed to act as an optimal forward estimator that continuously integrates efferent outflows and afferent inflows to modulate the ongoing motor command. In agreement with this view, a recent per-operative study, in humans, identified functional sites within DPPC that: (i) instantly disrupt hand movements when electrically stimulated; (ii) receive short-latency somatosensory afferences from intrinsic hand muscles. Based on these results, it was speculated that DPPC is part of a rapid grasp control loop that receives direct inputs from the hand-territory of the primary somatosensory cortex (S1) and sends direct projections to the hand-territory of the primary motor cortex (M1). However, evidence supporting this hypothesis is weak and partial. To date, projections from DPPC to M1 grasp zone have been identified in monkeys and have been postulated to exist in humans based on clinical and transcranial magnetic studies. This work uses diffusion-MRI tractography in two samples of right- (n = 50) and left-handed (n = 25) subjects randomly selected from the Human Connectome Project. It aims to determine whether direct connections exist between DPPC and the hand control sectors of the primary sensorimotor regions. The parietal region of interest, related to hand control (hereafter designated DPPChand), was defined permissively as the 95% confidence area of the parietal sites that were found to disrupt hand movements in the previously evoked per-operative study. In both hemispheres, irrespective of handedness, we found dense ipsilateral connections between a restricted part of DPPChand and focal sectors within the pre and postcentral gyrus. These sectors, corresponding to the hand territories of M1 and S1, targeted the same parietal zone (spatial overlap > 92%). As a sensitivity control, we searched for potential connections between the angular gyrus (AG) and the pre and postcentral regions. No robust pathways were found. Streamline densities identified using AG as the starting seed represented less than 5 % of the streamline densities identified from DPPChand. Together, these results support the existence of a direct sensory-parietal-motor loop suited for fast manual control and more generally, for any task requiring rapid integration of distal sensorimotor signals.

Adverse events of recreational cannabis use reported to the French addictovigilance network (2012-2017).

AIMS: To describe the adverse events (AEs) of recreational cannabis use in France between 2012 and 2017. METHODS: AEs related to recreational cannabis use, alone or in combination with alcohol and/or tobacco reported to the French Addictovigilance Network were analysed (excluding cannabidiol and synthetic cannabinoids). RESULTS: Reporting of AEs tripled between 2012 (n = 179, 6.3%, 95% confidence interval [CI] = 5.4-7.2) and 2017 (n = 562, 10.1%, 95% CI = 9.3-10.9), reaching 2217 cases. They concerned mainly men (76.4%) and users aged between 18 and 34 years (18-25: 30.9%; 26-34: 26.3%, range: 12-84 years). Cannabis was mainly inhaled (71.6%) and exposure was most often chronic (64.2%). Many types of AEs were reported: psychiatric (51.2%), neurological (15.6%), cardiac (7.8%) and gastrointestinal (7.7%), including unexpected AEs (n = 34, 1.1%). The most common effect was dependence, ranging from 10.1% (95% CI = 7.9-12.3) to 20.3% (95% CI = 17.3-23.2) over the study period. Cannabinoid hyperemesis syndrome (n = 87, 2.8%) emerged from 2015. Deaths accounted for 0.2% of all AEs (4 men and 3 women aged on average 35 years). A chronic pattern of cannabis use was reported in 4 of them (intracranial hypertension in the context of lung cancer, suicide, cerebral haematoma, neonatal death with concomitant chronic alcohol use), while in the other cases the toxicological analysis identified cannabis use (ruptured aneurysm and unknown aetiology). CONCLUSION: This study showed a multitude of AEs related to recreational cannabis use, including unexpected AEs and deaths. It highlights the problem of dependence and the emergence of cannabinoid hyperemesis syndrome.

Oxytocin and Serotonin Brain Mechanisms in the Nonhuman Primate.

Oxytocin (OT) is increasingly studied for its therapeutic potential in psychiatric disorders, which are associated with the deregulation of several neurotransmission systems. Studies in rodents demonstrated that the interaction between OT and serotonin (5-HT) is critical for several aspects of social behavior. Using PET scan in humans, we have recently found that 5-HT 1A receptor (5-HT1AR) function is modified after intranasal oxytocin intake. However, the underlying mechanism between OT and 5-HT remains unclear. To understand this interaction, we tested 3 male macaque monkeys using both [11C]DASB and [18F]MPPF, two PET radiotracers, marking the serotonin transporter and the 5-HT1AR, respectively. Oxytocin (1 IU in 20 µl of ACSF) or placebo was injected into the brain lateral ventricle 45 min before scans. Additionally, we performed postmortem autoradiography. Compared with placebo, OT significantly reduced [11C]DASB binding potential in right amygdala, insula, and hippocampus, whereas [18F]MPPF binding potential increased in right amygdala and insula. Autoradiography revealed that [11C]DASB was sensitive to physiological levels of 5-HT modification, and that OT does not act directly on the 5-HT1AR. Our results show that oxytocin administration in nonhuman primates influences serotoninergic neurotransmission via at least two ways: (1) by provoking a release of serotonin in key limbic regions; and (2) by increasing the availability of 5-HT1AR receptors in the same limbic areas. Because these two molecules are important for social behavior, our study sheds light on the specific nature of their interaction, therefore helping to develop new mechanisms-based therapies for psychiatric disorders.SIGNIFICANCE STATEMENT Social behavior is largely controlled by brain neuromodulators, such as oxytocin and serotonin. While these are currently targeted in the context of psychiatric disorders such as autism and schizophrenia, a new promising pharmaceutical strategy is to study the interaction between these systems. Here we depict the interplay between oxytocin and serotonin in the nonhuman primate brain. We found that oxytocin provokes the release of serotonin, which in turn impacts on the serotonin 1A receptor system, by modulating its availability. This happens in several key brain regions for social behavior, such as the amygdala and insula. This novel finding can open ways to advance treatments where drugs are combined to influence several neurotransmission networks.

High-resolution 3D diffusion tensor MRI of anesthetized rhesus macaque brain at 3T.

Diffusion Magnetic Resonance Imaging (dMRI) has been widely used to investigate human brain microstructure and connectivity and its abnormalities in a variety of brain deficits, whether acute, neurodevelopmental or neurodegenerative. However, the biological interpretation and validation of dMRI data modelling is still a crucial challenge in the field. In this respect, achieving high spatial resolution in-vivo dMRI in the non-human primate to compare these observations both with human dMRI on the one hand and 'ground truth' microstructural and histological data on the other hand is of outmost importance. Here, we developed a dMRI pulse sequence based on 3D-multishot Echo Planar Imaging (3D-msEPI) on a 3T human clinical scanner. We demonstrate the feasibility of cerebral dMRI at an isotropic resolution of 0.5 mm in 4 anesthetized macaque monkeys. The added value of the high-resolution dMRI is illustrated by focusing on two aspects. First, we show an enhanced descriptive power of the fine substructure of the hippocampus. Second, we show a more physiological description of the interface between cortex grey matter, superficial and deep white matter. Overall, the high spatial resolution dMRI acquisition method proposed in this study is a significant achievement with respect to the state of the art of dMRI on anesthetized monkeys. This study highlights also the potential of very high-resolution dMRI to precisely capture the microstructure of thin cerebral structures such as the hippocampus and superficial white matter.

[Interest of take-home naloxone for opioid overdose]. / Intérêt de la mise à disposition de la naloxone auprès des usagers de drogues pour le traitement d'urgence de surdosage d'opioïdes.

Over the course of these last decades, we observed a change on opioid use with the marketing of opiate maintenance treatment, an increase of opioids used for pain management and recent concerns have arisen around the use of synthetic opioid. The World Health Organization (WHO) reports around 70,000 people opioid overdose death each year. In France, according to the DRAMES program (fatalities in relation with abuse of licit or illicit drugs) of the French addictovigilance network, most of deaths are related to opioids overdose (especially methadone, following by heroin, buprenorphine and opioid used for pain management). Opioid overdose is treatable with naloxone, an opioid antagonist which rapidly reverses the effects of opioids. In recent years, a number of programs around the world have shown that it is feasible to provide naloxone to people likely to witness an opioid overdose. In 2014, the WHO published recommendations for this provision and the need to train users and their entourage in the management of opioid overdose. In this context, in July 2016, French drug agency has granted a temporary authorization for use of a naloxone nasal spray Nalscue®. Because different opioids can be used and because each opioid has specific characteristics (pharmacodynamics, pharmacokinetics, galenic form…), the risk of overdose may differ from one opioid to another and it may be necessary, depending on the clinical context, to use larger and repeated doses of naloxone.

Neural representations of ethologically relevant hand/mouth synergies in the human precentral gyrus.

Complex motor responses are often thought to result from the combination of elemental movements represented at different neural sites. However, in monkeys, evidence indicates that some behaviors with critical ethological value, such as self-feeding, are represented as motor primitives in the precentral gyrus (PrG). In humans, such primitives have not yet been described. This could reflect well-known interspecies differences in the organization of sensorimotor regions (including PrG) or the difficulty of identifying complex neural representations in peroperative settings. To settle this alternative, we focused on the neural bases of hand/mouth synergies, a prominent example of human behavior with high ethological value. By recording motor- and somatosensory-evoked potentials in the PrG of patients undergoing brain surgery (2-60 y), we show that two complex nested neural representations can mediate hand/mouth actions within this structure: (i) a motor representation, resembling self-feeding, where electrical stimulation causes the closing hand to approach the opening mouth, and (ii) a motor-sensory representation, likely associated with perioral exploration, where cross-signal integration is accomplished at a cortical site that generates hand/arm actions while receiving mouth sensory inputs. The first finding extends to humans' previous observations in monkeys. The second provides evidence that complex neural representations also exist for perioral exploration, a finely tuned skill requiring the combination of motor and sensory signals within a common control loop. These representations likely underlie the ability of human children and newborns to accurately produce coordinated hand/mouth movements, in an otherwise general context of motor immaturity.

Resveratrol distinctively modulates the inflammatory profiles of immune and endothelial cells.

BACKGROUND: The phenolic substance resveratrol (RES) is a plant metabolite known to modulate numerous physiological functions and to exert beneficial effects as a cancer-chemopreventing agent and on neurological, hepatic, and cardiovascular systems. Since the compound affects the lifespan of yeast and flies it might be an anti-aging substance. Mechanistically, RES is involved in down regulating the inflammatory response. The pleiotropic effects of RES in cells of the immune and endothelial system were examined in this study. RESULTS: Murine macrophages (RAW264.7 cells), human monocytic/leukemia cells (THP-1), PBLs and HUVECs were incubated with RES and activated with inflammatory stimuli such as LPS or TNF-α. Inflammatory mediators and adhesion molecules were measured by multiplex analysis and gene expression was quantified by RT-PCR. In PBLs, which were activated with LPS, RES blunted the production of TNF-α, CCL2/MCP-1, CCL5/RANTES, CXCL8/IL-8, whereas it increased the production of IL-1ß, IL-6, CCL4/MIP-1ß and CXCL10/IP-10. Thus, in the blood compartment chemokines attracting mainly monocytes were up-regulated by RES, while those attracting T lymphocytes or neutrophils were diminished. At conditions of endothelial dysfunction (ED), RES reduced the expression of cytokines, chemokines, ICAM and GM-CSF in TNF-α activated HUVECs, whereas eNOS expression was corrected to pre-ED homeostasis. In macrophages nitric oxide, PGE2, cytokines (TNF-α, IL-1ß, IL-6) and chemokines (CCL2/MCP-1, CCL4/MIP-1ß, CCL5/RANTES, CXCL10/IP-10) were reduced by the phenolic substance. CONCLUSIONS: RES had cell-specific and context-dependent effects, in particular on the expression of IL-1ß, IL-6, CCL4/MIP-1ß and CXCL10/IP-10. It enhanced cellular features that mirror increased alertness to disturbed immune homeostasis in the vascular-endothelial compartment (e.g. increased production of IL-1ß or IL-6), whereas it blunted inflammatory mediators in macrophages and consequently chronic inflammation. We infer from the present in vitro study, that RES has unique properties in the regulation of inflammatory and immune responses, which are controlled in a complex hierarchical and temporal order.

[Surveillance system on drug abuse: Interest of the French national OPPIDUM program of French addictovigilance network]. / Dispositif pharmacoépidémiologique de surveillance des substances psychoactives : intérêts du programme national OPPIDUM du Réseau français d'addictovigilance.

It is important to assess drug abuse liability in 'real life' using different surveillance systems. OPPIDUM ('Observation of illegal drugs and misuse of psychotropic medications') surveillance system anonymously collects information on drug abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. The aim of this article is to demonstrate the utility of OPPIDUM system using 2015 data. OPPIDUM is a cross-sectional survey repeated each year since 1995. In 2015, 5003 patients described the modality of use of 10,159 psychoactive drugs. Among them, 77% received an opiate maintenance treatment: 68% methadone (half of them consumed capsule form) and 27% buprenorphine (39% consumed generic form). Brand-name buprenorphine is more often injected than generic buprenorphine (10% vs. 2%) and among methadone consumers 7% of methadone capsule consumers have illegally obtained methadone (vs. 9% for syrup form). The proportion of medications among psychoactive drugs injected is important (42%), with morphine representing 21% of the total psychoactive drugs injected and buprenorphine, 16%. OPPIDUM highlighted emergent behaviors of abuse with some analgesic opioids (like tramadol, oxycodone or fentanyl), pregabalin, or quetiapine. OPPIDUM highlighted variations of drugs use regarding geographic approaches or by drug dependence care centers (like in harm reduction centers). OPPIDUM clearly demonstrated that collection of valid and useful data on drug abuse is possible, these data have an interest at regional, national and international levels.

Primary motor cortex changes after amputation correlate with phantom limb pain and the ability to move the phantom limb.

A substantial body of evidence documents massive reorganization of primary sensory and motor cortices following hand amputation, the extent of which is correlated with phantom limb pain. Many therapies for phantom limb pain are based upon the idea that plastic changes after amputation are maladaptive and attempt to normalize representations of cortical areas adjacent to the hand area. Recent data suggest, however, that higher levels of phantom pain are associated with stronger local activity and more structural integrity in the missing hand area rather than with reorganization of neighbouring body parts. While these models appear to be mutually exclusive they could co-exist, and one reason for the apparent discrepancy between them might be that no single study has examined the organisation of lip, elbow, and hand movements in the same participants. In this study we thoroughly examined the 3D anatomy of the central sulcus and BOLD responses during movements of the hand, elbow, and lips using MRI techniques in 11 upper-limb amputees and 17 healthy control subjects. We observed different reorganizational patterns for all three body parts as the former hand area showed few signs of reorganization, but the lip and elbow representations reorganized and shifted towards the hand area. We also found that poorer voluntary control and higher levels of pain in the phantom limb were powerful drivers of the lip and elbow topological changes. In addition to providing further support for the maladaptative plasticity model, we demonstrate for the first time that motor capacities of the phantom limb correlate with post-amputation reorganization, and that this reorganization is not limited to the face and hand representations but also includes the proximal upper-limb.

Carnosol and Related Substances Modulate Chemokine and Cytokine Production in Macrophages and Chondrocytes.

Phenolic diterpenes present in Rosmarinus officinalis and Salvia officinalis have anti-inflammatory and chemoprotective effects. We investigated the in vitro effects of carnosol (CL), carnosic acid (CA), carnosic acid-12-methylether (CAME), 20-deoxocarnosol and abieta-8,11,13-triene-11,12,20-triol (ABTT) in murine macrophages (RAW264.7 cells) and human chondrocytes. The substances concentration-dependently reduced nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated macrophages (i.e., acute inflammation). They significantly blunted gene expression levels of iNOS, cytokines/interleukins (IL-1α, IL-6) and chemokines including CCL5/RANTES, CXCL10/IP-10. The substances modulated the expression of catabolic and anabolic genes in chondrosarcoma cell line SW1353 and in primary human chondrocytes that were stimulated by IL-1ß (i.e., chronic inflammation In SW1353, catabolic genes like MMP-13 and ADAMTS-4 that contribute to cartilage erosion were down-regulated, while expression of anabolic genes including Col2A1 and aggrecan were shifted towards pre-pathophysiological homeostasis. CL had the strongest overall effect on inflammatory mediators, as well as on macrophage and chondrocyte gene expression. Conversely, CAME mainly affected catabolic gene expression, whereas ABTT had a more selectively altered interleukin and chemokine gene exprssion. CL inhibited the IL-1ß induced nuclear translocation of NF-κBp65, suggesting that it primarily regulated via the NF-κB signalling pathway. Collectively, CL had the strongest effects on inflammatory mediators and chondrocyte gene expression. The data show that the phenolic diterpenes altered activity pattern of genes that regulate acute and chronic inflammatory processes. Since the substances affected catabolic and anabolic gene expression in cartilage cells in vitro, they may beneficially act on the aetiology of osteoarthritis.

Tomato Aqueous Extract Modulates the Inflammatory Profile of Immune Cells and Endothelial Cells.

Nutrients transiently or chronically modulate functional and biochemical characteristics of cells and tissues both in vivo and in vitro. The influence of tomato aqueous extract (TAE) on the in vitro inflammatory response of activated human peripheral blood leukocytes (PBLs) and macrophages was investigated. Its effect on endothelial dysfunction (ED) was analyzed in human umbilical vein endothelial cells (HUVECs). Murine macrophages (RAW264.7 cells), PBLs and HUVECs were incubated with TAE. They were activated with LPS or TNF-α in order to induce inflammatory processes and ED, respectively. Inflammatory mediators and adhesion molecules were measured by immune assay-based multiplex analysis. Gene expression was quantified by RT-PCR. TAE altered the production of interleukins (IL-1ß, IL-6, IL-10, IL-12) and chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL5/RANTES, CXCL8/IL-8, CXCL10/IP-10) in PBLs. TAE reduced ED-associated expression of adhesion molecules (ICAM-1, VCAM-1) in endothelial cell. In macrophages, the production of nitric oxide, PGE2, cytokines and ILs (TNF-α, IL-1ß, IL-6, IL-12), which reflects chronic inflammatory processes, was reduced. Adenosine was identified as the main bioactive of TAE. Thus, TAE had cell-specific and context-dependent effects. We infer from these in vitro data, that during acute inflammation TAE enhances cellular alertness and therefore the sensing of disturbed immune homeostasis in the vascular-endothelial compartment. Conversely, it blunts inflammatory mediators in macrophages during chronic inflammation. A novel concept of immune regulation by this extract is proposed.

Introduction. Towards a Contemporary Historiography of Amateurs in Science (18th­20th Century).

The last few decades have seen considerable growth in the role played by amateurs in the sciences. With the development of new techniques for collecting information, new virtual networks and the emergence of new problematics calling for the participation of citizens, this role has also become more visible, while the modern boundary between professionalism and amateurism, first erected in the 19th century, has been shaken. These contemporary developments have changed our perspective on amateurs in science and brought forth questions and analyses that sometimes coincide with recent inflections in the history of science. Thus it is now possible to take a new approach to the historical study of amateurs in contemporary science. This introduction hopes to demonstrate this, while the essays brought together in this volume, some of which explore extreme cases, reveal the very relative nature of the definition of the "amateur" category and how complex and fertile its implementation has been in the history of science.

Umeclidinium in patients with COPD: a randomised, placebo-controlled study.

Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients. This was a randomised, placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 µg over 12 weeks. The primary end-point was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 85. Secondary end-points were 0-6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index, health outcomes (St George's Respiratory Questionnaire), pharmacokinetics and safety. 246 patients were enrolled; 168 completed the study. On day 85, umeclidinium 62.5 and 125 µg significantly improved least squares mean change from baseline in trough FEV1 (127 and 152 mL, respectively; p<0.001) compared with placebo. On day 84, umeclidinium 62.5 and 125 µg significantly improved least squares mean change from baseline in 0-6-h weighted mean (166 and 191 mL, respectively; p<0.001) and serial FEV1 at each time point (p≤0.003). Significant improvements in least squares mean transitional dyspnoea index focal score for UMEC 125 mg(1.3 units; p,0.05) and change from baseline St George's Respiratory Questionnaire total score for both UMEC doses (-7.9 and -10.87 units, for UMEC 62.5 mg and 125 mg, respectively; both p,0.001) were noted compared with placebo at week 12 [DOSAGE ERROR CORRECTED].The incidence of adverse events was low and similar across treatments. Umeclidinium 62.5 and 125 µg significantly improved lung function, dyspnoea and health status compared with placebo, and were well tolerated in chronic obstructive pulmonary disease patients over 12 weeks.

Mapping motor representations in the human cerebellum.

The cerebellum is a major motor structure. However, in humans, its efferent topographical organization remains controversial and indirectly inferred from neuroimaging and animal studies. Even central questions such as 'Can we evoke limb movements by stimulating the cerebellar cortex?' have no clear answer. To address this issue, we electrically stimulated the posterior cerebellum of 20 human patients undergoing surgery for tumours located outside this structure (e.g. pineal gland, quadrigeminal plate). Stimulation, delivered at a 60-Hz frequency for 2 s, evoked focal (single-joint) ipsilateral movements. Different regions were associated with the production of head (vermal lobule VI), face/mouth (hemispheric lobule VI) and lower-limb (hemispheric lobules VIIb-IX) responses. Upper-limb representations were more widely distributed. They intermingled with face/mouth representations in the superior posterior cerebellum (hemispheric lobule VI) and lower-limb representations in the inferior posterior cerebellum (hemispheric lobules VIIb-IX). No intra- or inter-limb somatotopy was found in these areas. Functionally, upper-limb (face/mouth movements) and upper limb-lower limb postural coordinations are major elements of our motor repertoire. Representation of these pairs of segments in common regions might favour the production of integrated motor behaviours. The intermediate region of the posterior cerebellum (hemispheric lobule VII and vermal lobules VII-VIII) was mostly silent. Latency results in conjunction with previous electrophysiological evidence in animals suggest that electrically evoked motor responses were not mediated by a cortical route but rather by brainstem structures. The potential role of this descending efferent pathway for fine motor control is discussed.

Effect of molecular adsorbents recirculating system treatment in children with acute liver failure caused by Wilson disease.

OBJECTIVES: Because fulminant Wilson disease (WD) has an extremely poor prognosis, the use of liver support that can bridge patients to liver transplantation is lifesaving. We report the experience of albumin dialysis in acute liver failure (ALF) caused by WD in children. METHODS: Chart review of children admitted for ALF secondary to acute WD and treated by the molecular adsorbents and recirculating system. Measures of copper level in blood and within the circuit during molecular adsorbents recirculating system (MARS) sessions were performed. Clinical and biological assessments after MARS session were reported. RESULTS: Four children, with a median age of 12.3 years, were treated from 2004 to 2009 for a severe ALF associated with acute renal failure, haemolysis, and severe cholestasis. All of the children had a new Wilson index >12. A total of 14 MARS sessions were performed, for a median duration of 7.5 hours. Tolerance was good, except for 1 child who experienced haemorrhage because of vascular injury following insertion of the dialysis catheter. A neurological improvement or stabilisation was noted in all of the children along with an improvement in the Fisher index and ammonia level after MARS treatment. MARS was able to remove copper, to decrease the serum copper level of 28% in mean, and to decrease the bilirubin and creatinin levels >25%. All of the children were subsequently underwent liver transplants with a good outcome without disability. CONCLUSIONS: MARS is able to remove copper and to stabilise children with ALF secondary to WD, allowing bridging to LT.

A novel rose hip preparation with enhanced anti-inflammatory and chondroprotective effects.

Rose hip powder (RHP) alleviates osteoarthritis (OA) due to its anti-inflammatory and cartilage-protective properties. Substances contained in RHP might contribute to its clinical efficacy. The activity of two RHP (i.e., RH-A, from the whole fruit, RH-B, from fruits without seeds) was investigated in human peripheral blood leukocytes (PBL) and primary chondrocytes (NHAC-kn). RH-A and RH-B diminished the secretion of chemokines and cytokines in LPS/IFN-γ-activated PBL, including CCL5/RANTES, CXCL10/IP-10, interleukin- (IL-) 6, and IL-12. Most effects were transcriptional, since gene expression levels were significantly influenced by RH-A and RH-B. In IL-1ß treated normal chondrocytes (NHAC-kn), both RH preparations reduced the expression of matrix metalloproteinase- (MMP-) 1, MMP-3, and MMP-13 and ADAMTS-4. These changes are associated with diminished inflammatory damage or cartilage erosion. Principal component analysis revealed that (1) RH-A and RH-B modified a large pattern of biomarkers, and (2) RH-B outperformed RH-A. Furthermore, RH-B contained more chondroprotective and anti-inflammatory constituents than RH-A. Thus, RHP contributed to restore cellular homeostasis in PBL and chondrocytes. RH preparations from fruits without seeds are thus expected to have an improved OA-preventive or OA-therapeutic profile, as subsequently shown in a related clinical trial.

The Polyunsaturated Fatty Acids Eicosapentaenoic Acid and Docosahexaenoic Acid, and Vitamin K1 Modulate the Gut Microbiome: A Study Using an In Vitro Shime Model.

Omega-3 polyunsaturated fatty acids (PUFAs) and vitamins exert multiple beneficial effects on host health, some of which may be mediated through the gut microbiome. We investigated the prebiotic potential of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and lipid-soluble phylloquinone (vitamin K1), each at 0.2x, 1x and 5x using the simulator of the human intestinal microbial ecosystem (SHIME®) to exclude in vivo systemic effects and host-microbe interactions.Microbial community composition and, diversity [shotgun metagenomic sequencing] and microbial activity [pH, gas pressure, and production of short-chain fatty acids (SCFAs)] were measured over a period of 48 h. Fermentations supernatants were used to investigate the effect on gut barrier integrity using a Caco-2/goblet cell co-culture model.We found that EPA, DHA and vitamin K1 increased alpha-diversity at 24 h when compared with control. Moreover, there was an effect on beta-diversity with changes in gut microbial composition, such as an increase in the Firmicutes/Bacteroidetes (F/B) ratio and a consistent increase in Veillonella and Dialister abundances with all treatments. DHA, EPA, and vitamin K1 also modulated metabolic activity of the gut microbiome by increasing total SCFAs which was related mainly to an increase in propionate (highest with EPA and vitamin K1 at 0.2x). Finally, we found that EPA and DHA increased gut barrier integrity with DHA at 1x and EPA at 5x (p < 0.05, respectively). In conclusion, our in vitro data further establish a role of PUFAs and vitamin K to modulate the gut microbiome with effects on the production of SCFAs and barrier integrity.

Potential implication of new torque teno mini viruses in parapneumonic empyema in children.

An unexplained increase in the incidence of parapneumonic empyema (PPE) in pneumonia cases has been reported in recent years. The present study investigated the genetic and biological specifications of new isolates of torque teno mini virus (TTMV) detected in pleural effusion samples from children hospitalised for severe pneumonia with PPE. A pathogen discovery protocol was applied in undiagnosed pleural effusion samples and led to the identification of three new isolates of TTMV (TTMV-LY). Isolated TTMV-LY genomes were transfected into A549 and human embryonic kidney 293T cells and viral replication was assessed by quantitative real-time PCR and full-length genome amplification. A549 cells were further infected with released TTMV-LY virions and the induced-innate immune response was measured by multiplex immunoassays. Genetic analyses of the three TTMV-LY genomes revealed a classic genomic organisation but a weak identity (<64%) with known sequences. We demonstrated the in vitro replication of TTMV-LY in alveolar epithelial cells and the effective release of infectious viral particles. We also showed a selective production of inflammatory mediators in response to TTMV infection. This study reports the description of replicative TTMV-LY isolated from parapneumonic effusions of children hospitalised with PPE, suggesting a potential role of the virus in the pathogenesis of pneumonia.

Circulating and adipose tissue immune cells in tissue-specific insulin resistance in humans with overweight and obesity.

OBJECTIVE: A proinflammatory adipose tissue (AT) microenvironment and systemic low-grade inflammation may differentially affect tissue-specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity. METHODS: Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n = 219) and the Maastricht Study (replication cohort; n = 1256) underwent a seven-point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined. In subgroups, flow cytometry was performed to identify circulating and aSAT immune cells, and aSAT gene expression was evaluated. RESULTS: The relative abundances of circulating T cells, nonclassical monocytes, and CD56dim CD16+ natural killer cells were inversely associated with liver, but not muscle, insulin sensitivity in the PERSON Study. The inverse association between circulating (classical) monocytes and liver insulin sensitivity was confirmed in the Maastricht Study. In aSAT, immune cell populations were not related to insulin sensitivity. Furthermore, aSAT gene expression of interleukin 6 and CD14 was positively associated with muscle, but not liver, insulin sensitivity. CONCLUSIONS: The present findings demonstrate that circulating immune cell populations and inflammatory gene expression in aSAT show distinct associations with liver and muscle insulin sensitivity.

Quantitative assessment of skeletal muscle degeneration in patients with myotonic dystrophy type 1 using MRI.

PURPOSE: To identify MRI biomarkers that could be used to follow disease progression and therapeutic efficacy in one individual muscle in patients with myotonic dystrophy type 1 (DM1). MATERIALS AND METHODS: Lower limb MRI and maximal ankle dorsiflexor strength assessment, using a hand-held dynamometer, were performed in 19 DM1 patients and 6 control subjects. The volume of residual muscle tissue of Tibialis Anterior (TA) muscle was chosen as an index for muscle atrophy, and the T2-relaxation-time of the residual muscle tissue was measured to evaluate edema-like lesions. The fat-to-water ratio was assessed using three-point Dixon images to quantify fat infiltration in the entire muscle. RESULTS: The intra-observer variability of MRI indices (∼5.2% for the residual muscle tissue volume and 2.5% for the fat-to-water ratio) was lower than that of the dorsiflexor torque measurement (∼11.5%). A high correlation (r = 0.91) was found between maximal ankle dorsiflexor strength and residual TA muscle tissue volume in DM1 patients. Increases in the fat-to-water ratio and T2-relaxation-time were associated with a decrease in maximal ankle dorsiflexor strength. CONCLUSION: MRI appears as a noninvasive method which can be used to follow disease progression and therapeutic efficacy.