Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus

Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties. Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TER(alb)) and hyaluronan catabolism were assessed as measures of vascular permeability. Both sublingual dimensions (0.64 [0.57-0.75] μm vs 0.78 [0.71-0.85] μm, p <0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] μm vs 8.89 [4.74-11.84] μm, p <0.05) were reduced in the type 2 diabetes group compared with the controls whereas TER(alb) was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p <0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p <0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] μm and to 5.88 [5.33-6.26] μm, respectively, p <0.05). In line, a trend towards TER(alb) normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p <0.05) were observed in the diabetes group. Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk. www.trialregister.nl NTR780/ http://isrctn.org ISRCTN82695186 An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037

Les stimulations bilatérales alternées dans la prise en charge des troubles du comportement de la personne âgée en EHPAD : Usage d’une technique de la psychothérapie EMDR en gérontologie

Many scientific studies validate the effectiveness of EMDR (Eye Movement Desensitization and Reprocessing) therapy for the treatment of PTSD (Post Traumatic Stress Disorder, DSM-5). The EMDR is developing an adaptive treatment of information that is established thanks to the specificity of its protocol in eight phases (Shapiro, 1989) and the action of Alternate Bilateral Stimulations (SBA). The therapeutic field of EMDR continues to expand towards mood disorders, phobias, addictions, chronic pain and health field (cancer announcement). Today, many EMDR protocols exist for children (Lovett, 1999), for people with intellectual deficits (Mevissen, Lievegoed, Seubert-Jongh, 2011), but little literature is interested in the elderly with major cognitive impairments. Hyer (1995) reports only clinical cases of EMDR sessions performed with patients with mild cognitive impairment. Amano et al., (2015) are the only researchers to have written a " nursing home field " protocol for severe cognitive impairment. Objective : The study of the University Hospital of Nice aims to establish a non-drug therapeutic method borrowed from EMDR with the aim of reducing behavioral disorders type verbal agitation in the elderly subject in nursing homes with major cognitive disorders. The management of emotions in the context of neurocognitive pathologies is in deficit in the same way as the medical processes. The symptoms of PTSD and those induced by dementia are similar: anxiety, hyper-vigilance, avoidance behaviour, etc. If ABSs produce an immediate appeasement of the parasympathetic system in PTSD, it is likely that we will find the same effect for BPSDs. Method : The protocol took place in nursing homes. The inclusion criteria are those of severe neurodegenerative pathologies (MMSE-10) as well as verbal agitation measured with health care teams (NPI-ES, Covi, CMAI scale). 15 residents were included in this feasibility study. Subjects were randomized and assigned in a control group and an ABS group after primary needs satisfaction verification. 10-minute SBA sessions were assigned to participants in the experimental group. For the control group: 10-minute sessions held the elderly person's hand (continuous tactile stimulation). The second phase of the study is training nursing's homes health care teams and long-term follow-up in a CPR to allow SBAs to integrate "usual care." Results : The descriptive statistitics showed a benefit of efficiency for the ABS group vs control concerning 5 on 6 items (Duration, Frequency, Intensity, Pittsburgh Scale and CMAI scale). The long-term follow-up of three residents confirmed the results of Cohen Mansfield's (2012) work on the correlation between cries, vocalizations and unmet primary needs. Discussion: The suitable ABS protocol for severe cognitive impairment could be recommended for non-drug communication approaches, although in nursing homes the lack of resources and the turn-over of health care teams is a hindrance to these approaches.De nombreuses études scientifiques valident l’efficacité de la thérapie EMDR (Eye Movement Desensitization and Reprocessing) pour le traitement du TSPT (Trouble de Stress Post Traumatique, DSM-5). L’EMDR s’édifie sur un traitement adaptatif de l’information qui s’établit grâce à la spécificité de son protocole en huit phases (Shapiro, 1989) et à l’action des Stimulations Bilatérales Alternées (SBA). Le champ thérapeutique de l’EMDR ne cesse de s’élargir vers les troubles de l’humeur, les phobies, les addictions, les douleurs chroniques et le champ sanitaire (annonce cancer). De nos jours, des protocoles EMDR existent pour les enfants (Lavett, 1999), pour les personnes avec déficits intellectuels (Mevissen, Lievegoed, Seubert & Jongh, 2011), mais peu de littérature s’intéresse à la personne âgée avec troubles cognitifs majeurs. Hyer (1995) reporte uniquement des cas cliniques de séances d’EMDR effectuées avec des patients présentant des troubles cognitifs légers. Amano et al., (2015) sont les seuls chercheurs à avoir rédigé un protocole « d’EMDR sur le champ » applicable aux troubles cognitifs sévères. Objectif : L’étude du CHU de Nice vise à mettre en place une méthode thérapeutique non médicamenteuse empruntée à l’EMDR dans le but de réduire les troubles du comportement de type agitation verbale chez le sujet âgé en EHPAD avec troubles cognitifs majeurs. La gestion des émotions dans le cadre des pathologies neurocognitives est déficitaire au même titre que les processus mnésiques. Les symptômes du TSPT et ceux induits par la démence sont similaires : angoisse, hyper vigilance, comportement d’évitement, etc. Si les SBA produisent un apaisement immédiat du système parasympathique dans le TSPT, il est probable que nous retrouvions ce même effet pour les SCPD . Méthode : Le protocole s’est déroulé en EHPAD. Les critères d’inclusion sont ceux de pathologies neurodégénératives à un stade sévère (MMSE<10) ainsi que l’agitation verbale mesurée avec les équipes soignantes (NPI-ES, Covi, CMAI scale). 15 résidents ont été inclus dans cette étude de faisabilité. Les sujets ont été randomisés et attribués dans un groupe contrôle et un groupe SBA après enquête étiologique. Des sessions de 10 minutes de SBA ont été attribuées aux participants du groupe expérimental. Pour le groupe contrôle : des sessions de 10 minutes ont permis de tenir la main de la personne âgée (stimulation tactile continue). Le second temps de l’étude consiste en un suivi à long terme de trois résidents. Les SBA seront administrées sur 45 sessions en 5 mois. Le protocole est encadré par une RCP afin de permettre aux SBA d’intégrer le « soin usuel ». Résultats : Les résultats quantitatifs retrouvent une tendance à une meilleure efficacité des SBA par rapport au groupe contrôle entre les interventions 1 et 2 pour 5 items (fréquence, durée, intensité, échelle de Pittsburgh, échelle CMAI) sur 6. Le suivi à long-terme des résidents a permis de confirmer les résultats des travaux de Cohen Mansfield (2012) concernant la corrélation entre cris, vocalisations et besoins primaires non assouvis. Discussion : le protocole SBA adapté pour les troubles cognitifs sévères pourrait faire l’objet de recommandations dans le cadre des approches communicationnelles non médicamenteuses, même si, en EHPAD, le manque de moyens et le turn-over des équipes soignantes constituent un frein à ces approches

Alternate bilateral stimulation in the management of behavioral disorders in nursing home : An EMDR psychotherapy approach in gerontology

De nombreuses études scientifiques valident l’efficacité de la thérapie EMDR (Eye Movement Desensitization and Reprocessing) pour le traitement du TSPT (Trouble de Stress Post Traumatique, DSM-5). L’EMDR s’édifie sur un traitement adaptatif de l’information qui s’établit grâce à la spécificité de son protocole en huit phases (Shapiro, 1989) et à l’action des Stimulations Bilatérales Alternées (SBA). Le champ thérapeutique de l’EMDR ne cesse de s’élargir vers les troubles de l’humeur, les phobies, les addictions, les douleurs chroniques et le champ sanitaire (annonce cancer). De nos jours, des protocoles EMDR existent pour les enfants (Lavett, 1999), pour les personnes avec déficits intellectuels (Mevissen, Lievegoed, Seubert & Jongh, 2011), mais peu de littérature s’intéresse à la personne âgée avec troubles cognitifs majeurs. Hyer (1995) reporte uniquement des cas cliniques de séances d’EMDR effectuées avec des patients présentant des troubles cognitifs légers. Amano et al., (2015) sont les seuls chercheurs à avoir rédigé un protocole « d’EMDR sur le champ » applicable aux troubles cognitifs sévères. Objectif : L’étude du CHU de Nice vise à mettre en place une méthode thérapeutique non médicamenteuse empruntée à l’EMDR dans le but de réduire les troubles du comportement de type agitation verbale chez le sujet âgé en EHPAD avec troubles cognitifs majeurs. La gestion des émotions dans le cadre des pathologies neurocognitives est déficitaire au même titre que les processus mnésiques. Les symptômes du TSPT et ceux induits par la démence sont similaires : angoisse, hyper vigilance, comportement d’évitement, etc. Si les SBA produisent un apaisement immédiat du système parasympathique dans le TSPT, il est probable que nous retrouvions ce même effet pour les SCPD . Méthode : Le protocole s’est déroulé en EHPAD. Les critères d’inclusion sont ceux de pathologies neurodégénératives à un stade sévère (MMSE<10) ainsi que l’agitation verbale mesurée avec les équipes soignantes (NPI-ES, Covi, CMAI scale). 15 résidents ont été inclus dans cette étude de faisabilité. Les sujets ont été randomisés et attribués dans un groupe contrôle et un groupe SBA après enquête étiologique. Des sessions de 10 minutes de SBA ont été attribuées aux participants du groupe expérimental. Pour le groupe contrôle : des sessions de 10 minutes ont permis de tenir la main de la personne âgée (stimulation tactile continue). Le second temps de l’étude consiste en un suivi à long terme de trois résidents. Les SBA seront administrées sur 45 sessions en 5 mois. Le protocole est encadré par une RCP afin de permettre aux SBA d’intégrer le « soin usuel ». Résultats : Les résultats quantitatifs retrouvent une tendance à une meilleure efficacité des SBA par rapport au groupe contrôle entre les interventions 1 et 2 pour 5 items (fréquence, durée, intensité, échelle de Pittsburgh, échelle CMAI) sur 6. Le suivi à long-terme des résidents a permis de confirmer les résultats des travaux de Cohen Mansfield (2012) concernant la corrélation entre cris, vocalisations et besoins primaires non assouvis. Discussion : le protocole SBA adapté pour les troubles cognitifs sévères pourrait faire l’objet de recommandations dans le cadre des approches communicationnelles non médicamenteuses, même si, en EHPAD, le manque de moyens et le turn-over des équipes soignantes constituent un frein à ces approches.Many scientific studies validate the effectiveness of EMDR (Eye Movement Desensitization and Reprocessing) therapy for the treatment of PTSD (Post Traumatic Stress Disorder, DSM-5). The EMDR is developing an adaptive treatment of information that is established thanks to the specificity of its protocol in eight phases (Shapiro, 1989) and the action of Alternate Bilateral Stimulations (SBA). The therapeutic field of EMDR continues to expand towards mood disorders, phobias, addictions, chronic pain and health field (cancer announcement). Today, many EMDR protocols exist for children (Lovett, 1999), for people with intellectual deficits (Mevissen, Lievegoed, Seubert-Jongh, 2011), but little literature is interested in the elderly with major cognitive impairments. Hyer (1995) reports only clinical cases of EMDR sessions performed with patients with mild cognitive impairment. Amano et al., (2015) are the only researchers to have written a " nursing home field " protocol for severe cognitive impairment. Objective : The study of the University Hospital of Nice aims to establish a non-drug therapeutic method borrowed from EMDR with the aim of reducing behavioral disorders type verbal agitation in the elderly subject in nursing homes with major cognitive disorders. The management of emotions in the context of neurocognitive pathologies is in deficit in the same way as the medical processes. The symptoms of PTSD and those induced by dementia are similar: anxiety, hyper-vigilance, avoidance behaviour, etc. If ABSs produce an immediate appeasement of the parasympathetic system in PTSD, it is likely that we will find the same effect for BPSDs. Method : The protocol took place in nursing homes. The inclusion criteria are those of severe neurodegenerative pathologies (MMSE-10) as well as verbal agitation measured with health care teams (NPI-ES, Covi, CMAI scale). 15 residents were included in this feasibility study. Subjects were randomized and assigned in a control group and an ABS group after primary needs satisfaction verification. 10-minute SBA sessions were assigned to participants in the experimental group. For the control group: 10-minute sessions held the elderly person's hand (continuous tactile stimulation). The second phase of the study is training nursing's homes health care teams and long-term follow-up in a CPR to allow SBAs to integrate "usual care." Results : The descriptive statistitics showed a benefit of efficiency for the ABS group vs control concerning 5 on 6 items (Duration, Frequency, Intensity, Pittsburgh Scale and CMAI scale). The long-term follow-up of three residents confirmed the results of Cohen Mansfield's (2012) work on the correlation between cries, vocalizations and unmet primary needs. Discussion: The suitable ABS protocol for severe cognitive impairment could be recommended for non-drug communication approaches, although in nursing homes the lack of resources and the turn-over of health care teams is a hindrance to these approaches

Ciężka sepsa na oddziałach intensywnej terapii w Polsce — badanie chorobowości punktowej w latach 2012 i 2013

BACKGROUND: Severe sepsis is associated with a high mortality rate, but the detailed epidemiology of sepsis is not well known in Polish hospitals. The aim of the study was to determine the prevalence and incidence of severe sepsis in Polish intensive care units (ICUs). METHODS: Two one-day, point-prevalence studies were performed on March 8th, 2012 and March 13th, 2013. An online questionnaire was sent to 320 accredited ICUs. Demographic data regarding hospitals, ICUs, number of patients with severe sepsis and septic shock, and number of patients mechanically ventilated with a central catheter or a urinary catheter were collected. The one-day prevalence of severe sepsis in ICUs was calculated, and the annual incidence of severe sepsis in Poland was estimated from the prevalence rate and the mean length of stay in ICUs. RESULTS: 1398 patients participated in the study in 2012, which accounted for 50% of all ICU beds registered by the National Health Care (NHC) system; 860 patients participated in 2013 (30% of all ICU beds). The daily prevalence of severe sepsis in ICUs was 26% in 2012 and 22% in 2013. Based on the data provided by the NHC system, the number of severe sepsis patients treated in accredited ICUs in Poland amounted to 24,905 patients per year, and the incidence of severe sepsis was 65/100,000 cases per year. CONCLUSIONS: Severe sepsis was observed in one-fourth of patients treated in ICUs in Poland. However, the actual number of severe sepsis patients is at least 2 times higher because many patients with severe sepsis were treated outside accredited ICUs. Severe sepsis constitutes a major health problem in Poland.BACKGROUND: Severe sepsis is associated with a high mortality rate, but the detailed epidemiology of sepsis is not well known in Polish hospitals. The aim of the study was to determine the prevalence and incidence of severe sepsis in Polish intensive care units (ICUs). METHODS: Two one-day, point-prevalence studies were performed on March 8th, 2012 and March 13th, 2013. An online questionnaire was sent to 320 accredited ICUs. Demographic data regarding hospitals, ICUs, number of patients with severe sepsis and septic shock, and number of patients mechanically ventilated with a central catheter or a urinary catheter were collected. The one-day prevalence of severe sepsis in ICUs was calculated, and the annual incidence of severe sepsis in Poland was estimated from the prevalence rate and the mean length of stay in ICUs. RESULTS: 1398 patients participated in the study in 2012, which accounted for 50% of all ICU beds registered by the National Health Care (NHC) system; 860 patients participated in 2013 (30% of all ICU beds). The daily prevalence of severe sepsis in ICUs was 26% in 2012 and 22% in 2013. Based on the data provided by the NHC system, the number of severe sepsis patients treated in accredited ICUs in Poland amounted to 24,905 patients per year, and the incidence of severe sepsis was 65/100,000 cases per year. CONCLUSIONS: Severe sepsis was observed in one-fourth of patients treated in ICUs in Poland. However, the actual number of severe sepsis patients is at least 2 times higher because many patients with severe sepsis were treated outside accredited ICUs. Severe sepsis constitutes a major health problem in Poland

Virtual Reality to Help Older People in Nursing Homes: A New Way to Reduce Psychological Symptoms?

Older people living in nursing homes often present with psychological symptoms such as depression, anxiety and apathy. Numerous studies focused on the effects of Virtual Reality (VR) in the older population. This innovative approach could lead to a significant reduction in psychological disorders in older adults and improve their quality of life.</jats:p