Connected in Bad Times and in Good Times: Empathy Induces Stable Social Closeness.

Humans need social closeness to prosper. There is evidence that empathy can induce social closeness. However, it remains unclear how empathy-related social closeness is formed and how stable it is as time passes. We applied an acquisition-extinction paradigm combined with computational modeling and fMRI, to investigate the formation and stability of empathy-related social closeness. Female participants observed painful stimulation of another person with high probability (acquisition) and low probability (extinction) and rated their closeness to that person. The results of two independent studies showed increased social closeness in the acquisition block that resisted extinction in the extinction block. Providing insights into underlying mechanisms, reinforcement learning modeling revealed that the formation of social closeness is based on a learning signal (prediction error) generated from observing another's pain, whereas maintaining social closeness is based on a learning signal generated from observing another's pain relief. The results of a reciprocity control study indicate that this feedback recalibration is specific to learning of empathy-related social closeness. On the neural level, the recalibration of the feedback signal was associated with neural responses in anterior insula and adjacent inferior frontal gyrus and the bilateral superior temporal sulcus/temporoparietal junction. Together, these findings show that empathy-related social closeness generated in bad times, that is, empathy with the misfortune of another person, transfers to good times and thus may form one important basis for stable social relationships.

Advances and challenges in serratiopeptidase topical formulation.

Enzymes are a key part of most metabolic processes and are required for the correct functioning of the human body, either directly or indirectly. Proteolytic enzymes aid in the digestion of proteins in the body. Proteolytic enzymes are created in the pancreas naturally, but they can also be found in certain diets. Serratiopeptidase is an enzyme found in the stomach wall of silkworms and produced from S. marcescens strain. Less solubility, toxicity, instability, incompatibility, and less penetration are all common issues with Serratiopeptidase drug delivery. Because of its proteinaceous nature, serratiopeptidase is susceptible to enzymatic breakdown in the gastrointestinal system. It also has a low permeability through the intestinal barrier due to its hydrophilic nature. Depending on the features of the medicine, a suitable delivery mechanism is required. Topical formulation may eliminate the risk of gastric degradation of drug and increase direct permeation through skin and show effects. Topical SRP may effectively lower inflammatory markers, as it has been found to have superior anti-inflammatory effects than topical NSAIDs. Serratiopeptidase topical formulations could be more effective than nonsteroidal anti-inflammatory medications in treating local inflammation. This article reviews studies on various topical formulations.

Evaluation of the in vivo and in vitro anti-inflammatory activity of a new hybrid NSAID tetrahydropyran derivative.

Evaluate the anti-inflammatory activity in vivo and in vitro of cis-(±)-acetate of 4-chloro-6-(naphtalene-1-yl)-tetrahydro-2H-pyran-2-yl) methyl 2-(2-(2,6-diclorofenylamine) phenyl (LS19). Male Swiss mice were analyzed in the paw edema, ear edema, and air pouch tests, and in vitro COX inhibition, cytotoxicity evaluation, and cytokine and nitric oxide determination tests. The compound showed effect on the carrageenan- and bradykinin-induced paw edema and capsaicin-induced ear edema tests. In addition, the compound was able to inhibit leukocyte migration to decrease the levels of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) and to increase the levels of the anti-inflammatory cytokine IL-10. The compound was also able to reduce levels of TNF-α, IL-6, and nitric oxide in the RAW 264.7 cell line and to inhibit COX activity. LS19 did not induce any significant changes in the viability of RAW 264.7 cells, demonstrating safety for these cell lines. The compound LS19 did not reduce the production of gastric mucus and induced a smaller increase in the extent of gastric lesions than that developed by the administration of diclofenac. In summary, the new compound proved to be safer and it had additional mechanisms compared to diclofenac.

Self-medication practice with analgesics (NSAIDs and acetaminophen), and antibiotics among nursing undergraduates in University College Farasan Campus, Jazan University, KSA.

OBJECTIVE: Self-medication practices are widely practiced globally as major form of self-care for pain management. Unfortunately, with COVID-19 pandemic, prescription only drugs are now increasingly being self-prescribed. Present study was therefore, conducted to generate data on self-medication practice with analgesics using non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, and the antibiotics among nursing students of University College Farasan Campus. MATERIALS AND METHODS: A cross-sectional descriptive study was conducted among 177 study participants (20±3 years) between December 2019 to February 2020 using questionnaire. Data analyses were done using origin software (6.1, Illinois, USA). Significance was considered at P<0.05. Study was conducted in Department of Nursing, University College Farasan Province, a premier educational institute of Farasan Island affiliated to Jazan university, KSA. RESULTS: Self-medication practices were high among nursing students (n=154 participants, 87%). Acetaminophen was highest used drug for analgesic purposes without prescriptions (n=101 participants, 57%). Among NSAIDs, Ibuprofen was most preferred for various analgesic purposes (n=35 participants, 20%) followed by diclofenac (n=9 participants, 5%) and meloxicam (n=5 participants, 3%). Azithromycine was the only antibiotic used by participants (n=4 participant, 2%). Most common causes of self-medication were headache (45%), menstrual pain (23%) and fever (14%). Main reason for self-medications was lack of time to consult doctor (68%). Furthermore, self-medication was significantly associated with study year (P<0.003). CONCLUSION: Results give rise to concern for general well-being of future nursing workforce. There is need to implement educational actions and awareness programmes to limit self-medication practices among educated youth of this beautiful Island.

An abdominal wall mass of exogenous insulin amyloidosis in setting of metastatic sarcoma.

Exogenous insulin amyloidosis (AIns) is an iatrogenic form of amyloidosis which is found in diabetic patients, generally localized to the site of subcutaneous insulin administration. It may form a discrete mass that could come to clinical attention, and can contribute to abnormal pharmacokinetics of the exogenous insulin, resulting in worsened control of diabetes. In this case report, we describe such a lesion in a 72-year-old man with a history of type 2 diabetes and primary adrenal gland epithelioid sarcoma and discuss the diagnostic challenges it poses.

Acide hyaluronique intra articulaire dans la gonarthrose: une étude long-terme, ouverte, de Phase IV, avec analyse détaillée par stade de Kellgren-Lawrence.

INTRODUCTION: Les injections intra articulaires (IA) d'acide hyaluronique (HA) désignées sous le nom de viscosupplémentation (VS), sont fréquemment utilisées dans le traitement symptomatique de la gonarthrose (OA), une affection ostéo-articulaire chronique douloureuse et handicapante, qui touche une fraction importante de la population âgée. La sévérité de la gonarthrose est en général décrite par la classification en stades radiologiques de Kellgren-Lawrence (KL). La VS a été largement étudiée à travers de nombreux essais cliniques; cependant, les résultats sont rarement analysés en détail, en fonction du stade KL. MÉTHODE: Une étude ouverte importante, portant sur 1 177 patients souffrant de gonarthrose, fut réalisée de 2004 à 2007. Chaque patient a reçu un traitement de VS consistant en 3 injections d'ARTHRUM H 2% (LCA Pharmaceutical, Chartres, France). A l'inclusion, les patients ont été décrits par leur profil démographique, leur indice de masse corporelle (IMC), leur stade KL et leur état clinique selon les sous-scores douleur et fonction de l'indice Western Ontario and McMaster Universities (WOMAC). Les visites de suivi étaient à M3, M6 et M9 (mois) après la VS. Cette large base de données a été entièrement retraitée en 2019, de manière à fournir une analyse séparée par stade KL, et fut complétée par l'évaluation des taux de patients répondeurs (%) au traitement, selon l'Outcome Measures in Rheumatoid Arthritis Clinical Trials & Osteoarthritis Research Society International (OMERACT-OARSI). L'analyse fut menée à la fois sur les populations en intention de traiter (ITT) et per protocole (PP) ayant terminé l'étude. RÉSULTATS: En analyse ITT du critère principal, les variations du sous-score WOMAC A (douleur) depuis l'inclusion jusqu'à la fin de l'étude, ont été respectivement de 19,8 ; 19,8 ; 17,8 et 14,2, sur une échelle de 0-100, pour les patients des stades KL I à KL IV. En analyse PP dans les mêmes conditions, ces variations ont été de 20,6 ; 19,9 ; 17,1 et 11,7. Tous ces résultats étaient significatifs par rapport aux valeurs à l'inclusion (p<0.001) et cliniquement pertinents à chaque stade KL. Des améliorations significatives ont été également observées pour le sous-score WOMAC C (fonction), et pour les autres critères secondaires. Le taux de répondeurs OMERACT-OARSI variait de 72 à 82% pour les patients KL I à III à M6 et M9. Pour les patients KL IV, le maximum atteint a été 47.7% à M6. Les autres paramètres tels que le sexe, l'IMC ou l'âge, ne furent pas identifiés comme des facteurs de pronostic pour la réponse à la VS. CONCLUSIONS: L'analyse détaillée par stade KL d'une large cohorte de patients suivis en ouvert, suggère le traitement de VS avec ARTHRUM H 2% est applicable à une grande variété de patients gonarthrosiques.

Mono-injection intra-articulaire d'acide hyaluronique dans la gonarthrose : Étude multicentrique prospective ouverte (ART-ONE 75) avec comparaison post hoc versus placebo.

INTRODUCTION: La viscosupplémentation du liquide synovial par injection intra-articulaire d'acide hyaluronique est un traitement symptomatique de l'arthrose, largement utilisé dans la gonarthrose (arthrose du genou). À côté des produits conçus pour être administrés par injections multiples (typiquement 3 à 5 injections à intervalles de 1 semaine), un intérêt particulier se porte sur produits en injection unique (mono-injection) qui offrent des avantages spécifiques tels que la réduction du nombre de visites au médecin et du nombre d'interventions invasives avec leurs risques associés. Il subsiste toutefois une question concernant l'efficacité de ces mono-injections, par rapport aux protocoles à injections multiples. MÉTHODES: Une étude post-commercialisation, prospective, multicentrique, ouverte (ART-ONE 75), a été réalisée avec le produit pour injection unique Arthrum 2,5 % (3 mL, 75 mg d'acide hyaluronique) (LCA Pharmaceutical, Chartres, France), sur 214 patients atteints de gonarthrose. Les patients ont été suivis à 30, 60, 120 et 180 jours. Le profil moyen des patients à l'inclusion était un âge de 62,9 ans, 56 % de femmes, un stade radiologique Kellgren-Lawrence de I à III (46 % KL III), un indice de masse corporelle de 27,2 kg/m2 et une antériorité de 4 ans pour la gonarthrose. Une comparaison post hoc a été réalisée par rapport à une injection intra-articulaire unique de placebo (326 patients regroupés à partir de 3 essais randomisés contrôlés), et présentant un profil similaire de patients. RÉSULTATS: Le critère principal était la variation par rapport à la baseline, de l'indice Western Ontario and McMaster Universities, sous-échelle de la douleur (WOMAC A) dont le score (base 0-100), était réduit à 60 jours, de 28,9 (17,4) pour la population en intention de traiter (199 patients), de 28,0 (17,8) pour la population per protocole à l'inclusion (175 patients), et de 27,7 (16.8) pour la population per protocole ayant terminé l'étude (143 patients). Les critères secondaires et accessoires comprenaient le score WOMAC A aux autres dates, le score WOMAC B (raideur), le score WOMAC C (fonction), la qualité de vie et le handicap à chaque date de suivi. Tous les indices étaient significativement améliorés et continuaient à s'améliorer à la fin de l'étude. L'évaluation thérapeutique à 180 jours a montré que plus de 75 % des patients étaient satisfaits de la réduction de la douleur, de l'amélioration de la mobilité et de la réduction de la consommation d'analgésiques et d'anti-inflammatoires non stéroïdiens. Le pourcentage de patients définis comme répondeurs selon les critères de l'OMERACT-OARSI Initiative était > 86 %, à partir de 60 jours. La tolérance globale était bonne, sans aucun évènement indésirable grave. Les résultats de la comparaison post hoc pour le score WOMAC A ont montré une taille d'effet variant de 0,33 (IC 95 % 0,15-0,51), à 60 jours à 0,65 (IC 95 % 0,45-0,85) à 180 jours (p < 0.001), versus placebo injecté (solution saline), qui est cliniquement significative en faveur d'Arthrum 2,5 %. CONCLUSION: La présente étude suggère l'efficacité clinique d'une mono-injection IA de 3 mL de solution viscoélastique contenant 75 mg d'AH natif de haut poids moléculaire (> 2 MDa).

Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute an important pharmacotherapeutic class that, over the past decade, have expanded in application to a panoply of medical conditions. They have been tested for neurodegenerative diseases such as Alzheimer's to reduce inflammation and also in the attempt to abrogate amyloid deposition. However, the use of NSAIDs as aggregation inhibitors has not been extensively studied in pancreatic amyloid deposition. Pancreatic amyloidosis involves the misfolding of islet amyloid polypeptide (IAPP) and contributes to the progression of type-2 diabetes in humans and felines. To ascertain their antiamyloidogenic activity, several NSAIDs were tested using fluorometric thioflavin-T assays, circular dichroism, photo-induced cross-linking assays, and cell culture. Celecoxib, diclofenac, indomethacin, meloxicam, niflumic acid, nimesulide, phenylbutazone, piroxicam, sulindac, and tenoxicam reduced fibrillization at a molar ratio of 1:10. The circular dichroism spectra of diclofenac, piroxicam, and sulindac showed characteristic spectral signatures found in predominantly α-helical structures. The oligomerization of human IAPP was abrogated with diclofenac and sulindac at a molar ratio of 1:5. The cytotoxic effects of pre-incubated human IAPP on cultured INS-1 cells were noticeably reduced in the presence of diclofenac, meloxicam, phenylbutazone, sulindac, and tenoxicam at a molar ratio of 1:10. Our results demonstrate that NSAIDs can provide chemical scaffolds to generate new and promising antiamyloidogenic agents that can be used alone or as a coadjuvant therapy.

[Not Available]. / À l'ère de l'automédication, que savent les femmes enceintes des anti-inflammatoires ?

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated in pregnancy because of the many foetalmaternal complications they can induce. Yet, NSAIDs can be massively found in family medicine cabinets and they are over the-counter drugs for most of them. Because of the actual trend of empowerment and public authorities encouraging self-medication, NSAIDs might be used. Our aim was to assess pregnant women's knowledge of NSAIDs. STUDY DESIGN: A descriptive study, through the distribution of 330 questionnaires to all pregnant women consulting at the Teaching hospital of Saint-Etienne, during a week, from February 11(th), 2014 to 19(th), 2014. RESULTS: The answering rate was 96.4%. Around 46% of pregnant women declared self-medicating. More than 1 in 3 women considered NSAIDs without danger starting from their 6th month of pregnancy. Eighty-six percent of women recognized ibuprofen as belonging to NSAISs. However, 1 in 2 women didn't consider Rhinadvil® (ibuprofene/pseudoephedrine) as such and approximately 40% for Aspegic® (lysine acetylsalicylate) and Aspirin® (acetylsalicylic acid). Danger's perception varied according to the galenic and the trade name: 60% of them thought that Rhinadvil® was without risks and around 1 in 2 women thought the same for Aspirin® and Aspegic®. Eighty-six per cent of women recognized ibuprofen as belonging to NSAIDs. However, 1 in 2 women didn't consider Rhinadvil® as such and approximately 40% for Apegic® and Aspirin®. CONCLUSION: Pregnant women's knowledge of NSAIDs is not satisfactory. They are not aware of their danger and do not know how to recognize them. Yet, self-medication is rising and its accessibility is made easier. A work on prevention and information is therefore essential.

Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome.

BACKGROUND & AIMS: Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). METHODS: We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. RESULTS: Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. CONCLUSIONS: Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.

Comprehensive investigation of insulin-induced amyloidosis lesions in patients with diabetes at clinical and histological levels: A systematic review.

INTRODUCTION: Insulin-derived amyloidosis (AIns), a skin complication in patients with diabetes, causes impaired insulin absorption. This systematic review aims to get a better understanding of this overlooked condition. METHODS: Comprehensive literature searches were performed in Scopus, PubMed, EMBASE, and Web of Science databases until June 17, 2023. From 19,343 publications, duplicate and irrelevant records were eliminated by title, and the full texts of the remaining studies were examined for validity. Clinical, pathological, and therapeutic findings were extracted from 44 papers. RESULTS: Forty-four articles were studied that covered 127 insulin-treated patients with diabetes. From the 62 patients with reported age and sex, males had a mean age of 58 years, and females 68.5 years. While AIns were twice as likely to develop in men (66.13 %) as in women (33.87 %), the administered insulin dose was significantly higher in males (p = 0.017). The most common insulin injection site was the abdominal wall (77.63 %). Histological findings showed the presence of amorphous material with the occasional presence of lymphocytes, plasma cells, macrophages, adipocytes, histocytes, and giant cells. The mean HbA1c level was 8.8 % and the need for receiving insulin was increased in AIns. Changing the site of insulin injections and/or surgically removing the nodules were the most common treatments to obtain better insulin uptake and controlled serum glucose levels. CONCLUSION: This study highlights the importance of AIns, proper rotation of insulin injection site, and post-treatment patient follow-up to recognize and prevent the development of amyloid nodules.

[Non-steroidal Anti-inflammatory Drugs and Cardiovascular Risk]. / Nicht-steroidale Antirheumatika und kardiovaskuläres Risiko.

Non-steroidal Anti-inflammatory Drugs and Cardiovascular Risk Abstract. Non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most frequently used drugs worldwide, although medically controlled prescription is missing most of the time. Beside well-known gastro-intestinal and renal side effects, the potentially increased cardiovascular risk under NSAIDs remains underestimated. Nonselective NSAIDs, but also selective COX-2 inhibitors may block and decrease prostacyclin, which itself physiologically would inhibit platelets and promote vasodilation. Furthermore, in selective COX-2 inhibitors a shift towards COX-1 activity may be observed, which further promotes platelet aggregation. Nonselective NSAIDs with a long half-life time are characterized by relatively stable plasma levels and thus a relatively stable platelet inhibition. Non-selective NSAIDs may additionally inhibit acetylsalicylic acid, which negatively affects its effect on platelet inhibition.

[Methods of analgesia and euthanasia in backyard poultry]. / Methoden der Analgesie und Euthanasie in der Hobby-Hühnerhaltung.

INTRODUCTION: The keeping of chickens in the backyard is growing in popularity in urban and suburban areas, numbers of animals are increasing and as a result small animal practitioners are more and more frequently faced with chickens as patient. Clinical conditions in backyard poultry often require the treatment of pain. The challenges regarding the adequate use of analgesics include: 1. Recognition and assessment of pain, which necessitates good knowledge of chicken behaviour, 2. Selection of the adequate drug and dosage based on evidence that is often not available for chickens, but spread over different species of birds, and 3. Implementation of food safety regulations, which result from the dual use of backyard poultry as «food producing pets¼. Analgesics used in chickens include opiates, nonsteroidal anti-inflammatory drugs and local analgesics. The opiate butorphanol has been shown to have an analgesic effect of approximately two hours in chickens. Tramadol and methadone show some promise as analgesics, but more evidence is needed especially regarding bioavailability. The nonsteroidal anti-inflammatory drugs meloxicam and carprofen appear to have an analgesic effect. Variable metabolism between breeds of chickens and the risk of accumulation, especially when used for periods exceeding five consecutive days, need to be taken into account regarding dosage. Lidocaine and bupivacaine have successfully been used in chickens for nerve blocks and spinal anaesthesia and should be included as part of multimodal analgesia especially during surgery. In cases, where termination of life is necessary the preferred method consists of an injectable anaesthesia followed by intravenous application of a barbiturate.

INTRODUCTION: L'élevage de volailles de basse-cour est de plus en plus populaire dans les zones urbaines et suburbaines, le nombre d'animaux augmente et les praticiens pour petits animaux sont, par conséquent, de plus en plus souvent confrontés à ces animaux en tant que patients. Les conditions cliniques des volailles de basse-cour nécessitent souvent le traitement de la douleur. Les défis liés à l'utilisation adéquate des analgésiques sont les suivants 1. La reconnaissance et l'évaluation de la douleur, qui nécessitent une bonne connaissance du comportement des volailles, 2. la sélection du médicament et du dosage adéquats sur la base de preuves qui ne sont souvent pas disponibles pour les volailles mais sont réparties entre différentes espèces d'oiseaux, et 3. la mise en œuvre des réglementations en matière de sécurité alimentaire, qui résultent de la double utilisation des volailles de basse-cour en tant qu'«animaux de compagnie producteurs de denrées alimentaires¼. Les analgésiques utilisés chez les poulets comprennent les opiacés, les anti-inflammatoires non stéroïdiens et les analgésiques locaux. Il a été démontré que l'opiacé butorphanol a un effet analgésique chez les poulets, d'une durée d'environ deux heures. Le Tramadol et la méthadone sont des analgésiques prometteurs, mais des preuves supplémentaires sont nécessaires, notamment en ce qui concerne leur biodisponibilité. Les anti-inflammatoires non stéroïdiens Meloxicam et Carprofen semblent avoir un effet analgésique. En ce qui concerne la posologie, il convient de tenir compte du métabolisme variable selon les races de poules et du risque d'accumulation, en particulier en cas d'utilisation pendant des périodes supérieures à cinq jours consécutifs. La lidocaïne et la bupivacaïne ont été utilisées avec succès chez les poules pour les blocs nerveux ainsi que pour l'anesthésie spinale et devraient être incluses dans l'analgésie multimodale, en particulier pendant la chirurgie. Dans les cas où il est nécessaire de mettre fin à la vie de l'animal, la méthode de choix consiste en une anesthésie injectable suivie d'une application intraveineuse d'un barbiturique.

Quorum Sensing Controls the CRISPR and Type VI Secretion Systems in Aliivibrio wodanis 06/09/139.

For bacteria to thrive in an environment with competitors, phages and environmental cues, they use different strategies, including Type VI Secretion Systems (T6SSs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to compete for space. Bacteria often use quorum sensing (QS), to coordinate their behavior as the cell density increases. Like other aliivibrios, Aliivibrio wodanis 06/09/139 harbors two QS systems, the main LuxS/LuxPQ system and an N-acyl homoserine lactone (AHL)-mediated AinS/AinR system and a master QS regulator, LitR. To explore the QS and survival strategies, we performed genome analysis and gene expression profiling on A. wodanis and two QS mutants (ΔainS and ΔlitR) at two cell densities (OD600 2.0 and 6.0) and temperatures (6 and 12°C). Genome analysis of A. wodanis revealed two CRISPR systems, one without a cas loci (CRISPR system 1) and a type I-F CRISPR system (CRISPR system 2). Our analysis also identified three main T6SS clusters (T6SS1, T6SS2, and T6SS3) and four auxiliary clusters, as well about 80 potential Type VI secretion effectors (T6SEs). When comparing the wildtype transcriptome data at different cell densities and temperatures, 13-18% of the genes were differentially expressed. The CRISPR system 2 was cell density and temperature-independent, whereas the CRISPR system 1 was temperature-dependent and cell density-independent. The primary and auxiliary clusters of T6SSs were both cell density and temperature-dependent. In the ΔlitR and ΔainS mutants, several CRISPR and T6SS related genes were differentially expressed. Deletion of litR resulted in decreased expression of CRISPR system 1 and increased expression of CRISPR system 2. The T6SS1 and T6SS2 gene clusters were less expressed while the T6SS3 cluster was highly expressed in ΔlitR. Moreover, in ΔlitR, the hcp1 gene was strongly activated at 6°C compared to 12°C. AinS positively affected the csy genes in the CRISPR system 2 but did not affect the CRISPR arrays. Although AinS did not significantly affect the expression of T6SSs, the hallmark genes of T6SS (hcp and vgrG) were AinS-dependent. The work demonstrates that T6SSs and CRISPR systems in A. wodanis are QS dependent and may play an essential role in survival in its natural environment.

[NSAID urticaria: Similar management to acute urticaria]. / Urticaire aux AINS : une prise en charge similaire à celle de l'urticaire aiguë.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common providers of immediate hypersensitivity reactions. Among these reactions, isolated acute urticaria is the most common clinical feature with a non-allergic origin. It is a pharmacological side effect resulting from the alteration of arachidonic acid metabolism induced by NSAIDs. Diagnosis of this acute urticaria is clinical, requiring no allergy testing. Currently, the recommended therapeutic management of NSAID urticaria is the avoidance of all NSAID with COX-1 inhibitor activity (even if when reintroduced, they are most often well tolerated) and the use of selective COX-2 inhibitors. This review focuses on urticaria reactions to NSAIDs, which are simple to manage.

Formalizing the Function of Anterior Insula in Rapid Adaptation.

Anterior insula (aIns) is thought to play a crucial role in rapid adaptation in an ever-changing environment. Mathematically, it is known to track risk and surprise. Modern theories of learning, however, assign a dominant role to signed prediction errors (PEs), not to risk and surprise. Risk and surprise only enter to the extent that they modulate the learning rate, in an attempt to approximate Bayesian learning. Even without such modulation, adaptation is still possible, albeit slow. Here, I propose a new theory of learning, reference-model based learning (RMBL), where risk and surprise are central, and PEs play a secondary, though still crucial, role. The primary goal is to bring outcomes in line with expectations in the reference model (RM). Learning is modulated by how large the PEs are relative to model anticipation, i.e., to surprise as defined by the RM. In a target location prediction task where participants were continuously required to adapt, choices appeared to be closer with to RMBL predictions than to Bayesian learning. aIns reaction to surprise was more acute in the more difficult treatment, consistent with its hypothesized role in metacognition. I discuss links with related theories, such as Active Inference, Actor-Critic Models and Reference-Model Based Adaptive Control.

Diclofenac pretreatment modulates exercise-induced inflammation in skeletal muscle of rats through the TLR4/NF-κB pathway.

Nonsteroidal anti-inflammatory drugs, such as diclofenac, are widely used to treat inflammation and pain in several conditions, including sports injuries. This study analyzes the influence of diclofenac on the toll-like receptor-nuclear factor kappa B (TLR-NF-κB) pathway in skeletal muscle of rats submitted to acute eccentric exercise. Twenty male Wistar rats were divided into 4 groups: control-saline, control-diclofenac, exercise-saline, and exercise-diclofenac. Diclofenac or saline were administered for 7 days prior to an acute eccentric exercise bout. The inflammatory status was evaluated through mRNA levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor alpha (TNF-α), and protein content of COX-2, IL-6, and TNF-α in vastus lateralis muscle. Data obtained showed that a single bout of eccentric exercise significantly increased COX-2 gene expression. Similarly, mRNA expression and protein content of other inflammation-related genes also increased after the acute exercise. However, these effects were attenuated in the exercise + diclofenac group. TLR4, myeloid differentiation primary response gene 88 (MyD88), and p65 were also upregulated after the acute eccentric bout and the effect was blunted by the anti-inflammatory drug. These findings suggest that pretreatment with diclofenac may represent an effective tool to ameliorate the pro-inflammatory status induced by acute exercise in rat skeletal muscle possibly through an attenuation of the TLR4-NF-κB signaling pathway.

Over-the-Counter Medicines and Diabetes Care.

OBJECTIVES: People with diabetes turn to over-the-counter (OTC) medicines for many ailments. The focus of this brief review is the impact common OTC medicines might have on this group of patients. METHODS: Three types of OTC medicines were selected as most deserving of attention: 3 herbal agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and cough/cold products. Existing literature was used to determine precautions that might be in order. RESULTS: Herbal/natural agents with the potential to impact blood sugar have been identified in various reports. In discussing 3, glucosamine and cinnamon (at doses recommended on commercial products) should have minimal impact on diabetic management, whereas St. John's wort is a concern involving potential drug interactions. For colds, of about 11 active ingredients, only decongestants (primarily oral) need be considered for their possible effects on blood sugar. Finally, NSAIDs (even at OTC doses) must be used with caution, given their cardiovascular, renal and gastrointestinal risks. Care guidelines do encourage patients to take ownership of their condition. Yet the ability to self-medicate safely is not a certainty. In spite of easy access and a reasonable level of safety, OTC medicines still can negatively impact a user. NSAIDs available without prescription continue to cause concern. CONCLUSIONS: Before the use of any medicine, a person must ensure it will be safe. A health-care provider can be asked for assistance, but that option may not always be employed. Package information is there to provide critical information in lieu of that, something the self-medicating patient will, it is hoped, embrace.

[Not Available]. / Atteintes rénales graves au cours d'un traitement par anti-inflammatoires non stéroïdiens arylcarboxyliques : bilan d'une enquête nationale de pharmacovigilance.

The non-steroidal anti-inflammatory drugs (NSAID) especially the arylcarboxylic, are widely prescribed for their different properties. The renal adverse events are rare but often serious. We have reviewed the French experience for the following eight years period: January 1995 to December 2002. Three hundred and nine cases have been reported to the French Pharmacovigilance system during that period including 275 adults, 29 children and 5 new-born babies. In 247 cases (80%), the presentation was an acute renal failure occuning few days after treatment onset but not always of the prerenal type. Overall 34 patients needed one or more dialysis session; the majority recovered either completely or partially, but nevertheless, we had to deplore 5 deaths. These major renal complications were observed with all available NSAID on the French market, including ibuprofen which was often prescribe as pain-reliever. With this data together with international information, the French Drug Agency decided to modify the summary of products characteristics of these NSAID.

Insulin amyloid at injection sites of patients with diabetes.

The formation of insulin amyloid can dramatically impact glycemic control in patients with diabetes, making it an important therapeutic consideration. In addition, the cost associated with the excess insulin required by patients with amyloid is estimated to be $3K per patient per year, which adds to the growing financial burden of this disease. Insulin amyloid has been observed with every mode of therapeutic insulin administration (infusion, injection and inhalation), and the number of reported cases has increased significantly since 2002. The new cases represent a much broader demographic, and include many patients who have used exclusively human insulin and human insulin analogs. The reason for the increase in case reports is unknown, but this review explores the possibility that changes in patient care, improved differential diagnosis and/or changes in insulin type and insulin delivery systems may be important factors. The goal of this review is to raise key questions that will inspire proactive measures to prevent, identify and treat insulin amyloid. Furthermore, this comprehensive examination of insulin amyloid can provide insight into important considerations for other injectable drugs that are prone to form amyloid deposits.