Repurposing of rituximab biosimilars to treat B cell mediated autoimmune diseases.

Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization of its many biosimilars. Currently, rituximab is prescribed worldwide to treat a vast range of autoimmune diseases mediated by B cells. Here, we present a comprehensive overview of rituximab repurposing in 115 autoimmune diseases across 17 medical specialties, sourced from over 1530 publications. Our work highlights the extent of its off-label use and clinical benefits, underlining the success of rituximab repurposing for both common and orphan immune-related diseases. We discuss the scientific mechanism associated with its clinical efficacy and provide additional indications for which rituximab could be investigated. Our study presents rituximab as a flagship example of drug repurposing owing to its central role in targeting cluster of differentiate 20 positive (CD20) B cells in 115 autoimmune diseases.

Role of the Gut Microbiome in the Development of Atherosclerotic Cardiovascular Disease.

Atherosclerotic cardiovascular disease (ASCVD) is the primary cause of death globally, with nine million deaths directly attributable to ischemic heart diseases in 2020. Since the last few decades, great effort has been put toward primary and secondary prevention strategies through identification and treatment of major cardiovascular risk factors, including hypertension, diabetes, dyslipidemia, smoking, and a sedentary lifestyle. Once labelled "the forgotten organ", the gut microbiota has recently been rediscovered and has been found to play key functions in the incidence of ASCVD both directly by contributing to the development of atherosclerosis and indirectly by playing a part in the occurrence of fundamental cardiovascular risk factors. Essential gut metabolites, such as trimethylamine N-oxide (TMAO), secondary bile acids, lipopolysaccharides (LPS), and short-chain fatty acids (SCFAs), have been associated with the extent of ischemic heart diseases. This paper reviews the latest data on the impact of the gut microbiome in the incidence of ASCVD.

Microbiota, a New Playground for the Omega-3 Polyunsaturated Fatty Acids in Cardiovascular Diseases.

Several cardioprotective mechanisms attributed to Omega-3 polyunsaturated fatty acids (PUFAs) have been studied and widely documented. However, in recent years, studies have supported the concept that the intestinal microbiota can play a much larger role than we had anticipated. Microbiota could contribute to several pathologies, including cardiovascular diseases. Indeed, an imbalance in the microbiota has often been reported in patients with cardiovascular disease and produces low-level inflammation. This inflammation contributes to, more or less, long-term development of cardiovascular diseases. It can also worsen the symptoms and the consequences of these pathologies. According to some studies, omega-3 PUFAs in the diet could restore this imbalance and mitigate its harmful effects on cardiovascular diseases. Many mechanisms are involved and included: (1) a reduction of bacteria producing trimethylamine (TMA); (2) an increase in bacteria producing butyrate, which has anti-inflammatory properties; and (3) a decrease in the production of pro-inflammatory cytokines. Additionally, omega-3 PUFAs would help maintain better integrity in the intestinal barrier, thereby preventing the translocation of intestinal contents into circulation. This review will summarize the effects of omega-3 PUFAs on gut micro-biota and the potential impact on cardiac health.

The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis.

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion by being implicated in several metabolic and inflammatory processes linked to several diseases including CVD. Studies have reported associations between bacterial metabolites and hypercholesterolemia. However, such associations remain poorly investigated and characterized. In this review, the mechanisms of microbial derived metabolites such as primary and secondary bile acids (BAs), trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) will be explored in the context of cholesterol metabolism. These metabolites play critical roles in maintaining cardiovascular health and if dysregulated can potentially contribute to CVD. They can be modulated via nutritional and pharmacological interventions such as statins, prebiotics, and probiotics. However, the mechanisms behind these interactions also remain unclear, and mechanistic insights into their impact will be provided. Therefore, the objectives of this paper are to present current knowledge on potential mechanisms whereby microbial metabolites regulate cholesterol homeostasis and to discuss the feasibility of modulating intestinal microbes and metabolites as a novel therapeutic for hypercholesterolemia.

Clinical importance of thrombocytopenia in patients with acute coronary syndromes: a systematic review and meta-analysis.

Thrombocytopenia (TP) is common in hospitalized patients. In the context of acute coronary syndromes (ACS), TP has been linked to adverse clinical outcomes. We present a systematic review and meta-analysis of the evidence on the clinical importance of preexisting and in-hospital acquired TP in the context of ACS. Specifically, we address (a) the prevalence and associated factors with TP in the context of ACS; and (b) the association between TP and all-cause mortality, major adverse cardiovascular events (MACEs), and major bleeding. We conducted systematic literature searches in MEDLINE and Web of Science. For the meta-analysis, we fit linear mixed models with a random study-specific intercept for the aggregate outcomes. A total of 16 studies and 190 915 patients were included in this study. Of these patients, 8.8% ± 1.2% presented with preexisting TP while 5.8% ± 1.0% developed TP after hospital admission. Preexisting TP was not statistically significantly associated with adverse outcomes. Acquired TP was associated with greater risk of all-cause mortality (risk difference [RD]: 4.3%; 95% confidence interval [CI]: 2-6%; p = 0.04), MACE (RD: 8.5%; 95% CI: 1-16.0%; p = 0.037), and major bleeding (RD: 11.9%; 95% CI: 5-19%; p = 0.005). In conclusion, TP is a prevalent condition in patients admitted for an ACS and identifies a high-risk patient population more likely to experience ischemic and bleeding complications, as well as higher mortality.

A high omega-3 fatty acid diet rapidly changes the lipid composition of cardiac tissue and results in cardioprotection.

The present study was designed to ascertain the effects of 3 diets with different omega-3/6 fatty acid ratios on infarct size and the modifications that these diets induce in the lipid composition of cardiac tissue. Sprague-Dawley rats were fed omega-3/6 fatty acid diets with 1:1, 1:5, or 1:20 ratios for at least 10 days, followed by occlusion of the left anterior descending artery for 40 min and 24 h of reperfusion. Infarct size was significantly smaller in the 1:1 group than in the other groups. Significantly higher concentrations of the omega-3 fatty acids eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were found in the 1:1 group than in the other groups. Omega-6 polyunsaturated fatty acid levels were similar between groups, although they were higher in the 1:5 and 1:20 groups than in the 1:1 group. Margaric acid concentrations were higher in the 1:1 group than in the other groups. Docosahexaenoic acid levels in cardiac tissue and infarct size were significantly correlated with no other significant links being apparent. The present study indicated that a 1:1 omega-3/6 fatty acid ratio protected against ischemia and was associated with increased omega-3 fatty acid composition of cardiac tissue.

Cardioprotective Effects of Omega-3 Polyunsaturated Fatty Acids: Dichotomy between Experimental and Clinical Studies.

The high-fat diet of North Americans has a major impact on cardiovascular disease occurrence. Notably, fatty acids have been identified as important factors that could modulate such diseases, especially myocardial infarction (MI). Experimentally, omega-3 polyunsaturated fatty acids (PUFA) have demonstrated positive effects on cardiovascular disorders and have also shown cardioprotection by decreasing MI size. Although many animal experiments have clearly established the benefits of omega-3 PUFA, clinical studies have not reached similar conclusions. In fact, the findings of recent clinical investigations indicate that omega-3 PUFA play only a minor role in cardiovascular health. This dichotomy between experimental and clinical studies may be due to different parameters that are not taken into account in animal experiments. We have recently observed that the high consumption of omega-6 PUFA results in significant attenuation of the beneficial effect of omega-3 PUFA on MI. We believe that part of the dichotomy between experimental and clinical research may be related to the quantity of omega-6 PUFA ingested. This review of the data indicates the importance of considering omega-6 PUFA consumption in omega-3 PUFA studies.

Cognitive Deficits Following a Post-Myocardial Infarct in the Rat Are Blocked by the Serotonin-Norepinephrine Reuptake Inhibitor Desvenlafaxine.

Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of treatment following MI using tricyclic antidepressants or selective serotonin uptake blockers. Here we used three different treatment schedules to test the short- and long-term effects of the combined serotonin-norepinephrine reuptake inhibitor desvenlafaxine on post-MI-associated cognitive deficits and caspase activation. MI was induced in 39 young adult rats, and 39 rats served as sham-operated controls. Desvenlafaxine (3 mg/kg/day, i.p.) or saline was administered according to one of three schedules: (1) for 2 weeks, starting right after surgery; (2) for 16 weeks, starting 2 weeks after surgery; (3) for 16 weeks, starting right after surgery. Behavior was tested 2 weeks (social interaction, passive avoidance) and 16 weeks (forced swimming, Morris water maze) after surgery. Caspase-3 and caspase-6 activities were measured 16 weeks after surgery. At 2 and 16 weeks post-surgery, saline-treated MI rats displayed performance deficits compared to desvenlafaxine-treated rats, regardless of the treatment schedule. Caspase-3 activity was higher in the amygdala (medial and lateral) and hippocampal CA3 region in untreated MI rats, whereas caspase-6 activity was higher in the CA1 region. Caspase-6 activity correlated positively with deficits in the Morris water maze. These results indicate that, independently of treatment schedules, various treatment schedules with desvenlafaxine can prevent MI-associated cognitive deficits and decrease caspase activities in the limbic system.

Resolvin D1 Reduces Infarct Size Through a Phosphoinositide 3-Kinase/Protein Kinase B Mechanism.

This study was designed to determine if Resolvin D1 (RvD1), a pro-resolution metabolite of the omega-3 polyunsaturated fatty acid docosahexaenoic acid, could decrease myocardial infarct size with delivered at the onset of ischemia. Male Sprague Dawley rats underwent 40 minutes of myocardial ischemia followed by reperfusion. These animals received 1 intraventricular injection of RvD1 (0.01, 0.1, or 0.3 µg RvD1) or vehicle (saline) before coronary occlusion. Infarct size and neutrophil accumulation were evaluated 24 hours after the onset of reperfusion. Caspase-3, caspase-8, protein kinase B (Akt) activities were evaluated 30 minutes after the reperfusion. Rats receiving 0.1 or 0.3 µg RvD1 showed a significant decrease of infarct size and caspase-3 and caspase-8 activities compared with the vehicle controls. Neutrophil accumulations were reduced in rats administered RvD1 compared with vehicle, independently of dose level. Akt activation was increased only in animals receiving 0.1 or 0.3 µg, whereas no change was observed in the 0.01 µg group. When they were treated with LY-294002, a phosphoinositide 3-kinase (PI3K)/Akt inhibitor, cardioprotection by RvD1 was abrogated. RvD1 treatment at the onset of ischemia decreases infarct size by a mechanism involving the PI3K/Akt pathway.

Resolvin D1, a metabolite of omega-3 polyunsaturated fatty acid, decreases post-myocardial infarct depression.

We hypothesized that inflammation induced by myocardial ischemia plays a central role in depression-like behavior after myocardial infarction (MI). Several experimental approaches that reduce inflammation also result in attenuation of depressive symptoms. We have demonstrated that Resolvin D1 (RvD1), a metabolite of omega-3 polyunsaturated fatty acids (PUFA) derived from docosahexaenoic acid, diminishes infarct size and neutrophil accumulation in the ischemic myocardium. The aim of this study is to determine if a single RvD1 injection could alleviate depressive symptoms in a rat model of MI. MI was induced in rats by occlusion of the left anterior descending coronary artery for 40 min. Five minutes before ischemia or after reperfusion, 0.1 µg of RvD1 or vehicle was injected in the left ventricle cavity. Fourteen days after MI, behavioral tests (forced swim test and socialization) were conducted to evaluate depression-like symptoms. RvD1 reduced infarct size in the treated vs. the vehicle group. Animals receiving RvD1 also showed better performance in the forced swim and social interaction tests vs. vehicle controls. These results indicate that a single RvD1 dose, given 5 min before occlusion or 5 min after the onset of reperfusion, decreases infarct size and attenuates depression-like symptoms.

Differences in Antihypertensive Medication Prescription Profiles Between 2009 and 2021: A Retrospective Cohort Study of CARTaGENE.

Background: Although blood pressure (BP) control is critical to prevent cardiovascular diseases, hypertension control rates in Canada are in decline. Objective: To assess this issue, we sought to evaluate the differences in antihypertensive medication prescription profiles in the province of Quebec between 2009 and 2021. Design: This is a retrospective cohort study. Setting: We used data from the CARTaGENE population-based cohort linked to administrative health databases. Patients: Participants with any drug claim in the 6 months prior to the end of follow-up were included. Measurements: Guideline-recommended antihypertensive drug prescription profiles were assessed at the time of enrollment (2009-2010) and end of follow-up (March 2021). Methods: Prescriptions practices from the 2 time periods were compared using Pearson's chi-square tests. A sensitivity analysis was performed by excluding participants in which antihypertensive drugs may not have been prescribed solely to treat hypertension (presence of atrial fibrillation/flutter, ischemic heart disease, heart failure, chronic kidney disease, or migraines documented prior to or during follow-up). Results: Of 8447 participants included in the study, 31.4% and 51.3% filled prescriptions for antihypertensive drugs at the beginning and end of follow-up. In both study periods, guideline-recommended monotherapy was applied in most participants with hypertension (77.9% vs 79.5%, P = .3), whereas optimal 2 and 3-drug combinations were used less frequently (62.0% vs 61.4%, P = .77, 51.9% vs 46.7%, P = .066, respectively). Only the use of long-acting thiazide-like diuretics (9.5% vs 27.7%, P < .001) and spironolactone as a fourth-line agent (8.3% vs 15.9%, P = .054) increased with time but nonetheless remained infrequent. Results were similar in the sensitivity analysis. Limitations: Specific indication of the prescribed antihypertensive medications and follow-up BP data was not available. Conclusions: Application of hypertension guidelines for the choice of antihypertensive drugs remains suboptimal, highlighting the need for education initiatives. This may be an important step to raise BP control rates in Canada.

Contexte: Bien que le contrôle de la pression artérielle (PA) soit essentiel pour prévenir les maladies cardiovasculaires, les taux de maitrise de l'hypertension artérielle sont en déclin au Canada. Objectifs: Pour traiter cette problématique, nous avons cherché à évaluer les différences dans les profils de prescription de médicaments antihypertenseurs dans la province de Québec entre 2009 et 2021. Conception: Étude de cohorte rétrospective. Cadre: Nous avons utilisé les données de la cohorte populationnelle CARTaGENE reliées aux bases de données administratives en santé. Sujets: Ont été inclus les participants qui ont présenté une demande de remboursement de médicament dans les six mois précédant la fin du suivi. Mesures: Les profils de prescription de médicaments antihypertenseurs recommandés dans les lignes directrices ont été évalués au moment de l'inclusion (2009-2010) et à la fin du suivi (mars 2021). Méthodologie: Les profils de prescription des deux périodes ont été comparés à l'aide des tests Chi-Square de Pearson. Une analyse de sensibilité a été réalisée en excluant les participants pour lesquels les antihypertenseurs n'avaient possiblement pas été prescrits uniquement pour traiter l'hypertension (présence de fibrillation auriculaire, cardiopathie ischémique, insuffisance cardiaque, insuffisance rénale chronique ou migraines documentées avant ou pendant le suivi). Résultats: Des 8 447 participants inclus dans l'étude, 31,4 % avait rempli des prescriptions de médicaments antihypertenseurs au début du suivi et 51,3 % à la fin du suivi. Dans les deux périodes à l'étude, la monothérapie recommandée par les directives a été appliquée chez la plupart des participants avec hypertension artérielle (77,9 % c. 79,5 %; P = 0,3), tandis que les combinaisons optimales de deux médicaments (62,0 % c. 61,4 %; P = 0,77) et de trois médicaments (51,9 % c. 46,7 % P = 0,066) ont été utilisées moins fréquemment. Seules les utilisations de diurétiques thiazidiques à action prolongée (9,5 % c. 27,7 %; P < 0,001) et de spironolactone en quatrième intention (8,3 % c. 15,9 %; P = 0,054) ont augmenté avec le temps, mais sont demeurées néanmoins peu fréquentes. Les résultats étaient similaires dans l'analyse de sensibilité. Limites: L'indication précise pour la prescription de médicaments antihypertenseurs et les données de suivi sur la pression artérielle n'étaient pas disponibles. Conclusion: L'application des lignes directrices sur l'hypertension artérielle pour le choix des médicaments antihypertenseurs reste sous-optimale, ce qui souligne un besoin pour des initiatives en matière d'éducation. Cela pourrait constituer une étape importante d'une stratégie visant l'augmentation des taux de contrôle de la PA au Canada.

Porcine model of intracoronary pulverization of stent struts by rotablation atherectomy.

OBJECTIVE: To evaluate the feasibility and safety of rotablation atherectomy in a suboptimally expanded stent. METHODS: Seven pigs underwent suboptimal stent expansion in the left anterior descending coronary. Pulverization of the stent struts was performed by rotablation atherectomy with two different burr sizes. Two types of control porcine models were used: pigs with fully expanded stents and pigs without stents. Continuous electrocardiogram readings as well as microscopic and radiologic analysis of cardiac tissue were performed. RESULTS: Rotablation atherectomy reduces the suboptimally expanded stent by (26.95 ± 5.03)%. Ninety-five percent of the metal microparticles, imbedded in the suboptimally expanded stent group cardiac tissue, are less than 15 µm. Transient vasospasm and ST segments elevations were observed during rotablation atherectomy, which returned to basal conditions at the end of the intervention. CONCLUSION: Our study demonstrated the feasibility and safety of using rotablation atherectomy to pulverize stent struts in a suboptimally expanded stent.

Attenuation of post-myocardial infarction depression in rats by n-3 fatty acids or probiotics starting after the onset of reperfusion.

Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the limbic system after myocardial infarction (MI). A PUFA n-3 diet or the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 probiotics, when given before the ischaemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. The present study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depression-like behaviour observed after MI. MI was induced by the occlusion of the left anterior descending coronary artery for 40 min in rats. After the onset of reperfusion, animals were fed with a high- or low-PUFA n-3 diet, combined or not with one billion live bacteria of L. helveticus and B. longum. At 3 d post-MI, caspase-3 enzymatic activities and terminal 2'-deoxyuridine, 5'-triphosphate (dUTP) nick-end labelling (TUNEL)-positive cells were decreased in the CA1, dentate gyrus (DG) and amygdala with the high-PUFA n-3 diet, as compared to the three other diets. Probiotics attenuated caspase-3 activity and TUNEL-positive cells in the DG and the medial amygdala. At 2 weeks post-MI, depression-like behaviour was observed in the low-PUFA n-3 diet without probiotics-group, and this behaviour was attenuated with the high-PUFA n-3 diet or/and probiotics. These results indicate that a high-PUFA n-3 diet or the administration of probiotics, starting after the onset of reperfusion, are beneficial to attenuate apoptosis in the limbic system and post-MI depression in the rat.

Hadamard multiplexing in laser ultrasonics.

In state-of-the-art laser ultrasonics (LU), the signal-to-noise ratio (SNR) is limited by the shot noise of the detected laser radiation. Further improving the SNR then requires averaging multiple signals or increasing generation and/or detection laser intensities. The former strategy is time consuming and the latter leads to surface damages. For signal-independent limiting noises, Hadamard multiplexing increases the SNR by averaging multiple signals in parallel using a single detector. Here we consider the use of Hadamard multiplexing in LU for the non-contact ultrasonic inspection of materials. By using 31 element Hadamard masks to modulate the spatial intensity distribution of the generation laser beam, the measured SNR is improved by a factor 2.8, in good agreement with the expected multiplexing or Fellgett advantage. In contrast to many other applications of Hadamard multiplexing, the SNR is improved for shot-noise-limited measurements since the shot noise level is independent of the signal in LU. The Hadamard multiplexing of the detection laser beam is also considered but can only lead to a throughput or Jacquinot advantage. However, for pulse-echo LU, the Hadamard multiplexing of both generation and detection laser beams allows using the synthetic aperture focusing technique (SAFT).

Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model.

Myocardial infarction (MI) in rats is accompanied by apoptosis in the limbic system and a behavioural syndrome similar to models of depression. We have already shown that probiotics can reduce post-MI apoptosis and designed the present study to determine if probiotics can also prevent post-MI depressive behaviour. We also tested the hypothesis that probiotics achieve their central effects through changes in the intestinal barrier. MI was induced in anaesthetised rats via 40-min transient occlusion of the left anterior coronary artery. Sham rats underwent the same surgical procedure without actual coronary occlusion. For 7 d before MI and between the seventh post-MI day and euthanasia, half the MI and sham rats were given one billion live bacterial cells of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 per d dissolved in water, while the remaining animals received only the vehicle (maltodextrin). Depressive behaviour was evaluated 2 weeks post-MI in social interaction, forced swimming and passive avoidance step-down tests. Intestinal permeability was evaluated by oral administration with fluorescein isothiocyanate-dextran, 4 h before euthanasia. MI rats displayed less social interaction and impaired performance in the forced swimming and passive avoidance step-down tests compared to the sham controls (P < 0·05). Probiotics reversed the behavioural effects of MI (P < 0·05), but did not alter the behaviour of sham rats. Intestinal permeability was increased in MI rats and reversed by probiotics. In conclusion, L. helveticus R0052 and B. longum R0175 combination interferes with the development of post-MI depressive behaviour and restores intestinal barrier integrity in MI rats.

Adenosine in Acute Myocardial Infarction-Associated Reperfusion Injury: Does it Still Have a Role?

The mainstay of acute myocardial infarction has long been timely reperfusion of the culprit obstruction. Reperfusion injury resulting from a multitude of pathophysiological processes has been demonstrated to negatively affect myocardial recovery and function post-infarction. Adenosine interacts directly with the sequential pathophysiological processes culminating in reperfusion injury by inhibiting them upstream. The evidence for adenosine's benefit in acute myocardial infarction has produced mixed results with regards to myocardial salvage and long-term mortality. The heterogenous evidence with regards to benefits on clinical outcomes has resulted in modest uptake of adenosine in the clinical setting. However, it is critical to analyze the variability in study methodologies. The goal of this review is to evaluate how adenosine dose, route of administration, timing of administration, and site of administration play essential roles in the molecule's efficacy. The benefits of adenosine, as highlighted in the following review, are clear and its role in the treatment of acute myocardial infarction should not be discounted.

Dysbiotic microbiota contributes to the extent of acute myocardial infarction in rats.

Increasing evidence suggests that the intestinal microbiota composition could play a role in specific pathologies such as hypertension, obesity and diabetes. This study aims to demonstrate that the intestinal microbiota modulated by a diet creating dysbiosis increased the size of the myocardial infarction and that probiotics could attenuate this effect. To do this, microbiota transplants from rats fed a dysbiotic or non-dysbiotic diet in the presence or absence of probiotics were performed for 10 days on rats whose microbiota had been previously suppressed by antibiotic therapy. Then, the anterior coronary artery of the transplanted rats was occluded for 30 min. Infarct size was measured after 24 h of reperfusion, while signaling pathways were evaluated after 15 min of reperfusion. Intestinal resistance, plasma concentration of LPS (lipopolysaccharides), activation of NF-κB and Akt and composition of the microbiota were also measured. Our results demonstrate a larger infarct size in animals transplanted with the dysbiotic microbiota without probiotics compared to the other groups, including those that received the dysbiotic microbiota with probiotics. This increase in infarct size correlates with a higher firmicutes/bacteroidetes ratio, NF-kB phosphorylation and plasma LPS concentration, and a decrease in intestinal barrier resistance and Akt. These results indicate that dysbiotic microbiota promotes an increase in infarct size, an effect that probiotics can attenuate.

Retrograde BMP signaling regulates trigeminal sensory neuron identities and the formation of precise face maps.

Somatosensory information from the face is transmitted to the brain by trigeminal sensory neurons. It was previously unknown whether neurons innervating distinct areas of the face possess molecular differences. We have identified a set of genes differentially expressed along the dorsoventral axis of the embryonic mouse trigeminal ganglion and thus can be considered trigeminal positional identity markers. Interestingly, establishing some of the spatial patterns requires signals from the developing face. We identified bone morphogenetic protein 4 (BMP4) as one of these target-derived factors and showed that spatially defined retrograde BMP signaling controls the differential gene expressions in trigeminal neurons through both Smad4-independent and Smad4-dependent pathways. Mice lacking one of the BMP4-regulated transcription factors, Onecut2 (OC2), have defects in the trigeminal central projections representing the whiskers. Our results provide molecular evidence for both spatial patterning and retrograde regulation of gene expression in sensory neurons during the development of the somatosensory map.

Pretreatment with pentoxifylline has antidepressant-like effects in a rat model of acute myocardial infarction.

We have observed that, after myocardial infarction (MI), rats display apoptosis in the limbic system that can be prevented by pentoxifylline (PTX), a proinflammatory cytokine inhibitor. We have hypothesized that reduction of apoptosis in the limbic system can attenuate the depressive behaviour occurring post-MI. The present study was, therefore, designed to assess the outcome of PTX on depressive behaviour manifesting after MI. Myocardial ischaemia, induced for 40 min in male Sprague-Dawley rats, was followed by reperfusion (MI groups). Sham groups were subjected to the same protocol without occlusion. PTX (10 mg/kg/day) or saline was administered intraperitoneally 15 min before ischaemia, and then every day until sacrifice. Two weeks after ischaemia, depression was evaluated by the forced swim test and the sucrose preference test. At the end of the experiment, the animals were sacrificed, and myocardial infarct size was examined along with plasma IL-1ß concentrations. MI rats drank less sucrose in the sucrose preference test and were more immobile in the forced swim test than the sham controls. PTX reversed these behaviours in the MI group to a level similar to that in the untreated sham group, without affecting infarct size. PTX reduced plasma IL-1ß concentrations in both sham and MI rats. We conclude that PTX administration significantly reverses the depressive-like behaviour seen after MI in rats.

[Irritable bowel syndrome: Role of gut microbiota]. / Syndrome de l'intestin irritable - Rôle du microbiote intestinal.

Irritable Bowel Syndrome (IBS) is a functional disorder of the gastrointestinal tract with high prevalence. IBS, in particular the diarrheic subtype, is associated with alterations in gut microbiota composition and functionality, called dysbiosis. However, the treatment of this disease mainly relies on the patient's symptoms without considering the gut microbiota perturbations. In this review, we present epidemiological data about IBS-D. Then, we describe the main pathophysiological mechanisms associated with this disease, by focusing on gut microbiota alterations. We end up discussing the current therapies now available.

TITLE: Syndrome de l'intestin irritable - Rôle du microbiote intestinal. ABSTRACT: Le syndrome de l'intestin irritable (SII) est un trouble fonctionnel digestif dont la prévalence est très élevée. Ce syndrome, et notamment son sous-type diarrhéique (SII-D), est associé à des perturbations de la composition et des fonctions du microbiote intestinal à l'origine d'une dysbiose. Pourtant, la maladie est principalement traitée en fonction des symptômes des patients atteints, sans que la perturbation de leur microbiote ne soit prise en compte. Dans cette revue, nous détaillerons les données épidémiologiques de la maladie. Nous traiterons ensuite des principaux mécanismes physiopathologiques, notamment de l'impact des perturbations du microbiote intestinal. Le sous-type diarrhéique (SII-D) étant le plus fréquent [1], nous nous concentrerons principalement sur celui-ci. Nous introduirons enfin les thérapies actuelles utilisées.