Newborn's neural representation of instrumental and vocal music as revealed by fMRI: A dynamic effective brain connectivity study.

Music is ubiquitous, both in its instrumental and vocal forms. While speech perception at birth has been at the core of an extensive corpus of research, the origins of the ability to discriminate instrumental or vocal melodies is still not well investigated. In previous studies comparing vocal and musical perception, the vocal stimuli were mainly related to speaking, including language, and not to the non-language singing voice. In the present study, to better compare a melodic instrumental line with the voice, we used singing as a comparison stimulus, to reduce the dissimilarities between the two stimuli as much as possible, separating language perception from vocal musical perception. In the present study, 45 newborns were scanned, 10 full-term born infants and 35 preterm infants at term-equivalent age (mean gestational age at test = 40.17 weeks, SD = 0.44) using functional magnetic resonance imaging while listening to five melodies played by a musical instrument (flute) or sung by a female voice. To examine the dynamic task-based effective connectivity, we employed a psychophysiological interaction of co-activation patterns (PPI-CAPs) analysis, using the auditory cortices as seed region, to investigate moment-to-moment changes in task-driven modulation of cortical activity during an fMRI task. Our findings reveal condition-specific, dynamically occurring patterns of co-activation (PPI-CAPs). During the vocal condition, the auditory cortex co-activates with the sensorimotor and salience networks, while during the instrumental condition, it co-activates with the visual cortex and the superior frontal cortex. Our results show that the vocal stimulus elicits sensorimotor aspects of the auditory perception and is processed as a more salient stimulus while the instrumental condition activated higher-order cognitive and visuo-spatial networks. Common neural signatures for both auditory stimuli were found in the precuneus and posterior cingulate gyrus. Finally, this study adds knowledge on the dynamic brain connectivity underlying the newborns capability of early and specialized auditory processing, highlighting the relevance of dynamic approaches to study brain function in newborn populations.

A two-million-year-long hydroclimatic context for hominin evolution in southeastern Africa.

The past two million years of eastern African climate variability is currently poorly constrained, despite interest in understanding its assumed role in early human evolution1-4. Rare palaeoclimate records from northeastern Africa suggest progressively drier conditions2,5 or a stable hydroclimate6. By contrast, records from Lake Malawi in tropical southeastern Africa reveal a trend of a progressively wetter climate over the past 1.3 million years7,8. The climatic forcings that controlled these past hydrological changes are also a matter of debate. Some studies suggest a dominant local insolation forcing on hydrological changes9-11, whereas others infer a potential influence of sea surface temperature changes in the Indian Ocean8,12,13. Here we show that the hydroclimate in southeastern Africa (20-25° S) is controlled by interplay between low-latitude insolation forcing (precession and eccentricity) and changes in ice volume at high latitudes. Our results are based on a multiple-proxy reconstruction of hydrological changes in the Limpopo River catchment, combined with a reconstruction of sea surface temperature in the southwestern Indian Ocean for the past 2.14 million years. We find a long-term aridification in the Limpopo catchment between around 1 and 0.6 million years ago, opposite to the hydroclimatic evolution suggested by records from Lake Malawi. Our results, together with evidence of wetting at Lake Malawi, imply that the rainbelt contracted toward the Equator in response to increased ice volume at high latitudes. By reducing the extent of woodland or wetlands in terrestrial ecosystems, the observed changes in the hydroclimate of southeastern Africa-both in terms of its long-term state and marked precessional variability-could have had a role in the evolution of early hominins, particularly in the extinction of Paranthropus robustus.

Effect of dolutegravir-based versus efavirenz-based antiretroviral therapy on excessive weight gain in adult treatment-naïve HIV patients at Matsanjeni health center, Eswatini: a retrospective cohort study.

BACKGROUND: There is limited data on dolutegravir (DTG)-associated weight gain from settings with a dual burden of HIV and overnutrition. METHODS: In Eswatini (at Matsanjeni), among 156 and 160 adult patients on DTG-based and EFV-based antiretroviral therapy (ART), respectively, we studied excessive weight gain (BMI at 24 months ART greater than baseline and ≥25 kg/m2). RESULTS: The median BMI increase in DTG-based patients was 1.09 (IQR:-0.28,3.28) kg/m2 compared to 0.20 (IQR:-0.85,2.18) kg/m2 in EFV-based patients (p value = 0.001). DTG-based ART predicted excessive weight gain (aOR 2.61;95% CI:1.39-4.93). CONCLUSION: Practitioners should consider DTG-based regimens as one of the risk factors for overweight/obesity.

MRI of brachial plexus using diffusion tensor imaging: a pilot study for the use of resolve sequence surgical and radiologic anatomy.

BACKGROUND: Clinical exam is the goldstandard for surgical indication. ENMG and conventional MRI are insufficient to understand the highly variable clinical presentation of brachial plexus (BP) lesions. DTI is based on motion of water molecules and can explore nerve function. PURPOSE: This pilot study of healthy subjects aimed to develop RESOLVE sequence for BP exploration using diffusion MRI. The main objective was to provide complete precise information from DTI cartography associated with anatomical data. METHODS: Six healthy volunteers were scanned using 3T PRISMA scanner with anatomic 3D STIR SPACE and RESOLVE diffusion sequences. Diffusion parametric maps of fractional anisotropy (FA) were extracted from RESOLVE acquisitions. A reproducible method for roots volumes and angles measurements was created using 3DSlicer. ROI were segmented on Mean B0 sequences. FA measurements were obtained with ROI on Mean B0 sequences. RESULTS: RESOLVE sequence was adapted to the BP. Mean FA was 0.30. Angles measurements on 3D STIR SPACE sequences showed increasing values from proximal to distal roots with an 0.6 ICC. Volume measurements on anatomic sequences varied widely from one root to another but did not show any significant difference on laterality. CONCLUSIONS: A new and reproducible method for BP exploration was developed, using MRI RESOLVE DTI sequences. Complete mapping was obtained but a low resolution of track density imaging did not allow to exploit distal nerves. Deterministic tractography principal limit was the lack of resolution. Extraction of diffusion, volumetric and angular parameters of the plexus roots, and scripts creation for image processing was adapted to the healthy BP.

Unusual presentation of Ramsay-Hunt Syndrome in kidney transplant patient.

Herpes Zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) in craniospinal sensory neurons and is characterized by a painful erythematous rash in the affected dermatome. Although kidney transplant recipients who are chronically maintained on immunosuppressive regimens are considered at risk, there are only a few cases described. We report a well-documented case of a 50-year-old male kidney transplant recipient who presented Ramsay-Hunt syndrome with atypical neurological finds.

Extreme spatial heterogeneity in carbonate accretion potential on a Caribbean fringing reef linked to local human disturbance gradients.

The capacity of coral reefs to maintain their structurally complex frameworks and to retain the potential for vertical accretion is vitally important to the persistence of their ecological functioning and the ecosystem services they sustain. However, datasets to support detailed along-coast assessments of framework production rates and accretion potential do not presently exist. Here, we estimate, based on gross bioaccretion and bioerosion measures, the carbonate budgets and resultant estimated accretion rates (EAR) of the shallow reef zone of leeward Bonaire - between 5 and 12 m depth - at unique fine spatial resolution along this coast (115 sites). Whilst the fringing reef of Bonaire is often reported to be in a better ecological condition than most sites throughout the wider Caribbean region, our data show that the carbonate budgets of the reefs and derived EAR varied considerably across this ~58 km long fringing reef complex. Some areas, in particular the marine reserves, were indeed still dominated by structurally complex coral communities with high net carbonate production (>10 kg CaCO3  m-2  year-1 ), high live coral cover and complex structural topography. The majority of the studied sites, however, were defined by relatively low budget states (<2 kg CaCO3  m-2  year-1 ) or were in a state of net erosion. These data highlight the marked spatial heterogeneity that can occur in budget states, and thus in reef accretion potential, even between quite closely spaced areas of individual reef complexes. This heterogeneity is linked strongly to the degree of localized land-based impacts along the coast, and resultant differences in the abundance of reef framework building coral species. The major impact of this variability is that those sections of reef defined by low-accretion rates will have limited capacity to maintain their structural integrity and to keep pace with current projections of climate change induced sea-level rise (SLR), thus posing a threat to reef functioning and biodiversity, potentially leading to trophic cascades. Since many Caribbean reefs are more severely degraded than those found around Bonaire, it is to be expected that the findings presented here are rather the rule than the exception, but the study also highlights the need for similar high spatial resolution (along-coast) assessments of budget states and accretion rates to meaningfully explore increasing coastal risk at the country level. The findings also more generally underline the significance of reducing local anthropogenic disturbance and restoring framework building coral assemblages. Appropriately focussed local preservation efforts may aid in averting future large-scale above reef water depth increases on Caribbean coral reefs and will limit the social and economic implications associated with the loss of reef goods and services.

Reproducibility of R2 * and quantitative susceptibility mapping (QSM) reconstruction methods in the basal ganglia of healthy subjects.

The basal ganglia are key structures for motor, cognitive and behavioral functions. They undergo several changes with aging and disease, such as Parkinson's or Huntington's disease, for example. Iron accumulation in basal ganglia is often related to these diseases, which is conventionally monitored by the transverse relaxation rate (R2 *). Quantitative susceptibility mapping (QSM) is a novel contrast mechanism in MRI produced by adding information taken from the phase of the MR signal to its magnitude. It has been shown to be more sensitive to subtle changes in Parkinson's disease. In order to be applied widely to various pathologies, its reproducibility must be evaluated in order to assess intra-subject variability and to disseminate into clinical and pharmaceutical studies. In this work, we studied the reproducibility and sensitivity of several QSM techniques. Fourteen subjects were scanned four times, and QSM and R2 * images were reconstructed and registered. An atlas of the basal ganglia was used to automatically define regions of interest. We found that QSM measurements are indeed reproducible in the basal ganglia of healthy subjects and can be widely used as a replacement for R2 * mapping in iron-rich regions. This reproducibility study could lead to several lines of research in relaxometry and susceptibility measurements, in vivo iron load evaluation as well as pharmacological assessment and biomarker development. Copyright © 2016 John Wiley & Sons, Ltd.

N-Acylethanolamine-hydrolyzing acid amidase inhibition increases colon N-palmitoylethanolamine levels and counteracts murine colitis.

N-Palmitoylethanolamine or palmitoylethanolamide (PEA) is an anti-inflammatory compound that was recently shown to exert peroxisome proliferator-activated receptor-α-dependent beneficial effects on colon inflammation. The actions of PEA are terminated following hydrolysis by 2 enzymes: fatty acid amide hydrolase (FAAH), and the less-studied N-acylethanolamine-hydrolyzing acid amidase (NAAA). This study aims to investigate the effects of inhibiting the enzymes responsible for PEA hydrolysis in colon inflammation in order to propose a potential therapeutic target for inflammatory bowel diseases (IBDs). Two murine models of IBD were used to assess the effects of NAAA inhibition, FAAH inhibition, and PEA on macroscopic signs of colon inflammation, macrophage/neutrophil infiltration, and the expression of proinflammatory mediators in the colon, as well as on the colitis-related systemic inflammation. NAAA inhibition increases PEA levels in the colon and reduces colon inflammation and systemic inflammation, similarly to PEA. FAAH inhibition, however, does not increase PEA levels in the colon and does not affect the macroscopic signs of colon inflammation or immune cell infiltration. This is the first report of an anti-inflammatory effect of a systemically administered NAAA inhibitor. Because NAAA is the enzyme responsible for the control of PEA levels in the colon, we put forth this enzyme as a potential therapeutic target in chronic inflammation in general and IBD in particular.

Feasibility and acceptability of injectable artesunate for the treatment of severe malaria in the Democratic Republic of Congo.

BACKGROUND: The Democratic Republic of the Congo (DRC) changed its national policy for the treatment of severe malaria in both children and adults in 2012 from intravenous quinine to injectable artesunate. The country is now planning to deploy nationwide injectable artesunate as the preferred treatment for the management of severe malaria. To support this process, the feasibility and acceptability of the use of injectable artesunate in the context of the DRC was assessed, from the perspective of both health care providers and patients/caretakers. METHODS: Questionnaires and observations were used to collect information from health care providers and patients/caretakers in eight health facilities in the Province of Kinshasa and in the Province of Bas-Congo. RESULTS: A total of 31 health care providers and 134 patients/care takers were interviewed. Seventy five percent (75%) of health care providers found it less difficult to prepare injectable artesunate compared to quinine. None of them encountered problems during preparation and administration of injectable artesunate. The large majority of care providers (93%) and patients/caretakers (93%) answered that injectable artesunate took less time than quinine to cure the symptoms of the patients. 26 (84%) health care providers reported that the personnel workload had diminished with the use of injectable artesunate. 7 (22.6%) health workers reported adverse drug reactions, of which a decrease in the haemoglobin rate was the most common (71.4%). All care providers and the vast majority of patients/caretakers (96%, N = 128) were either satisfied or very satisfied with injectable artesunate. CONCLUSIONS: These findings show that the use of injectable artesunate for the treatment of severe malaria is feasible and acceptable in the context of DRC, with appropriate training of care providers. Both care providers and patients/caretakers perceived injectable artesunate to be effective and safe, thus promoting acceptability.

Identifying risk factors for Plasmodium infection and anaemia in Kinshasa, Democratic Republic of Congo.

BACKGROUND: There is little data on the risk factors for malaria infection in large cities in central Africa and in all age groups. There may be different associations with the risk factors for areas with different malaria transmission intensities such as the effect of fever or age. This study aimed at identifying risk factors associated with Plasmodium infection and anaemia among children 6-59 months and individuals aged older than 5 years in Kinshasa, a large city with heterogeneity in malaria prevalence. METHODS: This study analysed data from 3342 children aged 6-59 months from 25 non-rural health zones (HZs) and for 816 individuals aged older than 5 years from two HZs in Kinshasa (non-rural), collected during a cross sectional malaria survey in 2011. Logistic regression with random effects was used to investigate predictors for malaria and anaemia. Differences in risk factors in areas with a prevalence of less than 10 and 10 % or greater were investigated. RESULTS: There was evidence of a different age-pattern in the two transmission settings. For children under 5 years, the highest prevalence of malaria was observed in the 48-59 months group in both transmission settings, but it increased more gently for the lower transmission HZs (p = 0.009). In a separate analysis in children over 5 years in two selected HZs, the peak prevalence was in 5-9 years old in the higher transmission setting and in 15-19 years old in the lower transmission setting. Reported fever was associated with malaria in both transmission strata, with no evidence of a difference in these associations (p = 0.71); however in children older than 5 years there was a significant interaction with a stronger association in the low transmission HZ. Insecticide-treated net (ITN) use was associated with a lower risk of malaria infection in children 6-59 months in the high transmission HZs. Similar estimates were found in children over 5 years and the lower transmission HZ but the associations there were not significant. There was no evidence of a difference in these associations by strata. The risk of anaemia decreased with increasing age in all strata, whereas it increased with malaria infection and reported fever. ITN use did not show evidence of protection against anaemia. Low socio-economic status was associated with malaria in high transmission setting in children 6-59 months and anaemia in low transmission setting. CONCLUSIONS: This study shows that in areas of low transmission in Kinshasa, the peak prevalence occurs in older age groups however ITN use was highest in children under 5 years. Targeted distribution of ITN to all age groups should be continued. For most risk factors, there was no evidence of an interaction with transmission intensity however the associations with age and with fever in the last 2 weeks did vary significantly.

Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6.

Proinflammatory macrophages are key mediators in several pathologies; thus, controlling their activation is necessary. The endocannabinoid system is implicated in various inflammatory processes. Here we show that in macrophages, the newly characterized enzyme α/ß-hydrolase domain 6 (ABHD6) controls 2-arachidonoylglycerol (2-AG) levels and thus its pharmacological effects. Furthermore, we characterize a unique pathway mediating the effects of 2-AG through its oxygenation by cyclooxygenase-2 to give rise to the anti-inflammatory prostaglandin D2-glycerol ester (PGD2-G). Pharmacological blockade of cyclooxygenase-2 or of prostaglandin D synthase prevented the effects of increasing 2-AG levels by ABHD6 inhibition in vitro, as well as the 2-AG-induced increase in PGD2-G levels. Together, our data demonstrate the physiological relevance of the interaction between the endocannabinoid and prostanoid systems. Moreover, we show that ABHD6 inhibition in vivo allows for fine-tuning of 2-AG levels in mice, therefore reducing lipopolysaccharide-induced inflammation, without the characteristic central side effects of strong increases in 2-AG levels obtained following monoacylglycerol lipase inhibition. In addition, administration of PGD2-G reduces lipopolysaccharide-induced inflammation in mice, thus confirming the biological relevance of this 2-AG metabolite. This points to ABHD6 as an interesting therapeutic target that should be relevant in treating inflammation-related conditions, and proposes PGD2-G as a bioactive lipid with potential anti-inflammatory properties in vivo.

Carbon footprints of various subtotal tonsillectomy techniques.

OBJECTIVES: The aim of the present study was to assess greenhouse gas emissions for the main current subtotal tonsillectomy techniques. MATERIALS AND METHODS: A retrospective study was conducted in 2 French university hospital pediatric ENT departments in 2022. The target techniques were radiofrequency with single-use or reusable needle, coblation, and dissection by cold instruments or by bipolar forceps. The medical devices required by each technique were listed and respective greenhouse gas emissions (carbon footprint, in kg eCO2) were calculated, according to weight, energy consumption and place of production. RESULTS: Coblation generated a carbon footprint of 8.6kg eCO2, versus 0.1-0.2kg eCO2 for the other techniques. CONCLUSION: Greenhouse gas emissions in subtotal tonsillectomy differ greatly according to technique. Bipolar dissection and radiofrequency have a smaller footprint than coblation. This type of data, which needs to be weighed over time according to medical benefit, should be systematically taken into account in choosing hardware for surgery.

[Tracheobronchial involvement in relapsing polychondritis and differential diagnoses]. / Atteinte trachéo-bronchique de la polychondrite atrophiante et diagnostics différentiels.

Relapsing polychondritis is a systemic auto-immune disease that mainly affects cartilage structures, progressing through inflammatory flare-ups between phases of remission and ultimately leading to deformation of the cartilages involved. In addition to characteristic damage of auricular or nasal cartilage, tracheobronchial and cardiac involvement are particularly severe, and can seriously alter the prognosis. Tracheobronchial lesions are assessed by means of a multimodal approach, including dynamic thoracic imaging, measurement of pulmonary function (with recent emphasis on pulse oscillometry), and mapping of tracheal lesions through flexible bronchoscopy. Diagnosis can be difficult in the absence of specific diagnostic tools, especially as there may exist a large number of differential diagnoses, particularly as regards inflammatory diseases. The prognosis has improved, due largely to upgraded interventional bronchoscopy techniques and the development of immunosuppressant drugs and targeted therapies, offering patients a number of treatment options.

Sarcoidosis and Emergency Hospitalization.

BACKGROUND: Sarcoidosis is an idiopathic systemic granulomatosis whose evolution is self-limiting in most cases. However, it can progress to organ damage that menaces the vital or functional prognosis of patients. Sarcoidosis itself, but also its comorbidities, can pose a threat to the patient, require rapid initiation of treatment, and justify emergency hospitalization. RESEARCH QUESTION: What are the reasons and prognosis of patients with sarcoidosis hospitalized in emergency? STUDY DESIGN AND METHODS: The objectives of our study were to describe the causes of admission, and to identify predictors of mortality in patients with sarcoidosis hospitalized in emergency. This is a retrospective monocentric study. We included patients hospitalized after a stay in the ED or ICU, or requiring an unscheduled hospitalization after telephone advice or a consultation, between January 1, 2017 and July 7, 2020. RESULTS: We identified 154 patients with sarcoidosis hospitalized in emergency, among which 14 (9%) required the ICU. There were 81 men, with a median age of 55.0 years (interquartile range, 44.0-67.0). Sarcoidosis was inaugural in 20 patients (14%). The primary reason for hospitalization was lower respiratory infections in 32 patients (21%), followed by acute pulmonary exacerbation of sarcoidosis in 17 (11%), suspected cardiac sarcoidosis in 13 (8.4%), and neurosarcoidosis in 12 (7.7%). The median length of stay was 6 days (interquartile range, 3.00-10.0). In-hospital mortality rate was 3.9%. The 2-year transplantation-free survival after hospitalization was 86.8% (95% CI, 81.4-92.5). The factors associated with a worse transplantation-free survival were Charlson Comorbidity Index (hazard ratio [HR], 1.29; 95% CI, 1.04-1.61; P = .021), pulmonary hypertension (HR, 2.53; 95% CI, 1.10-5.83; P = .029), and oxygen therapy during hospitalization (HR, 4.18; 95% CI, 1.55-11.29; P = .005). INTERPRETATION: The overall mortality of patients with sarcoidosis hospitalized in emergency is high. The presence of comorbidities and the severity of respiratory failure, as reflected by oxygen requirement, are important prognostic determinants.

3-Carboxamido-5-aryl-isoxazoles as new CB2 agonists for the treatment of colitis.

Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5-aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model.

Low-cost air quality portable sensors and their potential use in respiratory health.

Air pollution is an environmental risk for the general population and for patients with various diseases, particularly respiratory diseases. Little data are available on personal exposure, but the recent emergence of low-cost air quality sensors (LCSs) should enable a better understanding of the health impacts of air pollution at the individual level. However, the reliability and accuracy of most sensors in the market have not been established, and a thorough understanding of their strengths and limitations is needed. We therefore conducted a review to address the following questions: 1) What is an LCS and what is the extent of its possible application? 2) Is the data obtained a reliable indicator of exposure? 3) What are the advantages and disadvantages of LCSs? 4) Could LCSs be useful in investigating the impact of air pollution on respiratory health? Further studies are needed to promote the use of LCS in research settings and among respiratory patients. This will allow us to monitor exposure levels, provide alerts and study the respiratory effects of individual-level air pollution.

The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action.

BACKGROUND: The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated. METHODS: We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments. RESULTS: The N-arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol and N- palmitoylethanolamine (PEA) reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH) inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor. CONCLUSIONS: This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors. This may contribute to the improvement of long-term palliation or cure of melanoma.

Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions for which new therapeutic approaches are needed. Genetic and pharmacological data point to a protective role of CB(1) and CB(2) cannabinoid receptor activation in IBD experimental models. Therefore, increasing the endogenous levels of 2-arachidonoylglycerol, the main full agonist of these receptors, should have beneficial effects on colitis. 2-Arachidonoylglycerol levels were raised in the trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model by inhibiting monoacylglycerol lipase (MAGL), the primary enzyme responsible for hydrolysis of 2-arachidonoylglycerol, using the selective inhibitor JZL184. MAGL inhibition in diseased mice increased 2-arachidonoylglycerol levels, leading to a reduction of macroscopic and histological colon alterations, as well as of colonic expression of proinflammatory cytokines. The restored integrity of the intestinal barrier function after MAGL inhibition resulted in reduced endotoxemia as well as reduced peripheral and brain inflammation. Coadministration of either CB(1) (SR141716A) or CB(2) (AM630) selective antagonists with JZL184 completely abolished the protective effect of MAGL inhibition on TNBS-induced colon alterations, thus demonstrating the involvement of both cannabinoid receptors. In conclusion, increasing 2-arachidonoylglycerol levels resulted in a dramatic reduction of colitis and of the related systemic and central inflammation. This could offer a novel pharmacological approach for the treatment of IBD based on the new protective role of 2-arachidonoylglycerol described here.

Development and characterization of endocannabinoid hydrolases FAAH and MAGL inhibitors bearing a benzotriazol-1-yl carboxamide scaffold.

A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl)methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compound 29 (ML30) exhibited an IC(50) value of 0.54 nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC(50)<10 nM). In the phenylpiperazinyl series, compounds 37, 38, 42, and 43 displayed IC(50) values against MAGL in the nanomolar range, whilst being between one and two orders of magnitude less potent on the FAAH, while compounds 31 and 32 were potent FAAH inhibitors (IC(50)<20 nM) and over 12-fold selective versus MAGL. The key structural determinants driving the structure-activity relationships were explored by the minimization of the inhibitors inside the active site of both enzymes.

Lipid transport function is the main target of oral oleoylethanolamide to reduce adiposity in high-fat-fed mice.

We evaluated the biological basis of reduced fat gain by oleoylethanolamide (OEA) in high-fat-fed mice and sought to determine how degradation of OEA affected its efficiency by comparing its effects to those of KDS-5104, a nonhydrolyzable lipid OEA analog. Mice were given OEA or KDS-5104 by the oral route (100 mg/kg body weight). Sixty-eight variables per mouse, describing six biological processes (lipid transport, lipogenesis, energy intake, energy expenditure, endocannabinoid signaling, and glucose metabolism), spanning gene expression of biochemical and physiological parameters were examined to determine the primary target whereby OEA reduces fat gain. Although KDS-5104 but not OEA was resistant to fatty acid amide hydrolase hydrolysis, OEA was degraded by an unidentified hydrolysis system in the liver. Nevertheless, both compounds equally decreased body fat pads after 5 weeks (20%; P < 0.05). The six biological functions constructed from the 68 initial variables predicted up to 58% of adipose fat variations. Lipid transport appeared central to the explanation for body fat deposition (16%; P < 0.0001), in which decreased expression of the FAT/CD36 gene was the component most related to adipose depots. Lipid transport appears to be a determinant player in the OEA fat-lowering response, with adipose tissue FAT/CD36 expression being the most relevant bioindicator of OEA action.