Lipoprotein profile assessed by 1H NMR, BMI and blood pressure are associated with vascular alterations in children with familial hypercholesterolaemia.

BACKGROUND AND AIMS: Children with familial hypercholesterolaemia (FH) have elevated low-density lipoprotein cholesterol (LDL-C) concentrations since birth, which increases the risk of cardiovascular disease in adulthood. Arterial injury and stiffness parameters, including carotid intima media thickness (cIMT), pulse wave velocity (PWV) and distensibility (DIST), can be detected early in childhood. We studied the associations between cIMT, PWV and DIST with the lipoprotein profile assessed by proton nuclear magnetic resonance (1H NMR) and with influential variables such as blood pressure (BP) or body mass index (BMI) in children with FH. METHODS AND RESULTS: In this cross-sectional study, we included 201 children (96 with FH and 105 non-FH controls). Clinical history, physical examination and standard biochemical studies were performed. FH genetic testing was performed when clinically indicated. Carotid ultrasonography and an advanced lipoprotein profile by 1H NMR were performed. Multivariate and classification methods were used. There were no differences between cIMT, PWV and DIST between FH and non-FH children. FH children presented more total LDL and large, medium and small particles. Small LDL particles, BMI and systolic BP determined the presence of pathological IMT in the FH group. LDL size, high-density lipoproteins and very low-density lipoprotein particles together with blood pressure determined the presence of pathological arterial wall elasticity. CONCLUSIONS: Alterations in lipoprotein parameters assessed by are associated with early structural and functional arterial characteristics in children with FH. BMI and BP act as boosting factors. Cardiovascular prevention should start early in children with FH, encompassing all components of a healthy lifestyle.

The endocannabinoid 2-AG enhances spontaneous remyelination by targeting microglia.

Remyelination is an endogenous process by which functional recovery of damaged neurons is achieved by reinstating the myelin sheath around axons. Remyelination has been documented in multiple sclerosis (MS) lesions and experimental models, although it is often incomplete or fails to affect the integrity of the axon, thereby leading to progressive disability. Microglia play a crucial role in the clearance of the myelin debris produced by demyelination and in inflammation-dependent OPC activation, two processes necessary for remyelination to occur. We show here that following corpus callosum demyelination in the TMEV-IDD viral murine model of MS, there is spontaneous and partial remyelination that involves a temporal discordance between OPC mobilization and microglia activation. Pharmacological treatment with the endocannabinoid 2-AG enhances the clearance of myelin debris by microglia and OPC differentiation, resulting in complete remyelination and a thickening of the myelin sheath. These results highlight the importance of targeting microglia during the repair processes in order to enhance remyelination.

Endocannabinoids drive the acquisition of an alternative phenotype in microglia.

The ability of microglia to acquire diverse states of activation, or phenotypes, reflects different features that are determinant for their contribution to homeostasis in the adult CNS, and their activity in neuroinflammation, repair or immunomodulation. Despite the widely reported immunomodulatory effects of cannabinoids in both the peripheral immune system and the CNS, less is known about how the endocannabinoid signaling system (eCBSS) influence the microglial phenotype. The general aim of the present study was to investigate the role of endocannabinoids in microglia polarization by using microglia cell cultures. We show that alternative microglia (M2a) and acquired deactivated microglia (M2c) exhibit changes in the eCB machinery that favor the selective synthesis of 2-AG and AEA, respectively. Once released, these eCBs might be able to act through CB1 and/or CB2 receptors in order to influence the acquisition of an M2 phenotype. We present three lines of evidence that the eCBSS is critical for the acquisition of the M2 phenotype: (i) M2 polarization occurs on exposure to the two main endocannabinoids 2-AG and AEA in microglia cultures; (ii) cannabinoid receptor antagonists block M2 polarization; and (iii) M2 polarization is dampened in microglia from CB2 receptor knockout mice. Taken together, these results indicate the interest of eCBSS for the regulation of microglial activation in normal and pathological conditions.

Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors.

Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1ß, as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2A receptors participate in some of the anti-inflammatory effects of CBD, as the A2A antagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component.

A multicenter study of sensitization profiles in an allergic pediatric population in an area with high allergen exposure.

BACKGROUND AND OBJECTIVE: In areas with a high number of allergens and high allergen concentrations, it is essential to identify the main causes of allergy, especially in pediatric patients. This study was conducted in allergic patients aged 14 or less to identify sensitization profiles during an initial phase, and to then evaluate changes in these profiles after 3 years of follow-up. This article describes the first phase of our investigation. METHODS: A total of 187 patients aged between 2 and 14 years were included by 5 allergy units; all the children had symptoms suggestive of allergic disease (rhinoconjunctivitis andlor asthma). Allergy diagnosis was confirmed by evaluation of clinical history, allergen exposure, and in vivo or in vitro tests. Specific immunoglobulin E (slgE) to major allergens was tested. RESULTS: Patients were sensitized to both seasonal (especially grass, olive, cypress and Cynodon dactylon) and perennial allergens (Alternaria alternata) and to panallergens (especially profilin and lipid transfer protein). Almost 60% of the patients included were polysensitized. Sensitization to certain major allergens such as Cup s1, Phl p1, or Sal k1 seems to increase with age. Patients sensitized to profilin had a higher number of sensitizations than non-profilin-sensitized patients. This panallergen is a diagnostic confounding factor. CONCLUSIONS: A high percentage of allergic pediatric patients living in an area with high exposure levels to a large number of allergens are polysensitized and have a high percentage of sensitization to panallergens. The implementation of new diagnostic tools such as component-resolved diagnosis is crucial.

Gut microbiota is associated with metabolic health in children with obesity.

BACKGROUND AND AIMS: We aimed to describe and characterize the gut microbiota composition and diversity in children with obesity according to their metabolic health status. METHODS: Anthropometry, Triglycerides, HDL cholesterol, HOMA-IR, and systolic and diastolic blood pressure (SBP, DBP) were evaluated (and z-score calculated) and faecal samples were collected from 191 children with obesity aged from 8 to 14. All children were classified depending on their cardiometabolic status in either a "metabolically healthy" (MHO; n = 106) or "metabolically unhealthy" (MUO; n = 85) group. Differences in gut microbiota taxonomies and diversity between groups (MUO vs MHO) were analysed. Alpha diversity index was calculated as Chao1 and Simpson's index, and ß-diversity was calculated as Adonis Bray-Curtis index. Spearman's correlations and logistic regressions were performed to study the association between cardiometabolic health and the microbiota. RESULTS: Children in the MUO presented significantly lower alpha diversity and richness than those in the MHO group (Chao1 index p = 0.021, Simpson's index p = 0.045, respectively), whereas microbiota ß-diversity did not differ by the cardiometabolic health status (Adonis Bray-Curtis, R2 = 0.006; p = 0.155). The MUO group was characterized by lower relative abundances of the genera Christensenellaceae R7 group (MHO:1.42% [0.21-2.94]; MUO:0.47% [0.02-1.60], p < 0.004), and Akkermansia (MHO:0.26% [0.01-2.19]; MUO:0.01% [0.00-0.36], p < 0.001) and higher relative abundances of Bacteroides (MHO:10.6% [4.64-18.5]; MUO:17.0% [7.18-27.4], p = 0.012) genus. After the adjustment by sex, age, and BMI, higher Akkermansia (OR: 0.86, CI: 0.75-0.97; p = 0.033), Christensenellaceae R7 group (OR: 0.86, 95% CI: 075-0.98; p = 0.031) and Chao1 index (OR: 0.86, CI: 0.96-1.00; p = 0.023) represented a lower risk of the presence of one or more altered cardiovascular risk factors. CONCLUSION: Lower proportions of Christensenellaceae and Akkermansia and lower diversity and richness seem to be indicators of a metabolic unhealthy status in children with obesity.

Synchronous enteroid adenocarcinoma at the ureteral implantation site after ureterosigmoidostomy.

Ureterosigmoidostomy is considered to be the oldest urinary diversion technique performed for the first time in the 19th Century in patients with urinary malformations. However, the high rate of complications as well as the significant risk of developing tumors in the colonic portion of the ureteral anastomosis have given rise to other new intestinal urinary diversion techniques. We present the case of a patient with two synchronous enteroid adenocarcinomas, with a latency period of 66 years, at the site of both ureterocolonic anastomoses after ureterosigmoidostomy performed during childhood owing to bladder exstrophy.

[Cutaneous toxicity associated with cetuximab treatment in metastatic colorectal cancer]. / Toxicidad cutánea asociada a cetuximab en cáncer colorrectal metastásico.

OBJECTIVE: To evaluate the impact and type of side-effects in patients treated with cetuximab and provide a description of the general measures and treatment. METHODS: Retrospective safety study. We included all patients that received cetuximab from January to December 2009. All information was obtained from the Pharmacy and Oncology Department's Access databases and reviewed the patient's medical history. All data was registered in an Excel workbook. Skin toxicity was graded by the current National Cancer Institute-Common Toxicity Criteria (NCI-CTC). RESULTS: During the study period 43 patients received treatment with cetuximab. Acneiform eruption was present in 30 of the cases (69.8%): 14 patients with grade 1 (48.3%), 13 with grade 2 (44.8%) and 3 with grade 3 (10.3%). These adverse effects appeared in a median of seven (4-28) days. In a median of 40 (20-56) days, ten patients (23.3%) presented xerosis, and three (7%) suffered painful fissures in hands and feet after a median of 28 (21-35) days. Paronychia was present in two patients after a median of 42 (35-49) days. Finally, an alteration in hair growth was observed in two patients with overgrowth of facial hair and one patient with overgrowth of the eyelashes. Five patients presented important conjunctivitis. Three infusion reactions occurred. A grade-based treatment algorithm was used for all patients that presented cutaneous toxicity. CONCLUSIONS: A considerable number of patients treated with cetuximab develop dermatological side-effects which left untreated could represent a threat to the efficacy of the therapy. Therefore effective management is mandatory, patient education and immediate treatment based on a grade-based algorithm to alleviate symptoms is necessary, so that patient compliance is guaranteed.

Cluster immunotherapy with a glutaraldehyde-modified mixture of grasses results in an improvement in specific nasal provocation tests in less than 2.5 months of treatment.

BACKGROUND: Cluster immunotherapy is becoming increasingly used. It allows for a rapid build up phase and the administration of higher doses of allergen in a shorter period of time. OBJECTIVES: To evaluate the effect of short-term pre-seasonal immunotherapy using a glutaraldeyde-modified allergen vaccine in reducing specific nasal hyperreactivity in nasal challenge tests. MATERIALS AND METHODS: Thirty-three patients were selected. All patients had a positive history of allergic rhinitis and skin tests to grass pollen, although most of them (72.7%) were sensitized to other allergens as well. The study was conducted outside of the pollen season and the patients did not receive any pharmacological treatment during this period of time. Two randomized groups of patients were established; Group A: 22 patients (13 females and nine males) and Group B, 11 control patients (seven females and four males). Patients in Group A received immunotherapy with a vaccine containing 50% of the wild grasses Trisetum paniceum and Dactylis glomerata. All patients underwent titrated nasal provocation tests (NPT) before and after completion of the study (2.3 and 2.8 months for Groups A and B, respectively). The administration schedule consisted of 0.1 and 0.2 mL at day 1, followed by 0.3 and 0.5 mL at day 7, 0.5 mL after 2 weeks followed by 0.5 mL monthly. A single vial was used containing an allergen concentration of 10 000 TU/mL (105 microg of total protein and 24.6 microg of Group 1 plus 5 allergens/mL). A mean of 6.5 injections were administered to Group A patients between NPTs. RESULTS: There were no significant differences between both groups at the beginning of the study (P=0.48). At the end, only Group A patients needed significant greater threshold concentrations for a positive NPT than at the beginning (P=0.002). CONCLUSIONS: A short-term cluster pre-seasonal inmunotherapy with a modified vaccine containing a mixture of grass pollen is effective as determined by an objective measure after only a mean 2.3 months of treatment.

Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis.

The gut microbiota plays a fundamental role on the education and function of the host immune system. Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases and metabolic disorders frequently associated with inflammatory processes therefore is critical to explore novel mechanisms involved in maintaining the immune system homeostasis. The cannabinoid system and related bioactive lipids participate in multiple central and peripheral physiological processes that affect metabolic, gastrointestinal and neuroimmune regulatory mechanisms displaying a modulatory role and contributing to the maintenance of the organism's homeostasis. In this review, we gather the knowledge on the gut microbiota-endocannabinoids interactions and their impact on autoimmune disorders such as inflammatory bowel disease, rheumatoid arthritis and particularly, multiple sclerosis (MS) as the best example of a CNS autoimmune disorder. Furthermore, we contribute to this field with new data on changes in many elements of the cannabinoid system in a viral model of MS after gut microbiota manipulation by both antibiotics and probiotics. Finally, we highlight new therapeutic opportunities, under an integrative view, targeting the eCBS and the commensal microbiota in the context of neuroinflammation and MS.

Factors associated with implementation of the 5A's smoking cessation model.

BACKGROUND: Several health organizations have adopted the 5A's brief intervention model (Ask, Advise, Assess, Assist, Arrange), based on evidence-based guidelines for smoking cessation. We examine individual, cognitive, behavioral, and organizational factors associated with the 5A's performance among clinical healthcare workers in Catalonia. We also investigate how these factors interact and potentially predict the implementation of each component of the 5A's. METHODS: A cross-sectional survey was conducted among clinical health workers enrolled in an online smoking cessation training course (n = 580). The survey included questions about individual characteristics as well as cognitive, behavioral, and organizational factors previously identified in research. We assessed self-reported performance of the 5A's, assessed on a scale from 0 to 10, and used Multivariate regression to examine factors associated with its performance. RESULTS: The performance means (standard deviation) were moderate for the first 3A's [Ask: 6.4 (3.1); Advise: 7.1 (2.7); Assess: 6.3 (2.8)] and low for the last 2A's [Assist: 4.4 (2.9); Arrange: 3.2 (3.3)]. We observed a high correlation between Assist and Arrange (r = 0.704, p < 0.001). Having positive experiences and feeling competent were positively associated with performing the 5A's model and having organizational support with Assist and Arrange. Personal tobacco use among healthcare workers was negatively associated with Advice and Arrange. CONCLUSIONS: Our study found that clinical healthcare workers do not perform the 5A's completely. The main barriers identified suggest the need of training and making available practical guidelines in healthcare services. Organizational support is essential for moving towards the implementation of Assist and Arrange.

Gut dysbiosis and neuroimmune responses to brain infection with Theiler's murine encephalomyelitis virus.

Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4+ and CD8+ T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4+ and CD8+T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice.

Microglia activation states and cannabinoid system: Therapeutic implications.

Microglial cells are recognized as the brain's intrinsic immune cells, mediating actions that range from the protection against harmful conditions that modify CNS homeostasis, to the control of proliferation and differentiation of neurons and their synaptic pruning. To perform these functions, microglia adopts different activation states, the so-called phenotypes that depending on the local environment involve them in neuroinflammation, tissue repair and even the resolution of the inflammatory process. There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity. Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs. The expression of cannabinoid receptors - mainly CB2 - and the production of eCBs have been related to the activation profile of these cells and therefore, the microglial phenotype, emerging as one of the mechanisms by which microglia becomes alternatively activated. Here, we will discuss recent studies that provide new insights into the role of CBs and their endogenous counterparts in defining the profile of microglia activation. These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.

A Sativex(®) -like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.

BACKGROUND AND PURPOSE: Sativex(®) is an oromucosal spray, containing equivalent amounts of Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler's murine encephalomyelitis virus-induced demyelinating disease model of MS. EXPERIMENTAL APPROACH: A Sativex-like combination of phytocannabinoids and each phytocannabinoid alone were administered to mice once they had established MS-like symptoms. Motor activity and the putative targets of these cannabinoids were assessed to evaluate therapeutic efficacy. The accumulation of chondroitin sulfate proteoglycans (CSPGs) and astrogliosis were assessed in the spinal cord and the effect of Sativex on CSPGs production was evaluated in astrocyte cultures. KEY RESULTS: Sativex improved motor activity - reduced CNS infiltrates, microglial activity, axonal damage - and restored myelin morphology. Similarly, we found weaker vascular cell adhesion molecule-1 staining and IL-1ß gene expression but an up-regulation of arginase-1. The astrogliosis and accumulation of CSPGs in the spinal cord in vehicle-infected animals were decreased by Sativex, as was the synthesis and release of CSPGs by astrocytes in culture. We found that CBD-BDS alone alleviated motor deterioration to a similar extent as Sativex, acting through PPARγ receptors whereas Δ(9) -THC-BDS produced weaker effects, acting through CB2 and primarily CB1 receptors. CONCLUSIONS AND IMPLICATIONS: The data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair.

Synthesis and evaluation of fluorine-18 21-fluoroprednisone as a potential ligand for neuro-PET studies.

No-carrier-added fluorine-18-labeled fluoroprednisone ([18F]21-fluoroprednisone) was synthesized by tosylate displacement in 2%-8% radiochemical yield in 80 min end of cyclotron bombardment (EOB), and its metabolism and distribution were investigated. After intravenous administration to rats, [18F]21-fluoroprednisone was rapidly cleared from the blood and biotransformed into [18F]20-dihydro-21-fluoroprednisone. The suitability of [18F]21-fluorocorticoids for receptor imaging in humans with positron emitting tomography will depend on the synthesis of compounds with high binding affinity and low rate of carbonyl reduction at C-20.

New variant Ph translocation in chronic myeloid leukemia: t(Y;22)(p11;q11).

A 4-year-old boy with chronic myeloid leukemia (CML) was shown to have a variant Ph t(Y;22)(p11;q11). To our knowledge, this is the first report of a variant Ph translocation involving Y. Molecular analysis showed that the breakpoint on chromosome 22 is in the breakpoint cluster region (bcr), typical of CML with the classic t(9;22), suggesting that it might be a complex Ph translocation with the involvement of 9q34.

[Coronary ostial stenosis after an aortic valve replacement diagnosed by transesophageal echocardiography]. / Estenosis de ostium coronario tras recambio valvular aórtico diagnosticado mediante ecocardiografía transesofágica.

We submit the case of a 75-year-old man that underwent aortic valve replacement whose preoperative coronary angiography showed lesion-free coronaries. Two months after surgery he began to feel rapidly progressing effort angina pectoris. Transesophageal echocardiography showed prosthetic normal function while allowing the study of the great coronary trunks. We observed the presence of a 50% stenosis at the ostium of the left coronary artery trunk due to the use of selective coronary cannulation to supply cardioplegia solution during valve replacement. A second coronary angiography confirmed this finding. Transesophageal echocardiography may be used as an initial diagnostic method when coronary ostial stenosis is suspected after aortic valve replacement.

Legal consequences of nonunion dispute-resolution systems.

No longer is alternative dispute resolution merely a trendy topic of the conference circuit. For many employers, ADR is now a key aspect of human resources management. A growing number of employers have implemented their own incarnation of alternative dispute resolution; others are actively considering the option; and still others are interested but hesitant for any of a number of reasons. This article explores the legal benefits and drawbacks to implementing internal dispute-resolution systems in the nonunion setting. Special attention is given to the key issue of preclusion--that is, the weight or effect to be given the decision of the internal system in later judicial or administrative proceedings. The article concludes by addressing the question: What is the cost to an employer of chasing the golden goose of preclusion?

Mobilization of progenitors in the subventricular zone to undergo oligodendrogenesis in the Theiler's virus model of multiple sclerosis: implications for remyelination at lesions sites.

Remyelination involves the generation of new myelin sheaths around axons, as occurs spontaneously in many multiple sclerosis (MS) lesions and other demyelinating diseases. When considering repairing a diseased brain, the adult mouse subventricular zone (SVZ) is of particular interest since the stem cells in this area can migrate and differentiate into the three major cell types in the central nervous system (CNS). In Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), we assessed the relative contribution of the SVZ to the remyelination in the corpus callosum at preclinical stages in this MS model. CNPase, MBP and Luxol Fast Blue staining revealed prominent demyelination 35days post-infection (dpi), concomitant with a strong staining in GFAP(+) type B astrocytes in the SVZ and the increased proliferation in this area. The migration of oligodendrocyte progenitors from the SVZ contributed to the remyelination observed at 60 dpi, evident through the number of APC(+)/BrdU(+) mature oligodendrocytes in the corpus callosum of infected animals. These data suggest that the inflammation induced by the Theiler's virus not only provokes strong preclinical demyelination but also, it is correlated with oligodendrocyte generation in the adult SVZ, cells that along with resident progenitor cells contribute to the prompt remyelination observed in the corpus callosum.