Search

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., This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO SAF2013-42784-R, SAF2016 76449-R), and the Red Española de Esclerosis Múltiple (REEM: RD12/0032/0008, RD16/0015/0021) sponsored by the Fondo de Investigación Sanitaria (FIS).

Although aggravated multiple sclerosis (MS) disability has been reported in aged patients, the aging impact on immune cells remodeling within the CNS is not well understood. Here, we investigated the influence of aging on immune cells and the neuroinflammatory and neurodegenerative processes that occur in a well‐established viral model of progressive MS. We found an anomalous presence of CD4+ T, CD8+T, B cells, and cells of myeloid lineage in the CNS of old sham mice whereas a blunted cellular innate and adaptive immune response was observed in Theiler's murine encephalomyelitis virus (TMEV) infected old mice. Microglia and macrophages show opposite CNS viral responses regarding cell counts in the old mice. Furthermore, enhanced expression of Programmed Death‐ligand 1 (PD‐L1) was found in microglia isolated from old TMEV‐infected mice and not in isolated CNS macrophages. Immunocytochemical staining of microglial cells confirms the above differences between young and old mice. Age‐related axonal loss integrity in the mouse spinal cord was found in TMEV mice, but a less marked neurodegenerative process was present in old sham mice compared with young sham mice. TMEV and sham old mice also display alterations in innate and adaptive immunity in the spleen compared to the young mice. Our study supports the need of new or adapted pharmacological strategies for MS elderly patients., A review of CNS immune changes of Theiler's virus‐infected mice at young (12 weeks after infection) and old age (40 weeks after infection). The type of changes in the response to viral infection results of the comparison with the corresponding changes observed in young and old sham mice. The age‐associated immune dysfunction may reduce the ability of the immune system to respond efficiently to the pathological consequences induced by Theiler's murine encephalomyelitis virus during the later chronic phases of the disease.

A growing number of studies support that the bidirectional interactions between the gut microbiota, the immune system and the CNS are relevant for the pathophysiology of MS. Several studies have reported alterations in the gut microbiome of MS patients. In addition, a variety of studies in animal models of MS have suggested that specific members of the gut commensal microbiota can exacerbate or ameliorate neuroinflammation. Probiotics represent oral nontoxic immunomodulatory agents that would exert benefits when using in combination with current MS therapy. Here we investigate the effect of Vivomixx on the gut microbiome and central and peripheral immune responses in a murine model of primary progressive MS. Vivomixx administration was associated with increased abundance of many taxa such as Bacteroidetes, Actinobacteria, Tenericutes and TM7. This was accompanied by a clear improvement of the motor disability of Theiler’s virus infected mice; in the CNS Vivomixx reduced microgliosis, astrogliosis and leukocyte infiltration. Notably, the presence of Breg cells (CD19CD5CD1d) in the CNS was enhanced by Vivomixx, and while spinal cord gene expression of IL-1β and IL-6 was diminished, the probiotic promoted IL-10 gene expression. One of the most significant findings was the increased plasma levels of butyrate and acetate levels in TMEV-mice that received Vivomixx. Peripheral immunological changes were subtle but interestingly, the probiotic restricted IL-17 production by Th17-polarized CD4 T-cells purified from the mesenteric lymph nodes of Theiler’s virus infected mice. Our data reinforce the beneficial effects of oral probiotics that would be coadjuvant treatments to current MS therapies., This work was supported by grants from the Ministerio de Economía y Competitividad [MINECO SAF2016-76449-R] and the Red Española de Esclerosis Múltiple [REEM: RD16/0015/0001; RD16/0015/0004; RD16/015/0021], sponsored by the Fondo de Investigación Sanitaria (FIS)

Gut microbiota dysbiosis has been implicated in MS and other immune diseases, although it remains unclear how manipulating the gut microbiota may affect the disease course. Using a well-established model of progressive MS triggered by intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), we sought to determine whether dysbiosis induced by oral antibiotics (ABX) administered on pre-symptomatic and symptomatic phases of the disease influences its course. We also addressed the effects of microbiota recolonization after ABX withdrawn in the presence or absence of probiotics. Central and peripheral immunity, plasma acetate and butyrate levels, axon damage and motor disability were evaluated. The cocktail of ABX prevented motor dysfunction and limited axon damage in mice, which had fewer CD4+ and CD8+ T cells in the CNS, while gut microbiota recolonization worsened motor function and axonal integrity. The underlying mechanisms of ABX protective effects seem to involve CD4+CD39+ T cells and CD5+CD1d+ B cells into the CNS. In addition, microglia adopted a round amoeboid morphology associated to an anti-inflammatory gene profile in the spinal cord of TMEV mice administered ABX. The immune changes in the spleen and mesenteric lymph nodes were modest, yet ABX treatment of mice limited IL-17 production ex vivo. Collectively, our results provide evidence of the functional relevance of gut microbiota manipulation on the neurodegenerative state and disease severity in a model of progressive MS and reinforce the role of gut microbiota as target for MS treatment., This work was supported by grants from the Ministerio de Economía y Competitividad (MINNECO SAF2016-76449-R) and the Red Española de Esclerosis Múltiple (REEM: RD16/0015/0021), sponsored by the Fondo de Investigación Sanitaria (FIS).

JL was supported by the Nicolás Monardes Program from the Andalusian Health Service (C-0033-2015). This work was supported by a research grant from the Instituto de Salud Carlos III-FEDER (PI18/01947)., Pancreatic cancer is one of the most lethal cancers worldwide due to its symptoms, early metastasis, and chemoresistance. Thus, the mechanisms contributing to pancreatic cancer progression require further exploration. Circadian rhythms are the daily oscillations of multiple biological processes regulated by an endogenous clock. Several evidences suggest that the circadian clock may play an important role in the cell cycle, cell proliferation and apoptosis. In addition, timing of chemotherapy or radiation treatment can influence the efficacy and toxicity treatment. Here, we revisit the studies on circadian clock as an emerging target for therapy in pancreatic cancer. We highlight those potential circadian genes regulators that are commonly affected in pancreatic cancer according to most recent reports., Nicolás Monardes Program from the Andalusian Health Service (C-0033-2015), Instituto de Salud Carlos III-FEDER (PI18/01947)

This paper describes a system for allowing a therapist to record specific motions, as a part of a rehabilitation program, mainly aimed at the elderly people, by using a Natural User Interface based on gestures. Motions are sent to an exoskeleton robot which reproduces them in the patient's lower limbs. The proposed system is an early prototype implemented as a set of interconnected components, which run independently and remotely, under a distributed software architecture. Such prototype has been properly validated through different tests in a controlled environment. The obtained results and a discussion about benefits and drawbacks are also presented, together with preliminary ideas about future research for overcoming such drawbacks and transforming the prototype into a functional system to be tested in a real scenario with real patients.

Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/ Cannabinoid receptor type 2 (PPAR¿/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic, and neurodegenerative diseases. EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2% cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone induced microglial activation, astrogliosis and reduced axonal damage. Our results provide evidence that EHP- 101 showed potent anti-inflammatory activity, prevented demyelination, and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS., This work was supported by grants SAF2017–87701-R (EM), SAF2016–76449-R (GC) from the Ministry of the Economy and Competition (MINECO) co-financed with the European Union FEDER funds. GC was also supported by the Red Española de Esclerosis Múltiple (REEM: RD16/0015/0021) sponsored by the Fondo de Investigación Sanitaria (FIS) (GC). This work was also partially supported by Emerald Health Pharmaceuticals (San Diego, USA).

© The Author(s)., [Background]: The participation of microglia in CNS development and homeostasis indicate that these cells are pivotal for the regeneration that occurs after demyelination. The clearance of myelin debris and the inflammatory-dependent activation of local oligodendrocyte progenitor cells in a demyelinated lesion is dependent on the activation of M2c microglia, which display both phagocytic and healing functions. Emerging interest has been raised about the role of Wnt/β-catenin signaling in oligodendrogenesis and myelination. Besides, cytokines and growth factors released by microglia can control the survival, proliferation, migration, and differentiation of neural stem cells (NSCs), contributing to remyelination through the oligodendrocyte specification of this adult neurogenic niche., [Methods]:TMEV-IDD model was used to study the contribution of dorsal SVZ stem cells to newly born oligodendrocytes in the corpus callosum following demyelination by (i) en-face dorsal SVZ preparations; (ii) immunohistochemistry; and (iii) cellular tracking. By RT-PCR, we analyzed the expression of Wnt proteins in demyelinated and remyelinating corpus callosum. Using in vitro approaches with microglia cultures and embryonic NSCs, we studied the role of purified myelin, Wnt proteins, and polarized microglia-conditioned medium to NSC proliferation and differentiation. One-way ANOVA followed by Bonferroni’s post-hoc test, or a Student’s t test were used to establish statistical significance., [Results]: The demyelination caused by TMEV infection is paralleled by an increase in B1 cells and pinwheels in the dorsal SVZ, resulting in the mobilization of SVZ proliferative progenitors and their differentiation into mature oligodendrocytes. Demyelination decreased the gene expression of Wnt5a and Wnt7a, which was restored during remyelination. In vitro approaches show that Wnt3a enhances NSC proliferation, while Wnt7a and myelin debris promotes oligodendrogenesis from NSCs. As phagocytic M2c microglia secrete Wnt 7a, their conditioned media was found to induce Wnt/β-Catenin signaling in NSCs promoting an oligodendroglial fate., [Conclusions]: We define here the contribution of microglia to Wnt production depending on their activation state, with M1 microglia secreting the Wnt5a protein and M2c microglia secreting Wnt7a. Collectively, our data reveal the role of reparative microglia in NSC oligodendrogenesis with the involvement of Wnt7a., This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO SAF2016 76449-R) and the Red Española de Esclerosis Múltiple (REEM: RD16/0015/0021), sponsored by the Fondo de Investigación Sanitaria (FIS).

Serotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT1A receptor in ex vivo samples of different immune system conditions.

Next-generation sequencing (NGS) is progressively being used in clinical practice. However, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25-gene panel that contains predictive biomarkers for most current and near-future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin-fixed paraffin-embedded tissue. The workflow includes an automated bioinformatic pipeline that accounts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were detected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost-efficient alternative to multiple non-NGS assays and costly, large NGS panels. This kind of streamlined assay with automated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.

Aim Reports detailing the morbidity-mortality after left colectomy are sparse and do not allow definitive conclusions to be drawn. We aimed to identify risk factors for anastomotic leakage, perioperative mortality and complications following left colectomy for colonic malignancies. Method We undertook a STROBE-compliant analysis of left colectomies included in a national prospective online database. Forty-two variables were analysed as potential independent risk factors for anastomotic leakage, postoperative morbidity and mortality. Variables were selected using the 'least absolute shrinkage and selection operator' (LASSO) method. Results We analysed 1111 patients. Eight per cent of patients had a leakage and in 80% of them reoperation or surgical drainage was needed. A quarter of patients (24.9%) experienced at least one minor complication. Perioperative mortality was 2%, leakage being responsible for 47.6% of deaths. Obesity (OR 2.8, 95% CI 1.00-7.05, P = 0.04) and total parenteral nutrition (TPN) (OR 3.7, 95% CI 1.58-8.51, P = 0.002) were associated with increased risk of leakage, whereas female patients had a lower risk (OR 0.36, 95% CI 0.18-0.67, P = 0.002). Corticosteroids (P = 0.03) and oral anticoagulants (P = 0.01) doubled the risk of complications, which was lower with hyperlipidaemia (OR 0.3, P = 0.02). Patients on TPN had more complications (OR 4.02, 95% CI 2.03-8.07, P = 0.04) and higher mortality (OR 8.7, 95% CI 1.8-40.9, P = 0.006). Liver disease and advanced age impaired survival, corticosteroids being the strongest predictor of mortality (OR 21.5, P = 0.001). Conclusion Requirement for TPN was associated with more leaks, complications and mortality. Leakage was presumably responsible for almost half of deaths. Hyperlipidaemia and female gender were associated with lower rates of complications. These findings warrant a better understanding of metabolic status on perioperative outcome after left colectomy.

Hereditary xerocytosis is a rare disorder caused by defects of red blood cell permeability that are characterized by hemolytic anemia of variable degree and iron overload. Diagnosis is usually late and confused with other hemolytic anemias, which can lead to procedural indications, such as splenectomy, contraindicated in these patients. We report the clinical, haematological, and molecular characteristics of two patients from two unrelated families affected by hereditary xerocytosis. Both patients had dehydrated erythrocytes with a high concentration of mean corpuscular hemoglobin, non-pathognomonic smears, markers of hemolysis and a resistant osmotic fragility curve. The diagnosis was confirmed by the sequencing of the PIEZO gene. We emphasize the importance of recognizing the cause of hemolytic anemia to give an accurate therapeutic approach and give adequate genetic counseling.

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a rare disease characterized by congenital and progressive vascular lesions of the skin and gastrointestinal tract that may be associated with thrombocytopenia and possibly life-threatening gastrointestinal bleeding. Reports published on the disease and treatment strategies are scarce. We present two cases of MLT treated with sirolimus.

An intronic variant in ANKRD55, rs6859219, is a genetic risk factor for multiple sclerosis, but the biological reasons underlying this association are unknown. We characterized the expression of ANKRD55 in human PBMCs and cell lines. Three ANKRD55 transcript variants (Ensembl isoforms 001, 005, and 007) could be detected in PBMCs and CD4+ T cells but were virtually absent in CD8+, CD14+, CD19+, and CD56+ cells. Rs6859219 was significantly associated with ANKRD55 transcript levels in PBMCs and CD4+ T cells and, thus, coincides with a cis-expression quantitative trait locus. The processed noncoding transcript 007 was the most highly expressed variant in CD4+ T cells, followed by 001 and 005, respectively, but it was not detected in Jurkat, U937, and SH-SY5Y cell lines. Homozygotes for the risk allele produced more than four times more transcript copies than did those for the protective allele. ANKRD55 protein isoforms 005 and 001 were predominantly located in the nucleus of CD4+ T cells and Jurkat and U937 cells. ANKRD55 was produced by primary cultures of murine hippocampal neurons and microglia, as well as by the murine microglial cell line BV2, and it was induced by inflammatory stimuli. ANKRD55 protein was increased in the murine mouse model of experimental autoimmune encephalomyelitis. Flow cytometric analysis of CNS-infiltrating mononuclear cells showed that CD4+ T cells and monocytes expressed ANKRD55 in experimental autoimmune encephalomyelitis mice, with the higher fluorescence intensity found in CD4+ cells. A low percentage of microglia also expressed ANKRD55. Together, these data support an important role for ANKRD55 in multiple sclerosis and neuroinflammation.

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., The authors gratefully acknowledge support from the Spanish Network of Multiple Sclerosis Research, REEM, RD16/0015/0021 sponsored by the Fondo de Investigación Sanitaria (FIS) and SAF2016-76449-R from Ministry of the Economy and Competitiveness (MINECO, Spain).

La deficiencia de glucosa-6-fosfato deshidrogenasa es la enzimopatía eritrocitaria causada por mutaciones en el gen G6PD, cuya herencia está ligada al cromosoma X. Se analizan las características clínicas y de laboratorio de 24 individuos con deficiencia de G6PD durante 25 años. La edad mediana al momento del diagnóstico fue 10,2 años (rango: 0,6-56,4). El 54,2 % de los pacientes fueron asintomáticos, mientras que el 25 % presentó anemia hemolítica crónica no esferocítica; el 12,5 %, ictericia neonatal y anemia hemolítica posinfecciones, y el 8,3 %, anemia hemolítica aguda pos ingesta de habas. Los 24 pacientes estudiados presentaron variantes descritas previamente en la literatura. Las características clínicas observadas estuvieron acordes con las variantes encontradas. Veintiuna mujeres, pertenecientes a la rama materna de los individuos afectados, pudieron ser identificadas por biología molecular como portadoras de la deficiencia, por lo que recibieron el consejo genético correspondiente. Glucose-6-phosphate dehydrogenase deficiency is an erythrocyte enzyme disorder caused by mutations in the G6PD gene, which has an X-linked inheritance. Here we analyze the clinical and laboratory characteristics of 24 subjects with G6PD deficiency over 25 years. Their median age at diagnosis was 10.2 years (range: 0.6-56.4). No symptoms were observed in 54.2 % of patients, whereas 25 % had chronic non-spherocytic hemolytic anemia; 12.5 %, neonatal jaundice and postinfectious hemolytic anemia; and 8.3 %, acute hemolytic anemia after ingestion of fava beans. The 24 studied patients had variants that had been previously described in the bibliography. The clinical characteristics observed here were consistent with the variants found. A total of 21 women from the maternal line of affected subjects were identified as deficiency carriers using molecular biology techniques, so they received the corresponding genetic counseling.

[Background] Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages of the disease. Thus, immunosuppression is the goal standard for the inflammatory stage, and novel remyelination therapies are pursued to restore lost function. Cannabinoids such as 9Δ-THC and CBD are multi-target compounds already introduced in the clinical practice for multiple sclerosis (MS). Semisynthetic cannabinoids are designed to improve bioactivities and druggability of their natural precursors. VCE-004.8, an aminoquinone derivative of cannabidiol (CBD), is a dual PPARγ and CB2 agonist with potent anti-inflammatory activity. Activation of the hypoxia-inducible factor (HIF) can have a beneficial role in MS by modulating the immune response and favoring neuroprotection and axonal regeneration., [Methods] We investigated the effects of VCE-004.8 on the HIF pathway in different cell types. The effect of VCE-004.8 on macrophage polarization and arginase 1 expression was analyzed in RAW264.7 and BV2 cells. COX-2 expression and PGE2 synthesis induced by lipopolysaccharide (LPS) was studied in primary microglia cultures. The efficacy of VCE-004.8 in vivo was evaluated in two murine models of MS such as experimental autoimmune encephalomyelitis (EAE) and Theiler’s virus-induced encephalopathy (TMEV)., [Results] Herein, we provide evidence that VCE-004.8 stabilizes HIF-1α and HIF-2α and activates the HIF pathway in human microvascular endothelial cells, oligodendrocytes, and microglia cells. The stabilization of HIF-1α is produced by the inhibition of the prolyl-4-hydrolase activity of PHD1 and PDH2. VCE-004.8 upregulates the expression of HIF-dependent genes such as erythropoietin and VEGFA, induces angiogenesis, and enhances migration of oligodendrocytes. Moreover, VCE-004.8 blunts IL-17-induced M1 polarization, inhibits LPS-induced COX-2 expression and PGE2 synthesis, and induces expression of arginase 1 in macrophages and microglia. In vivo experiments showed efficacy of VCE-004.8 in EAE and TMEV. Histopathological analysis revealed that VCE-004.8 treatments prevented demyelination, axonal damage, and immune cells infiltration. In addition, VCE-004.8 downregulated the expression of several genes closely associated with MS physiopathology, including those underlying the production of chemokines, cytokines, and adhesion molecules., [Conclusions] This study provides new significant insights about the potential role of VCE-004.8 for MS treatment by ameliorating neuroinflammation and demyelination., This work was supported by grants SAF2014-53763-P (EM), SAF2017-87701-R (EM), and SAF2016-76449-R (GC) from the Ministry of the Economy and Competition (MINECO) co-financed with the European Union FEDER funds. GC was also supported by the Red Española de Esclerosis Múltiple (REEM: RD16/0015/0021) sponsored by the Fondo de Investigación Sanitaria (FIS); MAC was supported by the Instituto de Salud Carlos III (PIE14/00005) co-funded by the European Regional Development Fund/European Social Fund “Investing in your future”.

Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication and as possible therapeutic agents in inflammation-mediated demyelinating diseases, including multiple sclerosis (MS). In the present study, we investigated whether intravenously administered EVs derived from mesenchymal stem cells (MSCs) from human adipose tissue might mediate recovery in Theiler’s murine encephalomyelitis virus (TMEV)induced demyelinating disease, a progressive model of MS. SJL/J mice were subjected to EV treatment once the disease was established. We found that intravenous EV administration improved motor deficits, reduced brain atrophy, increased cell proliferation in the subventricular zone and decreased inflammatory infiltrates in the spinal cord in mice infected with TMEV. EV treatment was also capable of modulating neuroinflammation, given glial fibrillary acidic protein and Iba-1 staining were reduced in the brain, whereas myelin protein expression was increased. Changes in the morphology of microglial cells in the spinal cord suggest that EVs also modulate the activation state of microglia. The clear reduction in plasma cytokine levels, mainly in the Th1 and Th17 phenotypes, in TMEV mice treated with EVs confirms the immunomodulatory ability of intravenous EVs. According to our results, EV administration attenuates motor deficits through immunomodulatory actions, diminishing brain atrophy and promoting remyelination. Further studies are necessary to establish EV delivery as a possible therapy for the neurodegenerative phase of MS., This study was supported by Red Española de Esclerosis Múltiple Grants RD12/ 0032/0008 and RD16/0015/0021 (sponsored by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional [FEDER]) to C.G.

Background Colon cancer presents at high incidence and its treatment generates an important economic impact in hospitals. In Spain, it is mandatiory for the sponsors of clinical trials to supply the investigational drugs without charge to the national health system. Avoided cost is defined as the cost that would have had to be paid if the patient did not participate in a clinical trial with the free contribution of the drugs. The objective of the main study was to calculate the cost avoided in drugs derived from the participation of patients in clinical trials of colon cancer in a university hospital. Methods This was a retrospective observational study. A data cut was made in April 2018 and the active clinical trials in colon cancer were selected. All patients who had participated in them were included, regardless of the date of inclusion. Sources of data collection: Pharmacy Service database, Farmis Oncofarm® electronic Citostatic prescription program, and Clinical Records. The cost of the cycles received in the investigation was estimated for each patient and the cost of the standard treatment during the same period was calculated. For this, the following variables were collected: name of the trial, drug in research, number of cycles, duration, cost of treatment in the experimental arm and in the comparator or standard therapy. The costs of the medication associated with chemotherapy were not taken into account. Results Four clinical trials in colon cancer have been included, where a total of 16 patients with a mean age of 60.9 years participated and 5 investigational drugs were studied. The average duration of each patient’s treatment within the trial was 6.7 months. The global avoided cost in the 4 trials is 269,074.85 Euros, which means an average avoided cost per patient of 16,817.17 Euros and an average avoided cost for each trial in colon cancer of 67,268.71 Euros. Conclusions Clinical trials contribute to scientific advances, help the sustainability of the Public Health System and allow patients access to novel treatments. It is necessary to promote clinical research since it has proven to be favorable for patients, as well as for clinicians and institutions. Legal entity responsible for the study Hospital Universitario La Paz. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Sativex(®), an equimolecular combination of Δ(9)-tetrahydrocannabinol-botanical drug substance (Δ(9)-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain. However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components. In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice. We compared the effect of a Sativex-like combination of Δ(9)-THC-BDS (10 mg/kg) and CBD-BDS (10 mg/kg) with Δ(9)-THC-BDS (20 mg/kg) or CBD-BDS (20 mg/kg) administered separately by intraperitoneal administration to EAE mice. Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease. The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS. These effects were completely reproduced by the treatment with Δ(9)-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord. Next, we investigated the potential targets involved in the effects of Δ(9)-THC-BDS by selectively blocking CB(1) or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB(1) receptor antagonist. Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ(9)-THC-BDS acting through CB(1) receptors.

Background and Purpose Sativex® is an oromucosal spray, containing equivalent amounts of Δ9-tetrahydrocannabinol (Δ9-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-1β 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 Δ9-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.

The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2‐arachidonoylglycerol (2‐AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler's virus induced demyelination disease (TMEV‐IDD) as a model of acute neuroinflammation to investigate whether 2‐AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2‐AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti‐inflammatory state via CB2 receptors. Indeed, 2‐AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long‐term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2‐AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2‐AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions., This work was supported by grants to CG, DC and MLR from Ministry of the Economy and Competitiveness (CG: MINECO SAF2013–42784‐R, SAF2016 76449‐R; MLR: SAF2013–48271, DC: PI15/00963), the Comunidad de Madrid (CG: S2010/BMD‐2308 and MLR: S2010/BMD‐2353), the Red Española de Esclerosis Múltiple (CG: REEM: RD12/0032/0008; RD16/0015/0021; FC: RD12/0032/12, DC: RD16/0015/0019) sponsored by the Fondo de Investigación Sanitaria (FIS), partially financed by F.E.D.E.R.; European Union “Una manera de hacer Europa” and ARSEP Foundation to DC. Diego Clemente's group was sponsored by ADEM‐TO, Aciturri Aeronáutica S.L. and Vesuvius Ibérica LA. M.M. is a senior postdoctoral supported by the Comunidad de Madrid (S2010/BMD‐2308) and hired by MINECO; DC and IM‐D are hired by SESCAM.

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., This study was supported by the “Red Española de Esclerosis Múltiple” (REEM, RD 12/0008, RD16/0015/0021, F.J.C.S., L.M., M.M., A.F., C.G.; RD12/0032, RD16/0015/0001 L.M.V., J.C.A.C.; RD12/0017, RD16/0015/0004 C.E., X.M.), sponsored by the Fondo de Investigación Sanitaria (FIS) of the Instituto Nacional de Salud Carlos III, and the Spanish Ministry of Economy and Competitiveness and by the FIS PI12-00239, PI13/205 and SAF2013-42784R. CE and RdC are supported by the “Miguel Servet” program (CP07/00146; CP13/00028; CB05/00137) of the FIS of the Ministry of Economy and Competitiveness of Spain.

Cannabidiol (CBD), which constitutes up to 40% of the Cannabis sativa extract, have attracted special interest regarding putative therapeutic properties, excellent tolerability profile in humans, and lack of psychoactive actions. In animal models, CBD has been reported to act as an antiinflammatory, neuroprotective, and oligoprotective compound. The oromucosal spray administration of Sativex (a commercially available preparation containing CBD and Δ9-tetrahydrocannabinol, Δ9-THC) has been agreed for the treatment of pain and spasticity in multiple sclerosis (MS), a complex inflammatory disease with unknown etiology that courses with demyelination and neuronal injury in the brain and spinal cord. In this chapter, we will discuss about the different mechanisms of action of CBD, its beneficial effects on animal models of MS, and perspectives for human therapeutic treatment.

The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies., This work was supported by Ministry of the Economy and Competition (MINECO) Grants SAF2013-42784-R and SAF2016-76449-R, Comunidad de Madrid Grant S2011/BMD-2308, and Red Española de Esclerosis Múltiple Grants RD12/0032/0008 and RD16/0015/0021 (sponsored by the Fondo de Investigación Sanitaria) to C.G., Basque Government Grant IT764-13, MINECO/FEDER Grant SAF2015-65034-R, and University of the Basque Country Grant UPV/EHU UFI11/41 to P.G., and MINECO Grant SAF2013-48271-C2-1-R to M.L.-R. None of the funding bodies played any role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript. A.F. is a predoctoral fellow supported by MINECO Grant BES-2014-068459. We thank Laura Ramos for excellent technical support.

Polyphenols are a structural class of natural and synthetic, organic chemicals characterized mainly by the presence of phenol structural units. Numerous epidemiological and experimental studies have strongly suggested their beneficial effects for human health. This view is supported by their biological activities, which are associated with chemical and biochemical properties, including the ability to act as antioxidants, their antineoplastic effect and the regulation of gene expression in chronic degenerative diseases. These mechanisms of action could account for their preventive and therapeutic uses in human subjects. Moreover, in some therapeutic uses, such as antineoplastic effect, a prooxidant therapeutic action has been suggested. In the diet, numerous compounds could participate in the beneficial properties, and this likely could result in synergistic effects because the whole effect is better than the separately action of each compound. However, the pharmacokinetic and pharmacodynamic properties of these bioactive micronutrients are yet to be further characterized. More research is required to fully establish the therapeutic use of polyphenols against human disease. Based on biological and pharmacological properties of polyphenols both as diet components and supplements, the objective of this work is to show an updated version about the role that polyphenols could play in several chronic diseases such as hypertension, diabetes mellitus, cancer and neurodegenerative disorders.

Cardiovascular diseases are a leading cause of mortality and morbidity worldwide, with hypertension being a major risk factor. Numerous studies support the contribution of reactive oxygen and nitrogen species in the pathogenesis of hypertension, as well as other pathologies associated with ischemia/reperfusion. However, the validation of oxidative stress-related biomarkers in these settings is still lacking and novel association of these biomarkers and other biomarkers such as endothelial progenitor cells, endothelial microparticles, and ischemia modified albumin, is just emerging. Oxidative stress has been suggested as a pathogenic factor and therapeutic target in early stages of essential hypertension. Systolic and diastolic blood pressure correlated positively with plasma F2-isoprostane levels and negatively with total antioxidant capacity of plasma in hypertensive and normotensive patients. Cardiac surgery with extracorporeal circulation causes an ischemia/reperfusion event associated with increased lipid peroxidation and protein carbonylation, two biomarkers associated with oxidative damage of cardiac tissue. An enhancement of the antioxidant defense system should contribute to ameliorating functional and structural abnormalities derived from this metabolic impairment. However, data have to be validated with the analysis of the appropriate oxidative stress and/or nitrosative stress biomarkers.

Acute myocardial infarction (AMI) is the leading cause of mortality worldwide. Major advances in the treatment of acute coronary syndromes and myocardial infarction, using cardiologic interventions, such as thrombolysis or percutaneous coronary angioplasty (PCA) have improved the clinical outcome of patients. Nevertheless, as a consequence of these procedures, the ischemic zone is reperfused, giving rise to a lethal reperfusion event accompanied by increased production of reactive oxygen species (oxidative stress). These reactive species attack biomolecules such as lipids, DNA, and proteins enhancing the previously established tissue damage, as well as triggering cell death pathways. Studies on animal models of AMI suggest that lethal reperfusion accounts for up to 50% of the final size of a myocardial infarct, a part of the damage likely to be prevented. Although a number of strategies have been aimed at to ameliorate lethal reperfusion injury, up to date the beneficial effects in clinical settings have been disappointing. The use of antioxidant vitamins could be a suitable strategy with this purpose. In this review, we propose a systematic approach to the molecular basis of the cardioprotective effect of antioxidant vitamins in myocardial ischemia-reperfusion injury that could offer a novel therapeutic opportunity against this oxidative tissue damage.

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., This work was supported by the Spanish Ministry of Economy and Competitiveness SAF2013-42784R and “Red Española de Esclerosis Múltiple” (REEM, RD 12/0008).

Variant hemoglobins are the result of different types of mutations that occur in the globin genes. In many cases, these hemoglobinopathies are harmless, while in others they determine alterations in the physical and chemical properties raising clinical manifestations of variable severity. In the unstable hemoglobinopathies, the changes reduce solubility, inducing the formation of precipitates of denaturated hemoglobin (Heinz bodies), which damage the membrane and finally destroy the red blood cells prematurely. Up to now, more than 142 different unstable hemoglobins have been described, most of them cause chronic hemolysis, increased by infections or drugs. We report the clinical presentation of an unstable hemoglobin (hemoglobin Southampton) in a girl with severe hemolytic anemia, splenomegaly and red blood cell requirement.

Background Diagnostic guidelines for penicillin allergy in children recommend cumbersome protocols based partially on data from adults, which may be suboptimal for pediatric use. Objective To assess the accuracy of tools for diagnosis of penicillin allergy in children. Methods A prospective, multicenter study was conducted in children with reported adverse events related to penicillin, excluding severe reactions. All patients underwent a uniform diagnostic protocol that consisted of clinical history, skin tests, serum specific IgE (sIgE), and, regardless of these results, drug provocation tests (DPTs). Results A total of 732 children (mean age, 5.5 years; 51.2% males) completed the allergy workup, including DPTs. Amoxicillin triggered 96.9% of all reactions. None of the patients with an immediate index reaction (IR) developed a reaction on DPT. Penicillin allergy was confirmed in 35 children (4.8%): 6 immediate reactions (17%) and 29 nonimmediate reactions (83%) on the DPT. No severe reactions were recorded. The allergist diagnosis based on the clinical history was not associated with the DPT final outcome. In 30 of 33 allergic patients (91%), the results of all skin tests and sIgE tests were negative. A logistic regression model identified the following to be associated with penicillin allergy: a family history of drug allergy (odds ratio [OR], 3.03; 95% confidence interval [CI], 1.33-6.89; P = .008), an IR lasting more than 3 days vs 24 hours or less (OR, 8.96; 95% CI, 2.01-39.86; P = .004), and an IR treated with corticosteroids (OR, 2.68; 95% CI, 1.30-5.54; P = .007). Conclusion Conventional predictors of allergy to penicillin performed weakly. The authors propose straightforward penicillin provocation testing in controlled, experienced centers for the diagnosis of nonsevere penicillin allergy in children.

The temporary use of the bioenterics intragastric balloon in morbid obesity is increasing worldwide. Generally, this is an effective procedure that helps bring about satisfactory weight loss and improvement in comorbidities after 6 months. However, in some cases, it causes complications such as acute abdomen due to gastric perforation and even death. We describe the case of a type II obese female (weight, 88 kg; body mass index, 35.2 kg/m(2)) who underwent emergency surgery for gastric necrosis caused by bioenterics intragastric balloon; the patient required total gastrectomy and intensive care.

Obesity, the most significant metabolic problem in the world today, is associated with a wide range of diseases, including endocrine disorders. Paraganglioma is a rare chromaffin cell tumor that develops from the neural crest cells of the neuroendocrine system. Retroperitoneal paragangliomas can represent a surgical challenge due to their close relation to large vessels. We report two cases of functioning retroperitoneal paraganglioma in type-I obese patients (case 1: female; weight, 77 kg; body mass index, 30.1 kg/m(2); case 2: male; weight, 92 kg; body mass index, 31.1 kg/m(2)) who underwent elective endocrine surgery. The tumors (one interaortocaval and the other above the iliac artery) were completely excised by laparotomy without postoperative complications.

The results of a meeting of physicians convening in Latin America to develop expert opinions on the diagnosis, monitoring and treatment of iron overload are as follows. An accurate diagnosis can be obtained by neonatal screening for haemoglobinopathies, especially sickle cell disease and the thalassaemias. Disease-specific registries are needed to demonstrate the extent of the problem to health authorities. Disparities in the quantity and quality of blood products must be addressed, and uniform transfusion guidelines are necessary. Serum ferritin level is a feasible marker for iron overload in the region, while magnetic resonance imaging assessment can improve the diagnosis and monitoring of cardiac and liver iron content. Medical specialists, including radiologists, pathologists and others, and health authorities, can help to implement these methods and provide adequate resources. The recently available oral deferasirox can be used to conveniently administer iron chelation to transfusional iron-overloaded patients.

Beta thalassemia intermedia is a quantitative haemoglobinopathy covering a broad clinical spectrum, that results from the presence of one or two HBB gene mutations associated with secondary and/or tertiary genetic modifiers. We analyze the clinical and laboratory features of 29 patients with beta thalassemia intermedia, assessed over a period of 23 years. Median age was 10.8 years (range: 0.34-60.4). Hypochromic microcytic anemia was seen in 100% of the patients, while only 17.2% had splenomegaly and occasional transfusion requirement. The molecular analysis of patients detected: 3 with two HBB affected genes; 2 with one HBB affected gene and alpha quadruplicate/triplicate genes; 23 with one HBB affected gene and alpha triplicate genes and 1 with two HBB affected genes and polymorphisms of gamma genes. The adequate identification of these patients enables us to give appropriate genetic counseling and implementation of regular clinical follow up.

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., This work was supported by Grants from the Ministry of the Economy and Competition (MINECO SAF2013-42784-R and SAF2013-48271, the Comunidad de Madrid (S2010/BMD-2308 and S2010/BMD-2353) and the Red Española de Esclerosis Múltiple (REEM) RD12/0032/0008 (CG) sponsored by the Fondo de Investigación Sanitaria (FIS). A.R.Z. is a predoctoral fellow from UCM. M.M. is a senior postdoctoral supported by the Comunidad de Madrid (S2010/BMD-2308).

Las nauseas y los vomitos continuan siendo uno de los efectos adversos mas temidos por los pacientes en tratamiento con quimioterapia. Un control adecuado de la emesis inducida por la quimioterapia mejora la calidad de vida. La frecuencia de nauseas y vomitos depende principalmente del agente quimioterapeutico empleado. Con el tratamiento antiemetico actual (antagonistas de la serotonina y dexametasona) aproximadamente el 13% de los pacientes presenta vomitos en la fase aguda y casi un 50%, en la tardia. Los antagonistas del receptor de la neurocinina-1, asociados al tratamiento antiemetico estandar, mejoran significativamente el control de la emesis aguda y de la emesis tardia, aunque no son tan eficaces en la prevencion de las nauseas. Actualmente, se deberia conseguir el control completo de las nauseas y los vomitos en los pacientes con cancer en tratamiento quimioterapeutico.

Concepto. El tromboembolismo venoso (TEV) se considera un proceso multifactorial en el que confluyen diversas causas, congenitas y adquiridas, que superan el determinado "umbral trombotico". Factores de riesgo. Los deficits de antitrombina III (AT III), proteinas C y S, y especialmente el factor V Leiden, constituyen los principales factores de riesgo genetico de TEV. Otros recientemente identificados son la hiperhomocisteinemia, el nivel elevado del factor VIII coagulante y la resistencia a la proteina C activada. Diagnostico de la trombofilia venosa. Esta aceptado el estudio de trombofilia en pacientes menores de 45 anos con trombosis venosa, trombosis de localizaciones atipicas, recurrentes y necrosis cutanea al iniciar la terapia anticoagulante oral. Tratamiento. Para definir la duracion de la terapia anticoagulante es importante conocer la posible existencia de alteraciones trombofilicas que pueden aconsejar terapia indefinida.

El tratamiento de los pacientes con sindromes coronarios agudos comianza con la estratificacion del riesgo cardiovascular mediante estudios clinicos radiologicos. En pacientes con angina inestable e infarto agudo de miocardio sin elevacion ST se recomienda tratamiento con acido acetilsalicilico, clopidogrel y heparina de bajo peso molecular. En aquellos pacientes con riesgo elevado se asociaran inhibidores IIb/IIIa. Se realizara angiografia coronaria para decidir una estrategia invasiva (angioplastia o by-pass). Los pacientes con ictus de menos de tres horas de evolucion se beneficiaran de fibrinolisis con rt-PA.

Phytocannabinoids that do not produce psychotropic effects are considered of special interest as novel therapeutic agents in CNS diseases. A cannabigerol quinone, the compound VCE-003, has been shown to alleviate symptoms in a viral model of multiple sclerosis (MS). Hence, we studied T cells and macrophages as targets for VCE-003 and its efficacy in an autoimmune model of MS. Proliferation, cell cycle, expression of activation markers was assessed by FACs in human primary T cells, and cytokine and chemokine production was evaluated. Transcription was studied in Jurkat cells and RAW264.7 cells were used to study the effects of VCE-003 on IL-17-induced macrophage polarization to a M1 phenotype. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG35-55) immunization and spinal cord pathology was assessed by immunohistochemistry. Neurological impairment was evaluated using disease scores. We show here that VCE-003 inhibits CD3/CD28-induced proliferation, cell cycle progression and the expression of the IL-2Ra and ICAM-1 activation markers in human primary T cells. VCE-003 inhibits the secretion of Th1/Th17 cytokines and chemokines in primary murine T cells, and it reduces the transcriptional activity of the IL-2, IL-17 and TNFa promoters induced by CD3/ CD28. In addition, VCE-003 and JWH-133, a selective CB2 agonist, dampened the IL-17-induced polarization of macrophages to a pro-inflammatory M1 profile. VCE-003 also prevented LPS-induced iNOS expression in microglia. VCE-003 ameliorates the neurological defects and the severity of MOG-induced EAE in mice through CB2 and PPARc receptor activation. A reduction in cell infiltrates, mainly CD4T cells, was observed, and Th1 and Th17 responses were inhibited in the spinal cord of VCE-003-treated mice, accompanied by weaker microglial activation, structural preservation of myelin sheets and reduced axonal damage. This study highlights the therapeutic potential of VCE-003 as an agent for the treatment of human immune diseases with both inflammatory and autoimmune components. © 2014 Carrillo-Salinas et al.

The central nervous system (CNS) innate immune response includes an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons that is involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the CNS are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) Alzheimer's disease (AD) being primary examples. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. Neuroimmune regulatory proteins (NIReg) such as CD95L, CD200, CD47, sialic acid, complement regulatory proteins (CD55, CD46, fH, C3a), HMGB1, may control the adverse immune responses in health and diseases. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury as well as an adverse inflammatory response in acute and chronic settings. We will herein provide new emphasis on the role of the pair CD200-CD200R in MS and its experimental models: experimental autoimmune encephalomyelitis (EAE) and Theiler’s virus induced demyelinating disease (TMEV-IDD). The interest of the cannabinoid system as inhibitor of inflammation prompt us to introduce our findings about the role of endocannabinoids (eCBs) in promoting CD200-CD200 receptor (CD200R) interaction and the benefits caused in TMEV-IDD. Finally, we also review the current data on CD200-CD200R interaction in AD, as well as, in the aging brain.

The high prevalence of obesity is associated with diverse health problems, including endocrine disorders. Laparoscopic adrenalectomy has become the preferred approach for removal of the adrenal gland, but several authors still debate the role of laparoscopic adrenalectomy in pheochromocytoma. We describe a case of a morbidly obese man (weight, 142 kg; body mass index, 40.2 kg/m(2)) who underwent elective laparoscopic adrenalectomy for a large right pheochromocytoma without incidences.

This study was designed to identify the beta-thalassemia mutations in an Argentine population. Seventy-one pediatric patients and 101 available relatives were studied (85 chromosomes). Diagnosis of beta-thalassemia was made by conventional hematological procedures. Molecular studies were carried out by dot-blot and restriction endonuclease analysis on amplified DNA to detect the eight most frequent mutations in the Mediterranean area. We were able to identify 95.3% of the beta-thalassemia mutations in the subjects under study. The four common defects (C-39, 47%; IVS-I nt 110, 22.4%; IVS-I nt 1, 9.4%; and IVS-I nt 6, 5.9%) account for 84.7% of the beta-thalassemia alleles. The alleles and their distributions showed a close similarity to the spectrum of alleles in Italy. The differences might represent the influence of other immigrations, especially from Spain. We conclude that beta-thalassemia in Argentina originated mainly from Italian immigrants. This study will enable us to design an adequate approach to genetic counseling and/or prenatal diagnosis for couples at risk.

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-1β, 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. © 2013 The Authors.

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 35 days 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., We are grateful to the financial support of the Ministry of Economy and Competitivity (MINECO, project SAF-2010/17501), the Instituto de Salud Carlos III (RETICS programme, Red Española de Esclerosis Múltiple – REEM RD07/0060/0010 and RD12/0032/0008 co-supported by FEDER grants) and the Comunidad de Madrid (CAM - S2010/BMD-2308). Mecha M was supported by REEM.