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Background: Long-acting injectable antipsychotics (LAIAs) are an efficacious and well-tolerated treatment in adults with schizophrenia spectrum disorders (SSD). However, there is less evidence for their use in children and adolescents. Objectives: The aim of this systematic review was to summarize findings regarding the effectiveness and side effects of LAIA in children and adolescents with SSD. Methods: Four databases (Web of Science, PubMed, MEDES, and Dialnet) were systematically searched for articles published between inception and 12 March, 2022, with the following inclusion criteria: (1) original articles or case reports; (2) providing data on efficacy/effectiveness or safety/tolerability of LAIA treatment in children and adolescents diagnosed with SSD (schizophrenia, schizoaffective disorder, schizophreniform disorder, non-affective psychotic disorder); (3) mean age of samples ≤ 18 years; and (4) written in English or Spanish. Exclusion criteria were review articles, clinical guides, expert consensus as well as posters or oral communication in conferences. The risk of bias was assessed using the ROBIS tool. Results: From 847 articles found, 13 met the inclusion criteria. These included seven single case reports or case series, four retrospective chart reviews, a 24-week open-label trial, and one observational prospective study, covering a total of 119 adolescents (aged 12-17 years) with SSD. Almost all the articles described data on second-generation LAIA (53 patients on risperidone [once every other week], 33 on paliperidone palmitate [once monthly], 10 on aripiprazole [once monthly], and two on olanzapine pamoate [once monthly]). Twenty-one patients were reported to be only on first-generation LAIAs. Non-adherence was the main reason for starting an LAIA. In all of the studies, the use of LAIAs was associated with improvement in the patients' symptoms. Conclusions: There are few studies assessing the use of LAIAs in adolescents with SSD. Overall, these treatments have suggested good effectiveness and acceptable safety and tolerability. However, we found no studies examining their use in children aged < 12 years. The problems and benefits linked to this type of antipsychotic formulation in the child and adolescent population require further study, ideally with prospective, controlled designs.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage kidney disease. Currently, tolvaptan is the only treatment that has proven to delay disease progression. The most notable side effect of this therapy is drug-induced liver injury; however, recently, there have been two reports of creatine kinase (CK) elevation in ADPKD patients on tolvaptan treatment. We set out to monitor and determine the actual incidence of CK elevation and evaluate its potential association with other clinical factors. Methods: This is an observational retrospective multicenter study performed in rapidly progressive ADPKD patients on tolvaptan treatment from Barcelona, Spain. Laboratory tests, demographics, treatment dose, and reported symptoms were collected from October 2018 to March 2021. Results: Ninety-five patients initiated tolvaptan treatment during follow-up. The medication had to be discontinued in 31 (32.6%) patients, primarily due to aquaretic effects (12.6%), elevated liver enzymes (8.4%), and symptomatic or persistently elevated CK levels (3.2%). Moreover, a total of 27 (28.4%) patients had elevated CK levels, with most of them being either transient (12.6%), mild and asymptomatic (4.2%), or resolved after dose reduction (3.2%) or temporary discontinuation (2.1%). Conclusion: We pre­sent the largest cohort that has monitored CK levels in a real-life setting, finding them elevated in 28.4% of patients. More research and monitoring will help us understand the clinical implications and the pathophysiological mechanism of CK elevation in this population.

[cat] El càncer infantil és una de les principals causes de mortalitat durant la infància i l’adolescència. Segons l’Associació Espanyola contra el càncer, 1500 nens/es de 0 a 14 anys són diagnosticats anualment d’aquesta malaltia. Els tipus de càncer més freqüent són les leucèmies (28,8%), els tumors del sistema nerviós central (24%), els limfomes (11,2%) i altres tipus (36%). L'augment de la taxa de supervivència dels infants tractats de càncer ha augmentat en les últimes dècades. Aquesta major supervivència ha anat acompanyada d'un increment de les seqüeles en la dentició permanent. A diferència dels adults, el càncer infantil té una incidència molt més baixa, no es pot prevenir ni detectar per cribratge, requereix de teràpies diferents i respon als tractaments de manera molt diversa. El nostre objectiu era correlacionar el tipus de teràpia contra el càncer administrada als pacients durant la primera infància (0-5 anys) versus les seqüeles dentals registrades en supervivents (12-18 anys). Es va dur a terme un estudi de cohorts retrospectiu i unicèntric a l’Hospital Materno- Infantil Sant Joan de Déu (HSJD) de Barcelona. Es va analitzar una mostra de cent nou pacients de 12-18 anys, que havien rebut tractament contra el càncer durant la primera infància (0-5 anys). Van ser examinats aleatòriament i agrupats segons el diagnòstic i la teràpia anticancerosa rebuda. Determinar si el tipus de teràpia es correlacionava amb el nombre i la gravetat de lesions dentals que presentaven en l'adolescència. Vam proposar una nova classificació de les seqüeles dentals basada en la gravetat d’aquestes: i) lesions lleus (defectes del desenvolupament de l’esmalt i taurodontisme), ii) moderades (microdòncia), iii) lesions severes (agenèsia i escurçament radicular de més del 50%). El 85.3% dels pacients mostraven algun tipus de seqüela dental. La microdòncia va ser l'alteració dental més prevalent (52.3%), seguida dels canvis radiculars (45.9%), els defectes del desenvolupament de l’esmalt (31.2%), l’agenèsia (27.5%) i el taurodontisme (17.4%). Els agents alquilants juntament amb els alcaloides vegetals van ser els fàrmacs més administrats. Els pacients tractats amb agents alquilants tenien una major incidència d'agenèsia (p =0.02), alteracions radiculars (p=0.038) i microdòncia (p=0.001). Aquells que van rebre inhibidors de la topoisomerasa i antibiòtics citotòxics van mostrar una proporció més alta d'alteracions radiculars (p=0.039) i agenèsia (p=0.05). El tractament amb agents alquilants va presentar un risc relatiu 3.36 (1.18- 9.60) vegades més alt de presentar lesions moderades i de 2,29 (1,07-4,91) de lesions severes. Els inhibidors de la topoisomerasa i els antibiòtics citotòxics presenten un risc relatiu 1.6 (1.07-2.38) i 2.08 (1.02-4.26) vegades més alts d'alteracions radiculars i agenèsia respectivament. No vam poder demostrar cap correlació significativa entre la dosi de radiació acumulada i el nombre/tipus de lesions dentals. La majoria dels supervivents de càncer durant la primera infància van tenir almenys una seqüela dental. El nombre de lesions dentals disminueix de forma significativa a mesura que augmenta l’edat d’inici del tractament oncològic. Els infants que havien iniciat el tractament pel càncer abans dels 3 anys varen tenir el doble de risc de presentar lesions dentals. L’única alteració dental que va demostrar una associació significativa amb la durada del tractament va ser la microdòncia. El tractament amb agents alquilants juntament amb antibiòtics citotòxics i inhibidors de la topoisomerasa tenen un major risc relatiu de microdòncia, agenèsia i escurçament radicular., [eng] The increase in survival rates in children treated for cancer has been accompanied by a rise in sequelae in the permanent teeth. Our objective was to correlate the type of cancer therapy administered to patients during early childhood (0-5 years) and the dental sequelae recorded in survivors (12-18 years). In this single-center, Hospital Sant Joan de Déu (UB), a retrospective cohort study was performed. 109 patients aged 12-18 years who had received cancer treatment during early childhood (0-5 years) were randomly examined and grouped according to diagnosis and cancer therapy received. The type of therapy was correlated with the number and severity of dental lesions they presented in adolescence, according to a new classification proposed by the authors. Dental sequelae of some kind were present in 85.3% of patients. Microdontia was the most prevalent dental alteration (52.3%), followed by root changes (45.9%), enamel developmental defects (31.2%), agenesis (27.5%) and taurodontism (17.4%). Patients treated with alkylating agents had a higher incidence of agenesis (p =0.02), root changes (p=0.038) and microdontia (p=0.001). Those who received topoisomerase inhibitors and cytotoxic antibiotics showed a higher proportion of root alterations (p=0.03) and agenesis (p=0.05). Treatment with alkylating agents presented a 3.36 (1.18-9.60)-times higher relative risk of presenting moderate lesions and a 2.29 (1.07-4.91) of presenting severe ones. Topoisomerase inhibitors and cytotoxic antibiotics presented a relative risk of 1.6 (1.07-2.38) and 2.08 (1.02-4.26) of root alterations and agenesis respectively. No significant correlation between cumulative radiation dose and number/type of dental lesions could be demonstrated. Most childhood cancer survivors had at least one dental sequela. Treatment with alkylating agents together with cytotoxic antibiotics and topoisomerase inhibitors has a higher relative risk of microdontia, agenesis and root shortening.

Breast cancer; Apoptosis; Radiotherapy Cáncer de mama; Apoptosis; Radioterapia Càncer de mama; Apoptosi; Radioteràpia Background: Radiation-induced late effects are a common cause of morbidity among cancer survivors. The biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. We aimed to investigate the molecular basis underlying the distinctive RILA levels by using gene expression analysis in patients with and without late effects and in whom we had also first identified differences in RILA levels. Patients and Methods: Peripheral blood mononuclear cells of 10 patients with late severe skin complications and 10 patients without symptoms, selected from those receiving radiotherapy from 1993 to 2007, were mock-irradiated or irradiated with 8 Gy. The 48-h response was analyzed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. Irradiated and non-irradiated gene expression profiles were compared between both groups. Gene set enrichment analysis was performed to identify differentially expressed biological processes. Results: Although differentially expressed mRNAs did not reach a significant adjusted p-value between patients suffering and not suffering clinical toxicity, the enriched pathways indicated significant differences between the two groups, either in irradiated or non-irradiated cells. In basal conditions, the main differentially expressed pathways between the toxicity and non-toxicity groups were the transport of small molecules, interferon signaling, and transcription. After 8 Gy, the differences lay in pathways highly related to cell senescence like cell cycle/NF-κB, G-protein-coupled receptors, and interferon signaling. Conclusion: Patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype. This work has been funded by the Instituto de Salud Carlos III (ISCIII), an initiative of the Spanish Ministry of Economy and Innovation partially supported by the European Regional Development FEDER Funds, Grant/Award Number: PI05/2181. SG-E was supported by the ISCIII Miguel Servet II Program (CP16/00034). EA-F was supported by the ERAPerMed JTC2018, grant numbers: ERAPERMED2018-244 and SLT011/18/00005.

Introduction: Reduced drinking has been debated as a treatment goal for heavy drinking alcohol-dependent patients, in whom treatment based on abstinence is not always an option. Nalmefene was the first drug approved by the European Medicines Agency (2013) with the indication of reduced drinking in high drinking risk level alcohol-dependent patients. Six years after its introduction in Europe, data from clinical experience can be compared with those from preclinical studies and pivotal registration studies to evaluate what nalmefene has added to the treatment of AUD. Areas covered: Systematic review of efficacy and safety data of nalmefene use in humans from preclinical, phase III and phase IV studies, including systematic reviews, meta-analyses, cost-effectiveness analyses, and other secondary analyses. Expert opinion: Nalmefene introduces a paradigm change in the treatment of AUD that makes it appealing to patients that are reluctant to embrace abstinence, and facilitate patient-centered care in heavy users. However, information regarding safety data in special populations (e.g., patients with alcohol-related diseases, pregnancy, psychiatric disease), and direct comparisons with other potential drugs for alcohol reduction are further needed. Despite the promising role of nalmefene, there are still some factors that limit its wide prescription further than in specialized settings.

EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1-4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:41 issue:6 pages:716-721 ispartof: location:United States status: published

[Objective] To describe the clinical characteristics and outcomes in patients with refractory myasthenia gravis (MG) and to determine the effectiveness and side effects of the drugs used for their treatment., [Methods] This observational retrospective cross-sectional multicenter study was based on data from the Spanish MG Registry (NMD-ES). Patients were considered refractory when their MG Foundation of America post-interventional status (MGFA-PIS) was unchanged or worse after corticosteroids and two or more other immunosuppressive agents. Clinical and immunologic characteristics of drug-refractory patients, efficiency and toxicity of drugs used, and outcome (MGFA-PIS) at end of follow-up were studied., [Results] We included 990 patients from 15 hospitals. Eighty-four patients (68 of 842 anti-acetylcholine receptor [AChR], 5 of 26 anti-muscle-specific tyrosine kinase [MusK], 10 of 120 seronegative, and 1 of 2 double-seropositive patients) were drug refractory. Drug-refractory patients were more frequently women (p, [Interpretation] In this study, 8.5% of MG patients were drug-refractory. New more specific drugs are needed to treat drug-refractory MG patients., This work was funded by the Instituto de Salud Carlos III through the project PI19/01774 (cofunded by the European Union ERDF), PI I. Illa and E. Gallardo. E. Cortés-Vicente was supported by a Juan Rodés grant (JR19/00037) from the Fondo de Investigación en Salud, Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “A way to make Europe”/“Investing in your future”), Ministry of Health (Spain). R. Álvarez-Velasco was supported by grant SLT008/18/00207 from the Health Research and Innovation Strategic Plan (PERIS). The NMD-ES Project and F. Pla-Junca (data curator) are partially funded by the Centro de Investigación Biomédica en Red de Enfsermedades Raras (CIBERER).

Treballs Finals de Grau en Estadística UB-UPC, Facultat d'Economia i Empresa (UB) i Facultat de Matemàtiques i Estadística (UPC), Curs: 2020-2021, Tutor: Jose Antonio González Alastrúe, El trastorno por déficit de atención e hiperactividad genera muchas dificultades en el aprendizaje académico de los niños que lo padecen. Para remediarlo, existen diversos tratamientos; entre ellos el medicamente metilfenidato, un potente psicoestimulante del que se lleva tiempo estudiando si mejora el rendimiento académico de estos niños. Además, existe una gran controversia sobre su uso, ya que se ha observado que genera múltiples efectos secundarios, algunos de ellos bastante nocivos para la salud. Entonces, la finalidad de este trabajo es intentar recopilar todos los estudios que abarquen esta cuestión en la literatura para unificarlos y dar una estimación del efecto del fármaco sobre el rendimiento académico, y observar también cuáles son los efectos secundarios más comunes y más nocivos que pueda ocasionar.

Aromatase inhibitors (AI) are one of the main therapies to treat estrogen-receptor positive breast cancer. AI use is associated with several side effects that affects patient’s quality of life and reduces treatment adherence. Hence, it is necessary to make further efforts in elucidating and diminishing the AI-related side effects. In this line, this thesis provided new and additional evidence for this purpose. Starting by the importance of assessing vitamin D levels during AI treatment, especially to those who underwent to chemotherapy. We also studied the bone health evolution at the end and one-year after AI cessation, and the impact of oral bisphosphonates (BP). Moreover, we analyzed the arthralgia (VAS score) and health-related quality of life in osteoporosis (ECOS-16 score) progression during the AI treatment until one- year post-treatment. Then, fracture incidence and risk during AI therapy compared to tamoxifen (TAM) was analyzed, as well as the protective effect of BP. Finally, we studied the cardiovascular and thromboembolic risk, and overall survival benefit of AI compared to TAM. Our research leads us to state that bone health and circulant vitamin D levels monitoring, plus calcium and vitamin D supplementation is key for the clinical management of AI patients. BP treatment is proved to diminish bone loss and fracture risk, but cannot reverse risk levels towards patients at low fracture risk. Furthermore, prior TAM treatment enhances the odds to withdraw during the first year, increases bone loss during AI treatment, and restricts the recovery in lumbar spine location at one-year post-treatment. On the other hand, since there are no differences in cardiovascular and thromboembolic risk between AI and TAM users, but AI users have lower all-cause mortality, AI should be the preferable choice. In summary, it is mandatory to clinical monitoring AI patients, especially those who were previously treated with TAM, including fracture risk and related risk factors assessments. These would reduce early cessation of treatment and improve patients’ quality of life.

INTRODUCTION: Community-acquired pneumonia (CAP), a major cause of morbidity and mortality, is the leading infectious cause of death in the developed world. Population-based studies and systematic reviews have identified a large number of risk factors for the development of pneumonia in adults. In addition to age, lifestyle habits, and comorbidities, some forms of pharmacotherapy may also increase the risk for CAP. AREAS COVERED: MEDLINE, CENTRAL, and Web of Science were used in 2017 to search for case-control, cohort studies, as well as randomized controlled trials and meta-analysis that involved outpatient proton pump inhibitors (PPIs), inhaled corticosteroids (ICSs), antipsychotics, oral antidiabetics, and CAP diagnosis in patients aged >18 years. EXPERT OPINION: Our review confirmed that the use of ICSs, PPIs or antipsychotic drugs was independently associated with an increased risk for CAP. We also identified a positive association between specific oral antidiabetics and the development of pneumonia.

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer., Spanish Government and EU funds through the Fondo de Investigaciones Sanitarias (FIS, project PI13/ 00089) and from La Marat o de TV3 Foundation (project 20132730) to R. P erez-Tom as. R. Ramos was supported by the Sociedad Espa~nola de Neumología y Cirugía Tor acica (SEPAR, Project 017/2013), R. Quesada by the Consejería de Educación de la Junta de Castilla y León (project BU340U13) and by the La Marat o de TV3 Foundation (project 20132732) and A. Villanueva by the FIS (project PI13/01339).

Concerns regarding the external validity of phase-III trials are common to many medical disciplines, with relevant discrepancies found between experimental and clinical samples in some diseases such as hypertension. The aim of this study was to compare the samples included in the pivotal, phase-III clinical trials of nalmefene with that of a recently conducted phase-IV trial. Baseline characteristics of the studies were compared through univariate analysis. Significant differences were found in the percentage of low-risk drinkers included. Differences were also found in the prescription and intake pattern of nalmefene, as well as in the rate of psychiatric and addictive comorbidities, which were much higher in the phase-IV study. These data suggest that in the field of alcohol use disorders there are also relevant differences between experimental and clinical samples, a fact that reinforces the need for phase-III trials to be balanced with observational, phase-IV trials.

Background Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature. Methods Epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an independent cohort of TN patients and in TN cell lines. Results Twenty-four and 30 patients were included in the discovery and validation cohorts, respectively. In the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under the ROC curve (AUC) = 0.905 (95% CI = 0.805–1.000). Patients with a positive epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if signature were negative. Conclusions These results suggest that pCR in TNBC could be accurately predicted with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective validation of these findings is warranted. Electronic supplementary material The online version of this article (10.1186/s13148-019-0626-0) contains supplementary material, which is available to authorized users.

Background The aim of this study was to determine if the treatment with bisphosphonates other anti-resorptive and antiangiogenic agents influences the success of regenerative and / or implant treatments. Material and Methods We reviewed the literature from the last 5 years in the PubMed database, using the following words: “Sinus Floor Augmentation”[Mesh] OR “Dental Implants”[Mesh]) OR “Guided Tissue Regeneration”[Mesh]) AND “Osteonecrosis”[Mesh]. The articles were selected following the inclusion and exclusion criteria and were evaluated using the 22 items of the STROBE declaration. The following PICO clinical question was applied: Does the treatment with agents associated with drug osteonecrosis influence the success of regenerative and implant treatments? Results The initial search resulted in a total of 27 articles. After eliminating those that did not refer to the topic, were duplicated or did not meet the inclusion / exclusion criteria, a full reading of the articles was made evaluating their methodological quality, obtaining six studies with high methodological quality and two with moderate. Conclusions The literature regarding this topic is scarce, randomized clinical trials would be necessary to establish protocols relative to implant treatment in patients on antiresorptive treatments. The risk of developing an osteonecrosis associated with the regeneration / implant placement in patients with benign bone diseases is scarce, but it exists and it should not be underestimated. Especially, in the posterior areas of the jaw, if the duration of treatment with BP is greater than 3 years, and if the patient is under therapy with systemic corticosteroids. Key words:Bisphosphonates, monoclonal antibodies, implants, sinus lift, guided bone regeneration, osteonecrosis.

Scope The effect of chronic supplementation with simple-sugar solutions on leptin signaling in liver, hypothalamus, and visceral white adipose tissue (vWAT) is studied, which is designed to mimic the temporal pattern of consumption by humans. Methods and results Solutions of fructose or glucose are isocalorically supplemented (7 months) in female Sprague-Dawley rats consuming ad libitum rodent chow. After sacrifice, plasma and tissue samples (liver, hypothalamus, and vWAT) are collected. Zoometric parameters, plasma analytes, and the tissue expression and activity of markers of leptin signaling are determined by biochemical and molecular biological methods. The two sugars cause different types of adiposopathy. Both sugars induce increases in plasma nonesterified fatty acids, and leptin resistance in the liver and the hypothalamus. Only fructose-supplemented rats show hyperleptinemia, and increased body weight due to a hypertrophy of vWAT, with no signs of leptin-mediated lipolysis. Glucose-supplemented rats show no significant changes in these parameters but present elevated plasma adiponectin concentrations, lipolysis, and inflammatory markers in vWAT, indicating a shift to a nonexpandable adipose tissue phenotype. Conclusion Chronic consumption of fructose places a greater burden on metabolic homeostasis than equivalent consumption of glucose, inducing hyperleptinemia, generalized leptin resistance, and increased body weight due to expanded, hypertrophic vWAT.

Aim: to identify short-term and oncologic outcomes of pelvic exenterations (PE) for locally advanced primary rectal cancer (LAPRC) in patients included in a national prospective database. Methods: few studies report on PE in patients with LAPRC. For this study, we included PE for LAPRC performed between 2006 and 2017, as available, from the Rectal Cancer Registry of the Spanish Association of Surgeons [Asociación Española de Cirujanos (AEC)]. Primary endpoints included procedure-associated complications, 5-year local recurrence (LR), disease-free survival (DFS) and overall survival (OS). A propensity-matched comparison with patients who underwent non-exenterative surgery for low rectal cancers was performed as a secondary endpoint. Results: eight-two patients were included. The mean age was 61.8 ± 11.5 years. More than half of the patients experienced at least one complication. Surgical site infections were the most common complication (abdominal wound 18.3%, perineal closure 19.4%). Thirty-three multivisceral resections were performed, including two hepatectomies and four metastasectomies. The long-term outcomes of the 64 patients operated on before 2013 were assessed. The five-year LR was 15.6%, the distant recurrence rate was 21.9%, and OS was 67.2%, with a mean survival of 43.8 mo. R+ve resection increased LR [hazard ratio (HR) = 5.58, 95%CI: 1.04-30.07, P = 0.04]. The quality of the mesorectum was associated with DFS. Perioperative complications were independent predictors of shorter survival (HR = 3.53, 95%CI: 1.12-10.94, P = 0.03). In the propensity-matched analysis, PE was associated with better quality of the specimen and tended to achieve lower LR with similar OS. Conclusion: PE is an extensive procedure, justified if disease-free margins can be obtained. Further studies should define indications, accreditation policy, and quality of life in LAPRC.

Background: Salivary secretory disorders can be the result of a wide range of factors. Their prevalence and negative effects on the patient's quality of life oblige the clinician to confront the issue. Aim: To review the salivary secretory disorders, inducing drugs and their clinical management. Methods: In this article, a literature search of these dysfunctions was conducted with the assistance of a research librarian in the MEDLINE/PubMed Database. Results: Xerostomia, or dry mouth syndrome, can be caused by medication, systemic diseases such as Sjogren's Syndrome, glandular pathologies, and radiotherapy of the head and neck. Treatment of dry mouth is aimed at both minimizing its symptoms and preventing oral complications with the employment of sialogogues and topical acting substances. Sialorrhea and drooling, are mainly due to medication or neurological systemic disease. There are various therapeutic, pharmacologic, and surgical alternatives for its management. The pharmacology of most of the substances employed for the treatment of salivary disorders is well-known. Nevertheless, in some cases a significant improvement in salivary function has not been observed after their administration. Conclusion: At present, there are numerous frequently prescribed drugs whose unwanted effects include some kind of salivary disorder. In addition, the differing pathologic mechanisms, and the great variety of existing treatments hinder the clinical management of these patients. The authors have designed an algorithm to facilitate the decision making process when physicians, oral surgeons, or dentists face these salivary dysfunctions.

Several recent findings suggest that targeting the endogenous cannabinoid system can be considered as a potential therapeutic approach to treat Alzheimer's disease (AD). The present study supports this hypothesis demonstrating that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Moreover, THC + CBD reduced learning impairment in AβPP/PS1 mice. A significant decrease in soluble Aβ42 peptide levels and a change in plaques composition were also observed in THC + CBD-treated AβPP/PS1 mice, suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide. Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role. Here we observed reduced astrogliosis, microgliosis, and inflammatory-related molecules in treated AβPP/PS1 mice, which were more marked after treatment with THC + CBD than with either THC or CBD. Moreover, other cannabinoid-induced effects were uncovered by a genome-wide gene expression study. Thus, we have identified the redox protein thioredoxin 2 and the signaling protein Wnt16 as significant substrates for the THC + CBD-induced effects in our AD model. In summary, the present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD. This study was supported by grants from the Agrupació Mútua Foundation (XVII Award in the Elderly Field, to IF), Mutua Madrileña Foundation (IF), and BESAD-P project, CIBERNED, Instituto Carlos III (IF).

Treball Final de Grau de Podologia, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, curs: 2016-2017, Tutor: Antonio Zalacain, Un gran nombre dels pacients oncològics reben tractament quimioteràpic. La toxicitat derivada dels quimioteràpics (QT) genera, multitud d'afectes adversos, que poden repercutir negativament en la qualitat de vida del pacient. Des d’un punt de vista podològic, adquireixen un paper important, tots aquells efectes secundaris (EESS) que poden tenir repercussió en el peu, donat que identificant-los i analitzant-los, ens pot servir per millorar el benestar global del pacient. L'objectiu del treball és identificar i analitzar els possibles EESS dels QT més utilitzats a l’Hospital de la Santa Creu i Sant Pau (HSCSP) en el peu, així com valorar les possibles actuacions podològiques per abordar dits efectes. Metodològicament, s'ha realitzat una revisió bibliogràfica d’articles publicats en la base de dades PubMed, per identificar les publicacions més rellevants dels EESS dels QT que podem trobar en el peu i com tractar-los. S’han seleccionat un total de 25 articles. En l’anàlisi dels resultats, s’ha confrontat l'informació extreta dels diferents articles, fent evident algunes petites discrepàncies entre diferents autors. Com a conclusions, els efectes cutanis (eritrodisestèsia palmo-plantar (PPE), dermatomicosis, eritema tòxic, pseudocel·lulitis i diversos efectes unguials), conjuntament, amb la neuropatia perifèrica, esdevenen els EESS del QT més freqüents que podem trobar en el peu. Cap dels estudi cercats, defineix ni tracta les possibles actuacions podològiques per abordar aquets efectes.

Treball Final de Grau de Podologia, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, curs: 2016-2017, Tutor: Lourdes Carbonell Bardera, Aquest estudi es centra en els efectes adversos, d’interès podològic, provocats pels fàrmacs quimioteràpics. Aquests efectes els podem englobar bàsicament en dos grups: neuropatia perifèrica (CIPN) i toxicitat cutània que dóna lloc el síndrome d’eritrodèsia palmo-plantar (EPP). Els objectius principals d’aquest treball s’han vist enfocats en la identificació de quins són els efectes adversos més freqüents, d’àmbit podològic, produïts pels fàrmacs més utilitzats en el tractament de neoplàsies i l’avaluació de l’aparició de neuropatia i toxicitat cutània en pacients tractades amb quimioteràpia en l’ Institut Català d’Oncologia (ICO). Els fàrmacs quimioteràpics donen molta toxicitat en forma de toxicitat cutània i en forma de neuropatia perifèrica. Els agents antineoplàstics que solen produir més CIPN són els taxans. Mentre que la toxicitat cutània la provoquen majoritàriament els antimetabòlits. S’ha realitzat un estudi amb 25 casos clínics de pacients tractades amb paclitaxel i docetaxel (taxans), a l’efecte de demostrar l’aparició freqüent de la CIPN i 25 casos clínics de pacients que s’han tractat amb capecitabina (antimetabòlit) per demostrar la gran incidència que té l’EPP. Tots els casos clínics s’han obtingut a través de la col·laboració de l’Institut Català d’Oncologia (ICO). Tota la mostra estudiada tractada amb docetaxel o paclitaxel han presentat neuropatia perifèrica. En quan a la toxicitat cutània, 21 del total de la mostra han presentat toxicitat cutània i 4 pacients no. Es necessari la implantació dels podòlegs en les consultes oncològiques.

Colonization of the gut in early life can be altered through multiple environmental factors. The present study aimed to investigate the effects of 2&rsquo, fucosyllactose (2&rsquo, FL), a mixture of short-chain galactooligosaccharides/long-chain fructooligosaccharides (scGOS/lcFOS) 9:1 and their combination (scGOS/lcFOS/2&rsquo, FL) on dysbiosis induced during rotavirus (RV) diarrhea in neonatal rats, elucidating crosstalk between bacteria and the immune system. The dietary interventions were administered daily by oral gavage at days 2&ndash, 8 of life in neonatal Lewis rats. On day 5, RV SA11 was intragastrically delivered to induce infection and diarrhea assessment, microbiota composition, and gene expression of Toll-like receptors (TLRs) in the small intestine were studied. All dietary interventions showed reduction in clinical variables of RV-induced diarrhea. RV infection increased TLR2 expression, whereas 2&rsquo, FL boosted TLR5 and TLR7 expressions and scGOS/lcFOS increased that of TLR9. RV-infected rats displayed an intestinal dysbiosis that was effectively prevented by the dietary interventions, and consequently, their microbiota was more similar to microbiota of the noninfected groups. The preventive effect of 2&rsquo, FL, scGOS/lcFOS, and their combination on dysbiosis associated to RV diarrhea in rats could be due to changes in the crosstalk between gut microbiota and the innate immune system.

Importance Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). Conclusions and Relevance These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.

Background Several bleeding risk scores have been validated in patients with atrial fibrillation (AF). The ORBIT score has been recently proposed as a simple score with the best ability to predict major bleeding. The present study aimed to test the hypothesis that the ORBIT score was superior to the HAS-BLED score for predicting major bleeding and death in "real world" anticoagulated AF patients. Methods and results We analyzed the predictive performance for bleeding and death of 406 AF patients who underwent 571 electrical cardioversion procedures and 1,276 patients with permanent/persistent AF from the FANTASIIA registry. In the cardioversion population, 21 patients had major bleeding events and 26 patients died. The predictive performance for major bleeding of HAS-BLED and ORBIT were not significantly different (c-statistics 0.77 (95% CI 0.66-0.88) and 0.82 (95% CI 0.77-0.93), respectively; P=0.080). For the FANTASIIA population, 46 patients had major bleeding events and 50 patients died. The predictive performances for major bleeding of HAS-BLED and ORBIT were not significantly different (c-statistics 0.63 (95% CI 0.56-0.71) and 0.70 (95% CI 0.62-0.77), respectively; P=0.116). For death, the predictive performances of HAS-BLED and ORBIT were not significantly different in both populations. The ORBIT score categorized most patients as "low risk". Conclusions Despite the original claims in its derivation paper, the ORBIT score was not superior to HAS-BLED for predicting major bleeding and death in a "real world" oral anticoagulated AF population. (Circ J 2016; 80: 2102-2108).

Aim To assess the toxicity, tolerance, steroid-sparing capacity, effectiveness, and response rate to imatinib and dasatinib for the treatment of severe sclerotic chronic graftvs- host disease (scGVHD). Methods This retrospective study analyzed 8 consecutive patients with severe refractory scGVHD who received salvage therapy with imatinib. Patients intolerant and/or refractory to imatinib received dasatinib treatment. Results 7 patients discontinued imatinib treatment (1 achieved complete response, 5 were resistant and/or intolerant, and 1 developed grade IV neutropenia) and 1 patient achieved prolonged partial response, but died due to an infectious complication while on treatment. 5 patients started dasatinib treatment (3 achieved partial responses and discontinued dasatinib, 1 achieved a durable partial response, but died due to a consecutive rapid pulmonary cGVHD progression and 1 with stable disease discontinued treatment due to gastroenteric intolerance). The response rate (partial and/or complete responses) for severe scGVHD was 25% for imatinib and 60% for dasatinib. Conclusion In our series, dasatinib was better tolerated, safer, steroid-sparing, and had a low incidence of infectious complications, which suggests that it may be a more effective therapeutic alternative for patients with refractory scGVHD than imatinib. Treatment of scGVHD with effective antifibrotic drugs such as TKI, which block the kinase fibrotic pathway, may be a safe and effective therapeutic option, but further studies are needed to confirm our findings.

Quan prenem un medicament volem que sigui efectiu i no ens causi efectes secundaris. Per garantir-ho se segueix un protocol experimental molt estricte. Són les dues cares dels assajos clínics: per aconseguir la màxima seguretat cal que hi hagi voluntaris que s'arrisquin. Precisament, un dels objectius d'aquest protocol, que consta de sis fases consecutives, és garantir també la màxima seguretat per als voluntaris. En la immensa majoria de casos s'aconsegueix, però malauradament, en comptades ocasions, com ha passat a França aquesta setmana, hi ha voluntaris que en surten perjudicats, a vegades amb conseqüències greus.

The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 − and Abcd1 − /Abcd2 −/− mice) and X-ALD patient’s fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 − /Abcd2 −/− mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1655-9) contains supplementary material, which is available to authorized users.

Viscerotropic disease (VTD) is defined as acute multiple organ system dysfunction that occurs following vaccination. The severity of VTD ranges from relatively mild multisystem disease to severe multiple organ system failure and death. The term VTD was first used shortly after the initial published reports in 2001 of febrile multiple organ system failure following yellow fever (YF) vaccination. To date, VTD has been reported only in association with YF vaccine and has been thus referred to as YF vaccine-associated viscerotropic disease (YEL-AVD).

Cisplatin is a highly effective chemotherapeutic agent that is widely used to treat solid organ malignancies. However, serious side effects have been associated with its use, such as bilateral, progressive, irreversible, dose-dependent neurosensory hearing loss. Current evidence indicates that cisplatin triggers the production of reactive oxygen species in target tissues in the inner ear. A variety of agents that protect against cisplatin-induced ototoxicity have been successfully tested in cell culture and animal models. However, many of them interfere with the therapeutic effect of cisplatin, and therefore are not suitable for systemic administration in clinical practice. Consequently, local administration strategies, namely intratympanic adminis- tration, have been developed to achieve otoprotection, without reducing the antitumoral effect of cisplatin. While a considerable amount of pre-clinical information is available, clinical data on treatments to prevent cisplatin ototoxicity are only just beginning to appear. This review summarizes clinical and experimental studies of cisplatin ototoxicity, and focuses on understanding its toxicity mechanisms, clinical repercussions and prevention strategies.

Ototoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs). However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3′-iminodipropionitrile (IDPN). Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI) and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents) and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure., Summary: New forms of damage and repair have been identified in the vestibular sensory epithelium using a rat model of chronic ototoxicity and recovery that causes reversible vestibular dysfunction.

Purpose: The aim of the study was to evaluate the opinions and concerns of hospital doctors about adverse drug reactions (ADRs) and pharmacovigilance. Methods: A qualitative study was undertaken using focus groups in sessions on pharmacovigilance activities conducted in thirteen clinical services of a tertiary university hospital. A total of 296 physicians participated in these sessions by giving their opinions or expressing their doubts about ADR and pharmacovigilance activities which were recorded by different observers and subsequently analysed. Results: Doctors remarked on: a) the importance, concern, frequency and specific types of ADRs that were observed in clinical practice; b) problems of clinical decision making related to the suspected ADRs; c) methods for improving detection and reporting ADRs; d) monitoring of specific ADRs or ADRs caused by specific drugs; e) and measures to prevent and minimize the risk of ADRs. Physicians expressed doubts related to: a) the basic concepts of ADRs; b) the methods of ADR identification and evaluation; c) the objectives and procedures of pharmacovigilance programmes; d) and the impact of pharmacovigilance activities. Conclusions: Hospital doctors believe that ADRs are a matter for concern in their daily clinical practice, and monitoring ADRs as well as measures for preventing the risk of ADRs are needed. Nevertheless, doctors have doubts about what an ADR is, the accuracy of diagnostic methods, the development of pharmacovigilance activities and their impact on clinical practice. Pharmacovigilance should be better explained through a continuous feedback and close relationship with hospital doctors.

Computed tomography angiography (CTA) detects signs of large-vessel vasculitis (LVV) in about 67.5% of patients with giant-cell arteritis (GCA) at the time of diagnosis and early aortic dilatation in 15%. The outcome of CTA-findings of LVV upon glucocorticoid treatment has not been prospectively evaluated. The aim of our study was to prospectively assess glucocorticoid-induced changes in CTA findings of LVV in patients with GCA. Forty biopsy-proven GCA patients evaluated by CTA at diagnosis were prospectively followed and scheduled a new CTA approximately after 1 year of treatment. Vessel wall thickening, diameter, and contrast enhancement of the aorta and its tributaries were evaluated. Results were compared to those obtained at the time of diagnosis. CTA was repeated to 35 patients after a median follow-up of 13.5 months (IQ25–75% 12.4–15.8). Arterial wall thickening was still present in 17 patients (68% of the patients who initially had LVV). The number of affected segments and wall thickness at various aortic segments significantly decreased and no patients developed new lesions, new aortic dilation or increase in previous dilation. Contrast enhancement disappeared in 15 (93.75%) of 16 patients in whom this finding could be assessed. Signs of LVV improve with treatment. While contrast enhancement resolves in the majority of patients, vessel wall thickening persists in two thirds. However, the number of affected aortic segments as well as aortic wall thickness significantly decreases. Longer follow-up is necessary to determine the clinical significance of persisting wall thickening and its relationship with relapses or subsequent development of aortic dilatation or large-vessel stenoses.

Objectives It has been suggested that statins have an effect on the modulation of the cytokine cascade and on the outcome of patients with community-acquired pneumonia (CAP). The aim of this prospective, randomised, double-blind, placebo-controlled trial was to determine whether statin therapy given to hospitalised patients with CAP improves clinical outcomes and reduces the concentration of inflammatory cytokines. Setting A tertiary teaching hospital in Barcelona, Spain. Participants Thirty-four patients were randomly assigned and included in an intention-to-treat analysis (19 to the simvastatin group and 15 to the placebo group). Intervention Patients were randomly assigned to receive 20 mg of simvastatin or placebo administered in the first 24 h of hospital admission and once daily thereafter for 4 days. Outcome Primary end point was the time from hospital admission to clinical stability. The secondary end points were serum concentrations of inflammatory cytokines and partial pressure of arterial oxygen/fractional inspired oxygen (PaO2/FiO2) at 48 h after treatment administration. Results The trial was stopped because enrolment was much slower than originally anticipated. The baseline characteristics of the patients and cytokine concentrations at the time of enrolment were similar in the two groups. No significant differences in the time from hospital admission to clinical stability were found between study groups (median 3 days, IQR 2–5 vs 3 days, IQR 2–5; p=0.47). No significant differences in PaO2/FiO2 (p=0.37), C reactive protein (p=0.23), tumour necrosis factor-α (p=0.58), interleukin 6 (IL-6; p=0.64), and IL-10 (p=0.61) levels at 48 h of hospitalisation were found between simvastatin and placebo groups. Similarly, transaminase and total creatine kinase levels were similar between study groups at 48 h of hospitalisation (p=0.19, 0.08 and 0.53, respectively). Conclusions Our results suggest that the use of simvastatin, 20 mg once daily for 4 days, since hospital admission did not reduce the time to clinical stability and the levels of inflammatory cytokines in hospitalised patients with CAP. Trial registration number ISRCTN91327214.

Treballs Finals de Grau d'Enginyeria Informàtica, Facultat de Matemàtiques, Universitat de Barcelona, Any: 2015, Director: Laura Igual Muñoz, Nowadays the usage of web applications in order to manage and look up information is on the rise. These applications are known as data-driven applications because they use information as the base of their operation. They are mainly used by companies to make their workers jobs easier, thus minimizing the time wasted looking for information. During this project, an application programming interface (API) and a web application that will use said API will be implemented. The information that will be shown is from a table that was created as a result of a study done by the faculty of pharmacy of the University of Barcelona. This study was done with the collaboration of some doctors specialized in renal illnesses. The aims of this study were to determine the prevalence of dosing inadequacy as a consequence of renal impairment in patients over 65 that were taking 3 or more drug products and who were being attended in community pharmacies, and to evaluate the effectiveness of the community pharmacist intervention in addressing the problem of dosing inadequacy as a consequence of renal impairment in patients over 65 years that were taking 3 or more drugs when compared with usual care. This web application will allow doctors and pharmacists to access this table with ease. This document explains how the project has been developed using the framework Spring MVC, Java, AngularJS and JPA with Hibernate. It will detail its different parts: study of the possibilities, the configuration of the different technologies, the web and API development process and all the tests that have been made with the professors from the faculty of pharmacy of the University of Barcelona. The goal was to work with technologies, architectures and techniques used in the world of work in order to create a quality product as well as studying said technologies.

BACKGROUND: Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. METHODS: In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTS: The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; PLaila Hübbert vid avdelningen för kardiovaskulär medicin samt kardiologiska kliniken US, tillhör "AMBITION Investigators"

Background The effects of dual antiplatelet therapy (DAPT) and triple therapy (TT: DAPT plus oral anticoagulation) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) regarding to CHA2DS2-VASc score remain undefined.We compare the effect of TT vs. DAPT in this setting regarding the CHA2DS2-VASc score. Methods and results In a prospective multicenter registry, 585 patients (75.2% male, 73.2 ± 8.2 years) with AF undergoing PCI were followed up during 1 year. Of them, 157 (26.8%) had a CHA2DS2-VASc=1, and 428 (73.2%) had a CHA2DS2-VASc ≥2. TT was prescribed in 51.6% with CHA2DS2-VASc=1 and in 55.5% with CHA2DS2-VASc ≥ 2. Patients with CHA2DS2-VASc=1 receiving TT had a similar thromboembolism rate to those on DAPT (1.2% vs. 1.3%, P=0.73), but more total (19.5% vs. 6.9%, P=0.01) and a tendency to more major (4.9% vs. 0%, P=0.06) bleeding. However, patients with CHA2DS2-VASc ≥ 2 receiving TT had a lower thromboembolism rate (1.7% vs. 5.3%, P=0.03) and a trend towards more bleeds (21.8% vs. 15.6%, P=0.06), with an excess of major bleeding (8.4% vs. 3.1%, P=0.01). Rates of major adverse cardiac events (MACE) in both CHA2DS2-VASc subgroups were similar, irrespective of treatment. In a Cox multivariate analysis, TT was associated to major bleeding, but not with MACE. Conclusions In patients with AF and CHA2DS2-VASc=1 undergoing PCI, the use of TT involves a high risk of bleeding without a significant benefit in preventing thromboembolism.

Objective In agreement with EULAR recommendations, a DMARD in combination with a biotherapy is the reference treatment because of the superior long-term clinical and radiographic outcomes. Methotrexate (MTX) is the cornerstone of combination therapy but is in some cases contra-indicated or poorly tolerated. This observational study aimed to compare the effectiveness and safety of TCZ in combination with either MTX or leflunomide (LEF) in the treatment of patients with active rheumatoid arthritis (RA) and an inadequate response to one or more DMARDs and/or biological agents in a real-world setting. Methods We performed an ambispective review of 91 patients with active RA who were routinely treated with TCZ plus MTX or LEF. A comparative study between the two combinations of treatment was performed at 6 months of follow-up considering 3 outcomes: improvement of RA disease activity, evolution of functional disability, and tolerability and side effect profile. Results Of the 91 patients, 62 received TCZ with MTX and 29 received TCZ with LEF. Eighty-one patients were followed for 6 months, and the remaining 10 patients discontinued treatment due to serious adverse events. At baseline, there were no significant differences between the groups in terms of the main clinical and laboratory data or in the number of previous DMARDs and biological agents used. At 6 months, there were no significant differences between the combinations in terms of disease activity and functional disability. Serious adverse events occurred in 11% and 10% of the patients treated in combination with MTX and LEF, respectively. Conclusion Our preliminary data support the argument that LEF is an effective and safe (equivalent) alternative to MTX for combination treatment with TCZ.

BackgroundSmall vessel disease (SMD) remains a major challenge because of the increased risk of restenosis. We sought to assess the efficacy and safety of a paclitaxel-eluting balloon (PEB) in patients with SMD. Methods and ResultsOne-hundred and four patients with native coronary lesions in small vessels treated by using a PEB were included in this prospective multicenter registry. In each case, after regular balloon dilatation, a larger PEB was inflated for a minimum of 45-60 seconds. Patients were 6510 years old, 43% diabetic, and 58% presented acutely. Angiographic success was 93% (7% bailout BMS implantation due to coronary dissection). The rate of major adverse cardiac events (MACE) at 12 months was 4.8% (1.9% cardiac death, 1.0% MI, and 2.9% TLR). One definite stent thrombosis was reported at 6 months in a patient with bailout BMS implantation. At 7 months, late loss was 0.31 +/- 0.2mm. Bail-out BMS after DEB use, was an independent predictor of MACE, HR 18.74, 95%CI (2.58-135.84) and TLR, HR 30.99, 95%CI (2.79-344.07). ConclusionThe use of this PEB for the treatment of SMD provides excellent 1-year outcomes with only 4.8% MACE. The need for a bailout BMS was a strong predictor of MACE and TLR. (J Interven Cardiol 2015;28:430-438)

Objectius: Comparar l’efectivitat de la infusió de llantèn o clorhexidina al 0,12% versus la dissolució aqüosa de bicarbonat sòdic al 5%, en el tractament simptomàtic de la mucositis oral. Hipòtesi: El temps de curació de la mucositis oral mitjançant infusió de llantèn o clorhexidina al 0,12% serà inferior que amb bicarbonat sodic 5%. Metodologia: Estudi multicèntric, assaig clinic fase III aleatoritzat, triple cec. Mostra estimada de 45 pacients (15 per branca) afectes de tumor sòlid amb mucositis grau II-III durant la quimioteràpia (α:5%, β: 20). Període Inclusió: 2006 a 2009. Els pacients foren randomitzats a rebre durant un brot de mucositis: *Branca A: Bicarbonat sòdic 5% + Bicarbonat sòdic 5%; *Branca B: Bicarbonat sòdic 5% + infusió de llantèn; *Branca C: Bicarbonat sòdic al 5% + Clorhexidina al 0,12%; durant un període de tractament de 14 dies. Les variables d’estudi foren: grau de mucositis (OMS), dolor (EVA), qualitat de vida (EORTC QLQ-C30), nivells de neutròfils, fàrmac i dosi de quimioteràpia rebuda, pes, ingesta i dades sociodemogràfiques. Els pacients varen ser avaluats presencialment el dia 0, 7, 14 o curació; així com monitoritzats diàriament amb diari de camp i trucada telefònica. S’han obtingut els permisos necessaris de l’AEMPS i CEICs de referència. Resultats: Foren randomitzats 60 pacients dels quals han estat avaluats 50 participants per retirada de 10 pacients. El 38% (19) de la mostra se van rebre glopeig amb Bicarbonat-Clorhexidina, un 32% (16) va rebre Bicarbonat-Bicarbonat i la resta glopeig de Bicarbonat-Llanten. El 52% (26) dels casos foren dones, amb una edat situada en 59,5 anys (DS: 14,3). La mitjana de cicles de tractaments quimioteràpics realitzats fou de 3,6 (DS: 3,2). El 65,3% (32) dels pacients van rebre algun tipus de tractament mucotòxic en el darrer cicle de quimioteràpia. Els participants presentaren a l’inici de l’estudi un nivell de mucositis de grau II en el 86% (43) dels casos, essent la resta de grau III. El dolor mig basal fou de 4 punts (DS: 2,6) segons EVA. El temps mig de tractament per al global de la mostra fou de 8,8 dies (DS: 4,1), rang 2 a 14 dies. Dels 50 pacients inclosos, 34 d’ells arribaren a la curació total (grau 0), presentant una diferència de 2 dies d’evolució a favor del glopeig exclusiu de bicarbonat, 5 dies [IC 95%: 3,99-6,55] front als grups amb clorhexidina 7 dies [IC 95%: 5,33-8,98] i llanten 7 dies [IC 95%: 5,27-8,53] (p=0,991). El grau de dolor dels pacients va evolucionar favorablement durant els 14 dies de tractament situant-se al final de l’estudi amb un EVA=1 (DS:1,8), no s’apreciaren diferencies segons el glopeig (p=0,762). Al finalitzar els 14 dies de tractament, un 98% (49) dels pacients toleraven liquids i solids sense diferencies pel glopeig rebut (p=0,702). La qualitat de vida global basal fou de 53 punts (DS: 21,2) de mitjana (rang 0 a 83), sense millora a la resolució de la mucositis. No s’observa diferència en l’evolució de la qualitat de vida dels pacients entre el pre i el post tractament de la mucositis (p=0,670), ni segons glopeig (p=0,164) No existeixen diferències concloents vers el millor glopeig en el tractament de la mucositis oral, però cal destacar la rellevància clínica de l’ús dels glopejos de bicarbonat sòdic exclusivament, els quals milloren el temps de curació respecte a la resta. El procés evolutiu de la mucositis oral provoca una millora en el control del dolor amb el pas del temps. No s’aprecien diferències en la qualitat de vida dels pacients a l’inici i final de la mucositis. Les àrees emocionals i socials presenten major afectació, així com una major presència d’anorexia i fatiga., Objectives: To compare the effectiveness of Plantago major solution on the one hand and on the other Chlorhexidine 0.12% in the symptomatic treatment of oral mucositis compared to Bicarbonate 5% Aqueous solution (S.B.5%) on solid tumor cancer patients treated at the Catalan Institute of Oncology and the Hospital Spirit Sant Foundation between 2006 and 2009. Methodology: Multicenter, experimental, randomized phase III clinical trial, triple-blind study with three types of rinses to evaluate treatment of oral mucositis secondary to Chemotherapy. We estimated a sample of 45 patients (15 for arm) affected by solid tumor with mucositis grade II-III during (α: 5% β: 20). Patients were randomized to receive one of three treatment arms, with two types of oral rinses during a single outbreak of mucositis: (A) with S.B.5%+S.B.5% (B) with S.B.5%+Plantago Major solution, (C) with S.B.5%+Chlorhexidine 0.12%; during a treatment period of 14 days. Variables: demographics, neutrophil level, drug and dose of chemotherapy received, severity of mucositis (WHO scale), pain intensity (VAS) and Quality of life (EORTC QLQ-30). Results: Fifty patients were evaluated after excluding 10 of the 60 randomised patients that were eligible. Of the cases 52% (n=26) were women. All participants were Caucasian, with mean age 59.5 years (SD 14.3). Of the 50 patients enrolled, 34 (68%) achieved complete healing or degree 0, showing a difference of 2 days for the exclusive bicarbonate rinse - 5 days [CI 95%, 3.99-6.55] compared to Chlorhexidine groups - 7 days [CI 95%, 5.33-8.98] and Plantago Major – 7 days [CI 95%, 5.27-8.53]. Differences on the degree of pain did not show statistical significance with regard to any of the rises types (p=0.762). No difference was observed in the evolution of the quality of life of patients between the pre and post treatment of mucositis (p=0.670), or with the application or not of different types of experimental treatment (p=0.164) Conclusions: The bicarbonate solution improved the healing time and decreased the symptoms such as pain, compared to the rest of solutions; however no conclusive difference between the efficacy of the three solutions were found among this population.

Treballs Finals de Grau de l'Escola Universitaria d'Infermeria, Universitat de Barcelona, Curs: 2014-2015, Tutor: Núria Fabrellas i Padrès, La medicalització és el procés de convertir situacions normals de la vida quotidiana en quadres patològics, que es pretenen resoldre mitjançant intervencions mèdiques i farmacològiques. La societat de consum en la que estem immersos, on es viu a una velocitat exageradament ràpida, ha introduït la medicina en molts aspectes de la vida quotidiana (cesàries, relacions sexuals, ansiolítics), aquest fet ha generat, en molts casos, intervencions innecessàries o excessives. Objectiu: Realitzar una revisió bibliogràfica per conèixer el terme “medicalització de la vida” i el paper que té la infermera per fer front a aquesta tendència al llarg de les diferents etapes de la vida. Metodologia: S’ha realitzat una cerca de documents en les bases de dades CINAHL, IME, Cuidatge, Cuiden, ENFISPO i PubMed, dels darrers 5 anys. La cerca s’ha centrat en 2 conceptes: medicalització i promoció de la salut. Resultats: Després d’incloure els articles que complien els criteris de selecció, s’han identificat i analitzat 14 articles, dels quals 10 són en espanyol i 4 en anglès. Discussió: De l’anàlisi d’aquests articles s’han identificat cinc blocs: concepte medicalització, descripció dels responsables, conseqüències de la medicalització, actuació des d’infermeria, i propostes de desmedicalització. Conclusions: Una societat més medicalitzada és una societat amb una gran percepció de malestar i dependència dels serveis sanitaris. La intervenció infermera és fonamental per educar la població i impulsar la prevenció i promoció de salut des d’un camp menys farmacològic, per aconseguir que la població sigui autònoma en l’autocura i per disminuir el nivell d’intolerància al patiment i malestar en les diferents situacions de la vida.

The nitrile 3,3′-iminodipropionitrile (IDPN) causes a loss of hair cells in the vestibular epithelium of the inner ear in several species of both mammals and nonmammals. It is of interest as a model compound in ototoxicity and vestibular regeneration research, but its effects on the mouse, including the potential relevance of strain and sex differences for susceptibility, have not yet been thoroughly characterized. In this study, we compared the vestibular toxicity of IDPN in dose–response studies (0, 8, 12, 16, and 24 mmol/kg IDPN p.o.) in males and females of 2 different mouse strains (RjOrl:Swiss/CD-1 and 129S1/SvImJ). 3,3′-Iminodipropionitrile caused a dose-dependent loss of vestibular function in all sex and strain groups, as assessed by a specific battery of behavioral tests. However, large differences in systemic toxicity were recorded, with high systemic toxicity in 129S1 mice of both sexes compared to limited effects on the Swiss mice. Both male and female Swiss mice showed a marked increase of hindlimb stride width after exposure. The Swiss, but not the 129S1, mice treated with IDPN showed hyperactivity in the open field. The dose–response relationships in the behavioral effects were matched by the extent of hair cell loss assessed by scanning electron microscopy. Altogether, the data demonstrated prominent strain-dependent differences in the systemic toxicity of IDPN between 129S1 and Swiss mice, in contrast to no differences between the strains and small differences between the sexes in its vestibular toxicity. These results support the use of Swiss mice exposed to IDPN as a mouse lesion model for research in vestibular therapy and regeneration This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO)—FEDER (grant numbers BFU2012-31164 and BFU2015-66109-R) and the Generalitat of Catalonia (grant number 2014 SGR 943)

The mechanisms that control the emergence of different anterior pituitary cells from a common stem cell population are largely unknown. The immortalized GHFT cells derived from targeted expression of SV40 T antigen to mouse pituitary display characteristics of somatolactotropic progenitors in that they express the transcription factor GHF-1 (Pit-1) but not growth hormone (GH) or prolactin (PRL). We searched for factors capable of inducing lactotropic differentiation of GHFT cells. PRL gene expression was not observed in cells subjected to a variety of stimuli, which induce PRL gene expression in mature lactotropes. Only fibroblast growth factor-2 (FGF-2) was able to initiate the transcription, synthesis, and release of PRL in GHFT cells. However, induction of PRL expression was incomplete in FGF-2-treated cells, suggesting that additional factors are necessary to attain high levels of PRL transcription in fully differentiated lactotropes. We also show that the FGF-2 response element is located in the proximal PRL promoter. Stimulation of PRL expression by FGF-2 requires endogenous Ets factors and these factors as well as GHF-1 are expressed at low levels in the committed precursor, suggesting that these low levels are limiting for full PRL expression. Moreover, FGF-2 effect on lactotrope differentiation is mediated, at least partially, by stimulation of the Ras-signaling pathway. Our results suggest that, indeed, GHFT cells represent a valid model for studying lactotropic differentiation and that FGF-2 could play a key role both in initiating lactotrope differentiation and maintaining PRL expression.

The induction of cell death by aspirin was analysed in HT-29 colon carcinoma cells. Aspirin induced two hallmarks of apoptosis: nuclear chromatin condensation and increase in phosphatidylserine externalization. However, aspirin did not induce either oligonucleosomal fragmentation of DNA, decrease in DNA content or nuclear fragmentation. The effect of aspirin on Annexin V binding was inhibited by the caspase inhibitor Z-VAD.fmk, indicating the involvement of caspases in the apoptotic action of aspirin. However, aspirin did not induce proteolysis of PARP, suggesting that aspirin does not increase nuclear caspase 3-like activity in HT-29 cells. This finding may be related with the ‘atypical’ features of aspirin-induced apoptosis in HT-29 cells. © 1999 Cancer Research Campaign

[cat] L'aspirina i els fàrmacs antiinflamatoris no esteroïdals (AINEs ) es troben entre els fàrmacs més utilitzats en el món. En general són ben tolerats per la majoria dels individus, però hi ha una excepció en un subgrup particular de pacients asmàtics. Aquests pacients pateixen asma induïda per aspirina (AIA), una síndrome clínica caracteritzada per atacs d'asma provocats després de la ingestió d'AINEs. A més, aquests pacients sovint pateixen de rinosinusitis crònica acompanyada de poliposi nasal (CRSwNP). De fet, la prevalença de CRSwNP en pacients amb AIA és d'aproximadament 60-70 %. La patogènesi de l'AIA segueix sent poc coneguda, però s'accepta que les alteracions en el metabolisme de l'àcid araquidònic poden estar implicades. En aquests pacients s’ha descrit que la via de la 5-lipoxigenasa es troba molt activada, fet que resulta en l’increment de la producció de cisteinil leucotriens. Per contra, els estudis que s’han centrat en la via de la ciclooxigenasa en pacients amb asma induïda per aspirina s’han trobat resultats contradictoris, que van de la disminució a un increment en l’activitat de la via de la ciclooxigenasa. En aquesta tesi doctoral s’ha estudiat el metabolisme de l'àcid araquidònic en les vies respiratòries superiors de pacients que pateixen d'AIA. Aquesta investigació s'ha centrat sobretot en l'estudi de la via de la ciclooxigenasa i la seva regulació en cultius de fibroblasts procedents de mucosa nasal i pòlips nasals de pacients amb o sense AIA., [eng] Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in the world. They are usually well tolerated by most subjects but there is an exception in a particular subset of asthmatic patients. These patients suffer from so-called aspirin-induced asthma (AIA), a clinical syndrome characterized by asthma attacks triggered by the ingestion of NSAIDs. Furthermore, these patients frequently suffer from chronic rhinosinusitis with nasal polyposis (CRSwNP). In fact, the prevalence of CRSwNP in AIA patients is about 60-70%. The pathogenesis of AIA remains poorly understood but it is accepted that alterations in the arachidonic acid metabolism may be involved. An overactive 5-lipoxygenase pathway has been reported in these patients, resulting in increased cysteinyl leukotriene production. In contrast, studies focusing on the cyclooxygenase pathway in aspirin-induced asthma subjects have reported contradictory results, ranging from reduced to increased activity of the cyclooxygenase pathway. This doctoral thesis examines the arachidonic acid metabolism in the upper airways of patients suffering from AIA. This research has particularly focused on the study of the cyclooxygenase pathway and its regulation in fibroblasts cultured from nasal mucosa and nasal polyps of patients with or without AIA

Transforming growth factor-beta (TGF-beta), a growth regulator of fetal hepatocytes in primary culture, also regulates death of these cells. Dose-response analysis showed that the TGF-beta concentration needed to induce hepatocyte death (2.5 ng/ml) was 5 times that needed to inhibit growth in these cells (0.5 ng/ml). In response to TGF-beta, hepatocytes induced DNA fragmentation and the appearance of nuclei with a DNA content lower than 2C (diploid content), typical of a programmed cell death model. TGF-beta-induced apoptosis in fetal hepatocytes was preceded by an induction of reactive oxygen species production and a decrease in the glutathione intracellular content, indicating that this factor induces oxidative stress in fetal hepatocytes. Studies performed to analyze levels of c-fos mRNA, a gene whose expression is modulated by redox state, demonstrated that only high, apoptotic concentrations of TGF-beta (2.5 ng/ml) produced an increase in the mRNA levels of this gene, the level of induction being similar to that found when cells were incubated in the presence of tert-butyl hydroperoxide. Gel mobility shift assays showed that the c-fos-induced expression was coincident with an increase in AP-1 activity. Finally, cell death induced by TGF-beta in fetal hepatocytes was partially blocked by radical scavengers, which decreased the percentage of apoptotic cells, whereas these agents did not modify the growth-inhibitory effect elicited by TGF-beta in these cells. In summary, the results presented in this paper provide evidence for the involvement of an oxidative process in the apoptosis elicited by TGF-beta in fetal hepatocytes.

Introduction The emergence of multidrug resistant (MDR) Gram-negative bacteria (GNB), including carbapenemase-producing strains, has become a major therapeutic challenge. These MDR isolates are often involved in complicated urinary tract infection (cUTI), and are associated with poor clinical outcomes. The study has been designed to gain insight into the epidemiology, clinical management, outcome and healthcare cost of patients with cUTI, especially in countries with high prevalence of MDR GNB. Methods and analysis This multinational and multicentre observational, retrospective study will identify cases from 1 January 2013 to 31 December 2014 in order to collect data on patients with cUTI as a cause of hospital admission, and patients who develop cUTI during their hospital stay. The primary end point will be treatment failure defined as the presence of any of the following criteria: (1) signs or symptoms of cUTI present at diagnosis that have not improved by days 5–7 with appropriate antibiotic therapy, (2) new cUTI-related symptoms that have developed within 30 days of diagnosis, (3) urine culture taken within 30 days of diagnosis, either during or after completion of therapy, that grows ≥104 colony-forming unit/mL of the original pathogen and (4) death irrespective of cause within 30 days of the cUTI diagnosis. Sample size 1000 patients afford a power of 0.83 (α=0.05) to detect an absolute difference of 10% in the treatment failure rate between MDR bacteria and other pathogens. This should allow for the introduction of about 20 independent risk factors (or their interaction) in a logistic regression model looking at risk factors for failure. Ethics and dissemination Approval will be sought from all relevant Research Ethics Committees. Publication of this study will be considered as a joint publication by the participating investigator leads, and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). Trial registration number NCT02641015; Pre-results.

espanolEn los ultimos anos, el numero de pacientes que presenta osteonecrosis maxilar asociada al uso de bifosfonatos (BIONJ) se ha incrementado. Esto es debido al aumento en el consumo de bifosfonatos, los cuales se asocian al tratamiento de carcinomas con metastasis oseas, mieloma multiple, osteoporosis, osteopenia y enfermedades metabolicas como la enfermedad de Paget. Objetivo: Analizar el numero de casos de pacientes que han desarrollado osteonecrosis de maxilares asociado al uso de bifosfonatos, publicados desde Junio del ano 2006 hasta Abril 2010. Metodo: En esta revision, se consultaron las bases de datos Pubmed-Medline, Scielo e indice Medico Espanol, incluyendo limites en la busqueda, para recopilar los casos de BIONJ que se hayan publicado desde el ano 2006 hasta la actualidad. Los articulos seleccionados presentaban casos, en los cuales los pacientes que recibian bifosfonatos desarrollaban BIONJ. Resultados: Se encontraron 491 casos de BIONJ en total, de ellos 49,3% eran mujeres, 32% hombres y 18,7% no se establecia el genero. La mayoria de estos casos se presentaron en la mandibula y asociados particularmente al acido zolendronico. Conclusiones: En los proximos anos se espera que el numero de pacientes que desarrollen esta complicacion vaya en aumento, en particular en mujeres, a las cuales se les indica cada vez mas esta medicacion para el tratamiento de la osteoporosis. EnglishIn the last years, the number of patients presenting jaw osteonecrosis associated with the use of bisphosphonates (BIONJ) has increased. This is due to increased consumption of bisphosphonates, which are associated with the treatment of carcinomas with bone metastases, multiple myeloma, osteoporosis, osteopenia and metabolic diseases such as Paget's disease. The aim of this review is to analyze the number of cases of patients who developed jaws osteonecrosis-associated with the use of bisphosphonates, published from June 2006 to April 2010. In this review, we referred to the databases Pubmed-Medline, Scielo and Spanish Medical Index, including limits on the search to collect BIONJ cases published from 2006 up to now. The selected papers presented cases in which the patients who received bisphosphonates developed BIONJ. We found 491 cases of BIONJ in total, of which 49.3% correspond to women, 32% to men and 18.7%, did not establish gender. Most of these cases occurred in the mandible and associated particularly with zoledronic acid. In the coming years it is expected that the number of patients who develop this complication increase, particularly in women, who are more and more prescribed this medication for the osteoporosis treatment.

Personality differences based on fine motor precision performance were studied in early stage Parkinson’s patients and an age-matched control group under two different test conditions: Proprioceptive + visual information and proprioceptive information alone. A comparative data analysis for deviations of three measured movement types (transversal, frontal and sagittal) was done for both hands (dominant and non-dominant) with relation to personality di-mensions. There were found significant differences between the two groups in decision making dimension and emotionality. After splitting the data for gender subgroups, some significant differences were found for men but not for women. The differences in fine motor task performance varied, being better in some directions for the Parkinson’s patients and worse in others. The findings may suggest that medication has both positive and negative effects on motor per-formance and provoke personality changes, being more pronounced in men., Las diferencias de personalidad basadas en la precisión de la ejecución motora fina fueron estudiadas en pacientes con Parkinson en la etapa inicial de la enfermedad y en un grupo control de edad similar bajo dos con-diciones de ensayo diferentes: información propioceptiva + visual y solo información propioceptiva. Se hizo un análisis de datos comparativo de las desviaciones en los tres tipos de movimiento medidos (transversal, frontal y sagital) con las dos manos (dominante y no dominante) y en relación a las dimensiones de la personalidad. Se encontraron diferencias significativas entre los dos grupos en las dimensiones toma de decisiones y emotividad. Después de dividir los datos en subgrupos según el género, se encontraron algunas diferencias significativas para los hombres pero no para las mujeres. Las diferencias en el rendimiento en estas tareas variaron, siendo mejor en algunas direcciones para los pacientes de Parkinson y peor en otras. Los hallazgos sugieren que la medicación puede tener efectos tanto positivos como negativos en el rendimiento motor y provocar cambios en la personalidad, siendo más pronunciados en los hombres

Ritonavir-related adverse events have been reported in patients taking tipranavir/ritonavir at the licensed dosage of 500/200 mg twice daily (bid). The aim of this open-label, prospective, single-arm pilot study was to evaluate the efficacy and safety of a ritonavir dose reduction to 100 mg bid guided by the tipranavir virtual inhibitory quotient (vIQ) in HIV-infected patients receiving tipranavir/ritonavir 500/200 mg bid whose viral load was 60. Viral load, blood chemistry, and tipranavir and ritonavir trough concentrations (C(trough)) in plasma were determined at baseline and up to 48 weeks. If the tipranavir vIQ fell to

espanolLa osteonecrosis de los maxilares en pacientes con cancer se asociaba, hasta ahora, con la radioterapia, aunque recientemente se han reportado numerosos casos de osteoquimionecrosis de los maxilares (OQNM) relacionada con la quimioterapia, y mas concretamente con el uso de los bifosfonatos (agentes inhibidores de la actividad osteoclastica), utilizados para el tratamiento de las metastasis oseas. Los bifosfonatos inhiben la actividad osteoclastica dando lugar a una disminucion de la reabsorcion y la remodelacion del hueso, comprometiendo su irrigacion. Si bien la disminucion del aporte vascular en el hueso podria presentarse en cualquier localizacion, parece logico que en la mayoria de los casos afecte a los huesos maxilares debido a que su vascularizacion es de tipo terminal, y al hecho de que es un hueso expuesto a agresiones del medio exterior, ya sea a traves del periodonto o del conducto radicular. Se presentan las complicaciones observadas en 6 casos de OQNM desencadenadas tras la ejecucion de diversas terapias quirurgicas bucales en pacientes sometidos a un tratamiento con bifosfonatos por diferentes patologias y su manejo terapeutico. El tratamiento de este tipo de OQNM suele ser insatisfactorio, ya que ninguna de las opciones terapeuticas descritas en la literatura ha obtenido buenos resultados. Todos los pacientes que van a recibir o han recibido tratamiento con bifosfonatos deben ser considerados como pacientes de riesgo de OQNM, y deben someterse a las mismas medidas profilacticas descritas para la prevencion de la osteorradionecrosis. EnglishOsteonecrosis of the jaws in cancer patients is associated, until now, with radiotherapy. Many cases of maxillary osteoquimionecrosis (MOQN) related to chemotherapy have been reported recently, more specifically with the use of bisphosphonates (inhibitors agents of osteoclastic activity) to treat bone metastasis. Bisphosphonates Osteoquimioinhibit osteoclastic activity leading to a decrease of the resorption and the remodeling of bone and compromising its irrigation. Although the decrease in bone vascular contribution can be presented in any location, it seems logical that it most commonly affects the jaw, because of its terminal vascularization, and the fact that it is easily attackable by the external environment, either through the periodontium or the root canal. This article presents the complications observed in 6 cases of MOQN triggered after the execution of various oral surgical therapies in patients undergoing treatment with bisphosphonates for different diseases and their clinical management. The treatment of this type of MOQN is often unsatisfactory, since none of the treatment options described in the literature has given good results. All patients receiving or have received treatment with bisphosphonates should be considered as patients with risk of developing MOQN, and should be submitted to the same prophylactic measures outlined for the prevention of osteoradionecrosis.