Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation

This is the final version of the article. Available from Public Library of Science via the DOI in this record.TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system.This work was funded by grants from the Spanish Ministry of Science and Innovation and the European Regional Development Fund (ERDF/FEDER) (BFU2010-18971), Zaragoza University (UZ2014-BIO-03), European Social Found (ESF) and the Aragon Regional Government (B61) and the Foundation for the Study of Inflammatory Bowel Diseases in Aragón (ARAINF 012/2008). ARAID Foundation supported J.P. (SAF2014-54763-C2-1-R) and E. Layunta is a PhD student fellow from Aragon Regional Government (B022/13). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Toll-like receptor 9 activation affects intestinal serotonin transporter activity and expression in Caco-2 cells

Background: Toll-like Receptor 9 (TLR9) is expressed mainly in the endosomal membrane of intestinal cells and mediates intestinal host-microbiota interaction. Serotonin (5-HT) is an intestinal neuromodulator involved in the intestinal immunity and homeostasis. In addition, a high level of 5-HT has been described in intestinal inflammation. 5-HT intestinal availability is mainly regulated by the serotonin transporter (SERT) expressed in enterocytes. Aim: The interaction of TLR9 with serotoninergic system remains known. Therefore, the aim of the present study was to assess the effects of TLR9 activation on SERT activity and expression. Methods: Caco-2 cells and colon from wild type (WT) and TLR9 C57BL/10 mice were used in this study. SERT activity (5-HT uptake) in Caco-2 cells and SERT expression (RT-qPCR and western blotting) in both Caco-2 cells and colon from WT and TLR9 mice, were analyzed. TLR9 mRNA and protein levels were also measured in Caco-2 cells. Results: TLR9 activation in Caco-2 cells reduced SERT activity in a MyD88 independent-way. SERT mRNA and protein level in both cell lysate and brush border membrane, were also diminished. SERT protein expression in colon of TLR9 mice resulted augmented compared with WT mice. Interestingly, activation of TLR9 in Caco-2 cells diminished TLR9 mRNA and protein in the cell lysate; however, TLR9 protein in brush border resulted increased. Conclusions: The results of this work highlight the role of TLR9 as a mediator intestinal homeostasis and/or intestinal inflammation by regulating intestinal serotoninergic system

The Harvey–Bradshaw Index adapted to a mobile application compared with In-clinic assessment: the MediCrohn Study

[Abstract] Objectives: Mobile apps are useful tools in e-health and self-management strategies in disease monitoring. We evaluated the Harvey–Bradshaw index (HBI) mobile app self-administered by the patient to see if its results agreed with HBI in-clinic assessed by a physician. Methods: Patients were enrolled in a 4-month prospective study with clinical assessments at months 1 and 4. Patients completed mobile app HBI and within 48 h, HBI was performed by a physician (gold standard). HBI scores characterized Crohn's disease (CD) as remission <5 or active ≥5. We determined agreement per item and total HBI score and intraclass correlation coefficients (ICCs). Bland–Altman plot was performed. HBI changes in disease activity from month 1 to month 4 were determined. Results: A total of 219 patients were enrolled. All scheduled assessments (385 pairs of the HBI questionnaire) showed a high percentage of agreement for remission/activity (92.4%, κ = 0.796), positive predictive value (PPV) for remission of 98.2%, and negative predictive value of 76.7%. High agreement was also found at month 1 (93.15%, κ = 0.82) and month 4 (91.5%, κ = 0.75). Bland–Altman plot was more uniform when the HBI mean values were <5 (remission). ICC values were 0.82, 0.897, and 0.879 in all scheduled assessments, 1 and 4 months, respectively. Conclusions: We found a high percentage of agreement between patients' self-administered mobile app HBI and in-clinic physician assessment to detect CD activity with a remarkably high PPV for remission. The mobile app HBI might allow a strict control of inflammation by remote monitoring and flexible follow-up of CD patients. Reduction of sanitary costs could be possible

Impacto da exposição académica no estado de saúde de estudantes universitários

OBJECTIVE: To assess the impact of academic life on health status of university students. METHODS: Longitudinal study including 154 undergraduate students from the Universidade de Aveiro, Portugal, with at least two years of follow-up observations. Sociodemographic and behavioral characteristics were collected using questionnaires. Students' weight, height, blood pressure, serum glucose, serum lipids and serum homocysteine levels were measured. Regression analysis was performed using linear mixed-effect models, allowing for random effects at the participant level. RESULTS: A higher rate of dyslipidemia (44.0% vs. 28.6%), overweight (16.3% vs. 12.5%) and smoking (19.3% vs. 0.0%) was found among students exposed to the academic life when compared to freshmen. Physical inactivity was about 80%. Total cholesterol, high density lipoprotein-cholesterol (HDL-C), triglycerides, systolic blood pressure, and physical activity levels were significantly associated with gender (p<0.001). Academic exposure was associated with increased low density lipoprotein-cholesterol (LDL-C) levels (about 1.12 times), and marginally with total cholesterol levels (p=0.041). CONCLUSIONS: High education level does not seem to have a protective effect favoring a healthier lifestyle and being enrolled in health-related areas does not seem either to positively affect students' behaviors. Increased risk factors for non-transmissible diseases in university students raise concerns about their well-being. These results should support the implementation of health promotion and prevention programs at universities.OBJETIVO: Avaliar a influência da vida académica na saúde de estudantes universitários. MÉTODOS: Estudo longitudinal envolvendo 154 estudantes de graduação da Universidade de Aveiro, Portugal, por pelo menos dois anos de acompanhamento. Características sociodemográfi cas e comportamentais foram recordados, por meio de questionários. Foram medidos peso, altura,pressão arterial, glicemia, perfil lipídico e os níveis séricos de homocisteína dos alunos. Foi realizada análise de regressão com modelos lineares mistos considerando as medidas repetidas de cada sujeito. RESULTADOS: Estudantes expostos à vida académica, quando comparados àqueles de ingresso recente à universidade apresentaram proporção mais elevada de dislipidemia (44,0% versus 28,6%), sobrepeso (16,3% versus 12,5%) e tabagismo (19,3% versus 0,0%). No geral, foi observada alta proporção de sedentarismo (cerca de 80%). O colesterol total, lipoproteína de alta densidade, triglicérides, pressão arterial sistólica e níveis de atividade física apresentaram associação signifi cativa com o género (p < 0,001). A exposição académica apresentou-se associada com o aumento dos níveis das lipoproteínas de baixa densidade (cerca de 1,12 vezes), e marginalmente com os níveis de colesterol total (p = 0,041). CONCLUSÕES: Nem o alto nível de instrução parece ter papel protetor na adoção de estilo de vida saudável, tampouco o envolvimento com áreas de saúde muda o comportamento dos estudantes. Altas proporções de fatores de risco para doenças não-transmissíveis em jovens universitários podem afetar seu bem-estar. Os resultados podem servir de apoio às universidades no desenvolvimento de programas de prevenção e promoção da saúde

Chronic migraine plus medication overuse headache: two entities or not?

Chronic migraine (CM) represents migraine natural evolution from its episodic form. It is realized through a chronicization phase that may require months or years and varies from patient to patient. The transition to more frequent attacks pattern is influenced by lifestyle, life events, comorbid conditions and personal genetic terrain, and it often leads to acute drugs overuse. Medication overuse headache (MOH) may complicate every type of headache and all the drugs employed for headache treatment can cause MOH. The first step in the management of CM complicated by medication overuse must be the withdrawal of the overused drugs and a detoxification treatment. The goal is not only to detoxify the patient and stop the chronic headache but also to improve responsiveness to acute or prophylactic drugs. Different methods have been suggested: gradual or abrupt withdrawal; home treatment, hospitalization, or a day-hospital setting; re-prophylaxes performed immediately or at the end of the wash-out period. Up to now, only topiramate and local injection of onabotulinumtoxinA have shown efficacy as therapeutic agents for re-prophylaxis after detoxification in patients with CM with and without medication overuse. Although the two treatments showed similar efficacy, onabotulinumtoxinA is associated with a better adverse events profile. Recently, the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program proved that patients with CM, even those with MOH, are the ones most likely to benefit from onabotulinumtoxinA treatment. Furthermore, it provided an injection paradigm that can be used as a guide for a correct administration of onabotulinumtoxinA

Impact of biological agents on postsurgical complications in inflammatory bowel disease: A multicentre study of Geteccu

Background: The impact of biologics on the risk of postoperative complications (PC) in inflammatory bowel disease (IBD) is still an ongoing debate. This lack of evidence is more relevant for ustekinumab and vedolizumab. Aims: To evaluate the impact of biologics on the risk of PC. Methods: A retrospective study was performed in 37 centres. Patients treated with biologics within 12 weeks before surgery were considered “exposed”. The impact of the exposure on the risk of 30-day PC and the risk of infections was assessed by logistic regression and propensity score-matched analysis. Results: A total of 1535 surgeries were performed on 1370 patients. Of them, 711 surgeries were conducted in the exposed cohort (584 anti-TNF, 58 vedolizumab and 69 ustekinumab). In the multivariate analysis, male gender (OR: 1.5; 95% CI: 1.2–2.0), urgent surgery (OR: 1.6; 95% CI: 1.2–2.2), laparotomy approach (OR: 1.5; 95% CI: 1.1–1.9) and severe anaemia (OR: 1.8; 95% CI: 1.3–2.6) had higher risk of PC, while academic hospitals had significantly lower risk. Exposure to biologics (either anti-TNF, vedolizumab or ustekinumab) did not increase the risk of PC (OR: 1.2; 95% CI: 0.97–1.58), although it could be a risk factor for postoperative infections (OR 1.5; 95% CI: 1.03–2.27). Conclusions: Preoperative administration of biologics does not seem to be a risk factor for overall PC, although it may be so for postoperative infections

Clinical Predictors of Hyperperfusion Syndrome Following Carotid Stenting: Results From a National Prospective Multicenter Study

[Objectives] The aim of the HISPANIAS (HyperperfusIon Syndrome Post-carotid ANgIoplasty And Stenting) study was to define CHS rates and develop a clinical predictive model for cerebral hyperperfusion syndrome (CHS) after carotid artery stenting (CAS).[Background] CHS is a severe complication following CAS. The presence of clinical manifestations is estimated on the basis of retrospective reviews and is still uncertain.[Methods] The HISPANIAS study was a national prospective multicenter study with 14 recruiting hospitals. CHS was classified as mild (headache only) and moderate-severe (seizure, impaired level of consciousness, or development of focal neurological signs).[Results] A total of 757 CAS procedures were performed. CHS occurred in 22 (2.9%) patients, in which 16 (2.1%) had moderate-severe CHS and 6 (0.8%) had mild CHS (only headache). The rate of hemorrhages was 0.7% and was associated with high mortality (20%). Pre-operative predictors of moderate-severe CHS in multivariate analysis were female sex (odds ratio [OR]: 3.24; 95% confidence interval [CI]: 1.11 to 9.47; p = 0.03), older patients (OR: 1.09; 95% CI: 1.01 to 1.17; p = 0.02), left carotid artery treated (OR: 4.13; 95% CI: 1.11 to 15.40; p = 0.03), and chronic renal failure (OR: 6.29; 95% CI: 1.75 to 22.57; p = 0.005). The area under the curve of this clinical and radiological model was 0.86 (95% CI: 0.81 to 0.92; p = 0.001).[Conclusions] The rate of CHS in the HISPANIAS study was 2.9%, with moderate-severe CHS of 2.1%. CHS was independently associated with female sex, older age, history of chronic kidney disease, and a treated left carotid artery. Although further investigations are needed, the authors propose a model to identify high-risk patients and develop strategies to decrease CHS morbidity and mortality in the future.This study was supported by a Spanish grant from the Instituto de Salud Carlos III (ISCIII-FIS IP14/00971, 2014–2017). The ITRIBIS project has the registration number REGPOT-2013-1. Cooperative Cerebrovascular Disease Research Network (INVICTUS+) (RD16/0019/0015). Dr. Mancha is supported by a Río Hortega contract (CM16/00015). Abbott and Grifols have partial financial supported the conduction of the HISPANIAS project but had no role in the design of the study, interpretation of the data, or manuscript approval.Peer reviewe

Risk factors of migraine-related brain white matter hyperintensities: an investigation of 186 patients

Brain white matter hyperintensities are more prevalent in migraine patients than in the general population, but the pathogenesis and the risk factors of these hyperintensities are not fully elucidated. The authors analyzed the routine clinical data of 186 migraine patients who were referred to the Outpatient Headache Department of the Department of Neurology, Medical School, University of Pécs, Hungary between 2007 and 2009: 58 patients with white matter hyperintensities and 128 patients without white matter hyperintensities on 3 T MRI. Significant associations between the presence of white matter hyperintensities and longer disease duration (14.4 vs. 19.9 years, p = 0.004), higher headache frequency (4.1 vs. 5.5 attacks/month, p = 0.017), hyperhomocysteinemia (incidence of hyperintensity is 9/9 = 100%, p = 0.009) and thyroid gland dysfunction (incidence of hyperintensity is 8/14 = 57.1%, p = 0.038) were found. These data support the theory that both the disease duration and the attack frequency have a key role in the formation of migraine-related brain white matter hyperintensities, but the effects of comorbid diseases may also contribute to the development of the hyperintensities