Exomer Is Part of a Hub Where Polarized Secretion and Ionic Stress Connect.

Plasma membrane and membranous organelles contribute to the physiology of the Eukaryotic cell by participating in vesicle trafficking and the maintenance of ion homeostasis. Exomer is a protein complex that facilitates vesicle transport from the trans-Golgi network to the plasma membrane, and its absence leads to the retention of a set of selected cargoes in this organelle. However, this retention does not explain all phenotypes observed in exomer mutants. The Schizosaccharomyces pombe exomer is composed of Cfr1 and Bch1, and cfr1Δ and bch1Δ were sensitive to high concentrations of potassium salts but not sorbitol, which showed sensitivity to ionic but not osmotic stress. Additionally, the activity of the plasma membrane ATPase was higher in exomer mutants than in the wild-type, pointing to membrane hyperpolarization, which caused an increase in intracellular K+ content and mild sensitivity to Na+, Ca2+, and the aminoglycoside antibiotic hygromycin B. Moreover, in response to K+ shock, the intracellular Ca2+ level of cfr1Δ cells increased significantly more than in the wild-type, likely due to the larger Ca2+ spikes in the mutant. Microscopy analyses showed a defective endosomal morphology in the mutants. This was accompanied by an increase in the intracellular pools of the K+ exporting P-type ATPase Cta3 and the plasma membrane Transient Receptor Potential (TRP)-like Ca2+ channel Pkd2, which were partially diverted from the trans-Golgi network to the prevacuolar endosome. Despite this, most Cta3 and Pkd2 were delivered to the plasma membrane at the cell growing sites, showing that their transport from the trans-Golgi network to the cell surface occurred in the absence of exomer. Nevertheless, shortly after gene expression in the presence of KCl, the polarized distribution of Cta3 and Pkd2 in the plasma membrane was disturbed in the mutants. Finally, the use of fluorescent probes suggested that the distribution and dynamics of association of some lipids to the plasma membrane in the presence of KCl were altered in the mutants. Thus, exomer participation in the response to K+ stress was multifaceted. These results supported the notion that exomer plays a general role in protein sorting at the trans-Golgi network and in polarized secretion, which is not always related to a function as a selective cargo adaptor.

Analysis of the SNARE Stx8 recycling reveals that the retromer-sorting motif has undergone evolutionary divergence.

Fsv1/Stx8 is a Schizosaccharomyces pombe protein similar to mammalian syntaxin 8. stx8Δ cells are sensitive to salts, and the prevacuolar endosome (PVE) is altered in stx8Δ cells. These defects depend on the SNARE domain, data that confirm the conserved function of syntaxin8 and Stx8 in vesicle fusion at the PVE. Stx8 localizes at the trans-Golgi network (TGN) and the prevacuolar endosome (PVE), and its recycling depends on the retromer component Vps35, and on the sorting nexins Vps5, Vps17, and Snx3. Several experimental approaches demonstrate that Stx8 is a cargo of the Snx3-retromer. Using extensive truncation and alanine scanning mutagenesis, we identified the Stx8 sorting signal. This signal is an IEMeaM sequence that is located in an unstructured protein region, must be distant from the transmembrane (TM) helix, and where the 133I, 134E, 135M, and 138M residues are all essential for recycling. This sorting motif is different from those described for most retromer cargoes, which include aromatic residues, and resembles the sorting motif of mammalian polycystin-2 (PC2). Comparison of Stx8 and PC2 motifs leads to an IEMxx(I/M) consensus. Computer-assisted screening for this and for a loose Ψ(E/D)ΨXXΨ motif (where Ψ is a hydrophobic residue with large aliphatic chain) shows that syntaxin 8 and PC2 homologues from other organisms bear variation of this motif. The phylogeny of the Stx8 sorting motifs from the Schizosaccharomyces species shows that their divergence is similar to that of the genus, showing that they have undergone evolutionary divergence. A preliminary analysis of the motifs in syntaxin 8 and PC2 sequences from various organisms suggests that they might have also undergone evolutionary divergence, what suggests that the presence of almost-identical motifs in Stx8 and PC2 might be a case of convergent evolution.

Elaboración de mapas sistémicos como herramienta básica en la detección y resolución de necesidades farmacoterapéuticas / Development of systemic maps as a basic tool for detection and resolution of patient's medication-related needs

Se brindó Gestión Integral de la Farmacoterapia a una mujer de 58 años, fumadora, con osteoporosis, fracturas vertebrales, hiperlipemia, asma y EPOC, que tomaba 9 medicamentos como tratamiento. Las intervenciones fueron derivadas al elaborar un mapa sistémico utilizado como herramienta integradora de aspectos biomédicos y psicosociales, tras la evaluación de las condiciones clínicas y de la medicación. Esta información se obtuvo realizando entrevistas farmacoterapéuticas semiestructuradas con entrevistas en profundidad. Como parte del plan de cuidados, se elaboró un informe médico con 5 recomendaciones que fueron aceptadas por el médico de atención primaria y otras 3 fueron propuestas y aceptadas por la paciente. Tras evaluar los resultados se constató evolución favorable de 3 condiciones clínicas, manteniéndose otras 3 estables durante todo el proceso. Utilizar mapas sistémicos para interrelacionar aspectos cualitativos de la experiencia personal al evaluar la farmacoterapia, permite plantear intervenciones biopsicosociales adaptadas a la resolución integral de necesidades farmacoterapéuticas

Comprehensive Medication Management has been provided to a 58-year-old woman, a smoker, with osteoporosis, vertebral fractures, hyperlipidaemia, respiratory dysfunction, who was taking 9 medications to treat these clinical conditions. The proposed interventions were derived from developing a systemic map used as a tool to integrate biomedical and psychosocial aspects, after prior evaluation of the patient's clinical and medication conditions. This information was obtained by integrating semistructured pharmacotherapeutic interviews with in-depth interviews. As part of the care plan, a medical report was prepared with 5 recommendations that were accepted by the primary care physician and another 3 were proposed directly to the patient, also achieving acceptance. After evaluating the results, a favourable evolution of 5 clinical conditions was verified. Using systemic maps to interrelate qualitative aspects of the patient's personal experience with pharmacotherapy evaluation allows us to propose biopsychosocial interventions adapted to a comprehensive resolution of pharmacotherapeutic needs

Ent3 and GGA adaptors facilitate diverse anterograde and retrograde trafficking events to and from the prevacuolar endosome.

Carboxypeptidases Y (Cpy1) and S (Cps1), the receptor Vps10, and the ATPase subunit Vph1 follow the carboxypeptidase Y (CPY) pathway from the trans-Golgi network (TGN) to the prevacuolar endosome (PVE). Using Schizosaccharomyces pombe quantitative live-cell imaging, biochemical and genetic analyses, we extended the previous knowledge and showed that collaboration between Gga22, the dominant Golgi-localized Gamma-ear-containing ARF-binding (GGA) protein, and Gga21, and between Gga22 and the endosomal epsin Ent3, was required for efficient: i) Vps10 anterograde trafficking from the TGN to the PVE; ii) Vps10 retrograde trafficking from the PVE to the TGN; iii) Cps1 exit from the TGN, and its sorting in the PVE en route to the vacuole; and iv) Syb1/Snc1 recycling to the plasma membrane through the PVE. Therefore, monomeric clathrin adaptors facilitated the trafficking of Vps10 in both directions of the CPY pathway, and facilitated trafficking events of Cps1 in different organelles. By contrast, they were dispensable for Vph1 trafficking. Thus, these adaptors regulated the traffic of some, but not all, of the cargo of the CPY pathway, and regulated the traffic of cargoes that do not follow this pathway. Additionally, this collaboration was required for PVE organization and efficient growth under stress.

Tuberculosis por Mycobacterium bovis en la población de Castilla y León (España), 2006-2015 / Human Mycobacterium bovis infection in Castile and León (Spain), 2006-2015

Introducción: La incidencia anual de tuberculosis (TB) humana por Mycobacterium bovis ha disminuido considerablemente en los países industrializados desde inicios del sigloXX. El objetivo de este estudio fue conocer las características epidemiológicas, clínicas y microbiológicas de esta enfermedad en Castilla y León (CyL). Métodos: Estudio retrospectivo de los casos de TB por M. bovis de CyL en un periodo de 10 años, comparando la epidemiología, los factores de riesgo y la evolución entre las formas pulmonares (TBP) y extrapulmonares (TBEP). Resultados: Se recopilaron 75 casos de TB por M. bovis: 45 TBP y 31 TBEP. La incidencia acumulada de TB por M. bovis fue de 0,3 casos por 100.000 habitantes. Se mantuvo estable entre el primer y el segundo quinquenio (0,27 vs. 0,33, p = 0,656), a pesar del descenso de la incidencia global de la TB (13,58 vs. 10,71, p < 0,0001). La edad media fue de 66,2 + 21,3 años, principalmente varones (63%) y nacidos en España (92%). TBP fue significativamente más frecuente en varones, mayores de 66 años, con inmunosupresión o fumadores. La mortalidad fue del 9%, asociada a la edad, a la inmunosupresión o a un tratamiento diferente al recomendado por la OMS. Conclusiones: La incidencia de TB por M. bovis en CyL es superior a la de España y otros países europeos, y se mantuvo estable a pesar del descenso de la TB por MTC. Afectó mayoritariamente a población nacida en España que vivía en zonas rurales y con elevada media de edad

Introduction: The annual incidence of tuberculosis (TB) from Mycobacterium bovis in humans has considerably declined in industrialised countries since the early twentieth century. The objective of this study was to determine the epidemiological, clinical and microbiological characteristics of patients with this illness in Castile and León (CyL). Methods: Retrospective study of all M. bovis TB cases in CyL over a 10-year period, comparing the risk factors, the epidemiology and the clinical course between pulmonary (PTB) and extrapulmonary TB (EPTB). Results: 75 cases of TB were due to M. bovis: 45 PTB and 31 EPTB. The annual incidence of TB due to M. bovis was 0.3 cases per 100,000. It remained stable between the first and second five-year period (0.27 vs. 0.33, p = 0.656). However, the overall incidence of TB fell in both five-year periods (13.58 vs. 10.71, p < 0.0001). The mean age was 66.2 + 21.3 years, mainly men (63%) and Spanish patients (92%). PTB was significantly more frequent in men, aged over 66 years, with immunosuppressive conditions or who were smokers. Mortality was 9%, associated with higher age, immunosuppression or treatment different from that recommended by the WHO. Conclusions: The incidence of M. bovis TB in CyL was higher than that for Spain and for other European countries, and remained stable despite the decreased the TB due to MTC. It affected mostly Spanish-born patients who lived in rural areas and with a high mean age

Human Mycobacterium bovis infection in Castile and León (Spain), 2006-2015. / Tuberculosis por Mycobacterium bovis en la población de Castilla y León (España), 2006-2015.

INTRODUCTION: The annual incidence of tuberculosis (TB) from Mycobacterium bovis in humans has considerably declined in industrialised countries since the early twentieth century. The objective of this study was to determine the epidemiological, clinical and microbiological characteristics of patients with this illness in Castile and León (CyL). METHODS: Retrospective study of all M. bovis TB cases in CyL over a 10-year period, comparing the risk factors, the epidemiology and the clinical course between pulmonary (PTB) and extrapulmonary TB (EPTB). RESULTS: 75 cases of TB were due to M. bovis: 45 PTB and 31 EPTB. The annual incidence of TB due to M. bovis was 0.3 cases per 100,000. It remained stable between the first and second five-year period (0.27 vs. 0.33, p=0.656). However, the overall incidence of TB fell in both five-year periods (13.58 vs. 10.71, p<0.0001). The mean age was 66.2+21.3 years, mainly men (63%) and Spanish patients (92%). PTB was significantly more frequent in men, aged over 66 years, with immunosuppressive conditions or who were smokers. Mortality was 9%, associated with higher age, immunosuppression or treatment different from that recommended by the WHO. CONCLUSIONS: The incidence of M. bovis TB in CyL was higher than that for Spain and for other European countries, and remained stable despite the decreased the TB due to MTC. It affected mostly Spanish-born patients who lived in rural areas and with a high mean age.

Síndrome de Lady Windermere en Castilla y León / Lady Windermere syndrome in Castile and León

INTRODUCCIÓN: El síndrome de Lady Windermere (SLW) es una patología pulmonar causada por Mycobacterium avium complex (MAC). El objetivo es conocer su frecuencia y sus características en el área norte de la comunidad de Castilla y León. MÉTODOS: Estudio retrospectivo de pacientes con aislamientos de MAC en muestras respiratorias de cinco hospitales públicos de la comunidad a lo largo de seis años, siguiendo criterios de la ATS/IDSA. Las cepas de MAC se identificaron por sondas de hibridación inversa Genotype Mycobacterium o PCR-RFLP del gen hsp65. RESULTADOS: De 183 casos de MAC identificados, únicamente 5 (2,7%) mujeres de 68,8 ± 10,7 años cumplían criterios de SLW. En tres casos se aisló MAC conjunta e intermitentemente con otros patógenos. Solo un paciente se trató siguiendo criterios de la ATS/IDSA. DISCUSIÓN: El SLW permanece infraestimado, y al ser los afectados muy demandantes de recursos sanitarios durante largos periodos, es necesario un mayor conocimiento microbiológico y terapéutico

INTRODUCTION: Lady Windermere syndrome (LWS) is a pulmonary disease caused by Mycobacterium avium complex (MAC). The objective of this study is to ascertain its frequency and characteristics in the northern area of the autonomous community of Castile and León. METHODS: A retrospective study of patients with MAC isolates in respiratory samples from five public hospitals in the autonomous community over a six-year period, following the ATS/IDSA criteria. The MAC strains were identified by GenoType Mycobacterium reverse hybridisation probes or PCR-RFLP analysis of the hsp65 gene. RESULTS: Of 183 cases of MAC identified, only five women (2.7 %) aged 68.8± 10.7 years met LWS criteria. In three cases, MAC was isolated jointly and intermittently with other pathogens. Only one patient was treated according to ATS/IDSA criteria. DISCUSSION: LWS remains underestimated, with affected patients representing a significant burden on healthcare resources over long periods of time. As a result, greater microbiological and therapeutic knowledge of the syndrome is needed

Contribución de la microbiología al diagnóstico de la tuberculosis en Castilla y León: conclusiones del estudio GRUMICALE 2013 / Contribution of microbiology in the diagnosis of tuberculosis in Castile and León (Spain): Findings of the GRUMICALE 2013 study

Introducción y objetivos: Estudio retrospectivo que recoge datos microbiológicos de tuberculosis (TB) en Castilla y León durante el año 2013 para conocer los datos microbiológicos de incidencia y distribución de TB, resistencias a los fármacos antituberculosos y compararlos con los datos epidemiológicos ofrecidos por los servicios de vigilancia epidemiológica (SIVE). Material y métodos: Microbiólogos de los 14 hospitales de la red sanitaria pública de Castilla y León (GRUMICALE) han recogido datos epidemiológicos, microbiológicos y de funcionamiento de los laboratorios de microbiología de la comunidad durante el año 2013. Se consideró un solo aislamiento de Mycobacterium tuberculosis complex (MTC) por paciente. Resultados: Se obtuvieron 270 aislamientos de MTC (tasa de incidencia de 11,63 casos/100.000 hab./año). Según datos epidemiológicos, se recogieron un total de 288 casos de TB (11,43 casos/100.000 hab./año), 243 confirmados, 29 sospechosos y 16 probables. Predomina la localización pulmonar, seguida de lejos por la pleural y por el resto. Se procesaron un total de 27.620 muestras para micobacterias. En un 3,46% de los medios de cultivos líquidos se obtuvo crecimiento de micobacterias, y en un 50,37% la tinción directa (baciloscopia) fue positiva. Dieciséis aislamientos de Mycobacterium tuberculosis (MT) presentaron resistencia a algún fármaco antituberculoso, predominando la resistencia a isoniazida (5,92%). La provincia con mayor incidencia y número de aislamientos fue León (24,23 casos/100.000 hab./año), siendo la máxima en el área sanitaria de El Bierzo (30,46 casos/100.000 hab./año). Conclusiones: Una adecuada recogida de la información microbiológica es fundamental para el conocimiento de la epidemiologia de la TB en nuestra comunidad (AU)

Introduction and objectives: A retrospective study was conducted by collecting microbiological tuberculosis (TB) data in Castile and León during the year 2013 in order to determine the incidence and distribution of TB, and resistance to the tuberculostatic drug, and compare them with the epidemiological data provided by the Department of Epidemiological Surveillance (SIVE). Material and methods: Microbiologists of the 14 hospitals of the Castile and León public health network (GRUMICALE) collected epidemiological, microbiological, and management data from the Microbiology laboratories in the community during the year 2013. A single isolate of Mycobacterium tuberculosis complex (MTC) per patient was considered. Results: The study included a total of 270 MTC isolates (an incidence rate of 11.63 cases/100,000 inhab./year). A total of 288 cases of TB (11.43 cases/100,000 inhab. year) were recovered using epidemiological data, which included 243 confirmed, 29 suspected, and 16 as probable cases. Pulmonary TB was predominant, followed a long way off by the pleural TB and the remaining locations. A total of 27,620 samples were processed for mycobacterial detection. Mycobacterial growth was observed in 3.46% of automated fluid cultures, and 50.37% were positive by direct staining of the smear. Resistance to one tuberculostatic drug, mostly to isoniazid, was observed in 16 (5.92%) isolates of Mycobacterium tuberculosis (MT). The province with greater incidence and number of isolates was León (24.23 cases/100,000 inhab./year), with the highest being observed in El Bierzo health area (30.46 cases/100,000 inhab./year). Conclusions: An adequate collection of microbiological information is essential to determine the epidemiology of TB in our region (AU)

Lady Windermere syndrome in Castile and León. / Síndrome de Lady Windermere en Castilla y León.

INTRODUCTION: Lady Windermere syndrome (LWS) is a pulmonary disease caused by Mycobacterium avium complex (MAC). The objective of this study is to ascertain its frequency and characteristics in the northern area of the autonomous community of Castile and León. METHODS: A retrospective study of patients with MAC isolates in respiratory samples from five public hospitals in the autonomous community over a six-year period, following the ATS/IDSA criteria. The MAC strains were identified by GenoType Mycobacterium reverse hybridisation probes or PCR-RFLP analysis of the hsp65 gene. RESULTS: Of 183 cases of MAC identified, only five women (2.7%) aged 68.8±10.7years met LWS criteria. In three cases, MAC was isolated jointly and intermittently with other pathogens. Only one patient was treated according to ATS/IDSA criteria. DISCUSSION: LWS remains underestimated, with affected patients representing a significant burden on healthcare resources over long periods of time. As a result, greater microbiological and therapeutic knowledge of the syndrome is needed.

The ancient claudin Dni2 facilitates yeast cell fusion by compartmentalizing Dni1 into a membrane subdomain.

Dni1 and Dni2 facilitate cell fusion during mating. Here, we show that these proteins are interdependent for their localization in a plasma membrane subdomain, which we have termed the mating fusion domain. Dni1 compartmentation in the domain is required for cell fusion. The contribution of actin, sterol-dependent membrane organization, and Dni2 to this compartmentation was analysed, and the results showed that Dni2 plays the most relevant role in the process. In turn, the Dni2 exit from the endoplasmic reticulum depends on Dni1. These proteins share the presence of a cysteine motif in their first extracellular loop related to the claudin GLWxxC(8-10 aa)C signature motif. Structure-function analyses show that mutating each Dni1 conserved cysteine has mild effects, and that only simultaneous elimination of several cysteines leads to a mating defect. On the contrary, eliminating each single cysteine and the C-terminal tail in Dni2 abrogates Dni1 compartmentation and cell fusion. Sequence alignments show that claudin trans-membrane helixes bear small-XXX-small motifs at conserved positions. The fourth Dni2 trans-membrane helix tends to form homo-oligomers in Escherichia plasma membrane, and two concatenated small-XXX-small motifs are required for efficient oligomerization and for Dni2 export from the yeast endoplasmic reticulum. Together, our results strongly suggest that Dni2 is an ancient claudin that blocks Dni1 diffusion from the intercellular region where two plasma membranes are in close proximity, and that this function is required for Dni1 to facilitate cell fusion.

Contribution of microbiology in the diagnosis of tuberculosis in Castile and León (Spain): Findings of the GRUMICALE 2013 study. / Contribución de la microbiología al diagnóstico de la tuberculosis en Castilla y León: conclusiones del estudio GRUMICALE 2013.

INTRODUCTION AND OBJECTIVES: A retrospective study was conducted by collecting microbiological tuberculosis (TB) data in Castile and León during the year 2013 in order to determine the incidence and distribution of TB, and resistance to the tuberculostatic drug, and compare them with the epidemiological data provided by the Department of Epidemiological Surveillance (SIVE). MATERIAL AND METHODS: Microbiologists of the 14 hospitals of the Castile and León public health network (GRUMICALE) collected epidemiological, microbiological, and management data from the Microbiology laboratories in the community during the year 2013. A single isolate of Mycobacterium tuberculosis complex (MTC) per patient was considered. RESULTS: The study included a total of 270 MTC isolates (an incidence rate of 11.63 cases/100,000 inhab./year). A total of 288 cases of TB (11.43 cases/100,000 inhab. year) were recovered using epidemiological data, which included 243 confirmed, 29 suspected, and 16 as probable cases. Pulmonary TB was predominant, followed a long way off by the pleural TB and the remaining locations. A total of 27,620 samples were processed for mycobacterial detection. Mycobacterial growth was observed in 3.46% of automated fluid cultures, and 50.37% were positive by direct staining of the smear. Resistance to one tuberculostatic drug, mostly to isoniazid, was observed in 16 (5.92%) isolates of Mycobacterium tuberculosis (MT). The province with greater incidence and number of isolates was León (24.23 cases/100,000 inhab./year), with the highest being observed in El Bierzo health area (30.46 cases/100,000 inhab./year). CONCLUSIONS: An adequate collection of microbiological information is essential to determine the epidemiology of TB in our region.

Traffic Through the Trans-Golgi Network and the Endosomal System Requires Collaboration Between Exomer and Clathrin Adaptors in Fission Yeast.

Despite its biological and medical relevance, traffic from the Golgi to the plasma membrane (PM) is one of the least understood steps of secretion. Exomer is a protein complex that mediates the trafficking of certain cargoes from the trans-Golgi network/early endosomes to the PM in budding yeast. Here, we show that in Schizosaccharomyces pombe the Cfr1 and Bch1 proteins constitute the simplest form of an exomer. Cfr1 co-immunoprecipitates with Assembly Polypeptide adaptor 1 (AP-1), AP-2, and Golgi-localized, gamma-adaptin ear domain homology, ARF-binding (GGA) subunits, and cfr1+ interacts genetically with AP-1 and GGA genes. Exomer-defective cells exhibit multiple mild defects, including alterations in the morphology of Golgi stacks and the distribution of the synaptobrevin-like Syb1 protein, carboxypeptidase missorting, and stress sensitivity. S. pombe apm1Δ cells exhibit a defect in trafficking through the early endosomes that is severely aggravated in the absence of exomer. apm1Δ cfr1Δ cells exhibit a dramatic disorganization of intracellular compartments, including massive accumulation of electron-dense tubulovesicular structures. While the trans-Golgi network/early endosomes are severely disorganized in the apm1Δ cfr1Δ strain, gga21Δ gga22Δ cfr1Δ cells exhibit a significant disturbance of the prevacuolar/vacuolar compartments. Our findings show that exomer collaborates with clathrin adaptors in trafficking through diverse cellular compartments, and that this collaboration is important to maintain their integrity. These results indicate that the effect of eliminating exomer is more pervasive than that described to date, and suggest that exomer complexes might participate in diverse steps of vesicle transport in other organisms.

Nuevos tratamientos farmacológicos en el TDAH. A propósito de un caso clínico / New pharmacological treatments for ADHD. A case report

El Trastorno por Déficit de Atención/Hiperactividad (TDAH) es uno de los trastornos del neurodesarrollo más prevalentes en la infancia que frecuentemente se mantiene en la adolescencia y edad adulta. Los psicoestimulantes son generalmente el tratamiento farmacológico de primera línea para el TDAH, aunque alguno de estos pacientes no consiguen una remisión sintomática completa, especialmente los que tienen comorbilidad con el Trastorno Negativista Desafiante (TND). En estos casos, hay cada vez una mayor evidencia de que la combinación de psicoestimulantes y medicamentos no específicos para manejar el TDAH puede ser útil. La Guanfacina de liberación prolongada (GXR, Guanfacine Extended Release), un nuevo fármaco no psicoestimulante que actúa como agonista alfa 2 adrenérgico, ha sido aprobado recientemente por la Agencia Europea de Medicamentos como un nuevo tratamiento para el TDAH. En España se ha empezado a comercializar a finales de enero 2017. El objetivo de este estudio es evaluar la eficacia y tolerabilidad de la GXR administrada conjuntamente con dimesilato de lisdexanfetamina en un paciente con Trastorno por Déficit de atención e Hiperactividad (TDAH) y Trastorno Negativista Desafiante(TND)

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood, which shows diagnostic persistence and morbidity into adulthood. Psychostimulants are generally first-line pharmacotherapy for ADHD, but some patients do not achieve symptomatic remission, especially those who have Oppositional Defiant Disorder (ODD) comorbidity. In those cases, there is growing evidence that a combination of psychostimulants and nonscheduled medications to manage ADHD, may be useful. The alpha-2 adrenergic agonist guanfacine extended release (GXR), a non-stimulant treatment, has recently been approved by the European Medicines Agency (EMA) as new therapeutic option for ADHD. In Spain it has been available from the end of January 2017. The aim of this study is to test the efficacy and tolerability of a combined therapy of psychostimulant (lisdexamfetamine) and GXR in a patient with ADHD and ODD

The long life of an endocytic patch that misses AP-2.

Endocytosis is the process by which cells regulate extracellular fluid uptake and internalize molecules bound to their plasma membrane. This process requires the generation of protein-coated vesicles. In clathrin-mediated endocytosis (CME) the assembly polypeptide 2 (AP-2) adaptor facilitates rapid endocytosis of some plasma membrane receptors by mediating clathrin recruitment to the endocytic site and by connecting cargoes to the clathrin coat. While this adaptor is essential for early embryonic development in mammals, initial results suggested that it is dispensable for endocytosis in unicellular eukaryotes. The drastic effect of depleting AP-2 in metazoa and the mild effect of deleting AP-2 subunits in Saccharomyces cerevisiae have prevented a detailed analysis of the dynamics of endocytic patches in the absence of this adaptor. Using live-cell imaging of Schizosaccharomyces pombe endocytic sites we have shown that eliminating AP-2 perturbs the dynamics of endocytic patches beyond the moment of coat assembly. These perturbations affect the cell growth pattern and cell wall synthesis. Our results highlight the importance of using different model organisms to address the study of conserved aspects of CME.

The AP-2 complex is required for proper temporal and spatial dynamics of endocytic patches in fission yeast.

In metazoans the AP-2 complex has a well-defined role in clathrin-mediated endocytosis. By contrast, its direct role in endocytosis in unicellular eukaryotes has been questioned. Here, we report co- immunoprecipitation between the fission yeast AP-2 component Apl3p and clathrin, as well as the genetic interactions between apl3Δ and clc1 and sla2Δ/end4Δ mutants. Furthermore, a double clc1 apl3Δ mutant was found to be defective in FM4-64 uptake. In an otherwise wild-type strain, apl3Δ cells exhibit altered dynamics of the endocytic sites, with a heterogeneous and extended lifetime of early and late markers at the patches. Additionally, around 50% of the endocytic patches exhibit abnormal spatial dynamics, with immobile patches and patches that bounce backwards to the cell surface, showing a pervasive effect of the absence of AP-2. These alterations in the endocytic machinery result in abnormal cell wall synthesis and morphogenesis. Our results complement those found in budding yeast and confirm that a direct role of AP-2 in endocytosis has been conserved throughout evolution.

La dispensación como punto clave en la detección de necesidades farmacoterapeuticas de los pacientes / Dispensing medicines as a key point in the detection of patinent’s pharmacotherapeutic needs

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Rehabilitación oral integral en un niño con secuela de cirugía de linfangioma de piso de boca y lengua / Integral oral rehabilitation in a child with lymphangioma sequel surgery on floor of the mouth and tongue

Los linfangiomas son malformaciones del desarrollo caracterizadas por una proliferación benigna de los vasos linfáticos y representan hamartomas de los linfáticos malformados y tienen una marcada predilección por la región de la cabeza y el cuello. La localización más frecuente en la boca es el dorso de la lengua, seguido por los labios, la mucosa bucal, el paladar blando y el piso de la boca. Se presenta un caso clínico de una paciente con secuela de cirugías de linfangioma de piso de boca y lengua, con pérdida prematura de piezas dentarias y caries de aparición temprana, y su rehabilitación completa con restauraciones de resina, coronas de celuloide y mantenedores de espacio tipo prótesis parcial superior e inferior...

Lymphangiomas are developmental malformations wich are characterized by a benign proliferation of lymphatic vessels. They represent hamartomas of malformed lymphatics and have a strong predilection for the region of the head and neck. The most common location in the mouth is the dorsum of the tongue, followed by the lips, buccal mucosa, soft palate and fIoor of the mouth. The following case report is of a patient with lymphangioma sequel surgerie on fIoor of mouth and tongue, with premature loss of teeth and early childhood caries, and her complete rehabilitation with resin restorations, strip crowns, and removable space maintainers with artificial tooth...

Experiencias negativas previas a un tratamiento farmacológico pueden influir en la adherencia terapéutica / A negative experience related to a drug and its influence on the therapeutic adherence

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El derecho del paciente a decidir sobre su tratamiento: caso clínico de optimización de la farmacoterapia / The patient's right to decide on their treatment: a clinical report of medicines optimisation

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