Three new Alpha1-Antitrypsin deficiency variants help to define a C-Terminal region regulating conformational change and polymerization

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state

Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases

BACKGROUND: Primary sinonasal mucosal melanomas are aggressive tumors with a poor clinical control by current treatments, raising the urgent need of novel strategies. METHODS: By fluorescence in situ hybridization (FISH), direct sequencing, and immunohistochemistry, we investigate the spectrum of molecular abnormalities in a cohort of 32 cases of primary sinonasal mucosal melanomas. RESULTS: We found that all primary sinonasal mucosal melanomas lack BRAF V600E mutation; in addition, they are characterized by somatic mutations of NRAS (22%) and KIT (12.5%), together with amplification of RREB1 (100%) and loss of MYB (76%). The large majority of cases showed KIT protein expression (96.9%). Among tumor suppressor genes, primary sinonasal mucosal melanomas showed loss of PTEN (48.1%) and p16/INK4a (55.2%). All tested cases showed expression of pAkt and pErk, suggesting a combined activation of PI3K/Akt and RAS-mitogen-activated protein kinase (MAPK) pathways. CONCLUSIONS: This molecular fingerprint strongly argues against the clinical efficacy of BRAF-inhibitors, but could candidate primary sinonasal mucosal melanomas to therapeutic strategies targeting RAS and KIT mutations or inhibiting PI3K-Akt-mTOR pathway

Low in‑hospital mortality rate in patients with COVID‑19 receiving thromboprophylaxis: data from the multicentre observational START‑COVID Register

Abstract COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease,and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years

Condicionantes pronósticos del ictus isquémico: utilidad de los biomarcadores sanguíneos en su predicción

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018El ictus es una de las principales causas de mortalidad y discapacidad en nuestro medio. El pronóstico del ictus depende en gran parte de factores basales no modificables como la edad o la gravedad inicial del mismo, pero también de circunstancias que ocurren durante la historia natural del mismo y conllevan un mal desenlace. En la presente tesis doctoral nos focalizamos en éstas últimas, las complicaciones del ictus. Así, nuestros objetivos en el presente trabajo son, en primer lugar, establecer cuáles de las complicaciones del ictus presentan un mayor impacto sobre el pronóstico del mismo en nuestro medio. En segundo lugar, evaluar en qué indicaciones el uso de biomarcadores sanguíneos constituye una necesidad asistencial. En tercer lugar, evaluar la asociación de los biomarcadores sanguíneos al pronóstico del ictus y las complicaciones del mismo en la literatura y, finalmente testar el valor predictivo de biomarcadores candidatos para las indicaciones identificadas en los puntos anteriores. Para esto hemos realizado un análisis del registro de ictus de la Sociedad Española de Neurología (RENISEN), en el que identificamos que el edema cerebral con hipertensión intracraneal y las infecciones respiratorias son las complicaciones con un mayor impacto sobre la mortalidad del ictus, encontrándose en un segundo escalón las complicaciones cardiológicas. Un interesante hallazgo de este análisis es que el impacto de esas complicaciones depende de la gravedad del ictus. Por otra parte, hemos realizado una encuesta a neurólogos vasculares europeos en los que vemos que la indicación más demandada para el uso de biomarcadores en el ictus es el manejo de las terapias de reperfusión. A través de revisiones sistemáticas y metaanálisis, hemos detectado que el uso de biomarcadores para el manejo de las complicaciones del ictus ha sido poco estudiado. De entre los marcadores metaanalizados, la proteína C-reactiva constituye un candidato para el manejo de las infecciones asociadas al ictus. Respecto a los estudios experimentales, hemos identificado dos candidatos nuevos para guiar las terapias de reperfusión, la proteasa activadora del factor VII (FSAP) y la proteasa de clivaje del factor de Von Willebrand (ADAMTS13), relacionadas con la recanalización arterial, y hemos descrito la utilidad de la medición de troponina I ultrasensible en la fase aguda del ictus, identificando a los pacientes con mayor riesgo de desarrollar complicaciones cardiológicas. Si nuestros resultados se confirmasen en estudios prospectivos, podríamos llegar a implementar el uso de biomarcadores sanguíneos en pacientes con ictus isquémico para el manejo de las complicaciones del mismo.Stroke represents one of the main causes of mortality and disability. Stroke outcome depends mainly on baseline, non-modifiable factors, such as age or stroke severity, but also on several conditions that may occur across the natural history of stroke and leads to a poor outcome. In the present doctoral thesis we focus on these conditions, namely post-stroke complications. Therefore, our objectives in the present project are: first, to assess which post-stroke complications have the highest impact on stroke prognosis; second, to evaluate in which indications the use of blood biomarkers is more demanded by physicians; third, to evaluate across the literature whether the association between blood biomarkers and stroke outcome and complications has been assessed; and fourth, to test the predictive value of some candidates for the previously identified indications. To assess these objectives, we performed a comprehensive analysis of the stroke registry of the Spanish Neurological Society (RENISEN), finding that brain edema with increased intracranial pressure and respiratory tract infections were the complications with the highest impact on in-hospital mortality, followed by cardiologic complications in a second step. An interesting finding of the analysis is that the impact of these complications depends on stroke severity. Moreover, we performed a survey across European stroke neurologists, finding that the indication in which the use of biomarkers is more requested is the management of reperfusion therapies. By applying systematic reviews and meta-analysis, we have found that the use of biomarkers for the management of post-stroke complications has been poorly studied. From the meta-analyzed biomarkers, C-reactive protein appears as a surrogate biomarker for the management of post-stroke infections. Regarding experimental studies, factor seven activating protease (FSAP) and ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13), both associated with arterial recanalization, have emerged as candidates to guide reperfusion therapies. Moreover, we have described a role for high-sensitive troponin-I determination in acute stroke, in identifying those patients at the highest risk of suffering cardiologic complications. If our results are confirmed in future prospective studies evaluating the prognostic implications of the use of these biomarkers, such biomarkers could be translated into clinical practice for the management of post-stroke complications

Amiloidosis diagnosticada mediante punción aspiración de grasa subcutánea en un servicio de Medicina Interna

La amiloidosis es una enfermedad por depósito de amiloide en diferentes tejidos, produciendo su disfunción. Es infrecuente, con elevada mortalidad y escasas opciones terapéuticas. La punción de grasa subcutánea (PAG) es segura y sensible para diagnosticarla, pero por su clínica inespecífica, es necesario sospecharla. Estudio retrospectivo de las PAGs en 22 años de un Servicio de Medicina Interna. La quinta parte resultaron positivos. Se describen sus características clínicas y mortalidad, señalando las enfermedades predisponentes y parámetros del laboratorio más característicos. Se analiza la ecocardiografia en el diagnóstico y la dificultad de la PAG en pacientes con escaso panículo adiposo.L'amiloidosi és una malaltia per dipòsit d'amiloide als diferents teixits, produïnt la seva disfunció. És infreqüent, amb alta mortalitat i escasses opcions terapèutiques. La punció de greix subcutani (PAG) és segura i sensible per diagnosticar-la, però per la seva clínica inespecífica, és necessari sospitar-la. Estudi restrospectiu de les PAGs en 22 anys d'un Servei de Medicina Interna. La cinquena part van resultar positius. Es descriuen les seves característiques clíniques i mortalitat, assenyalant les malalties predisponents i paràmetres del laboratori més característics. S'analitza la ecocardiografia en el diagnòstic i la dificultad de la PAG als malalts amb escàs panícul adipós

Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases

BACKGROUND: Primary sinonasal mucosal melanomas are aggressive tumors with a poor clinical control by current treatments, raising the urgent need of novel strategies. METHODS: By fluorescence in situ hybridization (FISH), direct sequencing, and immunohistochemistry, we investigate the spectrum of molecular abnormalities in a cohort of 32 cases of primary sinonasal mucosal melanomas. RESULTS: We found that all primary sinonasal mucosal melanomas lack BRAF V600E mutation; in addition, they are characterized by somatic mutations of NRAS (22%) and KIT (12.5%), together with amplification of RREB1 (100%) and loss of MYB (76%). The large majority of cases showed KIT protein expression (96.9%). Among tumor suppressor genes, primary sinonasal mucosal melanomas showed loss of PTEN (48.1%) and p16/INK4a (55.2%). All tested cases showed expression of pAkt and pErk, suggesting a combined activation of PI3K/Akt and RAS-mitogen-activated protein kinase (MAPK) pathways. CONCLUSIONS: This molecular fingerprint strongly argues against the clinical efficacy of BRAF-inhibitors, but could candidate primary sinonasal mucosal melanomas to therapeutic strategies targeting RAS and KIT mutations or inhibiting PI3K-Akt-mTOR pathway

Fibrinogen storage disease without hypofibrinogenemia associated with estrogen therapy

BACKGROUND: Cytoplasmic inclusion bodies within hepatocytes may have different etiologies, including the Endoplasmic Reticulum Storage Diseases (ERSDs). ERSD is a pathological condition characterized by abnormal accumulation of proteins destined for secretion in the endoplasmic reticulum of hepatocytes; it may be congenital (primary) or acquired (secondary). Fibrinogen storage disease is a form of ERSD. CASE PRESENTATION: We present a case of fibrinogen storage disease secondary to estrogen replacement therapy. Its causal relationship to the drug is shown by histological, immunohistochemical and ultrastructural studies of paired liver biopsies obtained during and after the drug therapy. CONCLUSION: The liver biopsies of patients with idiopathic liver enzyme abnormalities should be carefully evaluated for cytoplasmic inclusion bodies and, although rare, fibrinogen deposits

Situational prevention and public transport crime in El Salvador

By any standard, there is a serious problem of crime on the public transport system in El Salvador. Guided by crime opportunity theory, this study undertook a rapid assessment of the problem consisting of a systematic observation of public transport in El Salvador and focus group discussions with passengers, bus operators, police and bus company owners/managers. The purposes were (1) to describe the main forms of crime and disorder afflicting the system, (2) to identify features of the system that contribute to the high levels of crime and disorder, and (3) to identify preventive measures, consistent with international experience. A program of situational crime prevention measures was identified which consisted of two main kinds: (1) measures relating to the operations of the bus system as a whole, intended to help to create a more orderly and secure transport environment and, (2) more specific measures designed to reduce opportunities for crimes occurring on buses or at bus stops, such as homicides, robberies, and sexual assaults on women. Future research and implementation of the preventive measures are discussed