Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function.

Implantable Cardiovascular Therapeutic Devices (CTD), while lifesaving, impart supraphysiologic shear stress to platelets, resulting in thrombotic and bleeding coagulopathy. We previously demonstrated that shear-mediated platelet dysfunction is associated with downregulation of platelet GPIb-IX-V and αIIbß3 receptors via generation of Platelet-Derived MicroParticles (PDMPs). Here, we test the hypothesis that sheared PDMPs manifest phenotypical heterogeneity of morphology and receptor surface expression and modulate platelet hemostatic function. Human gel-filtered platelets were exposed to continuous shear stress. Alterations of platelet morphology were visualized using transmission electron microscopy. Surface expression of platelet receptors and PDMP generation were quantified by flow cytometry. Thrombin generation was quantified spectrophotometrically, and platelet aggregation was measured by optical aggregometry. Shear stress promotes notable alterations in platelet morphology and ejection of distinctive types of PDMPs. Shear-mediated microvesiculation is associated with the remodeling of platelet receptors, with PDMPs expressing significantly higher levels of adhesion receptors (αIIbß3, GPIX, PECAM-1, P-selectin, and PSGL-1) and agonist receptors (P2Y12 and PAR1). Sheared PDMPs promote thrombin generation and inhibit platelet aggregation induced by collagen and ADP. Sheared PDMPs demonstrate phenotypic heterogeneity as to morphology and defined patterns of surface receptors and impose a bidirectional effect on platelet hemostatic function. PDMP heterogeneity suggests that a range of mechanisms are operative in the microvesiculation process, contributing to CTD coagulopathy and posing opportunities for therapeutic manipulation.

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function.

Objective: Implantable cardiovascular therapeutic devices (CTD) including stents, percutaneous heart valves and ventricular assist devices, while lifesaving, impart supraphysiologic shear stress to platelets resulting in thrombotic and bleeding device-related coagulopathy. We previously demonstrated that shear-mediated platelet dysfunction is associated with downregulation of platelet GPIb-IX-V and αIIbß3 receptors via generation of platelet-derived microparticles (PDMPs). Here, we test the hypothesis that shear-generated PDMPs manifest phenotypical heterogeneity of their morphology and surface expression of platelet receptors, and modulate platelet hemostatic function. Approach and Results: Human gel-filtered platelets were exposed to continuous shear stress and sonication. Alterations of platelet morphology were visualized using transmission electron microscopy. Surface expression of platelet receptors and PDMP generation were quantified by flow cytometry. Thrombin generation was quantified spectrophotometrically, and platelet aggregation in plasma was measured by optical aggregometry. We demonstrate that platelet exposure to shear stress promotes notable alterations in platelet morphology and ejection of several distinctive types of PDMPs. Shear-mediated microvesiculation is associated with the differential remodeling of platelet receptors with PDMPs expressing significantly higher levels of both adhesion (α IIb ß 3 , GPIX, PECAM-1, P-selectin, and PSGL-1) and agonist-evoked receptors (P 2 Y 12 & PAR1). Shear-mediated PDMPs have a bidirectional effect on platelet hemostatic function, promoting thrombin generation and inhibiting platelet aggregation induced by collagen and ADP. Conclusions: Shear-generated PDMPs demonstrate phenotypic heterogeneity as to morphologic features and defined patterns of surface receptor alteration, and impose a bidirectional effect on platelet hemostatic function. PDMP heterogeneity suggests that a range of mechanisms are operative in the microvesiculation process, contributing to CTD coagulopathy and posing opportunities for therapeutic manipulation.

Neuropathic or systemic chronic intoxication with Karwinskia humboldtiana (Buckthorn) fruit? Histopathological effect in myocardial and skeletal muscle.

In accidental intoxicated animals and humans, Karwinskia humboldtiana (Kh) causes lesions in the central and peripheral nervous system and organs like the kidney, liver, and lung. The objective was to evaluate the histology of myocardium and skeletal muscle after experimental chronic intoxication with mature fruit of Kh in Wistar rat. Twenty-five rats were used and divided into five groups (n = 5): four intoxicated and one control. Kh fruit was ground, dried, sieved, and administered by an orogastric tube. Intoxicated rats received 3.5 g/kg body weight fractionated in 5 doses. Control rats received only water. Animals were euthanized at 24, 48, 58, and 112 days, respectively. Samples of the myocardium and skeletal muscle were obtained and processed for light microscopy evaluation. Morphological analyses were performed, including a microdensitometric analysis. Results showed areas of necrosis in the muscle fibers, fibers with vacuolated cytoplasm, and disorganization of myofilaments, as well as staining variations in both myocardium and skeletal muscle time-depending. Zones with loss of continuity of the external lamina were identified with PAS with the diastase histochemical method. Immunolabeling with specific antibodies demonstrated diminution of actin and desmin myofilaments. The microdensitometric analysis showed a statistically significant difference between the intoxicated vs control group. These findings demonstrate that chronic intoxication of Kh fruit also causes damage in myocardial and skeletal muscle, these alterations will be useful to understand that the toxic effects of Kh fruit in accidently intoxicated humans are systemic, and not only over the nervous system.

Hiperamonemia como causa de diálisis no renal / Hyperammonemia as a cause of non-renal dialysis

Resumen La hiperamonemia es una condición frecuente en pacientes cirróticos y en el contexto de una causa no cirrótica se relaciona con aumento en la producción de amonio o alteración en su eliminación. La presentación clínica de esta condición es inespecífica: va desde alteración del comportamiento hasta estado de coma, siendo una de las causas de diálisis no renal por determinados valores o refractariedad a manejo médico. Se presenta el caso de una mujer de 35 años, quien ingresó al servicio de urgencias con alteración del estado de conciencia, niveles de amonio elevados y masa hipervascular en hígado. Los estudios de aminoácidos limitantes del ciclo de la urea y ácido orótico urinario fueron normales y la biopsia de la lesión hepática reportó carcinoma hepático fibrolamelar, al cual se atribuyó la presencia de shunt portosistémico que causaba la hiperamonemia. Se indicó diálisis por persistencia de elevaciones de amonio y poca respuesta al tratamiento médico. Dada la evolución de la paciente, fue necesario reiniciar la terapia reemplazo renal por reaparición de estado encefalopático al suspender la misma. Esta terapia se mantuvo hasta el trasplante hepático que se realizó como tratamiento del carcinoma, con posterior estabilización de niveles de amonio y suspensión de la diálisis.

Abstract Hyperammonemia is a common condition in cirrhotic patients. In the context of a non-cirrhotic cause, this is related to the increase in its production of ammonium or alteration in its elimination. The clinical presentation is nonspecific, from the alteration of the behavior to the coma, being one of the causes of non-renal dialysis due to certain values or refractoriness to medical management. The case of a 35-year-old woman is presented, who is admitted to the emergency department with altered state of consciousness, elevated ammonium levels and hypervascular mass in the liver. Biopsy of the liver lesion reports fibrolamellar liver carcinoma. The presence of a portosystemic shunt that causes hyperammonemia is attributed to this pathology. Dialysis is indicated by persistence of ammonium elevations with little response to medical treatment. In its evolution, it required a restart of renal replacement due to a reappearance of the encephalopathic state when it was suspended. This therapy is maintained until liver transplantation performed as a carcinoma treatment, with subsequent stabilization of ammonium levels and dialysis suspension.

Shear-mediated platelet activation in the free flow II: Evolving mechanobiological mechanisms reveal an identifiable signature of activation and a bi-directional platelet dyscrasia with thrombotic and bleeding features.

Shear-mediated platelet activation (SMPA) in the "free flow" is the net result of a range of cell mechanobiological mechanisms. Previously, we outlined three main groups of mechanisms including: 1) mechano-destruction - i.e. additive platelet (membrane) damage; 2) mechano-activation - i.e. activation of shear-sensitive ion channels and pores; and 3) mechano-transduction - i.e. "outside-in" signaling via a range of transducers. Here, we report on recent advances since our original report which describes additional features of SMPA. A clear "signature" of SMPA has been defined, allowing differentiation from biochemically-mediated activation. Notably, SMPA is characterized by mitochondrial dysfunction, platelet membrane eversion, externalization of anionic phospholipids, and increased thrombin generation on the platelet surface. However, SMPA does not lead to integrin αIIbß3 activation or P-selectin exposure due to platelet degranulation, as is commonly observed in biochemical activation. Rather, downregulation of GPIb, αIIbß3, and P-selectin surface expression is evident. Furthermore, SMPA is accompanied by a decrease in overall platelet size coupled with a concomitant, progressive increase in microparticle generation. Shear-ejected microparticles are highly enriched in GPIb and αIIbß3. These observations indicate the enhanced diffusion, migration, or otherwise dispersion of platelet adhesion receptors to membrane zones, which are ultimately shed as receptor-rich PDMPs. The pathophysiological consequence of this progressive shear accumulation phenomenon is an associated dyscrasia of remaining platelets - being both reduced in size and less activatable via biochemical means - a tendency to favor bleeding, while concomitantly shed microparticles are highly prothrombotic and increase the tendency for thrombosis in both local and systemic milieu. These mechanisms and observations offer direct clinical utility in allowing measurement and guidance of the net balance of platelet driven events in patients with implanted cardiovascular therapeutic devices.

Platelet Dysfunction During Mechanical Circulatory Support: Elevated Shear Stress Promotes Downregulation of αIIbß3 and GPIb via Microparticle Shedding Decreasing Platelet Aggregability.

[Figure: see text].

Impact of individual actions on the collective response of social systems.

In a social system individual actions have the potential to trigger spontaneous collective reactions. The way and extent to which the activity (number of actions-A) of an individual causes or is connected to the response (number of reactions-R) of the system is still an open question. We measure the relationship between activity and response with the distribution of efficiency, a metric defined as [Formula: see text]. Generalizing previous results, we show that the efficiency distribution presents a universal structure in three systems of different nature: Twitter, Wikipedia and the scientific citations network. To understand this phenomenon, we develop a theoretical framework composed of three minimal statistical models that contemplate different levels of dependence between A and R. The models not only are able to reproduce the empirical activity-response data but also can serve as baselines or null models for more elaborated and domain-specific approaches.

Relationship between ideology and language in the Catalan independence context.

Political polarization generates strong effects on society, driving controversial debates and influencing the institutions. Territorial disputes are one of the most important polarized scenarios and have been consistently related to the use of language. In this work, we analyzed the opinion and language distributions of a particular territorial dispute around the independence of Catalonia through Twitter data. We infer a continuous opinion distribution by applying a model based on retweet interactions, previously detecting elite users with fixed and antagonist opinions. The resulting distribution presents a mainly bimodal behavior with an intermediate third pole that shows a less polarized society with the presence of not only antagonist opinions. We find that the more active, engaged and influential users hold more extreme positions. Also we prove that there is a clear relationship between political positions and the use of language, showing that against independence users speak mainly Spanish while pro-independence users speak Catalan and Spanish almost indistinctly. However, the third pole, closer in political opinion to the pro-independence pole, behaves similarly to the against-independence one concerning the use of language.

Combination treatment of autologous bone marrow stem cell transplantation and hyperbaric oxygen therapy for type 2 diabetes mellitus: A randomized controlled trial.

The objective of this study was to compare standard treatment versus the combination of intrapancreatic autologous stem cell (ASC) infusion and hyperbaric oxygen treatment (HBOT) before and after ASC in the metabolic control of patients with type 2 diabetes mellitus (T2DM). This study was a prospective, randomized controlled trial. The combined intervention consisted of 10 sessions of HBOT before the intrapancreatic infusion of ASC and 10 sessions afterwards. ASCs were infused into the main arterial supply of the pancreas to maximize the presence of the stem cells where the therapeutic effect is most desired. A total of 23 patients were included (control group = 10, intervention group = 13). Age, gender, diabetes duration, number of medications taken, body weight and height, and insulin requirements were recorded at baseline and every three months. Also, body mass index, fasting plasma glucose, C-peptide, and HbA1c, C-peptide/glucose ratio (CPGR) were measured every three months for one year. HbA1c was significantly lower in the intervention group compared with control throughout follow-up. Overall, 77% of patients in the intervention group and 30% of patients in the control group demonstrated a decrease of HbA1c at 180 days (compared with baseline) of at least 1 unit. Glucose levels were significantly lower in the intervention group at all timepoints during follow-up. C-peptide levels were significantly higher in the intervention group during follow-up and at one year: 1.9 ± 1.0 ng/mL versus 0.7 ± 0.4 ng/mL in intervention versus control groups, respectively, p = 0.0021. CPGR was higher in the intervention group at all controls during follow-up. The requirement for insulin was significantly lower in the intervention group at 90, 180, 270, and 365 days. Combined therapy of intrapancreatic ASC infusion and HBOT showed increased metabolic control and reduced insulin requirements in patients with T2DM compared with standard treatment.

Caracterización de la mielitis transversa en un hospital referencia del sur colombiano / Characterization of patients with transverse myelitis in a referral hospital in southern Colombia

Objetivo: caracterizar a los pacientes con diagnóstico de mielitis transversa (MT) en un hospital de referencia del sur de Colombia durante los años 2007 a 2013. Materiales y métodos: Estudio transversal. Se incluyeron todos los pacientes con diagnóstico de MT, según los criterios The Transverse Myelitis Consortium Working Group. Resultados: En total 21 casos de MT (1,3 casos/10 000 ingresos), el 66,7% en edades entre 15-30 años, 57,1% de género femenino; 81,0% agudos. Todos presentaron déficit motor, 52,4% disfunción vesical autonómica, 81,0% nivel sensitivo. Se documentaron hallazgos imagenológicos de MT en resonancia magnética nuclear en el 71,4% de los casos e hiperproteinorraquia en 50%. En el 66,7% la etiología fue desconocida, en los casos en quienes se logró determinar la etiología fue: herpes simple tipo 1 (9,5%), varicela zoster (9,5%), leucemia mieloide aguda (4,8%), lupus eritematoso sistémico (4,8%) y deficiencia de vitamina B12 (4,8%). Conclusiones: La MT es un importante problema de salud pública, es necesario considerar sus características clínicas, establecer las formas idiopáticas y reconocer etiologías infecciosas dado el impacto terapeutico y pronóstico

Objective: To characterize patients with a diagnosis of transverse myelitis (TM) in a referral hospital in southern Colombia during years 2007 to 2013. Material and methods: This is a crosssectional study. All patients with a TM diagnosis were included, according to the criteria set by the Transverse Myelitis Consortium Working Group. Results: We had a total number of 21 cases of TM (1.3 cases/10,000 admissions). Two thirds (66,7%) of all patients were between 15-30 years of age, 57,1% were female; 81.0% had an acute presentation, 100% had motor deficit, 52.4% had autonomic bladder dysfunction, and 81.0% had sensitive level. MT findings were documented using magnetic resonance imaging in 71.4% of cases and 50% by high protein levels in the cerebrospinal fluid. Two thirds (66.7%) of the cases had an unknown etiology. In those cases in which their origin could be identified, the etiologies were: Type I Herpes Simplex (9.5%); Varicella Zoster (9.5%), acute myeloid leukemia (4.8%), systemic lupus erythematosus (4.8%) and vitamin B12 deficiency. Conclusion: MT is a major public health problem, and it is necessary to consider its clinical features, to establish its idiopathic forms and to recognize its infectious causes given their therapy impact and prognosis

Absceso hepático por Klebsiella pneumoniae, asociado con bacteriemia y meningitis. Reporte de un caso / Klebsiella pneumoniae liver abscess associated with bacteremia and meningitis. Case report

El absceso hepático, continúa siendo un importante problema de salud pública. El causado por Klebsiella pneumoniae, se ha descrito en un 29% de los casos en algunas series. Con una mortalidad hasta del 11,3%, se presenta con mayor frecuencia en pacientes con diabetes mellitus, relacionándose con complicaciones a distancia, como meningitis, absceso cerebral y afección pulmonar. Se presenta el caso de un hombre sin factores de riesgo, con síndrome de absceso hepático por Klebsiella pneumoniae con diseminación hematógena dado por la presencia de bacteriemia y meningitis. Fue manejado con cefepime y drenaje percutáneo, presentando mejoría clínica total. La infección por Klebsiella pneumoniae, representa una etiología emergente como causa de abscesos hepáticos con un comportamiento clínico diferente al resto de infecciones relacionadas con este microorganismo...

Liver abscess remains a major public health problem. Some series have reportedKlebsiella pneumoniae as the causative agent of liver abscesses in up to 29% of cases. This condition has a high mortality rate, up to 11.3%, and it occurs more often in patients with diabetes mellitus, being related to disseminated complications such as meningitis, brain abscess, and pulmonary complications. We report the case of a male patient with a liver abscess caused by Klebsiella pneumoniae and no underlying risk factors, associated with hematogenous spread with the occurrence of bacteremia and meningitis. The patient was treated with cefepime and percutaneous drainage, and he completely recovered. Klebsiella pneumoniae infection represents an emerging etiological cause of liver abscesses, with a different clinical behavior compared to other infections related to this microorganism...

Mielitis transversa asociada a virus herpes tipo-1 / Associated transverse myelitis herpes virus type -1

La mielitis transversa (MT) es un proceso inflamatorio que involucra áreas restringidas de la médula espinal (ME) ygenera síntomas motores, sensitivos y autonómicos. El término mielitis transversa aguda estaba reservado para los casos idiopáticos, pero en la actualidad se usa para abarcar el síndrome clínico general, así se desconozca su etiología.El virus herpes simple raramente se ha reportado como causa de mielitis. En pacientes inmunosuprimidos se ha encontrado que el virus herpes tipo 1 causa encefalitis y el herpes tipo 2 causa con mayor frecuencia mielitis.Aunque muchos pacientes presentan secuelas, un diagnóstico y tratamiento oportunos; combinando terapia antiviraly esteroides; disminuye el daño del sistema nerviosos central y mejoran la calidad de vida.

Transverse myelitis is an inflammatory process who involved restricted areas of the spinal cord causing motor,sensory and autonomic symptoms. The term acute transverse myelitis was reserved for idiopathic cases, but currently is used for the entire clinical syndrome include there of unknown cause.The herpes simplex virus has been rarely reported as a cause of myelitis.In Inmunosupressed patients the Herpes type 1 virus causes encephalitis and type 2 herpes most often cause myelitis.Although many patients have sequels, early diagnosis and treatment; combining antiviral therapy and steroids;decreases central nervous system damage and improved the quality of life.

Influencia de la posición con respecto a la fuerza de gravedad sobre la hidrodinámica de un modelo experimental de aneurisma sacular / Influence of the position in respecto to the gravitation force,upon the hydrodynamics of an experimental model of sacular aneurism

Para confirmar la hipótesis de que la hidrodinámica de los aneurismas cerebrales depende en parte de la posición de éstos, respecto a la fuerza de la gravedad, se desarrolló un modelo experimental de aneurisma en látex, sometido a flujo pulsátil. Con inyección de tintes y radioisótopos, se hicieron registros en 4 posiciones diferentes. Se diseñó un modelo físico que permitió el análisis cuantitativo de los resultados y que abre además la posibilidad de analizar matemáticamente la hidrodinámica de los aneurismas. Los resultados sugieren que cuando el aneurisma se encuentra orientado en contra de la fuerza de gravedad, tiene muy bajo riesgo de trombosis y la escasa turbulencia de su flujo condiciona un menor riesgo de crecimiento y ruptura respecto a cualquier otra posición. La mayor turbulencia en el flujo de la pared la tiene el aneurisma orientado hacia abajo, es decir, paralelo a la fuerza de gravedad. El aneurisma orientado hacia abajo es el que por su hidrodinámica, tiene más posibilidades de complicarse, ya que se tiene: a) un mayor riesgo de ruptura debido al impacto del chorro sobre la pared y la turbulencia que este impacto produce, b) un mayor riesgo de trombosis producida por la éstasis circulatoria que tiene en su cúpula. Esta combinación de factores (ruptura y trombosis) hace que estos aneurismas tiendan a crecer más que otros