Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer's Disease.

BACKGROUND: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer's disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. OBJECTIVE: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer's Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1-6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. METHODS: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. RESULTS: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. CONCLUSION: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

FTLD-TDP With and Without GRN Mutations Cause Different Patterns of CA1 Pathology.

Heterozygous loss-of-function mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A). PGRN is a highly conserved, secreted glycoprotein and functions in the central nervous system as a key modulator of microglial function. Hence, altered microglial function caused by PGRN deficiency may be tied to the pathogenesis of FTLD-TDP. Our previous studies showed that haploinsufficiency of GRN mutations extends to microglial PGRN expression in the hippocampal CA1 region. In this study, we found that the CA1 sector was associated with less neuronal loss and more frequent TDP-43 inclusions in FTLD-TDP type A cases with GRN mutations than in sporadic cases. In addition, the CA1 region in GRN mutation cases contained more rod-like microglia, which also had reduced PGRN expression. These findings suggest that the profile of TDP-43 inclusions, neuronal number, and microgliosis in the CA1 sector of FTLD-TDP type A cases may be influenced by GRN gene expression status.

[Haemostatic activation in head injury]. / Activación hemostática en el traumatismo creoencefálico.

A relationship between Central Nervous System and coagulation has been known since the work by Goodnight et al5. When an encephalic injury occurs tissue damage causes the release of thromboplastin-related products, mainly the Tissular Factor. This release produces an activation of the coagulation system specially through its extrinsic path. With this physiopathologic basis we attempt to improve the knowledge of this relation by performing a prospective study at the Intensive Care Unit of our Hospital. The study included 67 patients with cranioencephalic trauma alone, with an average Glasgow coma scale score of 10 and a control group consisting of 40 healthy subjects. Two peripheral vein blood extractions were performed, at admission and 24 hours later. Global coagulation parameters (prothrombin time, activated partial thromboplastin time, platelet count and fibrinogen), hypercoagulability markers (prothrombin fragments F1+2 and thrombin-antithrombin complex (TAT)) and thrombolisis markers (D-dimer) were determined. Our results show that early after head trauma an increase in fragments F1+2, TAT and Ddimer occur. After the first 24 hours a significant decrease in hypercoagulability markers levels is detected. Modification of the global coagulation parameters was also detected. In conclusion, early after a cranioencephalic trauma a simultaneous state of hypercoagulability and thrombolysis occur which may have the purpose of improving the hemostatic balance.

[Therapeutic attitude, evolution and prognosis of the cerebral hemorrhages of patients in dicumarinic treatment, in function of their supra or infratentorial localization]. / Actitud terapéutica, evolución y pronóstico de la hemorragia cerebral, según la localización supra o infratentorial, de pacientes en tratamiento dicumarínico.

INTRODUCTION: The anticoagulants are drugs with possible serious secondary effects, being one of the most serious the appearance of intracraneal hemorrhages, being able to vary the clinical course as they were hemorrhages in the deep supratentorial compartment (ST) or in the infratentorial (IT). OBJECTIVES: Compare the therapeutic attitude, the evolution and the prognostic of the cerebral hemorrhages in patient with warfarin treatment, in function of their localization ST or IT. PATIENTS AND METHODS: Descriptive and retrospective analysis of 42 patients; in 28 of the cases (66,6%) the localization was ST, and in 14 of the patients (33,3%) the localization was IT. We study risk vascular factors, age and the sex of the patients, the volume of the hemorrhage, the initial clinical state of the patients, the therapeutic attitude, the average stay and the mortality. As statistical tools, the t of Student and the c2 test were used, demanding a confidence interval of 95%. RESULTS: The factors of cardiovascular risk of our serie were similar to the existent ones in other studies. The hemorrhages IT are more frequent in women, existing significant differences in the age among sexes in function of the localization. 100% of the hemorrhages IT exceeded the therapeutic INR, in front of 39% of the ST. A bigger half stay is also demonstrated in the ST hemorrhages so much in the surviving as in the exitus. Statistical significance was not reached in the rest of the studied parameters. CONCLUSIONS: The presence of a INR that surpasses the therapeutic is an indicator of hemorrhage risk IT, in patient dicumarinic drawees, and that in this same subgrup, the stays stockings are sensibly inferior, in all the subgrups (medical treatment and surgical treatment). Also the feminine sex has a bigger incidence of processes ST, with a smaller presentation age.

Actitud terapéutica, evolución y pronóstico de la hemorragia cerebral, según la localización supra o infratentorial, de pacientes en tratamiento dicumarínico / Therapeutic attitude, evolution and prognostic of the cerebral hemorrhages of patients in dicumarinic treatment, in function of their supra or infratentorial localization

Introducción. La hemorragia intracraneal es uno de los efectos secundarios más graves de los anticoagulantes; el curso clínico puede variar según se trate de hemorragias supratentoriales (ST) profundas o infratentoriales (IT). Objetivo. Comparar la actitud terapéutica, la evolución y el pronóstico de los pacientes con hemorragia cerebral y tratamiento dicumarínico según la localización sea ST o IT. Pacientes y métodos. Análisis descriptivo y retrospectivo de 42 pacientes con hemorragia cerebral, ST profunda en 28 casos (66,6 por ciento), IT en los restantes 14 (33,3 por ciento). Estudiamos los factores de riesgo vascular, la edad, el sexo, el volumen de la hemorragia, el estado clínico inicial, la actitud terapéutica, la estancia media y la mortalidad. Como herramientas estadísticas empleamos la t de Student y el test de c2, con un intervalo de confianza del 95 por ciento. Resultados. Los factores de riesgo cardiovascular de nuestra serie son similares a los que presentan otros estudios. La hemorragia IT es más frecuentes en mujeres; existe una diferencia significativa en la edad entre sexos en función de la localización. Todos los pacientes con hemorragia IT excedían el INR terapéutico mientras que sólo lo hacía el 39 por ciento de los casos con hemorragia ST. La estancia media fue más prolongada entre los pacientes con hemorragia ST, tanto en los pacientes que sobrevivieron como entre los que fallecieron. No se alcanzó significación estadística en el resto de los parámetros estudiados. Conclusiones. La presencia de un INR que sobrepase el terapéutico es un indicador de riesgo para la hemorragia IT en pacientes en tratamiento dicumarínico. La estancia media del grupo IT es más corta (tanto en el subgrupo de pacientes que recibió tratamiento médico como en el que recibió tratamiento quirúrgico) que la del grupo ST. El sexo femenino tiene una mayor incidencia de procesos ST y una menor edad de presentación (AU)

Comparison of cuffed tunneled hemodialysis catheter survival.

Despite efforts to have hemodialysis patients begin renal replacement therapy with a mature arteriovenous shunt, many patients begin dialysis with a cuffed tunneled catheter as their access. An increasing number of differently designed tunneled hemodialysis catheters have become available in the last decade. The primary aim of this study is to compare catheter survival for Hickman (Bard, Salt Lake City, UT) and Opti-flow (Bard) catheters. The 16-month experience with 182 catheters, totaling 13,861 catheter-days, is reported. The probability of Hickman catheter failure at 30, 60, and 90 days was 29%, 49%, and 67%. The probability of Opti-flow catheter failure was significantly less at 10%, 24%, and 38% for the same times, respectively (P: < 0.05 for all time points). The difference in catheter failure rates was caused by a greater malfunction rate of Hickman catheters; the two catheters had similar infection rates. We conclude that survival of Opti-flow catheters was significantly better than that of Hickman catheters from 30 to 90 days, which is a clinically relevant period when patients are waiting for maturation of a permanent access or replacement of a failed access. Since the conclusion of our study, we documented 10 episodes of Opti-flow catheter malfunction within 4 months secondary to hairline fracture of the arterial hub. The Opti-flow catheter was recalled and is now available with retooled hubs.

Hypercoagulability state in hip and knee surgery: influence of ABO antigenic system and allogenic transfusion.

It is well know that people with blood group O have a lower risk for venous thromboembolic disease (VTED) than does the general population. Moreover blood transfusion has been identified as a risk factor for VTED in patients with major trauma. The aim of this work is to investigate the behaviour of several markers of hypercoagulability before and after substitutive surgery of hip and knee in order to evaluate the relationship between the plasmatic levels of these markers, the ABO antigenic system and the allogenic blood transfusion. The plasmatic levels of D dimer (D-D), thrombin-antithrombin complex (TAT), and fragment 1 + 2 of prothrombin (F1 + 2) have been determined by the ELISA method in 79 patients subject to substitutive surgery of hip or knee one day before and one day after surgery. The 41 patients with blood groups different from O had presurgical levels of F1 + 2 higher than those of group O (p = 0.004), while no differences could be found for D-D and TAT. The 28 patients who received allogenic blood presented higher levels of D-D one day after surgery than non-transfused patients (p = 0.043); the practice of transfusion did not modify significantly the levels of TAT and F1 + 2 after surgery. In accordance with these results we suggest that blood group and transfusion are risk factors for hypercoagulability, and therefore we advise for a restrictive policy of transfusion practice. New therapies such as aprotinin should be assayed in order to minimize blood loss.

[Myocardial infarction after mediastinal radiotherapy of Hodgkin's disease]. / Infarto de miocardio tras radioterapia mediastínica por enfermedad deHodgkin.

A 30 years old man having Hodgkin's disease was treated successfully by means of chemotherapy and radiotherapy. Two years after treatment he developed a myocardial infarction that was ascribed to the atherosclerosis-inducing effects of radiations.