Comparison of Patients' Phenotypes, Guideline-Directed Recommendations Compliance and Rates of Cardiotoxicity between Caribbean and United States Cardio-oncology Programs.

Background: Little is known about the characteristics of oncological patients, cancer therapy-induced cardiotoxicity, and guidelines-directed interventions in the Caribbean; analysis of cardio-oncology services may shed light on this and clarify links between ethnicity, cultural, and local socioeconomic factors. Objectives: This study compared patients' phenotypes, adherence to guidelines recommendations, and patterns of cardiotoxicity between two cardio-oncology programs: one in the Dominican Republic (DR) and the other in Chicago IL, United States (US). Methods: Patients being considered for or treated with potentially cardiotoxic drugs were followed before, during, and after chemotherapy through both cardio-oncology clinics, where we recorded and compared clinical, demographic, and echocardiographic data. Results: We studied 597 consecutive patients, 330 (55%) from the DR and 267 (45%) from the US. DR vs. US mean age 55± 13/52 ± 13 years; female 77/87% (p < 0.001); breast cancer 57/73% (p < 0.001); treated with anthracyclines + taxanes 47/40% (p = 0.151); monoclonal antibodies + taxanes or platins 37/45% (p < 0.001). Cardiotoxicity DR vs. US occurred in 15/7% (p = 0.001); multivariate logistic regression (OR 2.29; 95% CI, 1.31-3.99; p < 0.005) did not identify age >60, HTN, DM, BMI, tobacco or chemotherapy as predictors. Compliance with ASCO guidelines was similar among both cohorts. Conclusion: Compared to the US cohort, the Caribbean cohort of cancer patients has similar rates of CV risk factors but a higher likelihood of developing drug-induced LV dysfunction. Programs' compliance with ASCO guidelines was equivalent. While further research is needed to ascertain regional variations of cardiotoxicity, these findings underline the relevance of cardio-oncology services in nations with limited resources and high CV risk.

Schwannomatosis del nervio plantar interno. Presentación de caso / Schwannomatosis of the internal plantar nerve. Case presentation

Introducción: Las Schwannomatosis Mononeurales de los Miembros son entidades muy poco frecuentes, escasamente conocidas y raramente publicadas en la bibliografía internacional, éstas se encuentran caracterizadas por la existencia de múltiples formaciones nodulares o plexiformes con compromiso exclusivo de un solo nervio, todas con diagnóstico patológico de schwannoma, excluyéndose a otras entidades tumorales y fuera del contexto de una neurofibromatosis. Aquí se presenta un caso con compromiso del nervio plantar medial o interno. Material y método: Se evaluó y analizo el caso clínico, a nivel semiológico y Neurorradiológico, Neurofisilógico. Se definió la conducta terapéutica y quirúrgica. Se evaluaron resultados mediante: análisis semiológico y seguimiento con imágenes. Descripción y resultados: Paciente sexo masculino de 45 años de edad consulta por presentar múltiples tumoraciones palpables en región retromaleolar interna y plantar derecho y disestesias al apoyo, con antecedente de cirugía de schwannoma plantar. Al examen neurológico: masas palpables en los sectores previamente indicados y Tinel a nivel retromaleolar interno y plantar. RMN: múltiples nódulos con captación intermedia de contraste, hipertensos en T2.Se practicó resección quirúrgica mediante amplio abordaje, se identificaron múltiples nódulos, uno de ellos de aspecto plexiforme que involucraba la totalidad del nervio plantar interno imposibilitando la preservación del tronco por lo cual se practicó microneurorrafia con interposición de puente de safeno interno. Discusión y conclusión: Las Schwannomatosis Mononeurales de los Miembros son entidades extremadamente raras, se han reportado con una frecuencia un poco mayor a aquellas que involucran a los nervios mediano y cubital, en sus características macroscópicas las lesiones fueron publicadas como pertenecientes a la variante nodular para esa escasa mayoría. La configuración plexiforme de los schwannomas es menos frecuente que la nodular per se y, en general. está asociada a troncos menores, fuera de estos territorios, su rareza es extrema. Este caso clínico resulta aún más especial por tratarse de una Schwannomatosis Mononeural del Plantar Medial con variante de tipo mixto, es decir nodular con una masa plexiforme dominante. Esta entidad no la hemos encontrado en la bibliografía internacional.Por otro lado, la resección quirúrgica de estos tumores, cuando son nodulares es compatible con la preservación del tronco nervioso, sacrificando solamente, su fascículo de origen. Este caso, dada la configuración descripta del tumor principal, el cual involucraba la totalidad del tronco, se hizo imposible la preservación del nervio, para lo cual debió realizarse microneurorrafia con puente. Como consideración final, creemos que es de capital importancia la adecuada exploración y planificación pre e intraoperatoria de estos pacientes

Introduction: Mononeural Schwannomatosis located at limbs are very infrequent entities, the knowledge about its are very poor, and there are just a few publications related to them. This articles make reference multiple nodular or plexiform lesions with involvement oh only one nerve, every one whit diagnosis of schwannoma, excluding fibromatosis. In this article, we describe a patient with who suffered the involvement of multiples tumours with nodular and plexiform configuration. Material y method: The clinical case was analysed by different media, clinical, neuro physiological and by neuroimages. By this approaches were defined and evaluated the surgical outcomes and results. Clinical case: Male, 45 years old. Multiples tumours at plantar region. Tinel Sign with multiple palpable masses al retromaleolar sulcus and plantar region, plantar schwannoma operated on previously.RMN: multinodular configuration at level of medial plantar nerve, with intermediate contrast reinforcement.An extended approach was performed, from retromaleolar sulcus to medial aspect of the foot, and finishing inside the digital-plantar sulcus. Complete resection was performed, multiples nodulos were found, the bigger had a plexiform configuration, was imposible the preservation of the nerve trunk and the, the interposition of sural nerve was realized. With good evolution. Conclusions: For this very rare entities, the bigger frequency was reported et limbs.The most frequent locations was at medial nerve, second place occupied by the ulnar nerve, we didn't find on international literature a plexiform tumour inside the medial plantar nerve.On the other hand, we think that the complete resection for this tumours when are nodular, the complete resection with preservation of the main trunk, is feasible. Ehen the tumour has a plexiform pattern; complete resection is only feasible with trunk nerve resection and interposition of nerve graft

Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function.

The incidence of high blood pressure with advancing age is notably high, and it is an independent prognostic factor for the onset or progression of a variety of cardiovascular disorders. Although age-related hypertension is an established phenomenon, current treatments are only palliative but not curative. Thus, there is a critical need for a curative therapy against age-related hypertension, which could greatly decrease the incidence of cardiovascular disorders. We show that overexpression of human thioredoxin (TRX), a redox protein, in mice prevents age-related hypertension. Further, injection of recombinant human TRX (rhTRX) for three consecutive days reversed hypertension in aged wild-type mice, and this effect lasted for at least 20 days. Arteries of wild-type mice injected with rhTRX or mice with TRX overexpression exhibited decreased arterial stiffness, greater endothelium-dependent relaxation, increased nitric oxide production, and decreased superoxide anion (O2•-) generation compared to either saline-injected aged wild-type mice or mice with TRX deficiency. Our study demonstrates a potential translational role of rhTRX in reversing age-related hypertension with long-lasting efficacy.

Designer and natural peptide toxin blockers of the KcsA potassium channel identified by phage display.

Peptide neurotoxins are powerful tools for research, diagnosis, and treatment of disease. Limiting broader use, most receptors lack an identified toxin that binds with high affinity and specificity. This paper describes isolation of toxins for one such orphan target, KcsA, a potassium channel that has been fundamental to delineating the structural basis for ion channel function. A phage-display strategy is presented whereby ∼1.5 million novel and natural peptides are fabricated on the scaffold present in ShK, a sea anemone type I (SAK1) toxin stabilized by three disulfide bonds. We describe two toxins selected by sorting on purified KcsA, one novel (Hui1, 34 residues) and one natural (HmK, 35 residues). Hui1 is potent, blocking single KcsA channels in planar lipid bilayers half-maximally (Ki) at 1 nM. Hui1 is also specific, inhibiting KcsA-Shaker channels in Xenopus oocytes with a Ki of 0.5 nM whereas Shaker, Kv1.2, and Kv1.3 channels are blocked over 200-fold less well. HmK is potent but promiscuous, blocking KcsA-Shaker, Shaker, Kv1.2, and Kv1.3 channels with Ki of 1-4 nM. As anticipated, one Hui1 blocks the KcsA pore and two conserved toxin residues, Lys21 and Tyr22, are essential for high-affinity binding. Unexpectedly, potassium ions traversing the channel from the inside confer voltage sensitivity to the Hui1 off-rate via Arg23, indicating that Lys21 is not in the pore. The 3D structure of Hui1 reveals a SAK1 fold, rationalizes KcsA inhibition, and validates the scaffold-based approach for isolation of high-affinity toxins for orphan receptors.

Aspectos cuantitativos de la corteza cerebral humana / Cuantitative aspects of human cerebral cortex

Se considera a la corteza cerebral como un núcleo extendido en superficie que, como consecuencia de su tamaño, ha debido plegarse. Diversos autores dan diversas medidas del volumen cortical, que es mayor en el hemisferio derecho, probablemente por el mayor volumen de su lóbulo frontal. Otras asimetrías han sido descriptas para el plano temporal, la cisura de Silvio, el giro frontal inferiory el ventrículo lateral. El espesor cortical es variado, y para distintos autores se estima entre 1,5 y 5mm. Los datos varían de acuerdo a tamaño y edad de los individuos y con el peso cerebral total. El mayor plegamiento de la corteza cerebral se encuentra en las regiones de asociación frontal y témporo parieto occipital en ese orden.

It is assumed that the cerebral cortex is an extended nucleus that, because of its volume, has become plied. Several authors give different measures of the cortical volume. It is bigger on theright side because of the major volume of the right frontal lobe. Other assimetries have been described for the planum temporale, the silvian fissure, the inferior frontal gyrus and the lateral ventricle. The cortical thickness varies across its surface, and is estimated by different authors between 1,5 and 5mm. The data vary also after age and size of the individuals, and the total brain weight. The most plied regions are in descending order, the frontal, temporal and parieto occipital association cortices.

Structural basis for the coupling between activation and inactivation gates in K(+) channels.

The coupled interplay between activation and inactivation gating is a functional hallmark of K(+) channels. This coupling has been experimentally demonstrated through ion interaction effects and cysteine accessibility, and is associated with a well defined boundary of energetically coupled residues. The structure of the K(+) channel KcsA in its fully open conformation, in addition to four other partial channel openings, richly illustrates the structural basis of activation-inactivation gating. Here, we identify the mechanistic principles by which movements on the inner bundle gate trigger conformational changes at the selectivity filter, leading to the non-conductive C-type inactivated state. Analysis of a series of KcsA open structures suggests that, as a consequence of the hinge-bending and rotation of the TM2 helix, the aromatic ring of Phe 103 tilts towards residues Thr 74 and Thr 75 in the pore-helix and towards Ile 100 in the neighbouring subunit. This allows the network of hydrogen bonds among residues Trp 67, Glu 71 and Asp 80 to destabilize the selectivity filter, allowing entry to its non-conductive conformation. Mutations at position 103 have a size-dependent effect on gating kinetics: small side-chain substitutions F103A and F103C severely impair inactivation kinetics, whereas larger side chains such as F103W have more subtle effects. This suggests that the allosteric coupling between the inner helical bundle and the selectivity filter might rely on straightforward mechanical deformation propagated through a network of steric contacts. Average interactions calculated from molecular dynamics simulations show favourable open-state interaction-energies between Phe 103 and the surrounding residues. We probed similar interactions in the Shaker K(+) channel where inactivation was impaired in the mutant I470A. We propose that side-chain rearrangements at position 103 mechanically couple activation and inactivation in KcsA and a variety of other K(+) channels.

A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library.

Venomous animals immobilize prey using protein toxins that act on ion channels and other targets of biological importance. Broad use of toxins for biomedical research, diagnosis, and therapy has been limited by inadequate target discrimination, for example, among ion channel subtypes. Here, a synthetic toxin is produced by a new strategy to be specific for human Kv1.3 channels, critical regulators of immune T cells. A phage display library of 11,200 de novo proteins is designed using the alpha-KTx scaffold of 31 scorpion toxin sequences known or predicted to bind to potassium channels. Mokatoxin-1 (moka1) is isolated by affinity selection on purified target. Moka1 blocks Kv1.3 at nanomolar levels that do not inhibit Kv1.1, Kv1.2, or KCa1.1. As a result, moka1 suppresses CD3/28-induced cytokine secretion by T cells without cross-reactive gastrointestinal hyperactivity. The 3D structure of moka1 rationalizes its specificity and validates the engineering approach, revealing a unique interaction surface supported on an alpha-KTx scaffold. This scaffold-based/target-biased strategy overcomes many obstacles to production of selective toxins.

Tercer ventriculostomía endoscópica: mecanismos de fracaso y consideraciones sobre re fenestración o colocación de shunt / Endoscopic III ventriculostomy: Mechanisms of failure and considerations about refenestration of shuting

Objective: To evaluate retrospectively, a group of patients of our series, that had a failed ventriculostomy to try to determine the causes and the treatement offered to them. Material and method: 140 ETVs were performed in 132 patients; 120 of them are shunt free (90.90). Eight patients (5.71) showed closure of the ventriculostomy: in 4, it was presumed to be related to postoperative radiotherapy; 2 patients had an insufficient opening of the Lilliequist membrane and 2 showed ostoma closure of origin. In all of them a second ETV was performed, and the procedure was successful. Twelve patients (8.57) required shunt placement; 4, with a history of septated postmeningitis hydrocephalus, now only need a single ventricular catheter. Of the remaining, 3 presented with meningeal seeding from malignant tumors; 1 with racemous neurocysticerosis, 1 with multiple malformations and history meningitis; 2 with a previously unknown aresorptive component; 1 with history of post- shunt meningitis. Most patients with ETV failure developed CSF fistula. In all these cases, patency of the ostoma was confirmed during re-exploration, and consequently, a shunt was indicated. Discussion and conclusion: We consider ETV to be the standard treatment for obstructive hydrocephalus. With low morbidity in our series (4.68) and no mortality. Re-exploration and eventual re-fenestration are indicated in al cases of ETV failure, given the benefits of shunt independence.

Detection of the opening of the bundle crossing in KcsA with fluorescence lifetime spectroscopy reveals the existence of two gates for ion conduction.

The closed KcsA channel structure revealed a crossing of the cytosolic ends of the transmembrane helices blocking the permeation pathway. It is generally agreed that during channel opening this helical bundle crossing has to widen in order to enable access to the inner cavity. Here, we address the question of whether the opening of the inner gate is sufficient for ion conduction, or if a second gate, located elsewhere, may interrupt the ion flow. We used fluorescence lifetime measurements on KcsA channels labeled with tetramethylrhodamine at residues in the C-terminal end of TM2 to report on the opening of the lower pore region. We found two populations of channels with different fluorescence lifetimes, whose relative distribution agrees with the open probability of the channel. The absolute fraction of channels found with an open bundle crossing is too high to explain the low open probability of the KcsA-WT channel. We found the same distribution as in the WT channel between open and closed bundle crossing for two KcsA mutants, A73E and E71A, which significantly increase open probability at low pH. These two results strongly suggest that a second gate in the ion permeation pathway exists. The location of the mutations A73E and E71A suggests that the second gate may be the selectivity filter, which resides in an inactivated state under steady-state conditions. Since the long closed times observed in KcsA-WT are not present in KcsA-A73E or -E71A, we propose that KcsA-WT remains predominantly in a state with an open bundle crossing but closed (inactivated) second gate, while the mutations A73E and E71A sharply decrease the tendency to enter in the inactivated state, and as a consequence, the second gate is predominantly open at steady state. The ability to monitor the opening of the bundle crossing optically enables the direct recording of the movement of the pore helices while the channel is functioning.