Stroke Strikes in Silence: Bilateral Medial Medullary Infarction in a Patient With Complete Hearing Loss.

Bilateral medial medullary infarction (BMMI) is a rare stroke subtype that accounts for less than 1% of acute strokes. Common manifestations of this stroke include quadriparesis, bilateral hypoglossal palsy, bilateral sensory loss, and respiratory failure. We present the case of a 39-year-old male with deafness and mutism who was brought to the emergency department due to acute onset of altered mental status and generalized weakness, further decompensated, and was lately diagnosed with bilateral medial medullary infarction. This case hopes to illustrate a differential diagnosis to be considered and promptly managed when a patient presents with altered mental status and quadriparesis, especially in the acute setting where tissue plasminogen activator (tPA) can still be given.

Themes and variations in ER/SR calcium release channels: structure and function.

Calcium (Ca(2+)) release from reticular stores is a vital regulatory signal in eukaryotes. Recent structural data on large NH(2)-terminal regions of IP(3)Rs and RyRs and their tetrameric arrangement in the full-length context reveal striking mechanistic similarities in Ca(2+) release channel function. A common ancestor found in unicellular genomes underscores the fundamentality of these elements to Ca(2+) release channels.

Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation "hot spot" loop.

Muscle contraction and relaxation is regulated by transient elevations of myoplasmic Ca(2+). Ca(2+) is released from stores in the lumen of the sarco(endo)plasmic reticulum (SER) to initiate formation of the Ca(2+) transient by activation of a class of Ca(2+) release channels referred to as ryanodine receptors (RyRs) and is pumped back into the SER lumen by Ca(2+)-ATPases (SERCAs) to terminate the Ca(2+) transient. Mutations in the type 1 ryanodine receptor gene, RYR1, are associated with 2 skeletal muscle disorders, malignant hyperthermia (MH), and central core disease (CCD). The evaluation of proposed mechanisms by which RyR1 mutations cause MH and CCD is hindered by the lack of high-resolution structural information. Here, we report the crystal structure of the N-terminal 210 residues of RyR1 (RyR(NTD)) at 2.5 A. The RyR(NTD) structure is similar to that of the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor (IP(3)Rsup), but lacks most of the long helix-turn-helix segment of the "arm" domain in IP(3)Rsup. The N-terminal beta-trefoil fold, found in both RyR and IP(3)R, is likely to play a critical role in regulatory mechanisms in this channel family. A disease-associated mutation "hot spot" loop was identified between strands 8 and 9 in a highly basic region of RyR1. Biophysical studies showed that 3 MH-associated mutations (C36R, R164C, and R178C) do not adversely affect the global stability or fold of RyR(NTD), supporting previously described mechanisms whereby mutations perturb protein-protein interactions.

Inverse H-C ex situ HRMAS NMR experiments for solid-phase peptide synthesis.

The growing importance of solid-phase peptide synthesis (SPPS) has necessitated the development of spectroscopic experiments that can be used to obtain structural and conformational information on resin-bound peptides. Despite the utility of two-dimensional high-resolution magic angle spinning (HRMAS) NMR experiments that provide homonuclear shift correlations, experiments that provide heteronuclear shift correlations are necessary for complex conformational and structural elucidatory problems. Here we report the optimization and implementation of non-gradient inverse NMR experiments for acquiring the 1H-13C shift correlations of resin-bound peptides. The use of non-gradient experiments is advantageous as many magic angle spinning (MAS) probes do not possess gradient coils. An HRMAS BIRD-HMQC experiment with a reduced 1JCH constant has proven very suitable for obtaining one-bond correlations. Long-range correlations can be interpolated by using a non-gradient HRMAS CT-HMBC-1 experiment where the resulting data is processed with forward linear prediction. It has been shown that removing the effects of 1H-1H J-modulation is crucial in order to view cross peaks that correspond to long-range correlations. Additionally, both experiments prove extremely useful over routine one-dimensional 13C HRMAS experiments for extracting carbon chemical shift data. The non-gradient HRMAS BIRD-HMQC and CT-HMBC-1 experiments can be used to assist in conformational analysis and to identify and deconvolute situations where accidental equivalence and seemingly correlated isochronous signals arise.

Ryanodine receptor calcium release channels: lessons from structure-function studies.

Ryanodine receptors (RyRs) are the largest known ion channels. They are Ca(2+) release channels found primarily on the sarcoplasmic reticulum of myocytes. Several hundred mutations in RyRs are associated with skeletal or cardiomyocyte disease in humans. Many of these mutations can now be mapped onto the high resolution structures of individual RyR domains and on full-length tetrameric cryo-electron microscopy structures. A closely related Ca(2+) release channel, the inositol 1,4,5-trisphospate receptor (IP3 R), shows a conserved structural architecture at the N-terminus, suggesting that both channels evolved from an ancestral unicellular RyR/IP3 R. The functional insights provided by recent structural studies for both channels will aid in the development of rationale treatments for a myriad of Ca(2+)-signaled malignancies.

Type 2 ryanodine receptor domain A contains a unique and dynamic α-helix that transitions to a ß-strand in a mutant linked with a heritable cardiomyopathy.

Ryanodine receptors (RyRs) are large tetrameric calcium (Ca(2+)) release channels found on the sarcoplasmic reticulum that respond to dihydropyridine receptor activity through a direct conformational interaction and/or indirect Ca(2+) sensitivity, propagating sarcoplasmic reticulum luminal Ca(2+) release in the process of excitation-contraction coupling. There are three human RyR subtypes, and several debilitating diseases are linked to heritable mutations in RyR1 and RyR2 including malignant hypothermia, central core disease, catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Despite the recent appreciation that many disease-associated mutations within the N-terminal RyRABC domains (i.e., residues 1-559) are located in the putative interfaces mediating tetrameric channel assembly, the precise structural and dynamical consequences of the mutations are not well understood. We used solution nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to examine the effect of ARVD2-associated (i.e., R176Q) and CPVT-associated [i.e., P164S, R169Q and delta exon 3 (Δ3)] mutations on the structure and dynamics of RyR2A. Our solution NMR data exposed a mobile α-helix, unique to type 2; further, this α2 helix rescues the ß-strand lost in RyR2A Δ3 but remains dynamic in the hot-spot loop (HS-loop) P164S, R169Q and R176Q mutant proteins. Docking of our X-ray crystal/NMR hybrid structure into the RyR1 cryo-electron microscopy map revealed that this RyR2A α2 helix is in close proximity to dense "columns" projecting toward the channel pore. This is in contrast to the HS-loop mutations that cause structural changes largely localized to the intersubunit interface between adjacent ABC domains. Taken together, our data suggest that ARVD2 and CPVT mutations have at least two distinct structural consequences linked to channel dysfunction: perturbation of the HS-loop (i.e., domain A):domain B intersubunit interface and disruption of the communication between the N-terminal region and the channel domain.

La comuna san José en la mira: transformaciones urbanas y redes sociales vistas a través de la fotografía / The sa jose commmune in sight: urban transformations ad social networrks seen through photograpy

A través del "Macroproyecto de Interés Social Nacional para el Centro Occidente de Colombia, Comuna San José, Manizales", desde 2009 se produce una profunda intervención de la Comuna, concebida como renovación urbana. Los problemas en la planeación del proyecto han conducido a la demolición relativamente lenta de un importante patrimonio de la ciudad, tanto de las edificaciones gubernamentales, como de vestigios de una ciudad más importante en términos industriales y de la historia producida colectivamente en los barrios durante más de un siglo. Hasta ahora se aprecian casi mil metros pavimentados del par vial llamado Avenida Colón y los inicios del primer edificio para habitación multifamiliar. Es a través de la fotografía que exponemos el modo en el cual las redes sociales necesariamente se ven afectadas debido a los cambios en las lógicas en el uso del espacio público, así como en la modificación de la vida cotidiana propia de los vecindarios urbanos populares de las comunidades pobres, de manera intempestiva desplazados y con la probabilidad de ocupar apartamentos de 45,15 m². Estamos ante la afectación de la calidad de vida de las familias y personas de la Comuna. Sin embargo, este cambio no es mirado de la misma forma por los dirigentes políticos de la ciudad. Contamos parte de la historia de la Comuna, finalizando con un retrato de la misma en la imagen de Victorino, uno de sus personajes más conspicuos.

Through the "National Social Interest Macro Project for the Central-Western area in Colombia, San José Commune, Manizales", since 2009 a deep intervention in that Commune has been taking place, conceived as urban renovation. The problems in the project planning have led to the relatively slow demolition of an important patrimony for the city in both, governmental buildings and remains of a city more important in industrial terms and of the collectively produced history in the neighborhoods during more than a century. So far, more than one thousand paved meters can be seen from the parkway called Avenida Colón and the beginnings of the first apartment block. It is through photography that we expose how social networks are affected necessarily because of the changes in the logics of the use of public space as well as the modification in daily life routines proper from popular urban neighborhoods in poor communes, who are untimely displaced and with the possibility to move to 45.15 square meters apartments. This is the affectation of quality of life of families and people in the Commune. However, this change is not seen the same way by the city political leaders. We tall part of the Commune history, finishing with its portrait in the image of Victorino, one of its most notable characters.

Comparación entre Meloxicam y Naproxeno en el Tratamiento Sintomático de Faringoamigdalitis Aguda no Bacterianas / Comparison between meloxicam and naproxen in the symptomatic treatment of acute non bacterial pharyngo-tonsillitis

Objetivo. Comparar meloxicam a dosis de 7.5 y de 15 mg con naproxeno 1,100 mg en el tratamiento sintomático de faringoamigdalitis aguda no bacteriana. Material y métodos. Estudio doble-ciego, doble enmascaramiento de tratamiento, aleatorizado, comparativo en 274 pacientes mayores de 18 años, con prueba negativa para estreptococo beta-hemolítico. Previo consentimiento informado, los pacientes fueron aleatorizados a uno de los 3 grupos. Las variables primarias fueron: dolor faríngeo espontáneo y a la deglución; como secundarias, eventos adversos. Análisis Estadístico. Se usó el paquete estadístico SAS. Uni-variado: tendencia central y dispersión. Bi-variado: pruebas de Cochran-Mantel-Haenzel, de Kruskal y exacta de Fisher. Multi-variado, covarianza. Resultados: Tanto el dolor faríngeo espontáneo como el dolor a la deglución disminuyeron al final del tratamiento en los tres grupos, sin diferencia significativa. A las 8 horas de iniciado el tratamiento, la reducción en el dolor fue mayor en el grupo de meloxicam 15 mg que en el de naproxeno (p=0.01). Tanto los eventos adversos como el abandono fueron mayores en el grupo naproxeno que en el grupo meloxicam 7.5 mg (p=0.02). Los trastornos gastrointestinales fueron más frecuentes en el grupo de naproxeno. Conclusiones. Meloxicam 7.5 y 15 mg una vez al día son tan eficaces como naproxeno 550 mg, dos veces al día. Meloxicam 15 mg tiene un inicio de acción más rápido que meloxicam 7.5 mg y naproxeno. Meloxicam 7.5 y 15 mg presentaron menos eventos adversos y menor deserción de pacientes