Focal photodynamic intracellular acidification as a cancer therapeutic.

Cancer cells utilize an array of proton transporters to regulate intra- and extracellular pH to thrive in hypoxic conditions, and to increase tumor growth and metastasis. Efforts to target many of the transporters involved in cancer cell pH regulation have yielded promising results, however, many productive attempts to disrupt pH regulation appear to be non-specific to cancer cells, and more effective in some cancer cells than others. Following a review of the status of photodynamic cancer therapy, a novel light-activated process is presented which creates very focal, rapid, and significant decreases in only intracellular pH (pHi), leading to cell death. The light-activation of the H+ carrier, nitrobenzaldehyde, has been effective at initiating pH-induced apoptosis in non-cancerous and numerous cancerous cell lines in vitro, to include breast, prostate, and pancreatic cancers. Also, this intracellular acidification technique caused significant reductions in tumor growth rate and enhanced survival in mice bearing triple negative breast cancer tumors. The efficacy of an NBA-upconverting nanoparticle to kill breast cancer cells in vitro is described, as well as a discussion of the potential intracellular mechanisms underlying the pH-induced apoptosis.

Characterization of a triple-recombinant, reassortant rotavirus strain from the Dominican Republic.

We report the genome of a novel human triple-recombinant G4P[6-8_R] mono-reassortant strain identified in a stool sample from the Dominican Republic during routine facility-based rotavirus strain surveillance. The strain was designated as RVA/Human-wt/DOM/2013840364/2013/G4P[6-8_R], with a genomic constellation of G4-P[6-8_R]-I1-R1-C1-M1-(A1-A8_R)-N1-(T1-T7_R)-E1-H1. Recombinant gene segments NSP1 and NSP3 were generated as a result of recombination between genogroup 1 rotavirus A1 human strain and a genotype A8 porcine strain and between genogroup 1 rotavirus T1 human strain and a genotype T7 bovine strain, respectively. Analyses of the RNA secondary structures of gene segment VP4, NSP1 and NSP3 showed that all the recombinant regions appear to start in a loop (single-stranded) region and terminate in a stem (double-stranded) structure. Also, the VP7 gene occupied lineage VII within the G4 genotypes consisting of mostly porcine or porcine-like G4 strains, suggesting the occurrence of reassortment. The remaining gene segments clustered phylogenetically with genogroup 1 strains. This exchange of whole or partial genetic materials between rotaviruses by recombination and reassortment contributes directly to their diversification, adaptation and evolution.

The role of wall shear stress in the assessment of right ventricle hydraulic workload.

Pulmonary hypertension (PH) is a devastating disease affecting approximately 15-50 people per million, with a higher incidence in women. PH mortality is mostly attributed to right ventricle (RV) failure, which results from RV hypotrophy due to an overburdened hydraulic workload. The objective of this study is to correlate wall shear stress (WSS) with hemodynamic metrics that are generally accepted as clinical indicators of RV workload and are well correlated with disease outcome. Retrospective right heart catheterization data for 20 PH patients were analyzed to derive pulmonary vascular resistance (PVR), arterial compliance (C), and an index of wave reflections (Γ). Patient-specific contrast-enhanced computed tomography chest images were used to reconstruct the individual pulmonary arterial trees up to the seventh generation. Computational fluid dynamics analyses simulating blood flow at peak systole were conducted for each vascular model to calculate WSS distributions on the endothelial surface of the pulmonary arteries. WSS was found to be decreased proportionally with elevated PVR and reduced C. Spatially averaged WSS (SAWSS) was positively correlated with PVR (R (2) = 0.66), C (R (2) = 0.73), and Γ (R (2) = 0.5) and also showed promising preliminary correlations with RV geometric characteristics. Evaluating WSS at random cross sections in the proximal vasculature (main, right, and left pulmonary arteries), the type of data that can be acquired from phase-contrast magnetic resonance imaging, did not reveal the same correlations. In conclusion, we found that WSS has the potential to be a viable and clinically useful noninvasive metric of PH disease progression and RV health. Future work should be focused on evaluating whether SAWSS has prognostic value in the management of PH and whether it can be used as a rapid reactivity assessment tool, which would aid in selection of appropriate therapies.

Patient-specific computational modeling of blood flow in the pulmonary arterial circulation.

Computational fluid dynamics (CFD) modeling of the pulmonary vasculature has the potential to reveal continuum metrics associated with the hemodynamic stress acting on the vascular endothelium. It is widely accepted that the endothelium responds to flow-induced stress by releasing vasoactive substances that can dilate and constrict blood vessels locally. The objectives of this study are to examine the extent of patient specificity required to obtain a significant association of CFD output metrics and clinical measures in models of the pulmonary arterial circulation, and to evaluate the potential correlation of wall shear stress (WSS) with established metrics indicative of right ventricular (RV) afterload in pulmonary hypertension (PH). Right Heart Catheterization (RHC) hemodynamic data and contrast-enhanced computed tomography (CT) imaging were retrospectively acquired for 10 PH patients and processed to simulate blood flow in the pulmonary arteries. While conducting CFD modeling of the reconstructed patient-specific vasculatures, we experimented with three different outflow boundary conditions to investigate the potential for using computationally derived spatially averaged wall shear stress (SAWSS) as a metric of RV afterload. SAWSS was correlated with both pulmonary vascular resistance (PVR) (R(2)=0.77, P<0.05) and arterial compliance (C) (R(2)=0.63, P<0.05), but the extent of the correlation was affected by the degree of patient specificity incorporated in the fluid flow boundary conditions. We found that decreasing the distal PVR alters the flow distribution and changes the local velocity profile in the distal vessels, thereby increasing the local WSS. Nevertheless, implementing generic outflow boundary conditions still resulted in statistically significant SAWSS correlations with respect to both metrics of RV afterload, suggesting that the CFD model could be executed without the need for complex outflow boundary conditions that require invasively obtained patient-specific data. A preliminary study investigating the relationship between outlet diameter and flow distribution in the pulmonary tree offers a potential computationally inexpensive alternative to pressure based outflow boundary conditions.

Intracellular acidosis and pH regulation in central respiratory chemoreceptors.

Dysfunctions of brainstem regions responsible for central CO2 chemoreception have been proposed as an underlying pathophysiology of Sudden Infant Death Syndrome (SIDS). We recorded respiratory motor output and intracellular pH (pHi) from chemosensitive neurons in an in vitro tadpole brainstem during normocapnia and hypercapnia. Flash photolysis of the H+ donor nitrobenzaldehyde was used to induce focal decreases in pHi alone. Hypercapnia and flash photolysis significantly decreased pHi from normocapnia. In addition, chemoreceptors did not regulate pHi during hypercapnia, but demonstrated significant pHi recovery when only pHi was reduced by flash photolysis. Respiration was stimulated by decreases in pHi (hypercapnia and flash photolysis) by decreases in burst cycle. These data represent our ability to load the brainstem with nitrobenzaldehyde without disrupting the respiration, to quantify changes in chemoreceptor pHi recovery, and to provide insights regarding mechanisms of human health conditions with racial/ethnic health disparities such as SIDS and Apnea of Prematurity (AOP).

A propósito de enfermedad de Buerger: un caso / A propos of Buerger's disease: presentation of a case

Paciente masculino de 56 años de edad que en diciembre de 1994 inicia cuadro clínico con disminución de la sensibilidad en segundo, tercero y cuarto dedos de mano izquierda, agregándose parestesias, mialgias y dolor ocasional a lo largo del miembro torácico izquierdo; tornándose progresivo con disminución del llenado capilar y fenómeno de Raynaud, con posterior formación de ampollas y salida de líquido purulento y fétido. Se realizó el diagnóstico de piodermia gangrenosa. Se le practica flebografía que muestra trombosis axilar y subclavia izquierda; las arteriografías de miembro torácico izquierdo evidenciaron isquemia importante en mano; el miembro torácico derecho estaba normal y el pélvico derecho con disminución de la circulación en pierna y pie. Se decide efectuar amputación de falanges distal y media del segundo al quinto dedo, debido a que, a pesar del tratamiento, la necrosis continuó avanzando. El diagnóstico establecido con base en el estudio de histopatología resultó compatible con enfermedad de Buerger, una enfermedad oclusiva inflamatoria poco común, que involucra arterias y venas de pequeño y mediano calibre de las extremidades, y que afecta a pacientes con antecedentes de tabaquismo crónico.

Lo antiguo de la aminofilina y lo actual de la teofílina / The antique of aminophylline and the current of teophylline

La aminofilina fue descubierta en forma independiente por David I. Macht en 1921 y por Samson Hircht en 1922. Los primeros en usarla para el tratamiento del asma bronquial fueron Herman y Greene en los Estados Unidos. En México, Salazar mallén fue el primero en emplearla (1938). Los primeros en cuantificar la dosificación de este medicamento en la sangre fueron Wasler y Sack. El empleo de la teofilina de acción prolongada, así como su dosificación en la sangre de los pacientes, fueron establecidos en México por Montes y Amezcua. actualmente hay beta-2-agonistas de acción prolongada que posibilitan el control asmático día y noche. La teofilina también tiene esta acción. Su farmacológia consiste en la inhibición de la enzima fosfodiesterasa y en el bloqueo de los receptores A1; también potencia la contracción del músculo diafragmático y aumenta el flujo de sangre a los músculos intercostales; disminuye además la formación de los leucotrienos B4 y C4 y tiene efecto antiinflamatorio por aumento del cAMP intracelular. Las dosis mayores aumentan su toxicidad; cuando las concentraciones sanguíneas son mayores a 20 µg/mL, el paciente puede presentar convulsiones letales. La teofilina se puede usar con otros broncodilatadores y corticosteroides. Su dosis se ha ajustado a la baja con el fin de tener un efecto terapéutico sin toxicidad (5-7 mg/kg en 24 horas). Se recomienda que sus concentraciones en el suero sean de 5-10 µg/mL para conseguir tambíen el efecto antiinflamatorio. En el Servicio de Alergia e Inmunología Clínica del Hospital General de México se continúa usando como medicamento de primera elección para romper el broncoespasmo de los pacientes asmáticos