Incorporation of a Theranostic "Two-Tone" Luminescent Silver Complex into Biocompatible Agar Hydrogel Composite for the Eradication of ESKAPE Pathogens in a Skin and Soft Tissue Infection Model.

Microbial invasion and colonization of the skin and underlying soft tissues are among the most common types of infections, becoming increasingly prevalent in hospital settings. Systemic antibiotic chemotherapies are now extremely limited due to emergence of drug-resistant Gram-positive and multidrug-resistant Gram-negative bacterial strains. Topical administration of antimicrobials provides an effective route for the treatment of skin and soft tissue infections (SSTIs). Therefore, the development of new and effective materials for the delivery of these agents is of paramount importance. Silver is a broad-spectrum antibiotic used for the treatment and prevention of infections since ancient times. However, the high reactivity of silver cation (Ag+) makes its incorporation into delivery materials quite challenging. Herein we report a novel soft agar hydrogel composite for the delivery of Ag+ into infected wound sites. This material incorporates a Ag(I) complex [Ag2(DSX)2(NO3)2] (1; DSX = 5-(dimethylamino)- N, N-bis(pyridin-2-ylmethyl) naphthalene-1-sulfonamide) that exhibits a change in fluorescence upon Ag+ release and qualitatively indicates the end point of silver delivery. The antibacterial efficacy of the material was tested against several bacterial strains in an SSTI model. The complex 1-agar composite proved effective at eradicating the pathogens responsible for the majority of SSTIs. The theranostic (therapeutic/diagnostic) properties coupled with its stability, softness, ease of application, and removal make this material an attractive silver-delivery vehicle for the treatment and prevention of SSTIs.

A Luminescent Manganese PhotoCORM for CO Delivery to Cellular Targets under the Control of Visible Light.

A photoactive manganese carbonyl complex derived from dansylimidazole (Imdansyl), namely, [Mn(Imdansyl)(CO)3(phen)](CF3SO3) (1), has been synthesized and structurally characterized. This is the first luminescent manganese carbonyl-based photoCORM reported in the literature. This complex exhibits CO release under the exclusive control of low-power broadband visible light. The corresponding rhenium carbonyl complex, namely, [Re(Imdansyl)(CO)3(phen)](CF3SO3) (2), has also been reported, which is luminescent but sensitive only to UV-B (λ<315 nm) light. The entry of the manganese photoCORM into the human colorectal adenocarcinoma cells (HT-29) has been demonstrated with the aid of fluorescence microscopy. Irradiation of the photoCORM-loaded cancer cells to visible light leads to a dose-dependent apoptotic cell death.

Expression and functional relevance of UGT1A4 in a cohort of human drug-resistant epileptic brains.

PURPOSE: Brain drug bioavailability is regulated by the blood-brain barrier (BBB). It was recently suggested that cytochrome P450 (CYP) enzymes could act in concert with multidrug transporter proteins to regulate drug penetration and distribution into the diseased brain. The possibility that phase II metabolic enzymes could be expressed in the epileptic brain has been not evaluated. Phase II enzymes are involved in the metabolism of common antiepileptic drugs (AEDs). METHODS: Phase II enzyme UGT1A4 brain expression was evaluated in temporal lobe resections from patients with epilepsy. UGT1A4 expression was determined by western blot and immunocytochemistry in primary cultures of human drug-resistant brain endothelial human brain epileptic endothelial cells (EPI-EC)s and commercially available control cells human brain microvascular endothelial cells (HBMECs). Lack of DNA condensation measured by 4',6-diamidino-2-phenylindole (DAPI) was used as a surrogate marker of cell viability and was correlated to UGT1A4 expression high performance liquid chromatography ultraviolet detection (HPLC-UV) was used to quantify lamotrigine metabolism by EPI-EC and HBMEC. The appearance of the specific lamotrigine metabolite, 2-n glucuronide (MET-1), was also evaluated. Lamotrigine and MET-1 levels were measured in selected surgical brain and matched blood samples. KEY FINDINGS: UGT1A4 expression was observed in BBB endothelial cells and neurons. Our quantification study revealed variable levels of UGT1A4 expression across the brain specimens analyzed. Neurons devoid of UGT1A4 expression displayed nuclear DAPI condensation, a sign of cellular distress. UGT1A4 overexpression in EPI-EC, as compared to HBMEC, was reflected by a proportional increase in lamotrigine metabolism. The lamotrigine metabolite, MET-1, was formed in vitro by EPI-EC and, to a lesser extent, by HBMEC. HPLC-UV measurements of brain and blood samples obtained from patients receiving lamotrigine prior to surgery revealed the presence of lamotrigine and its metabolites in the brain. SIGNIFICANCE: These initial results suggest the presence of a phase II enzyme in the epileptic brain. Further studies are required to fully describe the pattern of brain UGT1A4 expression in relation to clinical variables and drug resistance.

Fish Oil Enriched Intravenous Lipid Emulsions Reduce Triglyceride Levels in Non-Critically Ill Patients with TPN and Type 2 Diabetes. A Post-Hoc Analysis of the INSUPAR Study.

There are no studies that have specifically assessed the role of intravenous lipid emulsions (ILE) enriched with fish oil in people with diabetes receiving total parenteral nutrition (TPN). The objective of this study was to assess the metabolic control (glycemic and lipid) and in-hospital complications that occurred in non-critically ill inpatients with TPN and type 2 diabetes with regard to the use of fish oil emulsions compared with other ILEs. We performed a post-hoc analysis of the Insulin in Parenteral Nutrition (INSUPAR) trial that included patients who started with TPN for any cause and that would predictably continue with TPN for at least five days. The study included 161 patients who started with TPN for any cause. There were 80 patients (49.7%) on fish oil enriched ILEs and 81 patients (50.3%) on other ILEs. We found significant decreases in triglyceride levels in the fish oil group compared to the other patients. We did not find any differences in glucose metabolic control: mean capillary glucose, glycemic variability, and insulin dose, except in the number of mild hypoglycemic events that was significantly higher in the fish oil group. We did not observe any differences in other metabolic, liver or infectious complications, in-hospital length of stay or mortality.

Evaluating Invasive EEG Implantations with Structural Imaging Data and Functional Scalp EEG Recordings from Epilepsy Patients.

Seizures in patients with medically refractory epilepsy (MRE) cannot be controlled with drugs. For focal MRE, seizures originate in the epileptogenic zone (EZ), which is the minimum amount of cortex that must be treated to be seizure free. Localizing the EZ is often a laborious process wherein clinicians first inspect scalp EEG recordings during several seizure events, and then formulate an implantation plan for subsequent invasive monitoring. The goal of implantation is to place electrodes into the brain region covering the EZ. Then, during invasive monitoring, clinicians visually inspect intracranial EEG recordings to more precisely localize the EZ. Finally, the EZ is then surgically ablated, removed or treated with electrical stimulation. Unfortunately success rates average at 50%. Such grim outcomes call for analytical assistance in creating more accurate implantation plans from scalp EEG. In this paper, we introduce a method that combines imaging data (CT and MRI scans) with scalp EEG to derive an implantation distribution. Specifically, scalp EEG data recorded over a seizure event is converted into a time-gamma frequency map, which is then processed to derive a spectrally annotated implantation distribution (SAID). The SAID represents a distribution of gamma power in each of eight cortical lobe/hemisphere partitions. We applied this method to 4 MRE patients who underwent treatment, and found that the SAID distribution overlapped more with clinical implantations in success cases than in failed cases. These preliminary findings suggest that the SAID may help in improving EZ localization accuracy and surgical outcomes.

Virtual Cortical Stimulation Mapping of Epilepsy Networks to Localize the Epileptogenic Zone.

Cortical stimulation mapping (CSM) is a common clinical procedure for mapping eloquent cortex in epilepsy patients. Electrical responses to the stimulation, or after-discharges (ADs), that occur in response to stimulation can point to unstable regions of cortex that are more prone to spontaneous seizures. Clinicians are interested in identifying regions that start seizures, i.e., the epileptogenic zone (EZ), so that they can target treatment. However, during CSM, not all regions are stimulated, as it would be time-consuming and potentially harmful to the patient. This limits the clinician's ability to fully explore ADs to reliably localize the EZ. In this paper, we develop a virtual CSM procedure that processes pre-seizure intracranial EEG recordings obtained from epilepsy patients being treated at three different epilepsy centers. First, we identify a linear time varying network (LTVN) model from electrocorticography (ECoG) and stereo-EEG (SEEG) data using sparse least squares estimation for each patient. We then construct an virtual CSM by applying impulse perturbations to each electrode contact in the LTVN model and then measuring the ADs of the network. We summarize the l2-norm of the responses in the form of a heatmap that shows the spatio-temporal evolution of the ADs before, during, and after seizures. Finally we compute an impulse response ratio (IRR) metric from each heatmap, that measures the ratio between the mean norm of ADs of clinically annotated EZ contacts and the mean norm of ADs of the remaining contacts. We find that the IRR is higher in maps derived from patients with successful surgical outcomes and lower in failed surgical outcomes. This suggests that virtual CSM may provide valuable information to clinicians regarding EZ location.

Synthesis and structures of photoactive rhenium carbonyl complexes derived from 2-(pyridin-2-yl)-1,3-benzothiazole, 2-(quinolin-2-yl)-1,3-benzothiazole and 1,10-phenanthroline.

Carbon monoxide (CO) has recently been identified as a gaseous signaling molecule that exerts various salutary effects in mammalian pathophysiology. Photoactive metal carbonyl complexes (photoCORMs) are ideal exogenous candidates for more controllable and site-specific CO delivery compared to gaseous CO. Along this line, our group has been engaged for the past few years in developing group-7-based photoCORMs towards the efficient eradication of various malignant cells. Moreover, several such complexes can be tracked within cancerous cells by virtue of their luminescence. The inherent luminecscent nature of some photoCORMs and the change in emission wavelength upon CO release also provide a covenient means to track the entry of the prodrug and, in some cases, both the entry and CO release from the prodrug. In continuation of the research circumscribing the development of trackable photoCORMs and also to graft such molecules covalently to conventional delivery vehicles, we report herein the synthesis and structures of three rhenium carbonyl complexes, namely, fac-tricarbonyl[2-(pyridin-2-yl)-1,3-benzothiazole-κ2N,N'](4-vinylpyridine-κN)rhenium(I) trifluoromethanesulfonate, [Re(C7H7N)(C12H8N2S)(CO)3](CF3SO3), (1), fac-tricarbonyl[2-(quinolin-2-yl)-1,3-benzothiazole-κ2N,N'](4-vinylpyridine-κN)rhenium(I) trifluoromethanesulfonate, [Re(C7H7N)(C16H10N2S)(CO)3](CF3SO3), (2), and fac-tricarbonyl[1,10-phenanthroline-κ2N,N'](4-vinylpyridine-κN)rhenium(I) trifluoromethanesulfonate, [Re(C7H7N)(C12H8N2)(CO)3](CF3SO3), (3). In all three complexes, the ReI center resides in a distorted octahedral coordination environment. These complexes exhibit CO release upon exposure to low-power UV light. The apparent CO release rates of the complexes have been measured to assess their comparative CO-donating capacity. The three complexes are highly luminescent and this in turn provides a convenient way to track the entry of the prodrug molecules within biological targets.

Linear time-varying model characterizes invasive EEG signals generated from complex epileptic networks.

Electrocorticography (ECoG) and stereotactic electroencephalography (SEEG) are popular tools for studying neural mechanisms governing behavior and neural disorders, such as epilepsy. In particular, clinicians are interested in identifying brain regions that start seizures, i.e., the epileptogenic zone (EZ) from such invasive recordings. Currently, they visually inspect signals from each electrode to locate abnormal activity, and are not informed by predictive models that can characterize such recordings and potentially increase accuracy in localizing the EZ. In this paper, we test whether a simple linear time varying (LTV) model is sufficient to characterize both ECoG and SEEG activity. Specifically, we construct linear time invariant models in consecutive time windows before, during and after seizure events creating an LTV model from data collected in one ECoG and one SEEG patient. We find that these LTV models accurately reconstruct both ECoG and SEEG time series measured suggesting that these LTV models can be used for EZ localization.

Análisis costo-efectividad de la farmacoterapia antirretroviral para los pacientes VIH/SIDA en Cuba / Cost-effectiveness analysis of the antiretroviral drug therapy for HIV/AIDS patients in Cuba

Se determinó el impacto económico-social en términos de salud por el empleo de los antirretrovirales extranjeros durante un año, y su comparación con la ausencia de este tratamiento. Otro aspecto fue la comparación en cuanto a costos y a eficiencia de estos esquemas de tratamiento, con la incorporación de los antirretrovirales de producción nacional, bajo la premisa de presentar una similar efectividad. Se realizó un estudio retrospectivo con 59 historias clínicas para la determinación de la efectividad, medida por la supervivencia de los pacientes, y expresada por el año de vida ganado, así como por su mejoría clínica e inmunológica. Se estimaron los costos incurridos con el empleo de la farmacoterapia y la hospitalización, y se realizó la evaluación económica mediante las técnicas de análisis costo-efectividad, y de minimización de costos para distintas alternativas de tratamiento. Se obtuvo una supervivencia del 96,6 por ciento de los pacientes, así como resultados favorables del 81,4 por ciento en la mejoría clínica e inmunológica de los casos, pero a un elevado costo promedio de US $ 5 523.7/paciente, para una relación costo-efectividad de $ 5 717.6/año de vida ganado y de $ 6 789.6/caso mejorado. El empleo de los antirretrovirales extranjeros producen unos beneficios en la salud, pero incrementan los costos de la farmacoterapia, aspecto que conspira en contra de la eficiencia del tratamiento. Por esto, se reafirma la conveniencia económica de la producción nacional de los antirretrovirales, ya que se podrá obtener este beneficio sobre la salud de los pacientes, a un costo más razonable para el país

Fármacos: servicio electrónico alternativo a la Guía Terapéutica Nacional

Se presenta un análisis de la edición electrónica de información sobre medicamentos disponible en el servidor de la Red Electrónica de Información de Slud. Se parter de una realidad actual: la no disponibilidad de un Guía Terapéutica Nacional actualizada que ofrezca a facultativos, profesionales de la medicina y usuarios en general, la información de los medicamentos que se producen en el país. Se enfoca el origen, diseño, mod de acceso, información disponible, nivel de actualización ew importancia de un servicio electrónico alternativo a la Guía Terapéutica Nacional

Análisis de la problemática para la adquisición de los antirretrovirales VIH/SIDA en los países del tercer mundo / Analysis of the problem to acquire HIV/AIDS antiretroviral drugs in the third world countries

El objetivo del presente trabajo es exponer la problemática existente para la adquisición de los medicamentos antirretrovirales para el VIH/SIDA en el ámbito mundial, fundamentalmente la situación que confrontan los países en vías de desarrollo, que para poder obtener el acceso global al tratamiento tienen que invertir recursos económicos suficientes en la esfera de la salud, no disponibles actualmente en los países más pobres. Esto es motivado por los altos precios que tienen los antirretrovirales en el mercado internacional por parte las compañías transnacionales farmacéuticas, aspecto que repercute considerablemente en el incremento de los costos del tratamiento, y es uno de los principales obstáculos para su disposición en los países del Tercer Mundo. Ante el dramático panorama del VIH/SIDA a escala mundial, la comunidad internacional se ha pronunciado en favor de concretar diferentes acuerdos entre los productores de antirretrovirales y los gobiernos de los países en vías de desarrollo, para lograr una reducción importante en el costo del tratamiento antirretrovírico. También existen iniciativas locales de algunas naciones del mundo subdesarrollado, de producir nacionalmente estos fármacos, con el objetivo de garantizar sostenidamente el acceso global de los pacientes a esta terapia. Todos estos esfuerzos están encaminadas a un mismo propósito, disponer de la mayor cantidad de antirretrovirales en el arsenal terapéutico para el tratamiento del VIH/SIDA, así como buscar distintas vías para la adquisición de estos fármacos en condiciones económicas más favorables para los países más pobres del mundo, que las existentes actualmente en el mercado farmacéutico internacional, y de esta forma, posibilitar la obtención del beneficio en términos de salud para los pacientes, a un costo más razonable para las maltrechas economías de los países subdesarrollados