Acciones del Sistema Nacional de Salud cubano para las investigaciones clínicas durante la pandemia por la COVID-19 / Actions of the Cuban National Health System for clinical investigations during the COVID-19 pandemic

Introducción: La infestación y mortalidad ocasionada por el coronavirus Sarv-Cov-2 (COVID-19) generó que los sistemas de salud desarrollaran acciones para promover nuevas investigaciones clínicas encaminadas a contar con esquemas de tratamientos efectivos, para un mejor manejo de esta enfermedad.En Cuba, con la existencia antes de la pandemia, de un plan de ensayos clínicos y la necesidad de promover nuevos, para hacer frente a la COVID-19; se propuso la elaboración de un sistema de acciones encaminadas a preservar la calidad de los mismos.Objetivo: Describir las principales acciones desarrolladas, por el Sistema Nacional de Salud cubano, para el desarrollo de las investigaciones clínicas durante la pandemia.Métodos: Se realizó una revisión bibliográfica en los principales sitios web regulatorios y vinculados con el tema de investigaciones clínicas en etapa de pandemia por la COVID-19. Los resultados alcanzados se tuvieron en cuenta para proponer un sistema de acciones propio, encaminado a respaldar los ensayos clínicos.Resultados: Se establecieron acciones en tres líneas de trabajo: el respaldo ético, los requerimientos regulatorios para las modificaciones a los estudios en curso y nuevos y para el control de los ensayos clínicos. El sistema de trabajo quedó conformado por 29 acciones encaminadas a que los ensayos clínicos tuvieran un respaldado ético, cumplieran con los requerimientos regulatorios en cuanto a los aspectos metodológicos, de diseño y de control para garantizar el cumplimiento de las Buenas Prácticas Clínicas. (AU)

Introduction: The infestation and mortality caused by the Sarv-Cov-2 (COVID-19) coronavirus led health systems to develop actions to promote new clinical research aimed at having effective treatment schemes for better management of this disease.In Cuba, with the existence before the pandemic, of a clinical trial plan and the need to promote new ones, to deal with COVID-19; it was proposed to develop a system of actions aimed at preserving their quality.Objective: Describe the main actions developed by the Cuban National Health System for the development of clinical research during the pandemic.Methods: A bibliographic review was carried out on the main regulatory websites and those related to the topic of clinical research in the pandemic stage of COVID-19. The results achieved were taken into account to propose an own action system, aimed at supporting clinical trials.Results: Actions were established in three lines of work: ethical support, regulatory requirements for modifications to ongoing and new studies, and the control of clinical trials. The work system was made up of 29 actions aimed at ensuring that clinical trials have ethical support, comply with regulatory requirements in terms of methodological, design aspects and their control to guarantee compliance with Good Clinical Practices. (AU)

Contribución del farmacéutico cubano a la calidad de un ensayo clínico / Contribution of the Cuban pharmaceutical to the quality of a clinical trial

Una de las etapas culminantes del desarrollo de un producto en investigación es el ensayo clínico. Esta investigación se lleva a cabo en sujetos humanos y se dirige a verificar o descubrir los efectos clínicos, farmacológicos y/o farmacodinámicos del producto o equipo que se estudia.Para garantizar la calidad de estas investigaciones se utiliza como estándar las Buenas Prácticas Clínicas, donde se establecen requisitos a cumplir por los participantes, para asegurar calidad de los datos y protección de los derechos, integridad y confidencialidad de los sujetos.Un copartícipe importante es el farmacéutico, por el rol que desempeña. Este trabajo se centró en mostrar los elementos a tener en cuenta por el farmacéutico cubano para contribuir a elevar la calidad de un ensayo clínico.Dentro de los elementos a cumplir se encontraron; la cualificación, el cumplimiento y dominio del protocolo en lo referido al manejo del producto, el completamiento adecuado y en tiempo de la documentación que se genera según las funciones en el ensayo, velar por las condiciones de almacenamiento, vencimiento y devolución del producto, además de estar preparado para recibir actividades de monitoreo, auditoría y/o inspecciones, trabajar con enfoque de riesgo y por la mejora continua.El farmacéutico que participa en un ensayo clínico deberá dominar y aplicar los elementos identificados para tributar a la protección de los sujetos y confiablidad de los datos, elevando la calidad de los ensayos clínicos. (AU)

One of the culminating stages of the development of a product under investigation is the clinical trial. This research is carried out in human subjects and is aimed at verifying or discovering the clinical, pharmacological and/or pharmacodynamic effects of the product or equipment being studied.To guarantee the quality of these investigations, the Good Clinical Practices are used as standard, where requirements are established to be met by the participants, to ensure data quality and protection of the rights, integrity and confidentiality of the subjects.An important partner is the pharmacist. This work focused on showing the elements to be taken into account by the Cuban pharmacist to help raise the quality of a clinical trial.Among the elements to meet were found; the qualification, compliance and mastery of the protocol in relation to the handling of the product, the adequate and timely completion of the documentation that is generated according to the functions in the test, ensure the storage conditions, expiration and return of the product, in addition to be prepared to receive monitoring, audit and/or inspection activities, work with a risk approach and for continuous improvement.The pharmacist participating in a clinical trial must master and apply the elements identified to contribute to the protection of the subjects and the reliability of the data, raising the quality of the clinical trials. (AU)

[Myasthenia gravis and treatment with intravenous immunoglobulins. Reply]. / Miastenia grave y tratamiento con inmunoglobulinas por via intravenosa. Replica.

Miastenia grave y tratamiento con inmunoglobulinas por via intravenosa. Replica.

Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12.

Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia-ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2α-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress.

Prevalence of parkinsonism and Parkinson's disease in the Arosa Island (Spain): a community-based door-to-door survey.

There are scarce epidemiological data on parkinsonism in Spain. Since the Arosa Island community (Northwestern Spain) has been for centuries relatively isolated, it represents a potentially useful setting to undercover genetic factors with a founder effect, as well as local environmental influences. We performed a one-stage door-to-door survey in the Arosa Island in 2004 to determine the prevalence of parkinsonism and Parkinson's disease (PD) in the population aged 65 years or over. Out of 41 individuals detected with parkinsonism, 15 were diagnosed with PD (36.6%), 13 with drug induced parkinsonism (31.7%), seven with vascular parkinsonism (17.1%), four patients had parkinsonism with associated features (9.8%) and two had unspecified parkinsonism (4.9%). We obtained a crude prevalence rate of parkinsonism of 5.44% (adjusted rate: 4.73%) and a crude prevalence rate of PD of 1.99% (adjusted rate 1.7%); both prevalence rates increased with advancing age. The prevalence rate for parkinsonism was higher than that in similar populations of Spain and other European countries while that for PD was in the range obtained from these populations. Among PD cases, 26.7% (n=4) were undiagnosed before the survey. Most cases of drug-induced parkinsonism were secondary to neuroleptics and had not been previously diagnosed. The relatively high proportion of undiagnosed drug-induced parkinsonisms and PD is surprising in a public health system which is free and universal. The lack of excess of late-onset PD among Arosans does not support the existence of specific genetic or environmental factors contributing to PD in this particular geographical area.

The bacterial community in 'taberna' a traditional beverage of Southern Mexico.

AIMS: To characterize the bacterial community of taberna, an alcoholic traditional beverage from the Southern part of Mexico produced by the fermentation of the coyol palm sap (Acrocomia aculeate). METHODS AND RESULTS: Bacterial 16S rDNA libraries were constructed from metagenomic DNA extracted during the fermentation process at 0, 60 and 108 h. A total of 154 clones were sequenced, and 13, 10 and nine unique sequences were found at each sampling time. At the onset of the fermentation, Zymomonas mobilis, Fructobacillus spp., Pantoea agglomerans and other Gammaproteobacteria were detected. After 60 h, lactic acid bacteria were found and 30% of clones in the library were related to Lactobacillus nagelii, L. sucicola and L. sp. By the end of the experiment, i.e. after 108 h, the bacterial community included Z. mobilis, Lact. nagelii and Acetobacter pasteurianus. CONCLUSIONS: Our results suggest that Z. mobilis population represented an important proportion of the bacterial community (60-80%), as well as the lactobacilli during the fermentation process. The bacterial diversity was low and decreased as the fermentation progressed. SIGNIFICANCE AND IMPACT OF THE STUDY: This culture-independent study suggests that Z. mobilis and lactobacilli play an important role in the alcoholic fermentation of the taberna beverage.

Resultados del tratamiento de la escoliosis idiopática del adolescente mediante instrumentación posterior híbrida / Adolescent idiopathic scoliosis: Results of treatment with hybrid posterior instrumentation

Objetivos: Describir los resultados clínicos y radiológicos así como la repercusión en la calidad de vida del enfermo tras el tratamiento quirúrgico de la escoliosis idiopática del adolescente mediante instrumentación posterior híbrida. Material y método: Estudio retrospectivo de 26 sujetos intervenidos desde 2001 hasta 2006, con un seguimiento medio de 37,8 meses. Se obtuvieron, mediante la clasificación de Lenke de las curvas, los siguientes resultados: el 42,3% fue de tipo i, el 46,2% fue de tipo iii, el 7,7% fue de tipo v y 3,8% fue de tipo vi. Se intervino a todos los sujetos mediante instrumentación posterior híbrida con tornillos pediculares distales y ganchos proximales. Se registraron las necesidades transfusionales y las complicaciones. Se realizó una evaluación clínica mediante el cuestionario SRS-22 (Scoliosis Research Society` Sociedad de Investigación de la Escoliosis¿). Asimismo, se realizó una evaluación radiológica prequirúrgica, posquirúrgica inmediata y al final del seguimiento. Resultados: Se registraron 3 infecciones superficiales, un hemotórax y una luxación de gancho. Mediante el cuestionario SRS-22 se obtuvieron las siguientes puntuaciones medias: 4,41 en dolor; 4,39 en actividad; 3,91 en autoimagen; 3,98 en salud mental, y 3,81 en satisfacción. La corrección radiológica media posquirúrgica en las curvas torácicas fue del 58% y en las curvas lumbares fue del 60%, con una pérdida media de 5,5° a 7° al final del seguimiento. No hubo casos de seudoartrosis. Discusión y conclusiones: La instrumentación y fusión posterior híbrida es una técnica eficaz y segura, con bajo índice de seudoartrosis y fracasos. Los resultados fueron buenos en cuanto al dolor y a la actividad, pero fueron discretos en cuanto a la autoimagen y a la satisfacción personal. No se encontró asociación estadísticamente significativa entre la edad de los sujetos, el grado de corrección de la curva y la puntuación del cuestionario SRS-22 (AU)

Purpose: Report on the clinical and radiological results obtained by surgical treatment of adolescent idiopathic scoliosis by means of hybrid posterior instrumentation. The repercussions of surgery on the patients¿ quality of life are also described. Materials and methods: Retrospective study of 26 patients operated between 2001 and 2006, with a mean follow-up of 37.8 months. In terms of the Lenke classification, 42.3% of patients had type 1 curves, 46.2% type 3 curves, 7.7% type 5 curves, and one case of type VI curves. All patients were subjected to a hybrid posterior instrumentation with distal pedicular screws and proximal hooks. Transfusion needs and complications were duly recorded. A clinical assessment was performed by means of the SRS-22 questionnaire. A radiological assessment was conducted preoperatively, postoperatively and at the end of follow-up. Results: There were three superficial infections, one hemothorax and one hook dislocation. The administration of the SRS-22 questionnaire produced the following mean scores: 4.41 for pain, 4.39 for activity, 3.91 for self-image, 3.98 for mental health and 3.81 for satisfaction. Mean post-surgical radiological correction for thoracic and lumbar curves was 58% and 60%, respectively, with a mean loss of 7 and 5.5 degrees at the end of follow-up. There were no cases of Pseudoarthrosis. Discussion and conclusions: Hybrid posterior instrumentation and fusion is an efficient and safe technique, with a low rate of pseudoarthrosis and failure. Results were good as regards pain and activity, but fair in terms of self-image and personal satisfaction. We found no statistically significant association between the patients´ age, the degree of curve correction and the score on the SRS-22 questionnaire (AU)

[Effect of surveillance on surgical site infection rate in knee and hip arthroplasty]. / Efecto de la vigilancia sobre la tasa de infección de la herida quirúrgica en prótesis de cadera y rodilla.

OBJECTIVE: To determine whether continuous surveillance of hospital-associated infections with regular feedback to the staff reduces the infection rate in orthopedic surgery. MATERIAL AND METHODS: Prospective surveillance in two time periods in an orthopedic surgery department at a Spanish university hospital. Two infection control nurses and an epidemiologist surveyed all patients over a 3-year period for infections and potential risk factors. After an initial 24-month period (period A), surveillance for 12 months was conducted (period B). Between them adherence to recommendations was reinforced. MAIN RESULTS: A total of 1,088 patients were surveyed. In period A, 3.3% of all operations were followed by an infection, compared with 2.0% in period B (p = 0.14). Adherence to recommended schedule of surgical prophylaxis increased from 8.7% in the first year to 32.7% in the last year (p < 0,001). We also determined the NNIS (National Nosocomial Infections Surveillance) index risk in 383 patients, the NNIS index-risk 2 being more frequent in period A (16.8%) than in period B (5.4%) (p<0.001). Renal failure frequency was higher in period A (3.4% vs. 1.6%; p = 0.04). However, diabetes and neoplasms were the same in both periods. In period B, chronic obstructive pulmonary disease (COPD) (14.6 vs. 11.0; p = 0.05) and obesity (12.8 vs. 10.3; p = 0.12) predominated. The means for surgical intervention, hospital stay, and age, were very similar in both periods. CONCLUSIONS: Surveillance of hospital-associated infections including regular feedback to the staff is accompanied by a reduction in infection rates, possibly with lower cost and most patient safety. Therefore, such a surveillance program for orthopedic surgery department seems to be beneficial.

Efecto de la vigilancia sobre la tasa de infección de la herida quirúrgica en prótesis de cadera y rodilla / Effect of surveillance on surgical site infection rate in knee and hip arthroplasty

Objetivo. Determinar la adherencia al protocolo de profilaxis quirúrgica y su influencia en la modificación de la tasa de infección de la herida quirúrgica en un departamento de Cirugía Ortopédica. Material y métodos. Los pacientes intervenidos de prótesis de cadera o rodilla en el Hospital Universitario Insular de Las Palmas de Gran Canaria fueron seguidos por personal entrenado en el control de infecciones durante tres años, recogiendo datos sobre infecciones y factores de riesgo en dos períodos de observación: período A, de 24 meses, y período B, de 12 meses. Entre ambos se realizaron actividades de promoción del uso adecuado de la pauta de profilaxis quirúrgica antibiótica. Resultados. Se estudiaron 1.088 pacientes. En el período A, el 3,3% de las intervenciones se infectaron, comparadas con el 2,0% del período B (p = 0,14). La profilaxis antibiótica adecuada pasó del 8,7% al 32,7% (p < 0,001). Se determinó el índice NNIS (National Nosocomial Infections Surveillance) en 383 pacientes, siendo más frecuente el riesgo 2 en el período A (16,8%) que en el B (5,4%) (p < 0,001). La frecuencia de insuficiencia renal fue mayor en el período A (3,4% frente al 1,6%; p = 0,04), la diabetes y la neoplasia fueron similares en ambos períodos; en el período B predominaron enfermedades pulmonares obstructivas crónicas (14,6 frente a 11,0; p = 0,05) y obesidad (12,8 frente a 10,3; p = 0,12). Las medias de duración de las intervenciones, edad y estancia fueron idénticas en ambos períodos. Conclusiones. La acción de mejora introducida, aunque no seguida por todos los traumatólogos, se acompaña de un descenso de la tasa de infecciones posquirúrgicas, posiblemente con menor coste para el hospital y más seguridad para los pacientes. Este programa de vigilancia parece ser beneficioso

Objective. To determine whether continuous surveillance of hospital-associated infections with regular feedback to the staff reduces the infection rate in orthopedic surgery. Material and methods. Prospective surveillance in two periods of time in an orthopedic surgery department at a Spanish university hospital. Two infection control nurses and an epidemiologist surveyed all patients over a 3-year period for infections and potential risk factors. After an initial 24-month period (period A), surveillance for 12 months was conducted (period B). Between these periods, adherence to recommendations was reinforced. Results. A total of 1,088 patients were surveyed. In period A, 3.3% of all operations were followed by an infection, compared with 2.0% in period B (p = 0.14). Adherence to recommended schedule of surgical prophylaxis increased from 8.7% in the first year to 32,7% in the last year (p = 0.001). We also determined the NNIS (National Nosocomial Infections Surveillance) index risk in 383 patients, with the NNIS index-risk 2 as more frequent in period A (16.8%) than the period B (5.4%) (p < 0.001). Renal failure frequency was higher in period A (3.4% vs. 1.6%; p = 0.04). However, diabetes and neoplasms were the same in both periods. In period B, chronic obstructive pulmonary disease (14.6 vs. 11.0; p = 0.05) and obesity (12.8 vs. 10.3; p = 0.12) predominated. The means for surgical intervention, hospital stay, and age, were very similar in both periods. Conclusions. Surveillance of hospital-associated infections including regular feedback to the staff is accompanied by a reduction in infection rates, possibly with lower cost and more patient safety. Thus, such a surveillance program for orthopedic surgery department seems to be beneficial

[Effect of surveillance on surgical site infection rate in knee and hip arthroplasty]. / Efecto de la vigilancia sobre la tasa de infección de la herida quirúrgica en prótesis de cadera y rodilla.

OBJECTIVE: To determine whether continuous surveillance of hospital-associated infections with regular feedback to the staff reduces the infection rate in orthopedic surgery. MATERIAL AND METHODS: Prospective surveillance in two periods of time in an orthopedic surgery department at a Spanish university hospital. Two infection control nurses and an epidemiologist surveyed all patients over a 3-year period for infections and potential risk factors. After an initial 24-month period (period A), surveillance for 12 months was conducted (period B). Between these periods, adherence to recommendations was reinforced. RESULTS: A total of 1,088 patients were surveyed. In period A, 3.3% of all operations were followed by an infection, compared with 2.0% in period B (p = 0.14). Adherence to recommended schedule of surgical prophylaxis increased from 8.7% in the first year to 32,7% in the last year (p = 0.001). We also determined the NNIS (National Nosocomial Infections Surveillance) index risk in 383 patients, with the NNIS index-risk 2 as more frequent in period A (16.8%) than the period B (5.4%) (p < 0.001). Renal failure frequency was higher in period A (3.4% vs. 1.6%; p = 0.04). However, diabetes and neoplasms were the same in both periods. In period B, chronic obstructive pulmonary disease (14.6 vs. 11.0; p = 0.05) and obesity (12.8 vs. 10.3; p = 0.12) predominated. The means for surgical intervention, hospital stay, and age, were very similar in both periods. CONCLUSIONS: Surveillance of hospital-associated infections including regular feedback to the staff is accompanied by a reduction in infection rates, possibly with lower cost and more patient safety. Thus, such a surveillance program for orthopedic surgery department seems to be beneficial.

Tratamiento tópico sobre úlceras varicosas de evolución tórpida con ampollas monodosis estériles de ciprofloxacino.La efectividad frente a suero fisiológico / Effectiveness of topical treatment of chronic varicose ulcers with sterile single-dose ciprofloxacin ampoules versus physiologic serum

OBJETIVO: Determinar la efectividad de la aplicación de solución tópica estéril de ciprofloxacino y suero fisiológico como tratamiento local en úlceras de etiología venosa, frente al empleo de suero fisiológico exclusivamente. DISEÑO: Estudio seudoexperimental cruzado. MATERIAL Y MÉTODO: Estudio cruzado, en donde se incluyeron pacientes con lesiones varicosas de más de tres semanas de evolución (n = 63), con una media de edad de 76,3 ñ 16,8 años, 21 varones (33 por ciento; 69,9 ñ 19,9 años) y 42 mujeres (67 por ciento; 80,2 ñ 12,3 años). La misma muestra fue distribuida para el análisis en dos grupos de pacientes; grupo A (N = 63), en el que se realizó una cura semioclusiva húmeda con ciprofloxacino (solución de cloruro sódico al 0,9 por ciento aplicada a chorro con jeringuilla de 20 ml y aguja desechable) junto con gasas (3-4 por acto) de entramado con algodón, ampollas monodosis estériles desechables de ciprofloxacino (n = 63), y grupo B, en el que se aplicó suero fisiológico sin ampollas monodosis (n = 63), utilizado durante un máximo de 2 semanas. RESULTADOS: En el estudio cruzado la respuesta fue positiva en 29 pacientes pertenecientes al grupo B y en 41 del grupo A (el 65 frente al 46 por ciento; p = 0,000). La disminución porcentual de la superficie fue del 31,2 frente al 9,3 por ciento (1,46 frente a 0,47 cm2; p = 0,00) en los grupos A y B, respectivamente. Los resultados de los cultivos para el estudio cruzado fueron: 37,5 por ciento Pseudomonas, 17,6 por ciento informado como estéril, 17,1 por ciento con Streptococcus grupo D, 14,1 por ciento como flora saprofita. CONCLUSIONES: El tratamiento con ciprofloxacino tópico sobre las lesiones varicosas de larga evolución junto al suero fisiológico parece ofrecer mejores porcentajes de respuesta inicial respecto al uso de suero fisiológico exclusivamente. La presencia de fibrina previa al tratamiento con suero no parece modificar la respuesta posterior al mismo. Añadir ciprofloxacino tópico en lesiones sin fibrina favorece la mejoría de la respuesta frente al uso únicamente de suero fisiológico. (AU)

Fractura de cadera en pacientes centenarios / Hip fracture in centenarians

La incidencia de fractura de cadera aumenta exponencialmente con la edad, siendo ésta la causa traumática de hospitalización más frecuente en el anciano. Dicha patología se asocia a una gran morbimortalidad, así como a un importante aumento del gasto hospitalario. El objetivo de este estudio es revisar retrospectivamente los pacientes de 100 años o más intervenidos en nuestro hospital, con el fin de valorar su evolución y complicaciones. Se realizó un estudio de 21 pacientes intervenidos por fractura de cadera entre 19952001. La serie consta de 2 hombres y 19 mujeres, con una media de edad de 101 años (100-105), con 8 fracturas derechas y 13 izquierdas; 6 subcapitales, de las cuales 2 impactadas, 14 pertrocantéreas y 1 subtrocantérea; ninguna fue abierta. El tiempo medio de espera para la cirugía fue 3,5 días y el tiempo medio de ingreso 18,8 (9-35) días. El mecanismo lesional más frecuente fue la caída casual. La síntesis utilizada fue en 13 enclavados gamma cortos y 1 largo, 4 artroplastias parciales tipo Moore, 2 síntesis con tornillos canulados AO, y 1 enclavado de Ender. Para la valoración de resultados se utilizó la escala de Barthel al ingreso y al alta, las complicaciones pre y postquirúrgicas durante el ingreso y la supervivencia. El índice de cormorbilidad fue de 3,4. El índice medio de Barthel al ingreso fue 37,2 siendo al alta de 25,3. Dos pacientes fallecieron durante el ingreso, 4 durante el primer año, 5 entre los 12-24 meses y 3 por encima de los 24 meses. Siguen vivos 3, realizando 1 de ellos vida cama-sillón y 2 caminando con andador. Los 4 casos restantes no pudieron ser localizados tras el alta hospitalaria, perdiéndose su seguimiento. El tiempo medio de supervivencia fue de 17,7 (0,5-48) meses. El aumento de la prevalencia de la población mayor de 85 años, así como por la mala calidad ósea que la acompaña indefectiblemente, provoca un alto índice de fracturas de cadera, que plantean un serio reto sociosanitario para nuestras instituciones (AU)

Synthesis, brain antihypoxic activity and cell neuroprotection of 1-substituted-3,7-dimethylxanthines.

Five newly synthesised original compounds were investigated for acute toxicity, influence on hexobarbital sleeping time, effect on the locomotor activity, and brain antihypoxic activity. Two of the compounds were tested in a model of glutamate induced neurotoxicity in the brain cell culture using a cell viability test. Our studies indicate that compounds 2a-c and 4 prolonged the survival time of mice in the model of anoxic hypoxia. Only compound 3 expressed antihypoxic activity in the model of circulatory hypoxia, evaluated with a statistical significant increase of the survival time. Compound 4 (1-[3-(2,3-dihydro-3-oxobenzisosulfonazol2-yl)-propyl]-3,7-dimethylxanthine) in concentration range 0.3-3 microM statistically significantly antagonised the glutamate induced neurotoxicity. Compound 4 is important for further investigations on in vivo models of brain dementia.

Polyamine uptake in cultured astrocytes: characterization and modulation by protein kinases.

The properties and regulation of the polyamine transport system in brain are still poorly understood. The present study shows, for the first time, the existence of a polyamine transport system in cerebellar astrocytes and suggests that polyamine uptake is mediated by a single and saturable high-affinity transport system for putrescine, spermine, and spermidine (K:(m) = 3.2, 1.2, and 1.8 microM:, respectively). Although substitution of NaCl by choline chloride produced a decrease in the putrescine, spermine, and spermidine uptake, it seems that polyamine transport in cerebellar astrocytes is not mediated by an Na(+) cotransport as in the presence of Na(+) and cholinium, polyamine uptake was much lower than when measured in a sucrose-based medium. On the other hand, ouabain, gramicidin (a Na(+) ionophore), and ionomycin (a Ca(2+) ionophore) produced a strong inhibition of polyamine uptake, suggesting that membrane potential could have an important role in the functioning of the astroglial polyamine uptake system. Moreover, protein kinase C inhibition produced an enhancement of polyamine uptake, whereas stimulation of protein kinase C with phorbol esters inhibited polyamine uptake. Alternatively, the tyrosine kinase inhibitor genistein caused a marked reduction in the uptake. No effects on polyamine uptake were observed with inhibitors and activators of cyclic AMP-dependent protein kinase or when Ca(2+)/calmodulin-dependent protein kinase II was inhibited with KN-62. These results suggest that the polyamine uptake system in cerebellar astrocytes could be modulated by protein kinase C and tyrosine kinase activities.

Indications for use of the long Gamma nail.

A retrospective analysis of 42 patients treated by intramedullary nailing with the Gamma nail with a mean followup of 22.4 months is reported. The indications for the use of this nail were subtrochanteric fractures in 31 cases, diaphyseal femoral fractures in 10 cases, and segmental fracture in one case. Seven cases of the diaphyseal fractures were renailings for a previously placed nail. There was one pathologic fracture in the subtrochanteric group and three in the diaphyseal group. The indications of this new technique and its complications are analyzed.

Extracellular acidification modifies Ca2+ fluxes in rat brain synaptosomes.

We examined the influence of external acidification on Ca2+ fluxes (45Ca2+ influx and 45Ca2+ efflux) in rat brain synaptosomes. A change on external pH (pHe) from 7.5 to 6.5 linearly decreased the 45Ca2+ uptake (5nmoles/mg protein/pHunit) and increased the 45Ca2+ efflux (1.5 fold/pH unit). These changes were both Na+ dependent and amiloride sensitive suggesting that the Na+/Ca2+ exchanger could be involved. The addition of the Ca2+ channel blockers (diltiazem, verapamil, nifedipine) did not prevent the decrease of the 45Ca2+ uptake evoked by acid pHe and so the involvement of the voltage-sensitive Ca2+ channels could be discarded. In order to determine whether the Na+/Ca2+ exchanger was directly activated by H+ or was indirectly activated by an internal mobilization of Ca2+ from intrasynaptosomal stores we examined the effect of pHe variation on phophoinositide hydrolisis. An increase on phosphoinositide hydrolisis was observed at acid pHe values (7 and 6.5). The hydrolisis was amiloride insensitive. On the other hand 1mM neomycin did inhibit the effect of acidic pHe on Ca2+ fluxes. Taken together, the results of our study provide evidence that external acidification stimulates phospholipase C leading to an increase in phosphoinositide hydrolisis and Ca2+ mobilization. The increase in intracellular Ca2+ would stimulate the Na+/Ca2+ exchanger, increasing Ca2+ efflux and reducing the global Ca2+ influx.