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Objetivo: Analizar las derivaciones dirigidas desde Atención Primaria a Cirugía Ortopédica y Traumatología. Como objetivo secundario, establecer 2escenarios de derivación, con el fin de conocer el impacto de la variabilidad en la derivación. Material y métodos: Estudio observacional de carácter transversal de análisis de las derivaciones de Atención Primaria a Cirugía Ortopédica y Traumatología durante el primer semestre de los años 2018, 2019 y 2021. Se ha examinado el número de derivaciones que emite cada facultativo y cada centro de salud de Atención Primaria, atendiendo a la clasificación de las distintas zonas básicas de salud. Resultados: Existe una gran variabilidad en el número de derivaciones, tanto según el tipo de zona básica de salud (p < 0,001) como por cada facultativo (p < 0,001). Las ratios de derivación se comportan de forma uniforme en el tiempo (p < 0,001). Debido al alto número de derivaciones, se han construido dosescenarios: en el primero de ellos la ratio de derivación se situaría en la zona media del espectro de la tasa de derivación. En el segundo escenario, se han tomado como referencia las menores ratios de derivación registradas. La reducción de la variabilidad en los 2escenarios supuestos proporciona una disminución importante de la demanda asistencial. Conclusiones: La reducción de la variabilidad tendría un efecto beneficioso sobre la capacidad asistencial del servicio de Cirugía Ortopédica y Traumatología.

Objective: To analyze referrals from Primary Care consultation to Orthopaedic Surgery reference department. As a secondary objective, to establish 2referral scenarios in order to determine the impact of variability on referral. Material and methods: Cross-sectional observational study, analyzing referrals from Primary Care to Orthopaedic Surgery during the first half of the years 2018, 2019, and 2021. The number of referrals issued by each doctor and each Primary Care Healthcare Center was examined, according to the classification of the different Basic Healthcare Zones. Results: There is great variability in the number of referrals, both according to the type of Basic Healthcare Zone and by each Primary Care facultative. The referral ratios behaved uniformly over time (P<0.001). Due to a large number of referrals, 2scenarios have been constructed: In the first scenario, the referral ratio would be in the middle of the referral rate spectrum. In the second scenario, the lowest referral ratios recorded have been taken as a reference. The reduction of variability in the 2scenarios assumed provides a significant reduction in the demand for care. Conclusion: Reducing variability would have a beneficial effect on the capacity of the Orthopaedic Surgery service to provide care.(AU)

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Objetivo: Analizar las derivaciones dirigidas desde Atención Primaria a Cirugía Ortopédica y Traumatología. Como objetivo secundario, establecer 2escenarios de derivación, con el fin de conocer el impacto de la variabilidad en la derivación. Material y métodos: Estudio observacional de carácter transversal de análisis de las derivaciones de Atención Primaria a Cirugía Ortopédica y Traumatología durante el primer semestre de los años 2018, 2019 y 2021. Se ha examinado el número de derivaciones que emite cada facultativo y cada centro de salud de Atención Primaria, atendiendo a la clasificación de las distintas zonas básicas de salud. Resultados: Existe una gran variabilidad en el número de derivaciones, tanto según el tipo de zona básica de salud (p < 0,001) como por cada facultativo (p < 0,001). Las ratios de derivación se comportan de forma uniforme en el tiempo (p < 0,001). Debido al alto número de derivaciones, se han construido dosescenarios: en el primero de ellos la ratio de derivación se situaría en la zona media del espectro de la tasa de derivación. En el segundo escenario, se han tomado como referencia las menores ratios de derivación registradas. La reducción de la variabilidad en los 2escenarios supuestos proporciona una disminución importante de la demanda asistencial. Conclusiones: La reducción de la variabilidad tendría un efecto beneficioso sobre la capacidad asistencial del servicio de Cirugía Ortopédica y Traumatología.

Objective: To analyze referrals from Primary Care consultation to Orthopaedic Surgery reference department. As a secondary objective, to establish 2referral scenarios in order to determine the impact of variability on referral. Material and methods: Cross-sectional observational study, analyzing referrals from Primary Care to Orthopaedic Surgery during the first half of the years 2018, 2019, and 2021. The number of referrals issued by each doctor and each Primary Care Healthcare Center was examined, according to the classification of the different Basic Healthcare Zones. Results: There is great variability in the number of referrals, both according to the type of Basic Healthcare Zone and by each Primary Care facultative. The referral ratios behaved uniformly over time (P<0.001). Due to a large number of referrals, 2scenarios have been constructed: In the first scenario, the referral ratio would be in the middle of the referral rate spectrum. In the second scenario, the lowest referral ratios recorded have been taken as a reference. The reduction of variability in the 2scenarios assumed provides a significant reduction in the demand for care. Conclusion: Reducing variability would have a beneficial effect on the capacity of the Orthopaedic Surgery service to provide care.(AU)

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OBJECTIVE: To analyze referrals from Primary Care consultation to Orthopaedic Surgery reference department. As a secondary objective, to establish 2referral scenarios in order to determine the impact of variability on referral. MATERIAL AND METHODS: Cross-sectional observational study, analyzing referrals from Primary Care to Orthopaedic Surgery during the first half of the years 2018, 2019, and 2021. The number of referrals issued by each doctor and each Primary Care Healthcare Center was examined, according to the classification of the different Basic Healthcare Zones. RESULTS: There is great variability in the number of referrals, both according to the type of Basic Healthcare Zone and by each Primary Care facultative. The referral ratios behaved uniformly over time (P<0.001). Due to a large number of referrals, 2scenarios have been constructed: In the first scenario, the referral ratio would be in the middle of the referral rate spectrum. In the second scenario, the lowest referral ratios recorded have been taken as a reference. The reduction of variability in the 2scenarios assumed provides a significant reduction in the demand for care. CONCLUSION: Reducing variability would have a beneficial effect on the capacity of the Orthopaedic Surgery service to provide care.

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OBJECTIVE: To analyse referrals from Primary Care consultation to Orthopaedic Surgery reference department. As a secondary objective, to establish 2 referral scenarios in order to determine the impact of variability on referral. MATERIAL AND METHODS: Cross-sectional observational study, analyzing referrals from Primary Care to Orthopaedic Surgery during the first half of the years 2018, 2019, and 2021. The number of referrals issued by each doctor and each Primary Care Healthcare Center was examined, according to the classification of the different Basic Healthcare Zones. RESULTS: There is great variability in the number of referrals, both according to the type of Basic Healthcare Zone and by each Primary Care facultative. The referral ratios behaved uniformly over time (p<0.001). Due to a large number of referrals, 2 scenarios have been constructed: In the first scenario, the referral ratio would be in the middle of the referral rate spectrum. In the second scenario, the lowest referral ratios recorded have been taken as a reference. The reduction of variability in the 2 scenarios assumed provides a significant reduction in the demand for care. CONCLUSION: Reducing variability would have a beneficial effect on the capacity of the Orthopaedic Surgery service to provide care.

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Introducción: El sobrepeso y obesidad infantil son temas de gran relevancia en el ámbito de la salud. El objetivo de este estudio fue determinar la prevalencia de sobrepeso y obesidad infantil en niños preadolescentes de entre 9 y 10 años de edad en el Principado de Asturias y evaluar la fiabilidad de las medidas de peso y altura informadas por los padres. Material y método: Una muestra de 291 sujetos, 142 niñas y 149 niños, fueron elegidos de forma aleatoria de la red de centros de enseñanza del Principado de Asturias. Fueron pesados y medidos individualmente en su centro de enseñanza. Todos traían el consentimiento firmado de sus padres, en el que figuraban también las estimaciones sobre las medidas antropométricas de sus hijos. Resultados: Los resultados muestran que el 28,17% de los niños de entre 9 y 10 años de edad del Principado de Asturias presenta sobrepeso y el 15,80%, obesidad. Esto supone que el 43,97% de la muestra tiene algún grado de exceso de peso. Los datos informados por los padres subestiman el peso tanto de los niños como de las niñas, con una media de 2,07 kg. Conclusiones: El elevado porcentaje de exceso de peso se explica por el sistema de categorización utilizado, el de la IOFT, y por la edad de la muestra. Los resultados ponen en cuestión las investigaciones realizadas con datos registrados de un modo indirecto (AU)

Introduction: Overweight and obesity in children is a very important issue in the field of health. The aim of this study was to determine the prevalence of overweight and obesity in pre-adolescent children aged 9 to 10 years old in the Principality of Asturias, and to assess the reliability of the measurements of weight and height reported by parents. Material and method: A sample of 291 subjects, 142 girls and 149 boys were chosen at random from the network of schools in the Principality of Asturias. They were weighed and measured individually at the school. All participants brought the signed consent of their parents, which also contained the anthropometric measurements of they made of their children. Results: The results showed that 28.17% of children aged 9 and 10 years old in the Principality of Asturias were overweight and 15.80% obese. This means that 44% of the sample had some degree of overweight. Data reported by parents underestimated the weight of both the boys and girls by an average of 2.07 kg. Conclusions: The high percentage of excess weight observed is due to the categorisation system used (IOFT) and the age of the sample. The results call into question the research with data indirectly recorded data (AU)

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INTRODUCTION: Overweight and obesity in children is a very important issue in the field of health. The aim of this study was to determine the prevalence of overweight and obesity in pre-adolescent children aged 9 to 10 years old in the Principality of Asturias, and to assess the reliability of the measurements of weight and height reported by parents. MATERIAL AND METHOD: A sample of 291 subjects, 142 girls and 149 boys were chosen at random from the network of schools in the Principality of Asturias. They were weighed and measured individually at the school. All participants brought the signed consent of their parents, which also contained the anthropometric measurements of they made of their children. RESULTS: The results showed that 28.17% of children aged 9 and 10 years old in the Principality of Asturias were overweight and 15.80% obese. This means that 44% of the sample had some degree of overweight. Data reported by parents underestimated the weight of both the boys and girls by an average of 2.07kg. CONCLUSIONS: The high percentage of excess weight observed is due to the categorisation system used (IOFT) and the age of the sample. The results call into question the research with data indirectly recorded data.

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Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from intracellular stores. In mice, HSL deficiency results in male sterility caused by a major defect in spermatogenesis. The testes contain high concentrations of PUFA and specific PUFA are essential for spermatogenesis. We investigated the fatty acid composition and the mRNA levels of key enzymes involved in fatty acid metabolism in testis of HSL-knockout mice. HSL deficiency altered fatty acid composition in the testis but not in plasma. The most important changes were decreases in the essential n-6 PUFA LNA and the n-3 PUFA ALA, and an increase in the corresponding synthesis intermediates C22:4n-6 and C22:5n-3 without changes in DPAn-6 or DHA acids. Mead acid, which has been associated with an essential fatty acid deficit leading to male infertility, was increased in the testis from HSL-knockout mice. Moreover, the expression of SCD-1, FADS1, and FADS2 was increased while expression of ELOVL2, an essential enzyme for the formation of very-long PUFA in testis, was decreased. Given the indispensability of these fatty acids for spermatogenesis, the changes in fatty acid metabolism observed in testes from HSL-knockout male mice may underlie the infertility of these animals.

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Haloperidol exerts its therapeutic effects basically by acting on dopamine receptors. We previously reported that haloperidol inhibits cholesterol biosynthesis in cultured cells. In the present work we investigated its effects on lipid-raft composition and functionality. In both neuroblastoma SH-SY5Y and promyelocytic HL-60 human cell lines, haloperidol inhibited cholesterol biosynthesis resulting in a decrease of the cell cholesterol content and the accumulation of different sterol intermediates (7-dehydrocholesterol, zymostenol and cholesta-8,14-dien-3beta-ol) depending on the dose of the drug. As a consequence, the cholesterol content in lipid rafts was greatly reduced, and several pre-cholesterol sterols, particularly cholesta-8,14-dien-3beta-ol, were incorporated into the cell membrane. This was accompanied by the disruption of lipid rafts, with redistribution of flotillin-1 and Fyn and the impairment of insulin-Akt signaling. Supplementing the medium with free cholesterol abrogated the effects of haloperidol on lipid-raft composition and functionality. LDL (low-density lipoprotein), a physiological vehicle of cholesterol in plasma, was much less effective in preventing the effects of haloperidol, which is attributed to the drug's inhibition of intracellular vesicular trafficking. These effects on cellular cholesterol homeostasis that ultimately result in the alteration of lipid-raft-dependent insulin signaling action may underlie some of the metabolic effects of this widely used antipsychotic.

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European regulations require the dose delivered to patients in CT examinations to be monitored and checked against reference levels. Dose estimation has traditionally been performed manually. This is time consuming and therefore it is typically performed on just a few patients and the results extrapolated to the general case. In this work an automated method to estimate the dose in CT studies is presented. The presented software downloads CT studies from the corporative picture archiving and communication system and uses the information on the DICOM headers to perform the dose calculation. Automation enables dose estimations to be performed on a larger fraction of studies, enabling more significant comparisons with diagnostic reference levels (DRLs). A preliminary analysis involving 5800 studies is presented with details of dose distributions for selected CT protocols in use at a university hospital. Average doses are compared with DRLs. Effective dose estimations are also compared with estimations based on the dose length product.

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In the year 1997 Siemens introduced the virtual wedge in its accelerators. The idea was that a dose profile similar to that of a physical wedge can be obtained by moving one of the accelerator jaws at a constant speed while the dose rate is changing. This work explores the observed behaviour of virtual wedge factors. A model is suggested which takes into account that at any point in time, when the jaw moves, the dose at a point of interest in the phantom is not only due to the direct beam. It also depends on the scattered radiation in the phantom, the head scatter and the behaviour of the monitoring system of the accelerator. Measurements are performed in a Siemens Primus accelerator and compared to the model predictions. It is shown that the model agrees reasonably well with measurements spanning a wide range of conditions. A strong dependence of virtual wedge factors on the dosimetric board has been confirmed and an explanation has been given on how the balance between different contributions is responsible for virtual wedge factors values.

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OBJECTIVES: To analyse the entered more frequent disease in an Internal Medicine Department, the reasons for hospital admission diagnosis at discharge (according to entrance symptom's guide), the group of affected population and its correlation among them. PATIENTS AND METHODS: Over a total of 758 internal medicine admissions of the University Hospital of Valladolid during the year 1999 based on the information of discharge and clinical histories, a descriptive and observational epidemic study was made using the variables of sex, age, reason for admission (guide symptom) and diagnosis at discharge. The obtained results were represented by mean of diagrams of sectors and bars according to the analyzed variables. The data synthesis was made by measures of central tendency and dispersion. SPSS 10.0 version for windows program was used for the statistical study. The non parametric analysis for independent samples was made by the test of median and the U of Mann Whitney, and the parametric by chi-squired test and resistance of Kolmogorov-Smirnov. RESULTS: The median of age is 70 years. Rank 84 years. Interquartile rank 23, fashion in men 75 years and in women 86. The distribution in sex men 51%, women 49%. The more frequent reasons for entrance are dyspnea (35%) and neurological focus (11%). The more frequent diagnosis at discharge are dyspnea and chronic obstructive lung disease worsened by respiratory infection (11%), pneumonia (8%) and acute ischemic stroke (7%). CONCLUSIONS: In-patients in this service, are advanced in years (mainly women) (alpha = 0.05). The age does not get a normal distribution (alpha = 0.05). The frequency of the distribution in sex is similar. The most frequent reason for admission is dyspnea (35%). The most frequent diagnoses at discharge are chronic obstructive lung disease (11%), pneumonia (8%) and acute ischemic stroke (7%). The primary and secondary prevention and an improvement of the therapeutic measures of chronic cardiopulmonary disease would reduce significantly the welfare pressure in Internal Medicine Department and they would improve the population's life quality given that we are opposed to the diseases which are among the four first mortality causes in the world.

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Objetivos: Analizar las patologías más frecuentes ingresadas en un servicio de Medicina Interna, los motivos de ingreso hospitalario, los diagnósticos al alta (según el síntoma guía de ingreso), el grupo de población afectada y su correlación entre ellos. Pacientes y métodos: Sobre un total de 758 ingresos en Medicina Interna del Hospital Universitario de Valladolid, durante el año 1999, en función de los informes de alta e historias clínicas, se realizó un estudio epidemiológico descriptivo observacional, utilizando las variables de sexo, edad, motivo de ingreso (síntoma guía) y diagnósticos al alta. Los resultados obtenidos fueron representados por medio de diagramas de sectores y de barras, en función de las variables analizadas. Para la síntesis de datos fueron utilizadas, medidas de tendencia central y de dispersión. El estudio estadístico empleado fue el programa SPSS versión 10.0 para Windows. El análisis no paramétrico para muestras independientes fue realizado con: la prueba de la mediana y U de Mann-Whitney, y el análisis paramétrico con el test 2 y contraste de Kolmogorov-Smirnov. Resultados: La mediana de edad es de 70 años, rango 84 años, rango intercuartílico de 23, con una moda en varones de 75 años y en mujeres de 86 años. La distribución por sexo: varones 51 por ciento, mujeres 49 por ciento. Los motivos de ingreso más frecuentes son: la disnea (35 por ciento) y la focalidad Neurológica (11 por ciento). Los diagnósticos al alta más frecuentes: EPOC reagudizado por infección respiratoria (11 por ciento), neumonía (8 por ciento) y ACVA isquémico (7 por ciento). Conclusiones: Los pacientes ingresados en este servicio son de edad avanzada (sobretodo en mujeres), ( = 0,05) significación estadística. La edad no sigue una distribución normal ( = 0,05) significación estadística. La frecuencia en la distribución por sexo es similar. El motivo de ingreso más frecuente es la disnea (35 por ciento). Los diagnósticos al alta más frecuentes son: La EPOC (11 por ciento), la neumonía (8 por ciento) y el ACVA isquémico (7 por ciento). La prevención 1ª y 2ª y una mejora de la medidas terapéuticas de las enfermedades crónicas cardiorrespiratorias, reduciría, significativamente la presión asistencial de los servicios de Medicina Interna y mejoraría la calidad de vida de la población, dado que estamos frente a enfermedades que están dentro de las cuatro primeras causas de mortalidad en el mundo (AU)

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The Wobbler mouse is a model of human motor neuron disease. Recently we reported the impairment of mitochondrial complex IV in Wobbler mouse CNS, including motor cortex and spinal cord. The present study was designed to test the effect of hyperbaric oxygen therapy (HBOT) on (1) mitochondrial functions in young Wobbler mice, and (2) the onset and progression of the disease with aging. HBOT was carried out at 2 atmospheres absolute (2 ATA) oxygen for 1 h/day for 30 days. Control groups consisted of both untreated Wobbler mice and non-diseased Wobbler mice. The rate of respiration for complex IV in mitochondria isolated from motor cortex was improved by 40% (P<0.05) after HBOT. The onset and progression of the disease in the Wobbler mice was studied using litters of pups from proven heterozygous breeding pairs, which were treated from birth with 2 ATA HBOT for 1 h/day 6 days a week for the animals' lifetime. A "blinded" observer examined the onset and progression of the Wobbler phenotype, including walking capabilities ranging from normal walking to jaw walking (unable to use forepaws), and the paw condition (from normal to curled wrists and forelimb fixed to the chest). These data indicate that the onset of disease in untreated Wobbler mice averaged 36+/-4.3 days in terms of walking and 40+/-5.7 days in terms of paw condition. HBOT significantly delayed (P<0.001 for both paw condition and walking) the onset of disease to 59+/-8.2 days (in terms of walking) and 63+/-7.6 days (in terms of paw condition). Our data suggest that HBOT significantly ameliorates mitochondrial dysfunction in the motor cortex and spinal cord and greatly delays the onset of the disease in an animal model of motor neuron disease.

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GH3 rat pituitary tumor cells produce GH and prolactin (PRL), but lack the GHRH receptor (GHRH-R). We expressed human GHRH-R (hGHRH-R) in GH3 cells using recombinant adenoviral vectors and studied the effects of GHRH antagonists. The mRNA expression of the GHRH-R gene in the cells was demonstrated by RT-PCR. An exposure of the GH3 cells infected with hGHRH-R to 10(-10), 10(-9) and 10(-8) m hGHRH for 1 or 2 h in culture caused a dose-dependent elevation of the intracellular cAMP concentration and the cAMP efflux. Exposure to hGHRH also elicited dose-dependent increases in GH and PRL secretion from these cells. Neither the uninfected nor the antisense hGHRH-R-infected control cells exhibited cAMP, GH and PRL responses to GHRH stimulation. GHRH antagonists JV-1-38 and jv-1-36 applied at 3x10(-8) m for 3 h, together with 10(-9) m GHRH, significantly inhibited the GHRH-stimulated cAMP efflux from the hGHRH-R-infected cells by 36 and 80% respectively. The more potent antagonist JV-1-36 also decreased the intracellular cAMP levels in these cells by 55%. Exposure to JV-1-36 for 1 h nullified the stimulatory effect of GHRH on GH secretion and significantly inhibited it by 64 and 77% after 2 and 3 h respectively. In a superfusion system, GHRH at 10(-10), 10(-9) and 10(-8) m concentrations induced prompt and dose-related high cAMP responses and smaller increases in the spontaneous GH secretion of the hGHRH-R-infected cells. Antagonists JV-1-36 and JV-1-38 applied at 3x10(-8) m for 15 min, together with 10(-9) m GHRH, inhibited the GHRH-stimulated cAMP response by 59 and 35% respectively. This work demonstrates that GHRH antagonists can effectively inhibit the actions of GHRH on the hGHRH-R. Our results support the view that this class of compounds would be active clinically.

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Disseminated microsporidiosis is diagnosed uncommonly in patients not infected with human immunodeficiency virus (HIV). We present a case of disseminated microsporidiosis in a renal transplant recipient who was seronegative for HIV. Chromotrope-based stains were positive for microsporidia in urine, stools, sputum, and conjunctival scrapings. Electron microscopy, immunofluorescence, polymerase chain reaction, and cultures of renal tissue identified the organism as Encephalitozoon cuniculi. The patient was treated with oral albendazole and topical fumagillin with clinical improvement. In addition, she underwent a transplant nephrectomy and immunosuppressive therapy was withdrawn. Follow-up samples were negative for microsporidia. However, the patient developed central nervous system manifestations and died. An autopsy brain tissue specimen demonstrated E. cuniculi by immunofluorescent staining. Disseminated microsporidiosis must be considered in the differential diagnosis of multiorgan involvement in renal allograft recipients.

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Splice variants (SV) of receptors for growth hormone-releasing hormone (GHRH) have been found in several human cancer cell lines. GHRH antagonists inhibit growth of various human cancers, including osteosarcomas and Ewing's sarcoma, xenografted into nude mice or cultured in vitro and their antiproliferative action could be mediated, in part, through these SV of GHRH receptors. In this study, we found mRNA for the SV(1) isoform of GHRH receptors in human osteosarcoma line MNNG/HOS and SK-ES-1 Ewing's sarcoma line. We also detected mRNA for GHRH, which is apparently translated into the GHRH peptide and secreted by the cells, as shown by the presence of GHRH-like immunoreactivity in the conditioned media of cell cultures. In proliferation studies in vitro, the growth of SK-ES-1 and MNNG/HOS cells was dose-dependently inhibited by GHRH antagonist JV-1-38 and an antiserum against human GHRH. Our study indicates the presence of an autocrine stimulatory loop based on GHRH and SV(1) of GHRH receptors in human sarcomas. The direct antiproliferative effects of GHRH antagonists on malignant bone tumors appear to be exerted through the SV(1) of GHRH receptors on tumoral cells.

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A cytotoxic analogue of LH-RH, AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to carrier [D-Lys6]LH-RH, was developed for targeted therapy of cancers expressing LH-RH-receptors. To determine its possible side-effects on the pituitary gland, we investigated the gene expression of pituitary LH-RH-receptors and LH secretion in ovariectomized female and normal male rats after treatment with the maximum tolerated dose of AN-207. The effect of AN-207 on the gene expression of the pituitary GH-RH-receptors and GH secretion was also assessed in male rats. Five hours after a single i.v. injection of AN-207 at 175 nmol/kg, there was a 39-51% decrease in mRNA expression for the pituitary LH-RH-receptors in male and female rats. The carrier, at an equimolar dose, caused a similar reduction (37-39%), whereas the cytotoxic radical AN-201, at an equitoxic dose (110 nmol/kg), produced only a 12-24% decrease (NS) in the mRNA expression of LH-RH-receptors. AN-207 and the carrier analogue induced a comparable 90-100-fold increase in serum LH concentrations in male rats, and the same 12-fold elevation in OVX rats at 5 h. Seven days after treatment with AN-207, the mRNA levels for the LH-RH receptors and the serum LH concentration were back to normal in both sexes. AN-207, the carrier, and AN-201 had no significant effect on the expression of mRNA for GH-RH-receptors in the pituitary. In vitro, a continuous perfusion of pituitary cells with 10 nM AN-207 did not affect the hormone-releasing function of the targeted LH cells or the nontargeted GH cells. Our results demonstrate that cytotoxic LH-RH analogue AN-207, at the maximum tolerated dose causes only a transient decrease in the gene expression of the pituitary LH-RH receptors, and the levels of mRNA for LH-RH receptor fully recover within 7 days. Moreover, the carrier hormone moiety, and not the cytotoxic radical in AN-207 is responsible for this transient suppression. Our findings suggest that the therapy with cytotoxic LH-RH analogues will not inflict permanent damage to pituitary function.

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Ischemic tolerance in brain develops when sublethal ischemic insults occur before "lethal" cerebral ischemia. Two windows for the induction of tolerance by ischemic preconditioning (IPC) have been proposed: one that occurs within 1 hour after IPC, and another that occurs 1 or 2 days after IPC. The authors tested the hypotheses that IPC would reduce or prevent ischemia-induced mitochondrial dysfunction. IPC and ischemia were produced by bilateral carotid occlusions and systemic hypotension (50 mm Hg) for 2 and 10 minutes, respectively. Nonsynaptosomal mitochondria were harvested 24 hours after the 10-minute "test" ischemic insult. No significant changes were observed in the oxygen consumption rates and activities for hippocampal mitochondrial complexes I to IV between the IPC and sham groups. Twenty-four hours of reperfusion after 10 minutes of global ischemia (without IPC) promoted significant decreases in the oxygen consumption rates in presence of substrates for complexes I and II compared with the IPC and sham groups. These data suggest that IPC protects the integrity of mitochondrial oxidative phosphorylation after cerebral ischemia.

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Talampanel [(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3] benzodiazepine] is an orally active noncompetitive antagonist of the AMPA subtype of glutamate excitatory amino acid receptors. The purpose of this study was to determine whether treatment with talampanel would protect in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, a fluid-percussion interface was positioned parasagittally over the right cerebral cortex. On the following day, fasted rats were anesthetized with 3% halothane, 70% nitrous oxide, and a balance of oxygen; mechanically ventilated and physiologically regulated; and subjected to right parieto-occipital parasagittal fluid-percussion injury (1.5-2.0 atm). The agent (talampanel, bolus infusion of 4 mg/kg followed by infusion of 4 mg/kg/h over 72 h) or vehicle was administered i.v. starting at either 30 min or 3 h after trauma. Seven days after TBI, brains were perfusion-fixed, coronal sections at various levels were digitized, and contusion areas were measured. Treatment with talampanel, when instituted 30 min after trauma, significantly reduced total contusion area compared to vehicle-treated rats (0.54 +/- 0.25 vs. 1.79 +/- 0.42 mm2, respectively). When talampanel treatment was begun at 3 h, the neuroprotective effect of the drug was lost. In addition, treatment with talampanel starting at 30 min significantly attenuated neuronal damage in all three subsectors of the hippocampal CA1 sector compared to vehicle-treated rats (normal-neuron counts, right (ipsilateral) medial CA1: 80.3 +/- 2.0 [talampanel] vs. 66.3 +/- 2.1 [vehicle] (mean +/- SEM); middle CA1: 71.5 +/- 2.0 vs. 60.3 +/- 2.2; lateral CA1: 74.5 +/- 3.0 vs. 63.0 +/- 3.2, respectively). By contrast, when talampanel treatment was begun at 3 h, normal pyramidal-neuron counts were almost identical in both groups. Our findings document that talampanel therapy instituted 30 min after trauma significantly reduces histological damage.

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Mild cerebral anoxic/ischemic/stress insults promote 'tolerance' and thereby protect the brain from subsequent 'lethal' anoxic/ischemic insults. We examined whether specific activation of PKC alpha, delta, epsilon, or zeta isoforms is associated with ischemic preconditioning (IPC) in rat brain. IPC was produced by a 2-minute global cerebral ischemia. Membrane and cytosolic fractions of the hippocampi were immunoblotted using specific antibodies for PKCalpha, delta, epsilon, and zeta. PKCalpha showed a significant translocation to the membrane fraction from 30 min to 4 h and PKCdelta at 4 h following IPC. In contrast, the membrane/cytosol ratio of PKCepsilon showed a tendency to decrease at 30 min and 8 h, and the membrane/cytosol ratio of PKCzeta was significantly decreased from 30 min to 24 h following IPC. These findings indicate PKC isoform-specific membrane translocations in the hippocampus after brief global brain ischemia and suggest that activation of PKCalpha and PKCdelta may be associated with IPC-induced tolerance in the rat hippocampus.

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