Perfil lipoproteico por espectroscopia nuclear magnética en pacientes con insuficiencia cardiaca crónica comparado con controles emparejados / 1H-magnetic resonance spectroscopy lipoprotein profile in patients with chronic heart failure versus matched controls

Introducción y objetivos El fenotipado avanzado de lipoproteínas es mejor predictor del riesgo aterosclerótico que el colesterol. El perfil de lipoproteínas en la insuficiencia cardiaca (IC) no está completamente caracterizado. Nuestro objetivo fue describir el perfil de lipoproteínas en IC crónica en comparación con una población de control emparejada. Métodos Estudio transversal entre mayo 2006 y abril 2014, que incluyó pacientes ambulatorios con IC crónica. Las concentraciones de lípidos y el tamaño de las principales fracciones de lipoproteínas (lipoproteínas de alta densidad [HDL], lipoproteínas de baja densidad [LDL] y lipoproteínas de muy alta densidad) y concentración de sus subfracciones (grandes, medianas y pequeñas) se evaluaron mediante espectroscopia de resonancia magnética. Resultados 429 pacientes con IC crónica se compararon con 428 controles. Los pacientes con IC crónica presentaron menor colesterol total y menor concentración de partículas de LDL (1.115 frente a 1.352 nmol/L; p <0,001) y HDL (25,7 frente a 27,9μmol/L; p <0,001), esta última mediada principalmente por la reducción de la subfracción pequeña de HDL (15,2 frente a 18,6μmol/L; p <0,001). El tamaño medio de las partículas lipoproteínas de muy alta densidad, LDL y HDL fue significativamente mayor en los pacientes con IC. Todas las diferencias relacionadas con la partícula HDL persistieron después del ajuste por clase funcional o índice de masa corporal. Encontramos fuertes correlaciones negativas entre biomarcadores cardiacos (fracción aminoterminal del propéptido natriurético cerebral y interleucina-1 tipo de receptor 1) con concentraciones de LDL y HDL, sus subfracciones pequeñas y el tamaño de la partícula HDL. Conclusione Los pacientes con IC crónica difieren significativamente en su perfil de lipoproteínas en comparación con controles emparejados. Se necesitan más investigaciones para comprender mejor la relevancia patogénica de esta diferencia (AU)

Introduction and objectives Advanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. Methods This cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. Results The 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P<.001) and HDL (25.7 vs 27.9μmol/L; P <.001) particle concentrations, with this last difference being mediated by a significantly lower concentration of the small subfraction of HDL (15.2 vs 18.6μmol/L; P <.001). Mean very low-density lipoprotein, LDL, and HDL particle size was significantly higher in patients with HF vs controls. All HDL-related differences from controls persisted after adjustment for New York Heart Association functional class or body mass index. We found strong negative correlations of known cardiac biomarkers (N-terminal pro-brain natriuretic peptide and interleukin-1 receptor-like 1) with total and small LDL and HDL fractions and HDL particle size. Conclusions Patients with chronic HF significantly differ in their lipoprotein profile compared with unaffected controls. Further research is needed to better understand the pathogenic relevance of this difference (AU)

Particle size and cholesterol content of circulating HDL correlate with cardiovascular death in chronic heart failure.

Evidence regarding any association of HDL-particle (HDL-P) derangements and HDL-cholesterol content with cardiovascular (CV) death in chronic heart failure (HF) is lacking. To investigate the prognostic value of HDL-P size (HDL-Sz) and the number of cholesterol molecules per HDL-P for CV death in HF patients. Outpatient chronic HF patients were enrolled. Baseline HDL-P number, subfractions and HDL-Sz were measured using 1H-NMR spectroscopy. The HDL-C/P ratio was calculated as HDL-cholesterol over HDL-P. Endpoint was CV death, with non-CV death as the competing event. 422 patients were included and followed-up during a median of 4.1 (0-8) years. CV death occurred in 120 (30.5%) patients. Mean HDL-Sz was higher in CV dead as compared with survivors (8.39 nm vs. 8.31 nm, p < 0.001). This change in size was due to a reduction in the percentage of small HDL-P (54.6% vs. 60% for CV-death vs. alive; p < 0.001). HDL-C/P ratio was higher in the CV-death group (51.0 vs. 48.3, p < 0.001). HDL-Sz and HDL-C/P ratio were significantly associated with CV death after multivariable regression analysis (HR 1.22 [95% CI 1.01-1.47], p = 0.041 and HR 1.04 [95% CI 1.01-1.07], p = 0.008 respectively). HDL-Sz and HDL-C/P ratio are independent predictors of CV death in chronic HF patients.

Propolis nasal spray effectively improves recovery from infectious acute rhinitis and common cold symptoms in children: a pilot study.

Currently, treatment for acute rhinitis (AR) is symptomatic but no clear agreement exists to control its development. Propolis extract may appear as a promising natural treatment for AR, but its beneficial effects have not yet been fully tested. Forty children suffering from AR and common cold symptoms aged between 2-12 years were enrolled in a prospective epidemiological multicentre study. A 7-day treatment with propolis nasal spray (3 times/day) was applied and a comparison of symptomatology, subjective global improvement and quality of life (QoL) between baseline (day 1) and final (day 7) visits were performed. The main goal was to evaluate the changes in symptom intensity using the Jackson’s scoring test. After 7 days of treatment there was a significant decrease of symptoms both in the total score (p less than 0.0001) and in regard to each AR symptom (p less than 0.01). On the whole, the sample reported no symptoms by day 7, and the resolution of symptoms occurred approximately at day 4. Furthermore, there was no need for supplementary treatment. Both the subjective global improvement impression and the QoL of patients appeared to significantly improve after treatment. No adverse events (AEs) were found globally. It can be concluded that propolis nasal spray effectively improves recovery from infectious AR and common cold symptoms in children and is an optimal alternative in the treatment of this disease without need for any adjuvant treatment.

Hepatic CD36 downregulation parallels steatosis improvement in morbidly obese undergoing bariatric surgery.

BACKGROUND: The notion that hepatic expression of genes involved in lipid metabolism is altered in obese patients is relatively new and its relationship with hepatic steatosis and cardiometabolic alterations remains unclear. OBJECTIVE: We assessed the impact of Roux-en-Y gastric bypass surgery (RYGB) on the expression profile of genes related to metabolic syndrome in liver biopsies from morbidly obese individuals using a custom-made, focused cDNA microarray, and assessed the relationship between the expression profile and hepatic steatosis regression. MATERIALS AND METHODS: Plasma and liver samples were obtained from patients at baseline and 12 months after surgery. Samples were assayed for chemical and gene expression analyses, as appropriate. Gene expression profiles were assessed using custom-made, focused TaqMan low-density array cards. RESULTS: RYGB-induced weight loss produced a favorable reduction in fat deposits, insulin resistance (estimated by homeostasis model assessment of insulin resistance (HOMA-IR)), and plasma and hepatic lipid levels. Compared with the baseline values, the gene expression levels of key targets of lipid metabolism were significantly altered: CD36 was significantly downregulated (-40%; P=0.001), whereas APOB (+27%; P=0.032) and SCARB1 (+37%; P=0.040) were upregulated in response to surgery-induced weight reduction. We also observed a favorable reduction in the expression of the PAI1 gene (-80%; P=0.007) and a significant increase in the expression of the PPARA (+60%; P=0.014) and PPARGC1 genes (+36%; P=0.015). Notably, the relative fold decrease in the expression of the CD36 gene was directly associated with a concomitant reduction in the cholesterol (Spearman's r=0.92; P=0.001) and phospholipid (Spearman's r=0.76; P=0.04) contents in this tissue. CONCLUSIONS: For the first time, RYGB-induced weight loss was shown to promote a favorable downregulation of CD36 expression, which was proportional to a favorable reduction in the hepatic cholesterol and phospholipid contents in our morbidly obese subjects following surgery.

Tratamientos vitamínicos para disminuir la concentración de homocisteína: ¿reducen el riesgo de enfermedad cerebrovascular en prevención primaria? / Vitamin treatments that lower homocysteine concentration: can they decrease cerebrovascular disease in primary prevention?

Introducción. La concentración plasmática elevada de homocisteína (Hcy) o hiperhomocisteinemia se asocia a un aumento del riesgo de enfermedad vascular en estudios de casos y controles, y, en menor grado, en estudios prospectivos. Desarrollo. Han finalizado ya diversos grandes estudios aleatorios, doble ciego y controlados con placebo, que se realizaron con el objetivo de estudiar si había una reducción del riesgo vascular al disminuir la concentración plasmática de Hcy mediante tratamientos vitamínicos específicos (folatos y/o vitaminas B12 y B6). Su objetivo era analizar si esta estrategia reducía el riesgo de enfermedad cardiovascular (estudios HOPE, NORVIT, WAFACS y WENBIT) y cerebrovascular (estudio VISP) en un contexto de prevención secundaria. Los resultados obtenidos a partir de estos estudios y un metaanálisis, que incluye otros más pequeños hasta un total de 12, mostraron que el tratamiento disminuye la concentración plasmática de Hcy, pero no el riesgo vascular. Es, sin embargo, interesante señalar que un metaanálisis reciente que analizó los efectos de estos tratamientos vitamínicos detectó un efecto protector significativo en la prevención primaria del ictus. Estos datos son consistentes con el hecho de que la hiperhomocisteinemia se relaciona más con el riesgo cerebrovascular que con el cardiovascular. Y también con la observación reciente de que la suplementación con ácido fólico en las harinas está asociada con una disminución en la mortalidad por ictus en Estados Unidos y Canadá. Conclusiones. Obviamente, estos datos requerirán de posterior confirmación, pero parece que ahora existen razones que permiten esperar un desenlace positivo de los estudios de intervención para disminuir la Hcy (AU)

Introduction. High plasma homocysteine (Hcy) concentration or hyperhomocysteinemia is associated with an increased vascular risk of disease in case-control studies and, to a lesser extent, in prospective studies. Development. Several large randomized, double-blind, placebo-controlled trials have been already conducted using specific vitamin therapies with the aim of reducing secondary cardiovascular (HOPE, NORVIT, WAFACS and WENBIT studies) and cerebrovascular (VISP study) disease risk. The results from these major secondary prevention trials and one meta-analysis, that included other smaller studies up to 12 of them, showed that treatment decreased plasma Hcy concentration but failed to reduce cardiovascular risk. It is nevertheless noteworthy that a recent meta-analysis addressing the effects of these vitamin treatments on cerebrovascular risk found a positive effect on primary stroke prevention. These data would be consistent with the fact that increased Hcy is known to be associated more strongly with stroke risk than with cardiovascular risk. Moreover, folic acid supplementation in grain food has recently been shown to be associated with a decreased stroke incidence in USA and Canada. Conclusions. Obviously, these data on primary stroke prevention will require extensive confirmation. However, there now appear to be more reasons to expect a positive outcome of Hcy intervention studies (AU)

[Back pain: do we follow the recommendations in the guidelines?]. / Lumbalgia: seguimos las recomendaciones de las guías?

OBJECTIVE: To describe how patients with back pain are usually handled at a health centre. DESIGN: Retrospective, descriptive study. SETTING: Urban health centre. PARTICIPANTS: All patients seen for back pain in the centre's general medical consultations during 2003. MAIN MEASUREMENTS: Patients' personal details, clinical characteristics of back pain (alarm signals), semiological data, request for further tests, treatments prescribed, referral to specialists. RESULTS: Five hundred and thirty eight clinical histories were included. 53.2% of patients were women, and 33.6% were over 55. 35% of patients were not questioned on pain characteristics; and in over half the cases (54.6%), there were no questions on the presence of alarm signals, either. Only in 0.6% of cases was any analogical visual scale used to assess pain. Only 46.8% of the x-rays taken were thought to be well indicated, in terms of pre-established criteria. Total rest was not normally advised (1.9%); the drugs most commonly prescribed were NSAIDs (39.6%). CONCLUSIONS: Clinical evaluation of patients with back pain is still inadequate in our centre, and x-rays are requested without adherence to formal or explicit criteria. We prescribe more NSAIDs than paracetamol for therapy.

Lumbalgia: ¿seguimos las recomendaciones de las guías? / Back pain: do we follow the recommendations in the guidelines?

Objetivo. Describir el tratamiento habitual de los pacientes con lumbalgia en un centro de salud. Diseño. Estudio descriptivo, retrospectivo. Emplazamiento. Centro de salud urbano. Participantes. Todos los pacientes atendidos por lumbalgia en las consultas de medicina general del centro durante el año 2003. Mediciones principales. Datos de filiación de los pacientes, características clínicas de la lumbalgia (señales de alarma), datos semiológicos, solicitud de pruebas complementarias, tratamientos prescritos y derivación a especialistas. Resultados. Se incluyeron 538 historias clínicas. El 53,2% correspondía a mujeres y el 33,6% tenía más de 55 años. No se realizó interrogatorio sobre las características del dolor en un 35% de pacientes, y en más de la mitad de los casos (54,6%) tampoco se interrogó sobre la presencia de señales de alerta. Respecto a la evaluación del dolor, sólo en el 0,6% de los casos se había utilizado una escala visual analógica (EVA). Únicamente el 46,8% de las radiografías realizadas se consideró bien indicado según criterios preestablecidos. El reposo absoluto no se recomendó de forma habitual (1,9%) y los fármacos más prescritos (39,6%) fueron los antiinflamatorios no esteroideos (AINE). Conclusiones. La evaluación clínica de los pacientes con lumbalgia sigue siendo inadecuada en nuestro centro y la solicitud de estudios radiológicos se realiza sin tener en cuenta criterios formales y explícitos. En el apartado terapéutico, prescribimos más AINE que paracetamol

Objective. To describe how patients with back pain are usually handled at a health centre. Design. Retrospective, descriptive study. Setting. Urban health centre. Participants. All patients seen for back pain in the centre's general medical consultations during 2003. Main measurements. Patients' personal details, clinical characteristics of back pain (alarm signals), semiological data, request for further tests, treatments prescribed, referral to specialists. Results. Five hundred and thirty eight clinical histories were included. 53.2% of patients were women, and 33.6% were over 55. 35% of patients were not questioned on pain characteristics; and in over half the cases (54.6%), there were no questions on the presence of alarm signals, either. Only in 0.6% of cases was any analogical visual scale used to assess pain. Only 46.8% of the x-rays taken were thought to be well indicated, in terms of pre-established criteria. Total rest was not normally advised (1.9%); the drugs most commonly prescribed were NSAIDs (39.6%). Conclusions. Clinical evaluation of patients with back pain is still inadequate in our centre, and x-rays are requested without adherence to formal or explicit criteria. We prescribe more NSAIDs than paracetamol for therapy

Comparación de la Tomografía Axial Computarizada con el estudio anatomopatológico en el estadiaje ganglionar del cáncer de pulmón / Comparison between computerized axial tomography and anatomicopathologic study of node staging of lung cancer

• Propósito: Evaluar la Sensibilidad, Especificidad, Valor predictivo positivo y Valor Predictivo Negativode la Tomografia Axial Computarizada (TAC) en el estadiaje ganglionar del cáncer de pulmón.• Material y métodos: Se han analizado 30 pacientes diagnosticados de carcinoma pulmonar entre Mayode 2003 y Mayo de 2004. A todos los pacientes se les realizó una TAC torácica, valorando la afectaciónganglionar mediastínica. A su vez, se les realizó o una mediastinoscopia o una resección pulmonar más linfadenectomíamediastínica, obteniendo así material para el estudio anatomo-patológico para confirmar o no laafectación ganglionar mediastínica y correlacionarla con los hallazgos de la TAC.• Resultados: Hemos obtenido una Sensibilidad del 72,2%, una Especificidad del 100%, un valor predictivopositivo del 100% y un valor predictivo negativo del 70,6% para la TAC, utilizando como “gold standar”el estudio anatomopatológico.• Conclusiones: La TAC torácica se considera una prueba de imagen de rutina en el diagnóstico del cáncerde pulmón; pero en muchos casos no es capaz de estadiar correctamente la afectación ganglionar mediastínica.Es en estos casos, donde es necesario realizar pruebas invasivas como la mediastinoscopia. Actualmente,la aparición de la PET permite estadiar mejor el tumor, ofreciendo mejor tratamiento a cada paciente, y en determinadoscasos evitar técnicas diagnósticas invasivas

• Purpose: To analise the sensitivity, specificity, and positive and negative predictive values of the computerized axial tomography (CT) in nodal stages of lung carcinoma. • Material and methods: Thirty patients suffering from lung carcinoma were analysed between May 2003 and May 2004. CT screening of the thorax was made to all the patients. Mediastinoscopy or lung resection samples plus systematic node dissection were performed, and the efficiency of CT analysed by comparing the obtained data with the histopathology results of nodal affection shown by mediastinoscopy and lymph node dissection. • Results: The sensitivity, specificity, and positive and negative predictive value of the computerized axial tomography (CT) for nodal staging involved in lung carcinoma were 72.2%, 100%, 100% and 70,6% respectively. • Conclusions: CT of the thorax is considered a usual imaging technique in lung carcinoma diagnosis; but in some cases it does not focalise correctly the nodal staging involved in lung carcinoma. In theses cases, it is necessarry to perform invasive techniques such as mediastinoscopy. At present, positron emission tomography (PET) is the technique that better permits to focalise the tumor offering the best data for the therapy of each patient, and avoiding invasive diagnosis techniques

Radioterapia postoperatoria exclusiva en carcinoma de recto / Single postoperative radiotherapy in rectal carcinoma

- Propósito: analizar los resultados del tratamiento radioterápico sin quimioterapia tras cirugía radical en cáncer rectal.- Material y métodos: se analizaron los resultados de 20 pacientes tratados entre enero 94 y enero 97, por un cáncer rectal estadio B2-C. Se administró radioterapia postoperatoria exclusiva por no cumplir los requisitos para la administración de quimioterapia (edad >75 años, mala función hepática, renal o hematológica). Edad mediana: 71 años. Todos recibieron 50 Gy sobre volumen pélvico, con fraccionamiento estándar y técnica de cuatro campos, con fotones de 23 MV (42,1 por ciento) o cobaltoterapia (57,9 por ciento) y tras planificación bidimensional. Se analizaron las cifras de supervivencia, control de la enfermedad y toxicidad.- Resultados: tras un seguimiento mediano de 76,64 meses, la supervivencia cáncer-específica y libre de enfermedad a 5 años fueron del 60,5 por ciento y del 58,1 por ciento, respectivamente. La probabilidad de control local fue del 66,6 por ciento a 5 años y de control a distancia del 80,1 por ciento. La incidencia de toxicidad aguda fue del 73,7 por ciento, pero con ningún grado 3-4 de la RTOG, ni interrupciones de la radioterapia u hospitalización por toxicidad. La incidencia de toxicidad tardía grado 3 fue de un 5,3 por ciento.- Conclusiones: en aquellos pacientes con cáncer rectal en estadios B2-C en los que no se pueda administrar quimioterapia, debería ofrecerse la posibilidad de administrar radioterapia adyuvante exclusiva, dada su baja morbilidad y sus buenos resultados (AU)

Efecto sobre la hemoglobina de dos esquemas de administración de eritropoyetina en cáncer de mama tratado con radioterapia / Effect of two administration schedules of erythropoietin upon hemoglobin in breast cancer patients treated with radiation therapy

- Introducción: Con este estudio queremos analizar la elevación de hemoglobina con eritropoyetina, así como las consecuencias cuando se interrumpe el tratamiento con eritropoyetina (EPO) antes de finalizar la radioterapia.- Material y métodos: 43 pacientes diagnosticadas de cáncer de mama no metastático y con niveles de hemoglobina por debajo de 12 g/dl. Todas ellas fueron tratadas con EPO, 21 pacientes a dosis de 10000 UI 3 veces por semana y 22 pacientes a dosis de 40000 UI semanales. Cuando los niveles fueron superiores a 12g/dl se suspendió el tratamiento con EPO.- Resultados: Los valores de hemoglobina para el grupo de 10000 UI han aumentado en 2.25 g/dl y para el grupo de 40000 UI 1.84 g/dl. El descenso medio total de hemoglobina una vez que se han alcanzado los 12 g/dl es de 0.588ñ0.88 g/dl y el ritmo semanal de descenso es de 0.12ñ0.22g/dl.- Conclusiones: El tratamiento con eritropoyetina aumenta los niveles de hemoglobina en los pacientes anémicos con cáncer y la pauta de 10.000 UI/tres veces a la semana es similar a la pauta de 40.000 UI/semanales (AU)

Fluoropirimidinas y radioterapia en cáncer gastrointestinal / Fluoropyrimidines and radiotherapy in gastrointestinalcancer

Las fluoropirimidinas son unos fármacos antineoplásicos cuya estructura química es similar a la de diversos sustratos imprescindibles en la síntesis de los ácidos nucleicos. Entre ellas destaca el 5-fluorouracilo (5-FU), una pirimidina fluorada que actúa como falso nucleótido. Diversos estudios experimentales han demostrado que la asociación de 5-FU y radioterapia aumenta la citotoxicidad de ésta, aunque el mecanismo de dicha radiopotenciación aun no es bien conocido. En este trabajo revisamos las principales características de las fluoropirimidinas, y recogemos los estudios más relevantes sobre el uso de 5-FU en asociación con radioterapia para el tratamiento de los tumores gastrointestinales (AU)

Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein.

Our understanding of apolipoprotein A-II (apoA-II) physiology is much more limited than that of apoA-I. However, important and rather surprising advances have been produced, mainly through analysis of genetically modified mice. These results reveal a positive association of apoA-II with FFA and VLDL triglyceride plasma concentrations; however, whether this is due to increased VLDL synthesis or to decreased VLDL catabolism remains a matter of controversy. As apoA-II-deficient mice present a phenotype of insulin hypersensitivity, a function of apoA-II in regulating FFA metabolism seems likely. Studies of human beings have shown the apoA-II locus to be a determinant of FFA plasma levels, and several genome-wide searches of different populations with type 2 diabetes have found linkage to an apoA-II intragenic marker, making apoA-II an attractive candidate gene for this disease. The increased concentration of apoB-containing lipoproteins present in apoA-II transgenic mice explains, in part, why these animals present increased atherosclerosis susceptibility. In addition, apoA-II transgenic mice also present impairment of two major HDL antiatherogenic functions: reverse cholesterol transport and protection of LDL oxidative modification. The apoA-II locus has also been suggested as an important genetic determinant of HDL cholesterol concentration, even though there is a major species-specific difference between the effects of mouse and human apoA-II. As antagonizing apoA-I antiatherogenic actions can hardly be considered the apoA-II function in HDL, this remains a topic for future investigations. We suggest that the existence of apoA-II or apoA-I in HDL could be an important signal for specific interaction with HDL receptors such as cubilin or heat shock protein 60.

Lipoprotein lipase and cholesterol transfer activities of lean and obese Zucker rats.

Adult female lean and obese Zucker rats maintained under standard conditions were used for the estimation of plasma, liver and white adipose tissue (WAT) activity of lipoprotein lipase, plasma and liver hepatic lipase and plasma lecithin-cholesterol acyltransferase. No differences in plasma or tissue levels of lipoprotein lipase between lean and obese rats were detected, but the larger WAT size of the obese rats resulted in higher lipase activity per unit of rat weight. Hepatic lipase levels in plasma were higher in the obese, but in liver, the higher activity was found in lean rats. No significant differences were found for lecithin-cholesterol acyltransferase activity, except when the levels in the HDL fraction were expressed per unit of protein weight, showing lower activity in the obese rats. In conclusion, the essentially maintained enzyme activities in obese rat tissues suggest that they cannot explain the deficient lipoproteins processing of obese rats, and, consequently their dislipidaemia.

Anomalous lipoproteins in obese Zucker rats.

AIMS: Obesity is characterized by dislipoproteinaemia with increased cholesterol and triacylglycerol levels and lower chylomicra disposal rates. We studied here whether these alterations were related to lipoprotein number and/or size and composition. METHODS: Plasma from lean and obese Zucker rats was fractionated into lipoprotein classes (chylomicra, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)) by differential centrifugation. The apoprotein and lipid composition of each fraction were measured. Lipoprotein particle size was estimated by dynamic light scattering and used to tabulate the mean diameter and volume of lipoprotein micelles. Particle mass was calculated from the density and volume. The mass of lipids and protein in each fraction/ml of plasma allowed the estimation of mean particle concentration and then the number of molecules of lipid and protein/unit of lipoprotein micelle. RESULTS: A large part of hyperlipidaemia of obese rats is due to the accumulation of chylomicra: 1.3 +/- 0.2 mg/ml in lean rats [LR] (34% of all lipoproteins) and 8.2 +/- 0.9 mg/ml in the obese rats [OR] (66% of all lipoproteins). Lipid percentage composition of lipoproteins was similar in both groups. The particle size of LDL and HDL was much higher in OR than in LR: LDLs weighed 31.1 +/- 7.5 ag (LR) vs. 273 +/- 81 ag (OR), and HDLs weighed 31.7 +/- 12.6 ag (LR) and 375 +/- 103 ag (OR). In chylomicra and VLDL there was a relative scarcity of apoproteins in OR compared with LR. The whole architecture of LDLs is altered in OR, with a predominance of surface lipids: phospholipid and free cholesterol, and lower amounts of core lipids: triacylglycerols and cholesterol esters, with surface/core lipids ratios of 0.74 (LR) and 1.89 (OR). The consequences of anomalous LDL and HDL composition, size and overall structure may result in magnified lipoprotein metabolism alterations that hamper their ability to transfer apolipoproteins to larger chylomicra and VLDL, and to alter cholesterol transfer and binding of their apoproteins to cell surface receptors. The smaller number of LDL and HDL particles may further compound these difficulties and thus change the free to esterified cholesterol ratios observed in OR. CONCLUSIONS: The main conclusions of this study are the key importance of chylomicron analysis for a better understanding of the transfer of lipids, and the altered lipoprotein size and apoprotein distribution in obese rats, which seriously hamper cholesterol interchange, resulting in hypercholesterolaemia, and thus triggering even more far-reaching consequences for the well-being of the obese.

ApoA-II expression in CETP transgenic mice increases VLDL production and impairs VLDL clearance.

Apolipoprotein (apo)A-II is a major high density lipoprotein (HDL) protein; however, its role in lipoprotein metabolism is largely unknown. Transgenic (Tg) mice that overexpress human apoA-II present functional lecithin: cholesterol acyltransferase deficiency, HDL deficiency, hypertriglyceridemia and, when fed an atherogenic diet, increased non-HDL cholesterol and increased susceptibility to atherosclerosis. In contrast to humans, mice do not present cholesteryl ester transfer protein (CETP) activity in plasma. To study the in vivo interaction of these two proteins, we crossbred human apoA-II and CETP-Tg mice. CETP x apoA-II-Tg mice fed an atherogenic diet, compared with CETP-Tg mice presented a 2-fold decrease in HDL cholesterol and a quantitatively similar increase in total plasma cholesterol and percentage of free cholesterol, non-HDL cholesterol, and free fatty acids, together with a remarkable 112-fold increase in plasma triglycerides. Plasma triglycerides in CETP x apoA-II-Tg mice were mainly associated with very low density lipoproteins (VLDL), which were also enriched in protein content, and resulted from a combination of higher production rate compared with both of their progenitors and non-Tg control mice, and decreased catabolism compared only with CETP-Tg mice. These results show CETP x apoA-II-Tg mice to be a good model with which to study mechanisms leading to VLDL overproduction and suggest that CETP and, in particular apoA-II, may play a role in the regulation of VLDL metabolism.

Increased production of very-low-density lipoproteins in transgenic mice overexpressing human apolipoprotein A-II and fed with a high-fat diet.

We investigated the mechanisms that lead to combined hyperlipidemia in transgenic mice that overexpress human apolipoprotein (apo) A-II (line 11.1). The 11.1 transgenic mice develop pronounced hypertriglyceridemia, and a moderate increase in free fatty acid (FFA) and plasma cholesterol, especially when fed a high-fat/high-cholesterol diet. Post-heparin plasma lipoprotein lipase and hepatic lipase activities (using artificial or natural autologous substrates), the decay of plasma triglycerides with fasting, and the fractional catabolic rate of the radiolabeled VLDL-triglyceride (both fasting and postprandial) were similar in 11. 1 transgenic mice and in control mice. In contrast, a 2.5-fold increase in hepatic VLDL-triglyceride production was observed in 11. 1 transgenic mice in a period of 2 h in which blood lipolysis was inhibited. This increased synthesis of hepatic VLDL-triglyceride used preformed FFA rather than FFA of de novo hepatic synthesis. The 11.1 transgenic mice also presented reduced epididymal/parametrial white adipose tissue weight (1.5-fold), increased rate of epididymal/parametrial hormone-sensitive lipase-mediated lipolysis (1.2-fold) and an increase in cholesterol and, especially, in triglyceride liver content, suggesting an enhanced mobilization of fat as the source of preformed FFA reaching the liver. Increased plasma FFA was reverted by insulin, demonstrating that 11.1 transgenic mice are not insulin resistant. We conclude that the overexpression of human apoA-II in transgenic mice induces combined hyperlipidemia through an increase in VLDL production. These mice will be useful in the study of molecular mechanisms that regulate the overproduction of VLDL, a situation of major pathophysiological interest since it is the basic mechanism underlying familial combined hyperlipidemia.

[Immunohistochemical markers of cell proliferation in laryngeal carcinoma]. / Marcadores inmunohistoquímicos de proliferación celular en el carcinoma de laringe.

Although several clinicopathological factors may contribute to the prognosis of laryngeal carcinoma, these factors are still uncertain because the carcinogenesis process and malignant behavior are not well known. Immunohistochemical methods using two important markers, PCNA and Ki67 antigen, were used to assess proliferative activity in malignant laryngeal lesions. We studied the correlation between expression of these markers and clinical factors in 72 patients with carcinoma of the larynx: age, sex, occupation, smoking, alcohol consumption, marital status, etc. We also analyzed other known biological and histopathological prognostic factors (tumor stage, histological grade, lymph node metastases, and local invasion). PCNA and Ki-67 expression differed significantly in relation to histological grade and lymph node involvement. No associations were seen between the expression of PCNA and Ki-67 antigens and other study parameters.

Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a common inherited hyperlipidemia and a major risk factor for atherothrombotic cardiovascular disease. The cause(s) leading to FCHL are largely unknown, but the existence of unidentified "major" genes that would increase VLDL production and of "modifier" genes that would influence the phenotype of the disease has been proposed. Expression of apolipoprotein A-II (apoA-II), a high density lipoprotein (HDL) of unknown function, in transgenic mice produced increased concentration of apoB-containing lipoproteins and decreased HDL. Here we show that expression of human apoA-II in apoE-deficient mice induces a dose-dependent increase in VLDL, resulting in plasma triglyceride elevations of up to 24-fold in a mouse line that has 2-fold the concentration of human apoA-II of normolipidemic humans, as well as other well-known characteristics of FCHL: increased concentrations of cholesterol, triglyceride, and apoB in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), reduced HDL cholesterol, normal lipoprotein lipase and hepatic lipase activities, increased production of VLDL triglycerides, and increased susceptibility to atherosclerosis. However, FCHL patients do not have plasma concentrations of human apoA-II as high as those of apoE-deficient mice overexpressing human apoA-II, and the apoA-II gene has not been linked to FCHL in genome-wide scans. Therefore, the apoA-II gene could be a "modifier" FCHL gene influencing the phenotype of the disease in some individuals through unkown mechanisms including an action on a "major" FCHL gene. We conclude that apoE-deficient mice overexpressing human apoA-II constitute useful animal models with which to study the mechanisms leading to overproduction of VLDL, and that apoA-II may function to regulate VLDL production.

[Study of bcl-2 oncogene in squamous-cell carcinoma of the larynx]. / Estudio del oncogén Bcl-2 en el carcinoma escamoso de laringe.

Apoptosis is a special type of programmed cell death that occurs in the embryonic period, in normal adult tissues, and in several pathological situations. The Bcl-2 gene (B-cell leukemia/lymphoma) is the first member of an oncogene family whose main function is to increase cell survival and inhibit apoptosis, thus participating in the carcinogenic process. This relationship motivated our study of antiapoptosis through the immunohistochemical expression of Bcl-2 oncogene in 72 patients with cancer of the larynx who underwent surgery in our department. The correlation between immunohistochemical expression and clinical factors was analyzed: age, sex, work, smoking and drinking history, marital status, etc., as well as other known biological and histopathological prognostic factors (tumoral stage, histological grade, neck metastases, and local invasion). Bcl-2 expression showed a statistically significant correlation with histological grade and regional lymph node involvement, but no correlation with the other parameters studied.