Factores de riesgo de la trombosis de rama en el tratamiento endovascular aórtico infrarrenal: nuestra experiencia / Experience of the risk factors of limb thrombosis in EVAR

Objetivo: Analizar la trombosis de rama en el tratamiento de aneurisma de aorta abdominal (EVAR) en nuestra serie y su relación con factores de riesgo predisponentes. Material y método: Se incluyeron todos los EVAR programados entre enero de 2007 y enero de 2103. Mediante angio-TC y seguimiento analizamos los factores de riesgo preoperatorios (calcificación, tortuosidad y angulación), tipo de material implantado, sobredimensión y arteria ilíaca de sellado; la incidencia y manejo de la trombosis. También analizamos las angio-TC de cada una de las trombosis. Con las variables estudiadas se realizó un análisis comparativo de casos (trombosis) y controles (libre de trombosis). Resultados: De los 151 pacientes tratados mediante EVAR, con un seguimiento medio de 41,7 meses, 11 pacientes (7,2%) presentaron oclusión de rama ilíaca. No se observaron diferencias entre los grupos. En el análisis por ilíacas, en el que se incluyeron 294 ilíacas tratadas (8 aortomonoilíacos) con 15 casos (5,1%) de oclusión ilíaca, se observó la asociación de la trombosis de rama con el sellado en ilíaca externa (p=0,001) y con la sobredimensión superior al 20% (p=0,003). Conclusión: El sellado distal en ilíaca externa y la sobredimensión ≥ 20% en el tratamiento del EVAR son factores de riesgo independientes asociados con la trombosis de rama en nuestra serie (AU)

Objective: To analyse the limb occlusion after endovascular aortic repair (EVAR) and its predisposing risk factors. Materials and methods: The study included all elective EVAR cases between January 2007 and January 2013. An assessment was made of predisposing risk factors using pre-surgical angioCT scan and follow-up. A pre-surgical analysis was performed on risk factors (calcification, tortuosity, and angulation), type of endograft implanted, oversizing, and the iliac artery landing zone used. A comparative analysis was performed of the cases (occlusion) and controls (occlusion free) to assess the variables. Results: The study included a total of 151 treated patients with follow-up time of 41.7 months, and 11 patients (7.2%) presented with limb occlusion. No differences were observed in the comparison between the patient groups. Of the 294 iliac arteries included in the study (with 8 aorto-uni-iliac endografts), there were 15 (5.1%) cases of limb occlusion. The analysis revealed an association between limb occlusion and using the external iliac artery as a landing zone vessel (P=.001). There was a statistically significant relationship between oversizing ≥ 20% and limb occlusion (P=.003). Conclusion: Using external iliac artery as a landing zone vessel and oversizing ≥ 20% during EVAR are independent risk factors for limb occlusion in our case series (AU)

Sellado distal en ilíaca externa: ramificación ilíaca frente a la exclusión de la arteria hipogástrica / Extern iliac as distal sealing: Iliac branch device versus hypogastric exclusion

Objetivo: Comparar los resultados del sellado distal del EVAR en ilíaca externa (IE) mediante ramificación ilíaca frente a la exclusión de la arteria hipogástrica. Pacientes: Incluimos a 67 pacientes desde 2007 hasta 2014, en los que incluimos 25 ilíacas con branched ilíaco (grupo I) y 77 con fijación en IE y exclusión hipogástrica (grupo II). Métodos: Mediante análisis retrospectivo valoramos factores sociodemográficos y comparamos parámetros intraoperatorios, estancia hospitalaria, complicaciones en la evolución como claudicación glútea ipsolateral, trombosis de rama, migración, reintervención y crecimiento de la ilíaca común (IC) mediante el seguimiento clínico y radiológico. Resultados: El seguimiento medio fue de 26,7 y 49,3 meses en el grupo I y II, respectivamente. Sin diferencias en estancia hospitalaria, el tiempo de escopia, la dosis de irradiación el tiempo quirúrgico y el contraste empleado fue mayor en el grupo I. En el 50,6% del grupo II se embolizó la hipogástrica. El éxito técnico del branched fue del 92%. La tasa de complicaciones entre grupo I y II: claudicación glútea del 4 y el 36% (p < 0,0001), la tasa de trombosis de rama a los 24 meses fue del 6 y el 10,4% (p < 0,2) y de reintervención del 6 y el 12% (p: 0,1) respectivamente. El grupo II presentó 4 casos de migración distal y 4 casos que precisaron extensión de rama. La disminución de la IC en el seguimiento fue de 3,4 cm y 2 cm, respectivamente (p: 0,09). Conclusión: En nuestra serie, la menor tasa de complicaciones del dispositivo ramificado en el sellado distal en IE, podría justificar su empleo en pacientes seleccionados (AU)

Objective: To compare the results of endovascular aneurysm repair (EVAR) in external iliac (EI) as distal sealing using an iliac branch device (IBD) versus the exclusion of the internal iliac artery. Patients: The study included 67 patients treated by EVAR between 2007 and 2014 that were divided into two groups. Group I included 25 iliac arteries receiving an iliac branch device, and group II with 77 iliac arteries in which their sealing was in EI with hypogastric exclusion. Methods: A retrospective study was conducted in an assessment and comparison was made using the characteristics, risk factors, intra-operative parameters, and days in hospital. Complications, such as ipsilateral buttock claudication, limb occlusion, device migration, re-interventions, and growth of common iliac (CI), were followed by physical and radiological examinations. Results: Mean follow-up was 26.7, and 49.3 months in the group I and II, respectively. There were no differences in days in hospital, but the fluoroscopy time, radiation dose, procedure time, and contrast was higher in group i. The hypogastric artery was embolised in 50.6% of group II, with 92% technical success with the IBD in group i. The complication rate between group I and II: buttock claudication was 4% and 36% (P < .0001), the limb occlusion rate at 24 months was 6% and 10.4% (P < .2), and re-intervention was 6% and 12% (P = .1), respectively. Group II had 4 cases of distal migration, and 4 cases requiring extension to EI. The CI diameter decreased by 3.4 cm and 2 cm, respectively (P = .09). Conclusion: In our series, the low rate of complications in distal sealing with iliac branch devices could justify their use in selected patients (AU)

Valor pronóstico de la clasificación WIfI en pacientes con pie diabético / WIfI classification system prognostic value in patients with diabetic foot

INTRODUCCIÓN: El pie diabético es una entidad clínica causante de una importante morbimortalidad en nuestro medio. En 2014, la Society of Vascular Surgery propuso una nueva clasificación que estima el riesgo de amputación para miembros inferiores e incluye a pacientes diabéticos. OBJETIVO: Evaluar el valor pronóstico que tendría la aplicación de la clasificación Wound, Ischaemia, and foot Infection classification system (WIfI) en la salvación de extremidad del pie diabético. MATERIAL Y MÉTODOS: Estudio de cohortes retrospectivo unicéntrico (2008-2013) de pacientes con pie diabético. Se calculó el riesgo de amputación y la recomendación de revascularización según la clasificación WIfI y se comparó con la actitud terapéutica real que se había realizado. El grupo A se compuso con pacientes en los que la recomendación obtenida aplicando la clasificación WIfI coincidía con la terapia realizada. En el grupo B se incluyó a pacientes en los que estos parámetros no eran coincidentes. Se calcularon las tasas a 12 meses de salvamento de extremidad, supervivencia global y supervivencia libre de amputación para ambos grupos. RESULTADOS: Se estudiaron 128 extremidades (93 en el grupo A y 35 en el grupo B). Ambos grupos eran comparables. La supervivencia libre de amputación para el grupo A fue del 90%, vs. el 78% del grupo B (p < 0,0001). La tasa a 12 meses de salvamento de extremidad fue del 97,2 vs. 68,1% (p < 0,0001) para el grupo A y B, respectivamente. No se encontraron diferencias en cuanto a la supervivencia global entre los grupos. CONCLUSIÓN: La aplicación de la clasificación WIfI en pacientes con pie diabético mejora el pronóstico a corto plazo, lo que aumenta la tasa de salvamento de extremidad

INTRODUCTION: Diabetic foot is an important cause of morbidity and mortality. In 2014, the Society of Vascular Surgery proposed a new classification system (Wound, Ischaemia, and foot Infection classification system [WIfI]) which estimates lower limb amputation risk, including diabetic patients. OBJECTIVE: To evaluate the WIfI classification prognostic value in salvage threatened limbs of patients with diabetic foot. MATERIAL AND METHODS: A retrospective single-centre cohort study (2008-2013) of patients with diabetic foot. The risk of amputation and revascularisation recommendation was calculated according to the WIfI classification and compared with the real therapeutic approach that was used. Group A included patients in whom the recommendation obtained by applying WIfI classification coincided with the therapy performed. Group B included patients in whom recommendation obtained and therapy performed was mis-matched. Limb salvage rate after 12-months, overall survival, and amputation-free survival for both groups, were calculated. RESULTS: A total of 128 limbs (93 in group A and 35 in group B) were included. Both groups were comparable. Limb salvage rate was 90% for group A and 78% for group B (P<.0001). Amputationfree survival was 97.2 versus 68.1% (P<.0001) for group A and B, respectively. No differences were observed in overall survival. CONCLUSION: The application of WIfI classification system in patients with diabetic foot improves short term prognosis, increasing the rate of limb salvage after 12 months

Resultados tras el cambio de estrategia en el sellado distal de endoprótesis aórticas infrarrenales / Results after a change in strategy in distal sealing zone of infrarenal aortic endoprostheses

INTRODUCCIÓN: Tras estudios propios referentes a la evolución del sellado distal modificamos la actitud en el sellado de las endoprótesis de aorta abdominal: sellando en iliacas primitivas (IP) si eran menores de 16mm de diámetro y en iliacas externas (IE) si eran mayores. El objetivo del trabajo es valorar los efectos del cambio de criterio en el sellado distal. PACIENTES Y MÉTODOS: Se incluyeron los aneurismas infrarrenales programados consecutivos tratados mediante endoprótesis, desde enero de 2008 a diciembre de 2012. Se evaluó el crecimiento iliaco medio y las tasas de incidencia de endofugas tipo I distales (Ib), reintervenciones iliacas, trombosis de rama, rotura aórtica, mortalidad global y mortalidad relacionada con el aneurisma. Se excluyeron los casos con un seguimiento radiológico menor a 12 meses, aunque sí que fueron incluidos para valorar la mortalidad. RESULTADOS: Se incluyeron un total de 81 pacientes y 126 iliacas. La fijación distal se realizó en 86 IP y 40 IE. El seguimiento medio fue de 30,6±14 meses. El crecimiento medio de las IP fue -0,17±3mm (+1mm si la fijación fue en IP y -2,6mm si la fijación fue en IE; p = 0,0001) y el de las IE fue de -0,10±1,4mm (-0,3mm si se fijó en IP y +0,4mm si se fijó en IE; p = 0,01). No se detectaron endofugas Ib ni rotura del aneurisma. La tasa de reintervenciones iliacas total fue del 3,2% (4 casos, 1,1% en IP y 7,5% en IE; p = 0,09). La tasa de trombosis de rama fue mayor en los pacientes con sellado en IE (10% frente a 0%; p = 0,009), al igual que una mayor incidencia de claudicación glútea (37,5% frente a 4,6%; p = 0,0001). La mortalidad postoperatoria fue del 2,5%. La mortalidad global y la relacionada con el aneurisma a los 3 años fue del 19,5% y 2,5% respectivamente (sin influir las reintervenciones en la mortalidad). CONCLUSIONES: Los resultados avalan el cambio de estrategia en el sellado distal eliminando el riesgo de fuga Ib y de rotura aórtica en nuestra experiencia. Sin embargo, el sellado distal en IE se asocia a mayor trombosis de rama (sin aumentar la mortalidad relacionada con el aneurisma) y de claudicación glútea

INTRODUCTION: After assessing the results our own studies regarding the outcomes of patients in relation to distal sealing strategy, we modified our previous sealing approach of abdominal aortic endografts. For this study, distal sealing on common iliac artery (CI) is proposed when its diameter was less than 16mm, and in external iliac artery (EI) for diameters greater than 16mm. The aim of this study is to assess the effects of the modification of fixation criteria during follow-up. PATIENTS AND METHODS: Patients consecutively treated for infrarenal aortic aneurysms by elective endovascular repair during the period between January 2008 and December 2012 were included. Average iliac growth, type I distal endoleak (Ib), limb thrombosis, re-interventions due to iliac related complications were assessed, as well as overall mortality and aneurysm related mortality. Patients with less than 12 months follow-up were excluded, although they were included in the analysis to assess mortality. RESULTS: A total of 81 patients accounting for 126 iliacs were included. Distal fixation was carried out at CI in 86 and EI in 40 cases, respectively. Mean follow-up was 30.6±14 months. Average CI growth rate was -0.17±3mm (+1mm when fixation was performed in CI and -2.6mm when for fixation in EI; P=.0001); and -0.10±1.4mm for EI (-0.3mm when fixation was performed in CI and +0.4mm for fixation in EI; P=.01). No type 1b endoleaks or aneurysm ruptures were detected during follow-up. Total iliac re-intervention rate was 3.2% (4 cases, 1.1% in CI vs 7.5% in EI; P=.09). Limb thrombosis rate was higher in patients with sealing in EI (10% Vs 0%; P=.009), as well as the incidence of buttock claudication (37.5% vs. 4.6%; P=.0001). Perioperative mortality rate was 2.5%. Overall and aneurysm-related mortality at 3 years was 19.5% and 2.5% respectively (re-interventions did not have any influence on mortality rates). CONCLUSIONS: The observed results support the strategy modification in distal sealing zone, eliminating the risk of Ib endoleaks and aneurysm rupture in our experience. However, distal sealing in EI was associated with a higher incidence of limb thrombosis (Without any increase in aneurysm-related mortality), and buttock claudication

Imaging of cellular aging in human retinal blood vessels.

To date two main aging vascular lesions have been reported in elderly human retinas: acellular capillaries and microaneurysms. However, their exact mechanism of formation remains unclear. Using high resolution microscopy techniques we revise cellular alterations observed in aged human retinal vessels, such as lipofuscin accumulation, caveolae malfunction, blood basement membrane disruption and enhanced apoptosis that could trigger the development of these aging vascular lesions. Moreover, we have generated a set of original images comparing retinal vasculature between middle and old aged healthy humans to show in a comprehensive manner the main structural and ultrastructural alterations occurred during age in retinal blood vessels.

Mimicking microvascular alterations of human diabetic retinopathy: a challenge for the mouse models.

Although it has become acceptable that neuroretinal cells are also affected in diabetes, vascular lesions continue to be considered as the hallmarks of diabetic retinopathy. Animal models are essential for the understanding and treatment of human diabetic retinopathy, and the mouse is intensively used as a model because of its similarity to human and the possibility to be genetically modified. However, until today not all retinal vascular lesions developed in diabetic patients have been reproduced in diabetic mice, and the reasons for this are not completely understood. In this review, we will summarize retinal vascular lesions found in diabetic and diabetic-like mouse models and its comparison to human lesions. The goal is to provide insights to better understand human and mice differences and thus, to facilitate the development of new mouse models that mimic better human diabetic retinopathy.

Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: role of beta-cell hyperplasia and hypertrophy.

We determined the beta-cell replicative rate, beta-cell apoptosis, cross-sectional beta-cell area, and pancreatic beta-cell mass throughout the entire postweaning lifespan (months 1, 3, 7, 10, 15, and 20) of Lewis rats. Beta-cell replication was progressively reduced in the initial months of life but remained stable after month 7 (month 1, 0.99 +/- 0.10%; month 3, 0.24 +/- 0.04%; month 7, 0.12 +/- 0.02%; month 10, 0.14 +/- 0.02%; month 15, 0.10 +/- 0.03%; month 20, 0.13 +/- 0.03%; analysis of variance [ANOVA], P < 0.001). Beta-cell apoptosis was low and did not change significantly from month 1 to 20 of life. Cross-sectional area of individual beta-cells increased progressively in the initial months, remained stable from month 7 to 15, and increased again on month 20. The estimated number of beta-cells per pancreas, calculated as the ratio of total beta-cell mass to individual beta-cell mass, tripled from month 1 to 7 but did not change significantly thereafter. Beta-cell mass increased approximately 8 times from month 1 to 20 (month 1, 2.04 +/- 0.28 mg; month 20, 15.5 +/- 2.32 mg; ANOVA, P < 0.001) and showed a strong and significant linear correlation with body weight (r = 0.98, P < 0.001). In summary, we have shown that beta-cell replication was maintained throughout the lifespan in normal rats, clearly establishing that the beta-cell birth rate does not fall to 0, even in very old rats. Beta-cell mass increased throughout the lifespan, closely matching the increment in total body weight at any time point. This increment was selective for beta-cells, since the growth of the endocrine non-beta-cell mass was limited to the initial months of life. Both beta-cell hypertrophy and hyperplasia contributed to increased beta-cell mass in young animals, but only beta-cell hypertrophy was responsible for the increased beta-cell mass found in old animals. This study provides a global perspective for understanding the dynamics of beta-cell mass in young, adult, and aged animals.

[Genetic association between the reduced amplitude of the P300 and the allele A1 of the gene which codifies the D2 dopamine receptor (DRD2) as possible biological markers for alcoholism]. / Asociación genética entre la amplitud reducida del P300 y el alelo A1 del gen que codifica el receptor D2 de dopamina (DRD2) como posibles marcadores biológicos del alcoholismo.

INTRODUCTION: Over the last twenty years much work has been done to study the P300 in alcoholism. A systematically reduced amplitude, both in patients and in populations at risk (children of alcoholics) was found. Besides, studies on twins indicate that the waves of the evoked potentials are under genetic control. Furthermore, advances in molecular genetic techniques have clarified the part played by the allele A1 of the gene which codifies the D2 dopamine receptor in alcoholism. Only in recent years have studies been published relating them and in these they are considered to be risk markers for alcoholism. However, contradictory results have been obtained. DEVELOPMENT: The objective of this study is to review part of the literature and find evidence for and against the characteristics observed in the P300 and the possible part played by the DRD2 gene in the aetiology of alcoholism and the relationship between them. At the same time we consider the most relevant theoretical aspects of the role played by dopamine in the central nervous system, since some studies have shown that it is involved in the generation of P300 and reinforcement due to alcohol consumptions. Finally, we discuss the advantages and disadvantages that should be taken into account when considering the low amplitude of P300 and the presence of the A1 allele as diagnostic markers to identify populations at risk and thus avoid appearance of the disorder.

Optimal insulin treatment in syngeneic islet transplantation.

Insulin-induced normoglycemia has shown to have a beneficial effect on the outcome of pancreatic islets transplanted to diabetic recipients. The aim of the study was to identify the insulin treatment that can maximize its beneficial effect on islet transplants. Six groups of streptozotocin diabetic C57Bl/6 mice were transplanted (Tx) with 100 syngeneic islets, an insufficient beta cell mass to restore normoglycemia, and were treated with insulin as follows: group 1 (n = 9): from day 10 before Tx to day 14 after Tx; group 2 (n = 11): from day 6 before Tx to Tx day; group 3 (n = 11): from Tx day to day 6 after Tx; group 4 (n = 7): from Tx day to day 14 after Tx; group 5 (n = 8): from day 10 to day 24 after Tx; group 6 (n = 18): Tx mice were not treated with insulin. Sixty days after Tx, normoglycemia was achieved in 100% of mice in groups 1, 4, and 5, in 73% of mice in group 2, and in only 45% and 33% of mice in groups 3 and 6, respectively (p < 0.01). Intraperitoneal glucose tolerance, determined only in normoglycemic mice, was similar in groups 1, 2, 4, and normal controls. In contrast, normoglycemic mice from groups 3, 5, and 6, exposed to more severe and prolonged hyperglycemia after Tx, showed higher glucose values after glucose injection, suggesting that hyperglycemia had a long-lasting deleterious effect on transplanted beta cell function. The initially transplanted beta cell mass was maintained in the grafts of normoglycemic mice, but was severely reduced in hyperglycemic mice. Transplanted beta cell mass was similar in normoglycemic groups with normal or impaired glucose tolerance, indicating that impaired glucose tolerance was not due to reduced beta cell mass. In summary, the beneficial effect of insulin-induced normoglycemia on transplanted islets was maximal when insulin treatment was maintained the initial 14 days after transplantation. Exposure to sustained hyperglycemia initially after transplantation had a long-lasting deleterious effect on transplanted islets.

Asociación genética entre la amplitud reducida del P300 y el alelo A1 del gen que codifica el receptor D2 de dopamina (DRD2) como posibles marcadores biológicos del alcoholismo / Genetic assocation between the reduced amplitude of the P300 and the allele al of the gene which codifies the D2 dopamne receptor (DRD2) as possible biological markers for alcoholism

Introduction. Over the last twenty years much work has been done to study the P300 in alcoholism. A systematically reduced amplitude, both in patients and in populations at risk (children of alcoholics) was found. Besides, studies on twins indicate that the waves of the evoked potentials are under genetic control. Furthermore, advances in molecular genetic techniques have clarified the part played by the allele A1 of the gene which codifies the D2 dopamine receptor in alcoholism. Only in recent years have studies been published relating them and in these they are considered to be risk markers for alcoholism. However, contradictory results have been obtained. Development. The objective of this study is to review part of the literature and find evidence for and against the characteristics observed in the P300 and the possible part played by the DRD2 gene in the aetiology of alcoholism and the relationship between them. At the same time we consider the most relevant theoretical aspects of the role played by dopamine in the central nervous system, since some studies have shown that it is involved in the generation of P300 and reinforcement due to alcohol consumptions. Finally, we discuss the advantages and disadvantages that should be taken into account when considering the low amplitude of P300 and the presence of the A1 allele as diagnostic markers to identify populations at risk and thus avoid appearance of the disorder (AU)

Introducción. A lo largo de las dos últimas décadas se ha desarrollado un cuerpo de trabajo dedicado al estudio del P300 enel alcoholismo y sistemáticamente se ha encontrado una amplitud disminuida, tanto en pacientes, como en poblaciones de riesgo (hijos de alcohólicos). Además, estudios con gemelos indican que las ondas de los potenciales evocados están bajo control genético. Por otro lado, avances en las técnicas de genética molecular han puesto de manifiesto el papel del alelo A1 del gen que codifica el receptor D2 de dopamina (DRD2) en el alcoholismo. Sólo en los últimos años han aparecido estudios que los relacionan y los consideran como marcadores de riesgo para el alcoholismo. Sin embargo, se han encontrado resultados contradictorios. Desarrollo. El objetivo del presente trabajo es revisar parte de la literatura y aportar pruebas a favor y en contra, tanto de las características observadas en el P300 como del posible papel del gen DRD2 en la etiología del alcoholismo y de la relación entre ambos. Todo ello considerando los aspectos más relevantes sobre el papel de la dopamina en el sistema nervioso central, ya que algunos estudios muestran que se halla implicada en la generación del P300 y en el refuerzo derivado del consumo del alcohol. Finalmente, se discuten las ventajas e inconvenientes de tomar en consideración la baja amplitud del P300 y la presencia del alelo A1 como marcadores diagnósticos para identificar poblaciones de riesgo y prevenir así la aparición del trastorno (AU)

Normoglycemia restores beta-cell replicative response to glucose in transplanted islets exposed to chronic hyperglycemia.

We studied the effects of chronic hyperglycemia on beta-cell replication and mass in transplanted (Tx) islets. Five groups of streptozocin-induced diabetic C57Bl/6 mice were transplanted with 100 (Tx-100) syngeneic islets, an insufficient beta-cell mass to restore normoglycemia. Groups 1 and 2 remained hyperglycemic throughout the study; after 30 days of hyperglycemia, a second transplantation of 250 islets (Tx-250) restored normoglycemia in groups 3, 4, and 5. Tx-250 was harvested on day 60 in all three groups, and transient mild hyperglycemia developed (10-12 days); thereafter, Tx-100 maintained blood glucose values in the normal range. Tx-100 was harvested 14 (group 1), 60 (groups 2 and 3), 74 (group 4), and 90 (group 5) days after transplantation. Hyperglycemia increased beta-cell replication after 14 days (group 1: 1.26 +/- 0.18%, P < 0.05) but not after 60 days (group 2: 0.59 +/- 0.13%) compared with islets exposed to normoglycemia (group 3: 0.51 +/- 0.07%) (analysis of variance [ANOVA], P < 0.0002). beta-cell replication in group 4 increased after Tx-250 harvesting (0.94 +/- 0.16%, P < 0.05). The initially Tx beta-cell mass (0.21 +/- 0.014 mg) was progressively reduced in hyperglycemic groups (group 1: 0.13 +/- 0.020 mg; group 2: 0.048 +/- 0.012 mg; P < 0.05) (ANOVA, P = 0.0001). Restoration of normoglycemia after Tx-250 did not modify beta-cell mass in Tx-100 grafts (group 3: 0.076 +/- 0.008 mg). However, after Tx-250 harvesting, beta-cell mass increased progressively (group 4: 0.11 +/- 0.018 mg; group 5: 0.14 +/- 0.026 mg, P < 0.05), although it was still reduced compared with the initially Tx beta-cell mass (P < 0.05). In summary, Tx islets exposed to severe chronic hyperglycemia showed a limited beta-cell replication and a progressive reduction in beta-cell mass. With normoglycemia, the Tx beta-cells recovered the replicative response to glucose and partially restored the initially Tx beta-cell mass, indicating that normoglycemia, even after long-term hyperglycemia, has a beneficial effect in islet transplantation.

Improved outcome of islet transplantation in insulin-treated diabetic mice: effects on beta-cell mass and function.

Insulin treatment may improve the outcome of islet transplantation. To determine the effects of insulin treatment on transplanted islets, 4 groups of streptozotocin-diabetic C57BL/6 mice were transplanted with 100 islets, an insufficient beta-cell mass to restore normoglycaemia. Groups 1 (n = 12) and 2 (n = 12), were kept normoglycaemic with insulin treatment from day 10 before transplantation to day 14 after transplantation; groups 3 (n = 12) and 4 (n = 18), were not treated with insulin. Grafts were harvested 14 (groups 1 and 3) or 60 (groups 2 and 4) days after transplantation and beta-cell mass and replication were measured. When insulin was discontinued all mice maintained normoglycaemia; in contrast, non-insulin-treated groups remained hyperglycaemic throughout the study. Fourteen days after transplantation the beta-cell mass was reduced both in group 1 (0.09 +/- 0.01 mg) and group 3 (0.14 +/- 0.02 mg) compared to the initially transplanted mass (0.22 +/- 0.02 mg, p < 0.01); beta-cell replication and area did not change in group 1, but were increased in group 3. Insulin content, expressed as a function of beta-cell mass, was maintained in group 1 grafts (12.5 +/- 2.0 micrograms/mg), but was severely reduced in group 3 (1.0 +/- 0.2 micrograms/mg) compared to non-transplanted islets (20.4 +/- 3.3 micrograms/mg). In group 2, beta-cell mass increased when insulin was discontinued; 60 days after transplantation beta-cell mass was similar to the initially transplanted mass (0.23 +/- 0.04 mg), glucose levels after an intraperitoneal glucose challenge were normal, and insulin content was preserved (19.6 +/- 2.7 micrograms/mg). In contrast, beta-cell mass was progressively reduced in group 4 (0.08 +/- 0.02 mg, p < 0.001). In summary, insulin treatment reduced the beta-cell mass needed to achieve normoglycaemia in islet transplantation. Islets transplanted to insulin-treated mice showed better beta-cell function, preserved insulin content, and were able to increase their beta-cell mass to meet an increased functional demand.

[The influence of clinical presentation and metabolic control of insulin dependent diabetes in the evolution of residual insulin secretion. A prospective study at five years]. / Influencia de la presentación clínica y del control metabólico de la diabetes insulinodependiente en la evolución de la secreción residual de insulina. Estudio prospectivo a cinco años.

BACKGROUND: To study the influence of clinical, metabolic and immunological parameters during the first years of the evolution of insulin-dependent diabetes mellitus (IDDM) on the long-term residual insulin secretion (IS). PATIENTS AND METHODS: 186 IDDM subjects diagnosed from 1986 to 1993 were included; 135 subjects have completed a two year follow-up, and 57 have completed a five year follow-up. The influence of individual characteristics at diagnosis (age, sex, clinical presentation, islet-cell antibodies) and during the first two years of follow-up (IS, metabolic control) on IS at five years was evaluated by multiple linear regression. Differences between groups were evaluated by non-parametric tests. RESULTS: 18 patients had a significant insulin secretion at five years (post-glucagon C-peptide > or = 0.15 nmol/l). They showed minor significant differences in sex (77.7 vs 48.7% of males, p = 0.03), duration of symptoms (12.9 vs 7.2 weeks, p = 0.01), ketoacidosis at diagnosis (23.3 vs 46.1%, p = 0.07) and ICA positivity at diagnosis (41.1 vs 69.4%, p = 0.05). They also had a better metabolic control (8.8 vs 10.8% of HbA1, p < 0.001) with lss insulin (0.48 vs 0.71 Ul/kg, p < 0.001) during the first two years of evolution. Initial IS was similar, but differences became significant at 6 months. In the multivariate analysis, only metabolic control during the second year of evolution (p = 0.008), ketoacidosis at diagnosis (p = 0.026) and sex (p = 0.026) had an independent influence on IS at five years. A more intensified therapeutic approach introduced in 1990 induced a better metabolic control and higher IS during the first years of follow-up. CONCLUSION: The absence of ketoacidosis at diagnosis and a good metabolic control during the first two years can have a positive influence in the long-term preservation of IS in IDDM patients.

Diminished fraction of blockable ATP-sensitive K+ channels in islets transplanted into diabetic mice.

The reasons for the poor outcome of islet transplantation in diabetic patients are not well known; a better understanding of the pathophysiology of transplanted islets is needed. To study the mechanism coupling secretagogue stimuli with insulin release in transplanted islets, we determined the effects of glucose, tolbutamide, and carbamylcholine on the beta-cell membrane potential and cytosolic calcium concentrations ([Ca2+]i) of islets syngeneically transplanted into normal and streptozocin-induced diabetic mice. In both groups, normoglycemia was maintained after transplantation. Islets transplanted into normal recipients showed similar changes in beta-cell membrane potential and [Ca2+]i oscillations to those in control islets. In contrast, when islets were transplanted into diabetic mice, bursts of electrical activity were triggered at lower glucose concentrations (5.6 mmol/l) than in control islets (11 mmol/l), and maximal electrical activity was achieved at lower glucose concentrations (11 mmol/l) than in control islets (22 mmol/l). When membrane potential was plotted as a function of glucose concentration, the dose-response curve was shifted to the left. Compared with control islets, glucose-induced [Ca2+]i oscillations were broader in duration (22.3 +/- 0.6 s vs. 118.1 +/- 12.6 s; P < 0.01) and higher in amplitude (135 +/- 36 nmol/l vs. 352 +/- 36 nmol/l; P < 0.01). Glucose supersensitivity was attributed to a resting decrease in the fraction of blockable ATP-sensitive K+ (K+(ATP)) channels in transplanted islets that maintained normoglycemia with a limited beta-cell mass.

Beta-cell growth and mass are preserved in long-term syngeneic islet transplantation in streptozocin-induced diabetic Lewis rats.

We determined beta-cell replication and mass in basal and stimulated conditions in long-term transplanted islets. Three groups of streptozocin-induced diabetic Lewis rats were transplanted with 1,000 islets (500 islets under left and right kidney capsules). At 2 (Tx-2), 5 (Tx-5), or 9 (Tx-9) months after transplantation, one of the two grafts (basal) was harvested; 14 days later, the contralateral graft (stimulated) was also harvested. Normoglycemia was achieved and maintained in all transplanted rats, although the capacity to respond to a glucose challenge deteriorated slightly 9 months after transplantation. Beta-cell replication remained stable in Tx-2, Tx-5, and Tx-9 basal grafts and was similar to replication in a control group of nontransplanted rats (0.28 +/- 0.06%); replication increased in Tx-2 (0.90 +/- 0.23%, P < 0.05) and Tx-9 (0.72 +/- 0.09%, P < 0.05) stimulated grafts. Beta-cell mass in basal grafts was similar to the initially transplanted mass (1.24 +/- 0.06 mg) and increased in stimulated grafts in Tx-2 (1.91 +/- 0.38 mg, P < 0.05) and Tx-5 (1.73 +/- 0.27 mg, P = 0.01) groups, compared with basal grafts, and in Tx-2 and Tx-9 groups (1.92 +/- 0.30 mg, P < 0.05), compared with initially transplanted mass. Therefore, beta-cell replication and mass were preserved up to 9 months after syngeneic transplantation, and beta-cells maintained the capacity to respond to increased metabolic demand, suggesting that replication is not a limiting factor in the survival of transplanted islets.

Ketoacidosis at diagnosis is predictive of lower residual beta-cell function and poor metabolic control in type 1 diabetes.

To determine the factors at diagnosis predictive of changes in residual beta-cell function and metabolic control in Type 1 diabetes, 125 patients older than 7 years of age consecutively diagnosed between March 1986 and June 1991 were followed prospectively for two years. The effect of age, gender and the presence of ketoacidosis (DKA) and islet-cell antibodies (ICA) on beta-cell function, metabolic control and insulin requirements were studied by multivariate analysis of variance (repeated measurements over time) in 90 patients who completed follow-up. DKA had an independent negative effect on residual beta-cell function over time (p = 0.001). ICA-positive patients had lower residual beta-cell function at the end of follow-up (p < 0.05), but overall differences were not significant. DKA and younger age had an independent negative influence on metabolic control (p < 0.05) and insulin requirements (p < 0.001) over time. It is concluded that residual beta-cell function in Type 1 diabetic patients two years after diagnosis was independently influenced by DKA and ICA at diagnosis. Moreover, DKA and age influenced metabolic control and could thus be used to predict those patients with rapidly deteriorating metabolic control who might benefit from a more intensive therapeutic approach.