Interaction between epidermal growth factor receptor and C-C motif chemokine receptor 2 in the ovulatory cascade.

The epidermal growth factor receptor (EGFR) signaling pathway is one of the main pathways responsible for propagating the luteinizing hormone (LH) signal throughout the cumulus cells and the oocyte. Recently, we have proposed the C-C motif chemokine receptor 2 (CCR2) and its main ligand (monocyte chemoattractant protein-1, MCP1) as novel mediators of the ovulatory cascade. Our previous results demonstrate that the gonadotropins (GNT), amphiregulin (AREG), and prostaglandin E2 (PGE2) stimulation of periovulatory gene mRNA levels occurs, at least in part, through the CCR2/MCP1 pathway, proposing the CCR2 receptor as a novel mediator of the ovulatory cascade in a feline model. For that purpose, feline cumulus-oocyte complexes (COCs) were cultured in the presence or absence of an EGFR inhibitor, recombinant chemokine MCP1, and gonadotropins [as an inducer of cumulus-oocyte expansion (C-OE), and oocyte maturation] to further assess the mRNA expression of periovulatory key genes, C-OE, oocyte nuclear maturation, and steroid hormone production. We observed that MCP1 was able to revert the inhibition of AREG mRNA expression by an EGFR inhibitor within the feline COC. In accordance, the confocal analysis showed that the GNT-stimulated hyaluronic acid (HA) synthesis, blocked by the EGFR inhibitor, was recovered by the addition of recombinant MCP1 in the C-OE culture media. Also, MCP1 was able to revert the inhibition of progesterone (P4) production by EGFR inhibitor in the C-OE culture media. Regarding oocyte nuclear maturation, recombinant MCP1 could also revert the inhibition triggered by the EGFR inhibitor, leading to a recovery in the percentage of metaphase II (MII)-stage oocytes. In conclusion, our results confirm the chemokine receptor CCR2 as a novel intermediate in the ovulatory cascade and demonstrate that the EGFR/AREG and the CCR2/MCP1 signaling pathways play critical roles in regulating feline C-OE and oocyte nuclear maturation, with CCR2/MCP1 signaling pathway being downstream EGFR/AREG pathway within the ovulatory cascade.

Production, Characterization, and Function of Pseudoislets from Perinatal Canine Pancreas.

We evaluated the cell composition and function of canine pancreatic pseudoislets (PIs) produced from 42- to 55-day-old fetuses, 1- to 21-day-old pups, and an adult dog pancreas. After mild collagenase treatment, partially digested tissues were cultured for 2-3 weeks. PI production started on culture day 3, was marked for 6 to 9 days, and then stopped. PI production was greatest with the neonatal specimens, reaching about 12 million aggregates per litter (55-day-old fetus) or per pancreas (1-day-old pup). Cell composition at all stages was similar to that in adult pancreatic islets, with predominant ß cells, scant α cells and, most importantly, presence of δ cells. Among pancreatic markers assessed by quantitative real-time PCR (qRT-PCR) mRNA assay, insulin showed the highest expression levels in PIs from newborn and adult pancreas, although these were more than 1000 times lower than in adult islets. Pdx1 mRNA expression was high in PIs from 55-day-old pancreases and was lower at later stages. Consistent with the qRT-PCR results, the insulin content was far lower than reported in adult dog pancreatic islets. However, insulin release by PIs from 1-day-old pups was demonstrated and was stimulated by a high-glucose medium. PIs were transplanted into euglycemic and diabetic SCID mice. In euglycemic animals, the transplant cell composition underwent maturation and transplants were still viable after 6 months. In diabetic mice, the PI transplants produced insulin and partially controlled the hyperglycemia. These data indicate that PIs can be produced ex vivo from canine fetal or postnatal pancreases. Although functional PIs can be obtained, the production yield is most likely insufficient to meet the requirements for diabetic dog transplantation without further innovation in cell culture amplification.

Purity of islet preparations and 5-year metabolic outcome of allogenic islet transplantation.

In allogenic islet transplantation (IT), high purity of islet preparations and low contamination by nonislet cells are generally favored. The aim of the present study was to analyze the relation between the purity of transplanted preparations and graft function during 5 years post-IT. Twenty-four patients with type 1 diabetes, followed for 5 years after IT, were enrolled. Metabolic parameters and daily insulin requirements were compared between patients who received islet preparations with a mean purity <50% (LOW purity) or ≥50% (HIGH purity). We also analyzed blood levels of carbohydrate antigen 19-9 (CA 19-9)-a biomarker of pancreatic ductal cells-and glucagon, before and after IT. At 5 years, mean hemoglobin A1c (HbA1c levels) (P = .01) and daily insulin requirements (P = .03) were lower in the LOW purity group. Insulin independence was more frequent in the LOW purity group (P < .05). CA19-9 and glucagon levels increased post-IT (P < .0001) and were inversely correlated with the degree of purity. Overall, our results suggest that nonislet cells have a beneficial effect on long-term islet graft function, possibly through ductal-to-endocrine cell differentiation. ClinicalTrial.gov NCT00446264 and NCT01123187.

Genetic analysis of five sedentary fish species in middle Laranjinha River (upper Paraná River basin): A case study.

Most studies of diversity and genetic structure in neotropical fish have focused on commercial species from large rivers or their reservoirs. However, smaller tributaries have been identified as an important alternative migratory route, with independent pools of genetic diversity. In this context, the present study aimed to evaluate genetic diversity and structure in five neotropical fish species from a region of Laranjinha River in the upper Paraná River basin. PCR-RAPD (random amplified polymorphic DNA) markers were used to characterize around 40 individuals of each species distributed upstream and downstream of Corredeira Dam that interrupts the river. The descriptive index of genetic diversity (P = 30.5-82%; HE 0.122-0.312) showed that the populations have acceptable levels of genetic diversity. The values for Nei's genetic distance (DN min 0.0110 and max 0.0306) as well as the genetic structure index and the analysis of molecular variance (AMOVA, ϕST min 0.0132 and max 0.0385) demonstrated low, but significant levels of genetic structure. Bayesian analysis of assignment found two k clusters, including several individuals with mixed ancestry for all populations from the five species analyzed. These findings along with historical data on rainfall and the low dimensions of the dam studied here support the hypothesis that periodic floods enable the transit of individuals between different localities mitigating the differentiation process between populations.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

Islet survival and function following intramuscular autotransplantation in the minipig.

The liver may not be an optimal site for islet transplantation due to obstacles by an instant blood-mediated inflammatory response (IBMIR), and low revascularization of transplanted islets. Therefore, intramuscular islet transplantation (IMIT) offers an attractive alternative, based on its simplicity, enabling easier access for noninvasive graft imaging and cell explantation. In this study, we explored the outcome of autologous IMIT in the minipig (n = 30). Using the intramuscular injection technique, we demonstrated by direct histological evidence the rapid revascularization of islets autotransplanted into the gracilius muscle. Islet survival assessment was performed using immunohistochemistry staining for insulin and glucagon up to a period of 6 months. Furthermore, we showed the crucial role of minimizing mechanical trauma to the myofibers and limiting exocrine contamination. Intramuscular islet graft function after transplantation was confirmed by documenting the acute insulin response to intravenous glucose in 5/11 pancreatectomized animals. Graft function after IMIT remained however significantly lower than the function measured in 12 out of 18 minipigs who received a similar islet volume in the liver through intraportal infusion. Collectively, these results demonstrated in a clinically relevant preclinical model, suggest IMIT as a promising alternative to intraportal infusion for the transplantation of ß cells in certain medical situations.

Adaptive changes of human islets to an obesogenic environment in the mouse.

AIMS/HYPOTHESIS: In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment. METHODS: Non-diabetic Rag2 (-/-) mice (n = 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbA(lc) or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation. RESULTS: Transplanted mice on an HFD gained significantly more weight (p < 0.001) and had higher fasting glycaemia (2-12 weeks; p = 0.0002) and consistently higher fasting human C-peptide levels (2-12 weeks; p = 0.04) compared with those on the control diet. Histology demonstrated doubling of human islet graft volume at 12 weeks in animals on the HFD and increased beta cell volume (p < 0.001), but no change in alpha cell volume. Human islet function (hyperbolic product HOMA2%BS) at 12 weeks was four times lower in HFD animals (p < 0.001 vs controls) because of insufficient beta cell adaptation to decreased (70%) sensitivity (HOMA%S). Human islets obtained from donors with metabolic dysfunction failed to adapt to the HFD. CONCLUSIONS/INTERPRETATION: This longitudinal study provides direct evidence that human islets adapt both endocrine and beta cell mass, function and gene expression to obesity in vivo. The present model will facilitate the identification of mechanisms by which human islets adapt to obesity in vivo and the cell type(s) responsible, and factors predisposing human beta cells to decompensation.

TCF7L2 promotes beta cell regeneration in human and mouse pancreas.

AIMS/HYPOTHESIS: Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. METHODS: Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. RESULTS: TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/STAT3 pathway. CONCLUSIONS/INTERPRETATION: The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.

TCF7L2 rs7903146 impairs islet function and morphology in non-diabetic individuals.

AIMS/HYPOTHESIS: Transcription factor 7-like 2 (TCF7L2) is a Wnt-signalling-associated transcription factor. Genetic studies have clearly demonstrated that DNA polymorphisms within TCF7L2 confer the strongest known association with increased risk of type 2 diabetes. However, the impact of the TCF7L2 type-2-diabetes-associated rs7903146 T allele on biological function and morphology of human pancreatic islets is unknown. METHODS: Paraffin sections of pancreases from 187 brain-deceased donors (HbA(1c) <6.5% [48 mmol/mol]) were used to genotype the TCF7L2 variant rs7903146 and evaluate its impact on islet morphology and alpha and beta cell subpopulations following immunostaining for glucagon and C-peptide. Following islet isolation, we investigated the correlation between TCF7L2 genotype and in vitro islet functional variables from our in-house pancreatic database. RESULTS: TCF7L2 rs7903146 (T/T) was associated with reduced basal and glucose-stimulated insulin secretion in isolated human islets, and reduced islet density in whole pancreas. Morphological analysis demonstrated islet size was increased in T/T carriers. Furthermore, rs7903146 was associated with an increased glucagon/C-peptide ratio, especially in bigger islets. CONCLUSION/INTERPRETATION: The TCF7L2 variant rs7903146 risk allele is associated with impaired insulin secretion, reduction of total islet number and quantitative as well as qualitative morphological changes in human islets. Understanding how the TCF7L2 genotype modulates its activity and how TCF7L2 impacts the islet morphology may aid the design of new therapeutic approaches for the treatment of type 2 diabetes.

TOSO promotes ß-cell proliferation and protects from apoptosis.

Decreased ß-cell mass reflects a shift from quiescence/proliferation into apoptosis, it plays a crucial role in the pathophysiology of diabetes. A major attempt to restore ß-cell mass and normoglycemia is to improve ß-cell survival. Here we show that switching off the Fas pathway using Fas apoptotic inhibitory protein (Faim/TOSO), which regulates apoptosis upstream of caspase 8, blocked ß-cell apoptosis and increased proliferation in human islets. TOSO was clearly expressed in pancreatic ß-cells and down-regulated in T2DM. TOSO expression correlated with ß-cell turnover; at conditions of improved survival, TOSO was induced. In contrast, TOSO downregulation induced ß-cell apoptosis. Although TOSO overexpression resulted in a 3-fold induction of proliferation, proliferating ß-cells showed a very limited capacity to undergo multiple rounds of replication. Our data suggest that TOSO is an important regulator of ß-cell turnover and switches ß-cell apoptosis into proliferation.

Relative importance of patient, procedural and anatomic risk factors for early vein graft thrombosis after coronary artery bypass graft surgery.

AIM: The aim of the present study was to investigate the relative importance of a wide array of patient demographic, procedural, anatomic and perioperative variables as potential risk factors for early saphenous vein graft (SVG) thrombosis after coronary artery bypass graft (CABG) surgery. METHODS: The patency of 611 SVGs in 291 patients operated on at four different hospitals enrolled in the Reduction in Graft Occlusion Rates (RIGOR) study was assessed six months after CABG surgery by multidetector computed tomography coronary angiography or clinically-indicated coronary angiography. The odds of graft occlusion versus patency were analyzed using multilevel multivariate logistic regression with clustering on patient. RESULTS: SVG failure within six months of CABG surgery was predominantly an all-or-none phenomenon with 126 (20.1%) SVGs totally occluded, 485 (77.3%) widely patent and only 16 (2.5%) containing high-grade stenoses. Target vessel diameter ≤ 1.5 mm (adjusted OR 2.37, P=0.003) and female gender (adjusted OR 2.46, P=0.01) were strongly associated with early SVG occlusion. In a subgroup analysis of 354 SVGs in which intraoperative graft blood flow was measured, lower mean flow was also significantly associated with SVG occlusion when analyzed as a continuous variable (adjusted OR 0.984, P=0.006) though not when analyzed dichotomously, <40 mL/min versus ≥ 40 mL/min (adjusted OR 1.86, P=0.08). CONCLUSION: Small target vessel diameter, female gender and low mean graft blood flow are significant risk factors for SVG thrombosis within six months of CABG surgery in patients on postoperative aspirin therapy. This information may be useful in guiding revascularization strategies in selected patients.

Diabetes cell therapy: a decade later.

Type 1 diabetes is an intrinsically unstable condition because of the loss of both insulin secretion and glucose sensing. Guidelines to treat type 1 diabetes have become stricter since results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. Therapeutic strategies first require the treatment of underlying organic causes of the brittleness associated with the optimization of insulin therapy including continuous subcutaneous insulin infusion and glucose monitoring. Alternative approaches may still be needed for the most severely affected patients. During the last decade, islet transplantation has gone from an inconsistent 1-year rate of insulin independence of 10% to 80% and could reach 50% at 5 years, at the expense of non-negligible side effects. Among potential causes of islet transplantation success, sufficient islet mass and low levels of cellular autoimmunity are of critical importance. The main issues are currently the availability of an unlimited source of insulin-secreting cells, and the immunosuppressive drug side effects. Today, islet alone and islet after kidney transplantation are offered in a limited number of isolation centres, usually in clinical trials. Islet after kidney transplantation can be considered in type 1 diabetic patients with end-stage kidney disease that are ineligible for double kidney-pancreas transplantation. Islet transplantation alone is proposed to C-peptide negative adult diabetic patients with a body weight <80 kg or low daily insulin needs with creatinine clearance above 60 ml/min, albuminuria lower than 300mg/24H and without desire for pregnancy in women. Currently and until a more complete assessment of the 5- and probably 10-year overall benefit-risk ratio is available, islet transplantation remains a clinical research procedure.

Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells.

AIMS/HYPOTHESIS: Glucose and incretins regulate beta cell function, gene expression and insulin exocytosis via calcium and cAMP. Prolonged exposure to elevated glucose (also termed glucotoxicity) disturbs calcium homeostasis, but little is known about cAMP signalling. We therefore investigated long-term effects of glucose on this pathway with special regard to the incretin glucagon-like peptide 1 (GLP-1). METHODS: We exposed INS-1E cells and rat or human islets to different levels of glucose for 3 days and determined functional responses in terms of second messengers (cAMP, Ca(2+)), transcription profiles, activation of cAMP-responsive element (CRE) and secretion by measuring membrane capacitance. Moreover, we modulated directly the abundance of a calcium-sensitive adenylyl cyclase (ADCY8) and GLP-1 receptor (GLP1R). RESULTS: GLP-1- or forskolin-mediated increases in cytosolic calcium, cAMP-levels or insulin secretion were largely reduced in INS-1E cells cultured at elevated glucose (>5.5 mmol/l). Statistical analysis of transcription profiles identified cAMP pathways as major targets regulated by glucose. Quantitative PCR confirmed these findings and unravelled marked downregulation of the calcium-sensitive adenylyl cyclase ADCY8 also in rat and in human islets. Re-expression of ADCY8, but not of the GLP1R, recovered GLP-1 signalling in glucotoxicity in INS-1E cells and in rat islets. Moreover, knockdown of this adenylyl cyclase showed that GLP-1-induced cAMP generation, calcium signalling, activation of the downstream target CRE and direct amplification of exocytosis by cAMP-raising agents (evaluated by capacitance measurement) proceeds via ADCY8. CONCLUSIONS/INTERPRETATION: cAMP-mediated pathways are modelled by glucose, and downregulation of the calcium-sensitive ADCY8 plays a central role herein, including signalling via the GLP1R.

A fast-starting mechanical fish that accelerates at 40 m s(-2).

We have built a simple mechanical system to emulate the fast-start performance of fish. The system consists of a thin metal beam covered by a urethane rubber, the fish body and an appropriately shaped tail. The body form of the mechanical fish was modeled after a pike species and selected because it is a widely-studied fast-start specialist. The mechanical fish was held in curvature and hung in water by two restraining lines, which were simultaneously released by a pneumatic cutting mechanism. The potential energy in the beam was transferred into the fluid, thereby accelerating the fish. We measured the resulting acceleration, and calculated the efficiency of propulsion for the mechanical fish model, defined as the ratio of the final kinetic energy of the fish and the initially stored potential energy in the body beam. We also ran a series of flow visualization tests to observe the resulting flow patterns. The maximum start-up acceleration was measured to be around 40 m s(-2), with the maximum final velocity around 1.2 m s(-1). The form of the measured acceleration signal as function of time is quite similar to that of type I fast-start motions studied by Harper and Blake (1991 J. Exp. Biol. 155 175-92). The hydrodynamic efficiency of the fish was found to be around 10%. Flow visualization of the mechanical fast-start wake was also analyzed, showing that the acceleration peaks are associated with the shedding of two vortex rings in near-lateral directions.

Modelo de regresión de Cox de la pérdida auditiva en trabajadores expuestos a ruido y fluidos de mecanizado o humos metálicos / Cox regression model of hearing loss in workers exposed to noise and metalworking fluids or welding fumes

Fundamento. Los trabajos sobre pérdida auditiva laboralse han centrado clásicamente en el estudio del ruidocomo causa principal. En la rama del metal es muy comúnla presencia de contaminantes físicos y químicos.En este artículo se analizan ambos junto con ciertoshábitos personales, con la finalidad de ver su influenciaconjunta en la pérdida auditiva laboral.Material y métodos. Se analiza una muestra de 558 trabajadoresmediante regresión de Cox con una finalidadexplicativa. Se define el carácter de las relaciones causa-efecto existentes entre las variables consideradas,con respecto a tres situaciones: sano/alterado; recuperable/no recuperable; sin caídas en conversacionales/con caídas en conversacionales.Resultados. El análisis refleja que los fluidos de mecanizado,en presencia de ruido, retrasan la adquisición delos diversos grados de alteración auditiva; efecto contrarioal que producen los humos metálicos, que adelantanla adquisición de dichos estadios. El hábito defumar se reconoce como influyente en la adquisición deun trauma acústico inicial; la exposición a ruido extralaboralinfluye en la adquisición de un trauma acústicoavanzado; y por otro lado, los equipos de protecciónauditiva son protectores del ruido pero no de la ototoxicidadde los humos metálicos.Conclusión. Se pone de manifiesto el efecto antagónicode los fluidos de mecanizado y el sinérgico de los humosmetálicos frente al ruido, explicando la variacióntemporal en la evolución de la alteración auditiva, relacionadacon estas atmósferas; se comprueba la influenciadel tabaco y del ruido extralaboral, en la adquisicióndel trauma acústico(AU)

Background. Works on labour-related hearing losshave traditionally been centred on the study of noise asthe principal cause. The presence of physical and chemicalpollutants is very common in the metalworkingbranch. This article analyses both, together with certainpersonal habits, with the aim of determining theirjoint influence on labour-related hearing loss.Methods. A sample of 558 workers was analysed usingCox regression with an explicative aim. The characterof the cause-effect relations existing between the variablesconsidered is defined with respect to three situations:healthy/altered; recoverable/non-recoverable;with falls in conversational abilities/without falls inconversational abilities.Results. The analysis reflects the fact that metalworkingfluids, in the presence of noise, delay the acquisitionof different degrees of auditory alteration; an effectcontrary to that produced by welding fumes, whichaccelerate such states. The habit of smoking is recognisedas having an influence on the acquisition of aninitial acoustic trauma; exposure to noise outside theworkplace influences the acquisition of an advancedacoustic trauma; and, on the other hand, the auditoryprotective equipment provides protection against noisebut mot of the ototoxicity of welding fumes.Conclusion. The antagonistic effect of metalworkingfluids and the synergic effect of welding fumes in theface of noise are made evident in relation to these environments,explaining the temporal variation in the evolutionof auditory alteration; the influence of tobaccoand noise outside the workplace in the acquisition ofacoustic trauma are confirmed(AU)

Who should benefit from diabetes cell therapy?

Type 1 diabetes are intrinsically unstable conditions because of the loss of both insulin secretion and glucose sensing. Guidelines to treat type 1 diabetes have become stricter since the Diabetes Control and Complications Trial (DCCT) results demonstrated the close relationship between microangiopathy and HbA1c levels, whereas the deleterious role of glucose variability on macroangiopathy has been more recently suspected. Therapeutic strategies first require the treatment of underlying organic causes of the brittleness whenever possible and, secondly, the optimization of insulin therapy using analogues, multiple injections and consideration of continuous subcutaneous insulin infusion. Alternative approaches may still be needed for the most severely affected patients, including islet transplantation. We propose islet after kidney transplantation in diabetic patients with end-stage kidney disease ineligible for double kidney-pancreas transplantation (i.e C peptide negative patients over 45 years of age or with severe macroangiopathy) if creatinine blood levels are stable below 20mg/l at least six months after kidney transplantation and steroid discontinuation. Islet transplantation alone is proposed to (1) C peptide negative diabetic patients, (2) aged 18-65 with a duration of diabetes of at least five years, (3) treated with intensive subcutaneous insulin therapy, but unable to obtain a glycated hemoglobin level below 7% without hypoglycemia and / or with brittleness and unpredictable hyper- and hypoglycemia altering quality of life, (4) with normal body weight (< 80 kg) and / or low daily insulin needs (the lower, the better), (5) with renal function close to normal (creatinine clearance above 60 ml/min with albuminuria lower than 300 mg/24 h), (6) with no desire for pregnancy in women. Currently and until more complete assessment of the 5-year overall benefit-risk ratio, islet transplantation remains a clinical research procedure. As already provided for other types of transplantation, and once recognized as a "routine" procedure, prioritization of enlisted patients for islet transplantation could be aided by the calculation of a score that should be determined by a multidisciplinary team.

Effect of anti-platelet factor-4/heparin antibody induction on early saphenous vein graft occlusion after coronary artery bypass surgery.

BACKGROUND: Antibodies to complexes of heparin and platelet factor 4 (PF4) are capable of causing heparin-induced thrombocytopenia (HIT). Recent evidence suggests that anti-PF4/heparin antibodies may be prothrombogenic even in the absence of thrombocytopenia and clinically-recognized HIT. OBJECTIVES: To determine if induction of anti-PF4/heparin antibodies is an independent risk factor for early saphenous vein graft (SVG) occlusion or adverse clinical outcome after coronary artery bypass graft (CABG) surgery. PATIENTS/METHODS: Anti-PF4/heparin antibody titers were measured in 368 patients prior to and then 4 days, 6 weeks and 6 months after CABG surgery. Serotonin release assay (SRA) and antibody isotype analysis were also performed on 6-week samples. SVG patency was determined in 297 patients 6 months after surgery by multidetector computed tomography coronary angiography. RESULTS: Six weeks after surgery, 52% of patients were anti-PF4/heparin seropositive and 9% were SRA positive. Six months after surgery, neither the percentage of occluded SVG (19% vs. 20%, P = NS), the percentage of patients with an occluded SVG (33% vs. 33%, P = NS) nor the incidence of adverse clinical events (21% vs. 24%, P = NS) differed between seropositive and seronegative groups. Neither IgG isotype nor SRA positivity was additionally predictive of SVG occlusion or adverse clinical outcome. CONCLUSION: Induction of anti-PF4/heparin antibodies, even those capable of heparin-dependent platelet activation, is not independently associated with early SVG occlusion or adverse clinical outcomes after CABG surgery.

Accidente laboral. ACSOM una nueva orientación para gestión automática del riesgo / Work accidents. ACSOM a new orientation for automatic risk management

Fundamento. Analizar la accidentalidad laboral en todotipo de empresas, a través de los riesgos que la provocan,teniendo en cuenta que el objetivo final es estableceruna clasificación de riesgos prioritarios. Estainformación permite abordar las acciones preventivasoportunas sobre los riesgos más vulnerables.Material y Métodos. Se aplica un conjunto de técnicasestadístico-matemáticas, basadas fundamentalmenteen contrastes estadísticos, a los accidentes laboralesacaecidos durante tres años, en un organismo de investigacióny desarrollo español (I+D) con 8.780 trabajadores.Se utiliza como patrón de referencia en esteestudio, para un análisis comparativo, el conjunto deaccidentes en España durante un periodo de 11 años.Resultados. Tras la aplicación de la nueva metodología,los dos primeros riesgos que requieren acciones preventivasprioritarias son interacción con substanciasagresivas y accidentes con maquinaria móvil. Si únicamentese hubieran considerado los dos riesgos confrecuencias más elevadas, sin tener en cuenta la vulnerabilidadde cada uno de ellos, los riesgos prioritarioshubieran sido sobreesfuerzos y caídas al mismo nivel.Conclusiones. El análisis proporciona una relación delos riesgos más vulnerables (puntos débiles), sobrelos cuales actuar y de esta forma ser más efectivos a lahora de reducir la accidentalidad(AU)

Background. To analyse workplace accidents, by consideringthe risks that provoke such accidents, bearingin mind that the final aim is to establish a classificationof priority risks. This information will make it possibleto undertake the opportune preventive actions againstthe most vulnerable risks.Material and Methods. A set of statistical-mathematicaltechniques, essentially based on statistical contrasts,was applied to work accidents taking place during athree year period in a Spanish Research and Development(R+D) organisation with 8,780 workers. The referencestandard used for comparative analysis was theensemble of accidents in Spain over an 11 year period.Results. After application of the new methodology, thetwo risks requiring priority preventive actions are interactionwith aggressive substances and accidents withmoving machinery. If the two risks with the highestfrequency had been considered alone, without takinginto account the vulnerability of each, the priority riskswould have been overexertion and falls at the same level.Conclusions. The analysis provides a list of the mostvulnerable risks accidents on which action should betaken and thus achieve greater effectiveness in establishingwhich actions should be considered opportune(AU)