When ß-cells fail: lessons from dedifferentiation.

Diabetes is caused by a combination of impaired responsiveness to insulin and reduced production of insulin by the pancreas. Until recently, the decline of insulin production had been ascribed to ß-cell death. But recent research has shown that ß-cells do not die in diabetes, but undergo a silencing process, termed "dedifferentiation." The main implication of this discovery is that ß-cells can be revived by appropriate treatments. We have shown that mitochondrial abnormalities are a key step in the progression of ß-cell dysfunction towards dedifferentiation. In normal ß-cells, mitochondria generate energy required to sustain insulin production and its finely timed release in response to the body's nutritional status. A normal ß-cell can adapt its mitochondrial fuel source based on substrate availability, a concept known as "metabolic flexibility." This capability is the first casualty in the progress of ß-cell failure. ß-Cells lose the ability to select the right fuel for mitochondrial energy production. Mitochondria become overloaded, and accumulate by-products derived from incomplete fuel utilization. Energy production stalls, and insulin production drops, setting the stage for dedifferentiation. The ultimate goal of these investigations is to explore novel treatment paradigms that will benefit people with diabetes.

[Blood transfusion and inflammation]. / Transfusion sanguine et inflammation.

Transfusion of labile blood products (LBPs) generates occasional inflammatory : type, hazards; for a large part of these, no antigen/antibody conflict is thus, detected. Residual leucocytes used to account for a large part of such incidents - rarely accidents. Since, however, the systematic leukoreduction of LBPs, leucocytes are the less and less incriminated in adverse events. Platelets themselves proved capable of secreting copious amounts of inflammatory mediators, even in the absence of any deliberated stimulation. Meanwhile, even though exceptionally, inflammation can be observed after red blood cell transfusion. It has been noticed that the collection mode of cellular compounds, as well as the preparation and storage conditions are capable of inflicting lesions to the cell membranes and to activate those cells, and thus promoting inflammatory responses. Storage lesions as well as ageing of the stored cells alongside with cell apoptosis contribute to inflammatory responses. This present 'State of the Art' paper aims at encompassing the primary and secondary components of the LBPs, along with the various types of molecules displaying pro-inflammatory properties that can be encountered in transfusion. A better knowledge of causes of inflammatory transfusion-linked hazards is indeed instrumental to the implementation of safety measures aimed at reducing or suppressing these unwanted effects.

[Transfusion-associated circulatory overload]. / Œdèmes aigus pulmonaires de surcharge post-transfusionnels.

A working group of the French National Hemovigilance Committee has been in charge of heightening awareness of Transfusion-Associated Circulatory Overload (TACO) among physicians and nurses. This multidisciplinary group has produced the present document that focuses on epidemiological data provided by the French haemovigilance network, physiopathology, diagnosis, treatment and specific actions that could prevent or minimize the risk of TACO.

[Post-transfusion pulmonary oedema: the French hemovigilance network classification method]. / Œdèmes pulmonaires transfusionnels: classification des cas notifiés en hémovigilance.

Pulmonary oedema after transfusion of blood products may be hydrostatic (transfusion-associated circulatory overload [taco]) or exsudative (transfusion-related acute lung injury [trali]). Both conditions have been recognized as major hazards to transfusion recipients. Risk characterization is necessary to improve safety and to monitor trends in the national blood transfusion system. A collaborative multidisciplinary working group of the French National Hemovigilance Committee has proposed an analysis framework for case definitions and classification. The method relies on internationally used definitions and is adapted to the codification procedures used in the french transfusion incident reports electronic data management.

[Post-transfusion acute lung injury (Trali) after plasma infusion in a patient having a constitutional thrombotic microangiopathy]. / Syndrome d'oedème pulmonaire lésionnel aigu post-transfusionnel (Trali) après perfusion de plasma frais congelé au cours d'une microangiopathie thrombotique congénitale.

INTRODUCTION: Transfusion-related acute lung injury is a post-transfusion interstitial lung injury. CASE REPORT: We reported a post-transfusion acute lung injury in a 23-years old woman having a chronic thrombotic microangiopathy related to an ADAMTS 13 constitutional deficiency receiving monthly plasma infusion for six years. The temporal relationship between the lung injury and the infusion of fresh frozen plasma led to the diagnosis of transfusion-related acute lung injury. The finding in the donor of the transfused plasma of an anti-HLA class II antibody recognizing HLA-DR52 present on leucocytes of the recipient suggests a causal relationship between this antigen-antibody conflict and the triggering of the TRALI. This chronic pathologic state requiring monthly plasma transfusions for thrombotic accident prevention raises the question of the selection of plasma obtained from non-immunized donors. CONCLUSION: The occurrence of a post transfusion pulmonary edema without cardio-vascular overload, must lead to consider a TRALI especially in predisposing clinical situations. In the case reported the role of constitutional ADAMTS 13 deficiency in genesis of TRALI is considered.

[Transfusion-related acute lung injury]. / Oedème pulmonaire lésionnel aigu post-transfusionnel ou Trali.

OBJECTIVES: The transfusion-related acute lung injury frequency was for a long time underestimated since it lacked both a widely accepted clinical definition and a comprehensive etiologic description. Recent clinical and biological data have underlined its frequency and have allowed a better understanding of its mechanisms. CURRENT KNOWLEDGE AND KEY POINTS: Trali is an interstitial lung injury occurring within 6 hours after the beginning of a blood transfusion. This time relationship between blood injection and the occurrence of lung edema is sufficient for a positive diagnosis, if any other cause of interstitial lung edema have been excluded. The clinical definition relies on a desaturation of arterial blood associated to a lack of any cardiac failure or circulation overload. The link between transfusion and lung edema is not univocal and several categories of mechanisms have been discussed. At least 2 of them are well identified; the first one is an immune conflict, and the second one is an activation of neutrophils by injection of biological modifiers such as lipids or CD40 soluble ligand. Evidences exist for the occurrence of Trali only in predisposing condition that mostly consists of a preceding leucostase in lung capillaries. Trali is treated like other lung interstitial edema by oxygen therapy and mechanical ventilation. FUTURE PROJECTS: A better knowledge of Trali offers the opportunity of improving the understanding of the role of blood transfusion in lung edema occurring in complex situations and open the way for a better definition of at risk patient and at risk blood components.

[Autoimmunity induced by low doses of interferon in melanoma stage I]. / Auto-immunité induite par l'interféron à faible dose dans le mélanome stade I.

INTRODUCTION: The principal aim of this work was to determine the prevalence of antinuclear antibodies and antinucleosomes antibodies during a treatment by interferon alpha with low dose for 18 months among patients with a melanoma stage I. The secondary objective consisted to seek the existence or not of a correlation with the clinical relapse, to determine the prevalence of appearance of clinical signs of autoimmune diseases and dysthyroidie. PATIENT AND METHODS: It was an exploratory study. The patients included in the study had a melanoma stage I (French classification), whose excision was realized for 6 weeks maximum, with a Breslow index equal or higher than 1,5 mm. The statistical model of logistic regression was used. RESULTS: Eighty-forth patients were included (38 women and 46 men) old from 21 to 75 years. The prevalence of antinuclear antibodies was 39%. None of the following variables: age, sex, phototype, localisation of melanoma in exposed photo zone, index of Breslow or Clark, were significantly associated with the presence of antinuclear antibodies. As the percentage of patients with anti-nucleosomes was low (5%), no statistical study was carried out. The prevalence of clinical and/or biological dysthyroidie was 37%. 60% of the patients presented at a moment in the evolution antinuclear antibodies or a dysthyroidie. The prevalence of relapses and death different was not correlated significantly with antinuclear antibodies and/or a dysthyroidie. DISCUSSION: Many studies report the appearance of antinuclear antibodies, generally without clinical lesions during the treatment by interferon alpha for cancers (tumours carcinoids, hemopathies) and viral chronic hepatitis. Our study is, to our knowledge, the first evaluating the induction of an autoimmunity during the adjuvant treatment by interferon alpha of melanoma stage I. The induction of autoantibody during the treatment by interferon alpha could constitute a marker of effectiveness of the treatment with improvement of the survival of these patients. In our study, however auto immunity markers do not appear as factors of severity of evolution of the melanoma or predictive factors.

[Combining corticosteroid and aspirin for the prevention of recurrent villitis or intervillositis of unknown etiology]. / Association des corticoïdes à l'aspirine pour la prévention des récidives de villite ou d'intervillite chroniques d'étiologie indéterminée.

We report the cases of two patients who had a favorable outcome with aspirin and corticosteroid therapy during pregnancy for chronic villitis of unknown etiology complicated by labor asphyxia and further intrauterine fetal demise in one gravida 3 patient and for chronic intervillositis of unknown etiology diagnosed after three perinatal deaths in another patient (gravida 4). Chronic villitis of unknown etiology (CVUE) is detected in 7 to 33% of placentas, mainly after intrauterine growth retardation (IUGR), unexplained prematurity, preeclampsia, perinatal asphyxia and intrauterine fetal death (IUFD). The less frequent chronic intervillositis of unknown etiology (CIUE) (0.6 to 0.9/1.000) has been implicated in recurrent severe pregnancy complications, such as spontaneous abortions, IUGR and IUFD. Histopathology and immunohistology are in favor of an immune response against the foreign fetal allograft. The favorable results obtained with corticosteroids and aspirin remain to be confirmed by larger series.

[TRALI: from diagnosis to prevention]. / Le TRALI : du diagnostic à la prévention.

Transfusion-Related Acute Lung Injury (TRALI) is a post-transfusion acute respiratory distress syndrome (ARDS). TRALI is a non-cardiogenic lung oedema occurring within 6 hours following the infusion of a blood component. Its frequency has been estimated from 1 in 5.000 to 1 in 500.000 injected blood products. Its aetiology is still controversial. Antibodies against HLA class I molecules or granulocyte surface molecules recognizing recipient leukocyte antigens were implicated at first. More recently anti HLA class II were involved in some cases. Finally granulocyte activating lipids released from cells during blood storage were claimed to account for cases in which no antibody were detected. Nevertheless, in most cases, none of these triggering factors alone seems sufficient to induce a TRALI. A predisposing condition, associated with leucostasis in pulmonary vessels, is required. Whatever the mechanism, the pulmonary lesion is eventually due to release of neutrophil granule content in contact with endothelial cells of lung micro-capillary vessels. The basement membrane damages leads to fluid and cell extravasations in interstitial and alveolar spaces. Among blood donors multiparous women are the most frequently involved. Up to now there are neither definite guidelines regarding detection of harmful antibodies nor regulation for deferral of potentially dangerous blood donors.

[French training program for medical students in transfusion medicine. Transfusion Medicine Teachers' College]. / Programme en transfusion des étudiants en médecine. Collège des enseignants en transfusion sanguine.

In France, transfusion medicine training program has been updated. A national committee of professors in transfusion medicine propose a series of 13 items which represent the minimum knowledge that general practitioners should possess. This overview of transfusion medicine is far below the level that specialists should reach and they will need an additional specialized training. Several French universities have set up their own training program which is quite similar to the work of the committee of professors. The following recommendations are not strict guidelines but is a common basis which will be improved in 2005 according to new evidence based transfusion medicine.