[Mad cow disease: 20 years after]. / La vache folle : 20 ans après.

Mad cow disease: 20 years after. Twenty years after the peak of the mad cow disease crisis, an overview was made by the National Food Council about the public health consequences, scientific advances, management measures taken to control the disease, persistent uncertainty about long-term impact on human health, and the difficulty to communicate in such a critical context. An in depth work to follow and explain the evolution of food production and transformation methods is indispensable. In a critical phase, the expression of the multiple actors requires to be made as coherent and coordinated as possible.

La vache folle : 20 ans après. Vingt ans après le pic de la crise de la vache folle, le Conseil national de l'alimentation a voulu tirer des leçons de la crise en termes de communication. Après un bilan des conséquences de santé publique, des avancées scientifiques, des mesures de gestion qui ont été prises pour maîtriser la maladie, et des incertitudes persistantes pour la santé humaine, les difficultés de communication dans un tel contexte ont été analysées. Un travail de suivi et de pédagogie sur l'évolution des techniques de production dans le secteur agroalimentaire est indispensable. En période de crise, l'expression des multiples acteurs de ce secteur gagne à être rendue aussi cohérente et coordonnée que possible.

[Global health security at the time of Nagoya]. / La sécurité sanitaire mondiale à l'heure de Nagoya.

The International Health Regulations are the main legal instrument to prevent the international propagation of diseases, particularly related to infectious agents. It supports the exchange of samples between countries. These exchanges have raised expectations, in many countries, about the sharing of the benefits resulting from these exchanges. About influenza viruses with pandemic potential, the 2011 pandemic influenza preparedness framework Agreement is a response to these expectations. These exchanges are also influenced by the progress made in genetics.The Nagoya Protocol, which came into force in 2014, creates a new framework concerning the use of genetic resources, including about pathogens. It will have a positive impact on public health, if it facilitates the exchanges of gene sequence data about pathogens and if it permits benefits sharing internationally. Such a result is possible, if its implementation builds upon the pandemic influenza preparedness framework Agreement.

[National health security agencies: facts and perspectives]. / Les agences nationales de sécurite sanitaire : constats et perspectives.

Despite major changes in its composition over the past two decades, the French health security infrastructure, currently consisting of eight agencies, has endured. This infrastructure has reinforced the French state's capacity to protect the health of its population, but it did not yet provide total protection. The future of national health agencies will depend on their ability to maintain the priority given to public health security ; to preserve credible, high-level scientific expertise ; to meet the challenges of healthcare safety ; and to organize health security at the European level.

[National plan for the prevention and control "influenza pandemic"]. / Plan national de prévention et de lutte contre une pandémie grippale.

France has developed a national plan for the prevention and control of an influenza pandemic with the aim of reducing its health impact and its consequences on the economic and social life of the country. The main objectives of the plan are to prepare the country to face an epizootic of avian influenza due to a highly pathogenic virus, to detect the first manifestation of a new flu virus, to curb its spread by adopting early and appropriate public health measures and to protect the French population, as well as French citizens abroad. Ensuring that the population has the best possible access to prevention and care, through the organisation and adaptation of the health system facing a pandemic, is one of the major goals of the plan. The plan, and organisation associated to it, forms the foundation of a coherent and adaptable system which every citizen should feel ownership of.

Liver repopulation trial using bone marrow cells in a retrorsine-induced chronic hepatocellular injury model.

OBJECTIVES: The aim of this study was to determine the potential of bone marrow derived cells to participate in liver repopulation. In this model, the injected cells had a "selective growth advantage" compared to the native hepatocytes whose proliferation was blocked by retrorsine. METHODS: Total bone marrow cells were isolated from male Fisher 344 rats not deficient in dipeptidyl peptidase activity (F344, DPP IV+). The animals were given an injection of retrorsine and were divided in 2 groups: 1/group R (N=13): female F344 rats received 4.106 male cells at day 0 (labeled by chromosome Y). 2/group RH (N=19): Male F344 DPP IV- rats received 4.106 male DPP IV+ cells after hepatectomy at day 0 (labelled by DPP IV activity). RESULTS: Group R: no male cell was detected by PCR at day 14, 28, 56 and 84. Group RH: isolated DPP IV+ transplanted cells were observed at days 14 and 28 in the periportal areas. Later, these cells were no longer visible. Liver regeneration occurred by proliferation of small clusters of hepatocytes. CONCLUSIONS: In this experimental model the capacity of transplanted bone marrow cells to repopulate the liver was tested against the same capacity of native liver stem cells. Liver regeneration occurred via native liver cells seen as small hepatocytes. In this model the small hepatocytes may be considered as hepatic stem cells.

[The Direction Générale de la Santé today]. / La Direction générale de la santé aujourd'hui.

The Direction générale de la santé, created fifty years ago as part of the French Ministry of Health, is devoted to public health. Among the current challenges which the Direction générale de la santé must meet are various types of potential health crisis, preparing the country for major health threats, reinforcing disease prevention and risk management, coordinating health institutions at the national level, and promoting French health policies within Europe and internationally.

[Health international agreements: what are they? For what purpose?]. / Quels sont et à quoi servent les accords internationaux de santé ?

Health international agreements: what are they? for what purpose?. Under the auspices of the World Health Organization, the efforts made to strengthen public health at the world level are reflected in three international agreements. The commitment of Member States to contribute to the protection of the health of the world population is underlined in the International Health Regulation and in the Pandemic influenza preparedness Framework. The Framework Convention on tobacco control aims at protecting the population of each Member State from the major health risks linked to tobacco use.

Quels sont et à quoi servent les accords internationaux de santé ?. Trois accords internationaux soulignent les efforts faits, sous l'égide de l'Organisation mondiale de la santé, en vue de renforcer la santé publique au niveau mondial. Le Règlement sanitaire international et le Cadre de préparation en cas de grippe pandémique soulignent l'engagement des États membres à contribuer à la protection de la santé de la population mondiale. La convention-cadre de lutte anti-tabac vise à protéger la population de chaque État membre vis-à-vis du risque sanitaire majeur auquel expose l'usage du tabac.

The case to abandon human leukocyte antigen matching for kidney allocation: would it be wise to throw out the baby with the bathwater?

Since major histocompatibility (MHC) antigen matching was introduced in the early 1970s as the key factor determining kidney transplant allocation, several studies, mainly arising from organ-sharing organizations in the United States and Europe, have debated this complex issue. The first fundamental concern is the interaction of human leukocyte antigen matching with other transplant outcome risk factors, for example, prolongation of ischemia and matching for age. Much concordant data advocate restraining MHC antigen-based allocation in terms of space and time limits. The second fundamental concern is the balancing of the advantages of better antigen matching in terms of improved graft survival and the improved transplantation rate in immunologically high-risk patients with the major drawback of inequitable access for ethnic minorities and patients with rare MHC haplotypes. These issues have led to considering renewed kidney allocation rules, discarding human leukocyte antigen matching from algorithms, or modifying the specificity allocation level by using cross-reactive group matching or class II MHC antigen matching. The evolving concepts in the field of histocompatibility support the need for periodically updated, flexible, and hybrid allocation systems, as designed in France by the Etablissement français des Greffes.

Geographic disparities in access to organ transplant in France.

BACKGROUND: Allocation of organs is organized on a regional basis in France. We assessed regional differences in access to organ transplant. MATERIAL AND METHODS: We used the recipient database and the waiting list database from the year 1994 onward. We estimated median waiting time by region and organ. The probability of receiving a transplant was estimated using the Kaplan-Meier method. Between-region comparisons used the log-rank test, with adjustment for blood type and disease category. RESULTS: At the end of a 4-month follow-up period, 49% of 3,553 patients had received transplants: 64% of 797 benefited from liver transplants, 52% of 549 from heart transplants, and 22% of 2,207 from kidney transplants. Death rates on the waiting lists were 10%, 14%, and 1% for patients selected for liver, heart, and kidney transplant, respectively. Transplantation percentage (all organs) decreased from 63% in the West to 43% in the Paris region and mortality increased from 2% in the West to 7% in the Southeast. All tests of inter-regional differences were statistically significant. CONCLUSION: Factors explaining geographic differences related to the background of transplant teams, activity of organ procurement, and severity of patients on the list.

Interleukin-15 production during liver allograft rejection in humans.

BACKGROUND: The activity of interleukin (IL)-15, a cytokine produced by macrophages, is similar to that of IL-2. We investigated whether IL-15 plays a role in liver allograft rejection. METHODS: We evaluated plasma levels and intrahepatic expression of IL-15 in 35 patients after liver transplantation, and then analyzed in vitro the influence of anticalcineurin drugs or steroids on IL-15 production and secretion. Finally, we examined the effects of IL-15 on lymphocyte proliferation in mixed lymphocyte culture in the presence or absence of anticalcineurin drugs or steroids. RESULTS: Plasma levels and in situ expression of IL-15 were enhanced during liver allograft rejection, particularly during steroid-resistant acute rejection and during chronic rejection. In vitro, IL-15 production and secretion were inhibited by neither anticalcineurin drugs nor steroids. Exogenous IL-15 enhanced cell-mediated immune response, and this effect was not inhibited by immunosuppressive drugs. CONCLUSIONS: IL-15 can play a role in the initiation and outcome of acute and chronic rejection. Anti-IL-15 therapy in combination with classic immunosuppression therapy might thus be beneficial in the prevention of acute, and especially chronic, allograft rejection.

Defective inhibition of peripheral CD8+ T cell IL-2 production by anti-calcineurin drugs during acute liver allograft rejection.

BACKGROUND: The aim of this study was to evaluate calcineurin activity and interleukin-2 (IL-2) expression by peripheral blood cells as a means of assessing the immune status of liver transplant recipients. METHODS: Twenty-one patients were studied in a randomized study comparing cyclosporine and tacrolimus as the main immunosuppressive drug. Calcineurin activity was determined after separation of phosphorylated and dephosphorylated products of a calcineurin specific peptide substrate by high performance liquid chromatography(HPLC). Intracellular IL-2 expression was measured by flow cytometry. In 34 additional patients, intracellular IL-2 expression was prospectively measured. RESULTS: Calcineurin activity fell after transplantation. Values were marginally higher in patients with acute rejection (P=0.059). The percentage of IL-2-producing T cells fell after transplantation. This percentage did not differ between patients with and without rejection. In contrast, the proportion of IL-2-producing CD8+ T cells was higher in patients with acute rejection than in patients free of acute rejection (P=0.003). Moreover, pretransplantation IL-2 expression by CD8+ T cells was higher in patients who subsequently developed acute rejection, suggesting that IL-2 production may be constitutively higher in those patients. The results obtained in the 34 additional patients confirmed these results. CONCLUSIONS: These data suggest that quantification of intracellular IL-2 in CD8+ T cells may be a useful index of immune status in liver transplant recipients. Preoperative IL-2 levels might serve to individually tailor the immunosuppressive regimen.

MDR1 gene expression in hepatocellular carcinoma and the peritumoral liver of patients with and without cirrhosis.

P-glycoprotein (P-gp) and MDR1 mRNA expressions were assessed in tumoral and peritumoral specimens from patients with hepatocellular carcinoma (HCC) and in cirrhotic livers without HCC, using immunohistochemistry (C494 monoclonal antibody) and reverse transcription-polymerase chain reaction (RT-PCR) analysis. P-gp overexpression was detected in 24/28 tumoral livers (85%). In the peritumoral liver, staining was strong in cirrhotic nodules, and fainter in non-cirrhotic specimens. P-gp expression was as intense in the cirrhotic specimens free of HCC as in the peritumoral tissue of HCC developing in cirrhotic patients. These results were confirmed by RT-PCR analysis.

Functional results after laparoscopic Heller myotomy for achalasia: A comparative study to open surgery.

BACKGROUND: Prospective studies comparing laparoscopic to open Heller myotomy for esophageal achalasia are lacking. The aim of this study was to compare functional outcome after laparoscopic and open Heller myotomy for esophageal achalasia. METHODS: Eighty-two patients who underwent Heller-Dor myotomy for achalasia, via laparoscopy (n=52) or open surgery (n=30) were recorded prospectively (1993-2002). Median follow-up was 51 (12-111) months. Perioperative functional data were assessed via dysphagia and overall clinical (dysphagia, chest pain, regurgitation, gastroesophageal reflux) scores. RESULTS: In laparoscopy patients, the operative time was longer (145 [95-290] vs 120 [70-230] minutes, P <.0001); the postoperative hospital stay and feeding resumption time was shorter (4 [2-25] vs 7.5 [5-18] days, P <.0001 and 2 [1-15] vs 4 [1-14] days, P <.0001). Three mucosal tears necessitated conversion to open surgery (6%). The rates of " excellent" or " satisfactory" results after laparoscopic and open surgery were 92% (n=48/52) versus 93% (n=28/30), and 83% (n=43/52) versus 83% (n=25/30) on overall clinical score. In both groups, the overall clinical score indicated significant improvement during 12-month follow-up. The laparoscopy and open surgery symptomatic gastroesophageal reflux rates were 10% and 7%, respectively. CONCLUSIONS: Laparoscopic Heller myotomy favorably compares with open surgery regarding dysphagia relief and gastroesophageal reflux rate. Overall clinical score indicates gradual improvement in patient functional status during 12-month follow-up.

Total vascular exclusion of the liver enhances the efficacy of retroviral-mediated associated thymidine kinase and interleukin-2 genes transfer against multiple hepatic tumors in rats.

BACKGROUND: Recent advances in gene transfer technology render gene therapy an attractive treatment of disseminated liver metastases for which other treatments remain disappointing. In this setting, total vascular exclusion of the liver could improve gene transfer to cancer cells and prevent extrahepatic vector spreading during portal infusion of therapeutic genes. We evaluate the efficiency of combined herpes simplex virus type-1 thymidine kinase (HSV1-TK) and interleukin-2 retrovirus-mediated gene transfer through the portal vein, under total vascular exclusion of the liver, in a model of macroscopic multiple liver metastases in rats. METHODS: Multifocal liver metastases were established in BDIX rats with intraportal injection of DHDK12 colon cancer cells. On randomization, rats received either vector-producing cells or saline solution under total vascular exclusion of the liver. Vector-producing cells released retroviral vectors encoding Lac-Z in marking studies or HSV1-TK or interleukin-2 in therapeutic studies. Rats were either killed for pathologic studies, or followed for survival. RESULTS: Total vascular exclusion of the liver markedly improved gene transfer efficacy in marking studies. In therapeutic studies we observed a significant reduction in tumor volume of treated rats compared with untreated controls (2170 +/- 310 mm(3)). Although singular HSV1-TK or interleukin-2 gene transfer showed significant efficacy, the greatest tumor volume regression was observed in rats treated with combined HSV1-TK + interleukin-2 gene therapy (145 +/- 60 mm(3); P =.0001 vs control). This translated into an increased median survival rate compared with either control rats (P =.006) or rats treated with single gene therapy. CONCLUSION: In a rat model, a significant antitumoral effect against macroscopic multifocal liver metastases can be observed after retrovirus-mediated HSV1-TK and interleukin-2 gene transfer through the portal vein under total vascular exclusion of the liver, followed by ganciclovir administration. We believe that this well-tolerated and efficient therapeutic approach deserves clinical evaluation in patients with disseminated colorectal liver metastases.

Major liver resection without clamping: a prospective reappraisal in the era of modern surgical tools.

BACKGROUND: Hemorrhage and transfusions remain the main causes of mortality and morbidity from liver resection. In cases of extended resection, especially performed on diseased liver, ischemia-reperfusion injury related to pedicle clamping may be a significant risk factor of postoperative liver dysfunction. The ideal alternative would be to perform major hepatectomy without clamping and without significant bleeding. STUDY DESIGN: This prospective study aimed to reconsider the risk of major hepatectomy performed without pedicle clamping and under low venous pressure in the light of modern surgical tools. Inclusion criteria were adults requiring a resection of more than three segments on healthy or pathologic livers but not on preoperative documented cirrhosis. RESULTS: Fifty patients, with a mean age of 53 +/- 15 years were included. Twenty-two patients had underlying liver disease. The main indications were colorectal metastases, primary liver tumors, and living donation. Twenty-six right hepatectomies, 17 extended right hepatectomies, and 7 extended left hepatectomies were performed. Unclamping method was successful in 96% of patients on an intention-to-treat basis. Seventy-four percent of patients were not transfused and no patients died. Surgical complication rate was 16% but no complication led to reoperation. Medical complication rate was 20%, including three transient liver dysfunctions. CONCLUSIONS: Major hepatectomy without clamping can be performed safely. The low rate of postoperative liver dysfunction, especially in cases of underlying liver disease, suggests good preservation of the small and diseased remnant liver.

[Conservative management of esophageal perforation after pneumatic dilatation for achalasia]. / Traitement conservateur des perforations oesophagiennes après dilatation pneumatique pour achalasie.

PURPOSE: To assess the results and indications of conservative management of esophageal perforation following pneumatic dilatation for achalasia. PATIENTS AND METHODS: Thirteen esophageal perforations complicating 524 dilatations in 412 patients (3%) were diagnosed by esophagogram. Medical treatment consisted of nasogastric succion, antibiotics and pleural drainage, if necessary. Conservative surgical treatment included left thoracophrenotomy, perforation closure, controlateral myotomy and anterior fundoplication. Surgical decision was based upon clinical and radiological parameters. Functional outcome was assessed by the means of the Eckardt's grading score. RESULTS: Six patients were successfully managed by medical treatment. Seven patients underwent conservative surgery, three of whom after failure of medical treatment. The presence of a pneumomediastinum at initial presentation led to immediate (n=2) or delayed (n=2) surgery in all instances. No patients died. In the surgical group, morbidity consisted of one wound infection, one pleural effusion and one venous thrombosis. One severe chest infection occurred in the medical group. Oral feeding was reintroduced after a median of 10 and 11 days in the surgical and medical groups, respectively. Functional results were satisfactory and similar in both groups. CONCLUSION: Conservative medical or surgical management of oesophageal perforation following pneumatic dilatation is safe, if the diagnosis is done early. Pneumomediastinum at initial presentation seems to predict failure of conservative medical treatment.