Severity of chronic experimental Chagas' heart disease parallels tumour necrosis factor and nitric oxide levels in the serum: models of mild and severe disease

Heart tissue inflammation, progressive fibrosis and electrocardiographic alterations occur in approximately 30% of patients infected by Trypanosoma cruzi, 10-30 years after infection. Further, plasma levels of tumour necrosis factor (TNF) and nitric oxide (NO) are associated with the degree of heart dysfunction in chronic chagasic cardiomyopathy (CCC). Thus, our aim was to establish experimental models that mimic a range of parasitological, pathological and cardiac alterations described in patients with chronic Chagas’ heart disease and evaluate whether heart disease severity was associated with increased TNF and NO levels in the serum. Our results show that C3H/He mice chronically infected with the Colombian T. cruzi strain have more severe cardiac parasitism and inflammation than C57BL/6 mice. In addition, connexin 43 disorganisation and fibronectin deposition in the heart tissue, increased levels of creatine kinase cardiac MB isoenzyme activity in the serum and more severe electrical abnormalities were observed in T. cruzi-infected C3H/He mice compared to C57BL/6 mice. Therefore, T. cruzi-infected C3H/He and C57BL/6 mice represent severe and mild models of CCC, respectively. Moreover, the CCC severity paralleled the TNF and NO levels in the serum. Therefore, these models are appropriate for studying the pathophysiology and biomarkers of CCC progression, as well as for testing therapeutic agents for patients with Chagas’ heart disease.

Perioperative anemia management in colorectal cancer patients: A pragmatic approach.

Anemia, usually due to iron deficiency, is highly prevalent among patients with colorectal cancer. Inflammatory cytokines lead to iron restricted erythropoiesis further decreasing iron availability and impairing iron utilization. Preoperative anemia predicts for decreased survival. Allogeneic blood transfusion is widely used to correct anemia and is associated with poorer surgical outcomes, increased post-operative nosocomial infections, longer hospital stays, increased rates of cancer recurrence and perioperative venous thromboembolism. Infections are more likely to occur in those with low preoperative serum ferritin level compared to those with normal levels. A multidisciplinary, multimodal, individualized strategy, collectively termed Patient Blood Management, minimizes or eliminates allogeneic blood transfusion. This includes restrictive transfusion policy, thromboprophylaxis and anemia management to improve outcomes. Normalization of preoperative hemoglobin levels is a World Health Organization recommendation. Iron repletion should be routinely ordered when indicated. Oral iron is poorly tolerated with low adherence based on published evidence. Intravenous iron is safe and effective but is frequently avoided due to misinformation and misinterpretation concerning the incidence and clinical nature of minor infusion reactions. Serious adverse events with intravenous iron are extremely rare. Newer formulations allow complete replacement dosing in 15-60 min markedly facilitating care. Erythropoiesis stimulating agents may improve response rates. A multidisciplinary, multimodal, individualized strategy, collectively termed Patient Blood Management used to minimize or eliminate allogeneic blood transfusion is indicated to improve outcomes.

L'autopsie moléculaire de la mort subite cardiaque: de la salle d'autopsie au cabinet du praticien [Molecular autopsy of sudden cardiac death: from postmortem to clinical approach]

Sudden cardiac death is one of the most prevalent cause of death in developed countries. Its aetiology varies according to the age. Some cardiac diseases may explain sudden death with minimal or no anatomic findings. However, many cardiac diseases, as for example channelopathies and hypertrophic cardiomyopathy have a genetic basis. Therefore genetic analyses (molecular autopsy) are becoming a useful tool in forensic medicine to identify the cause of sudden cardiac death and to improve the early diagnosis of asymptomatic carriers among relatives.

Influencia de la angina preinfarto en la semana previa en la morbimortalidad cardiovascular tardía tras el alta hospitalaria.

The occurrence of angina in the week preceding myocardial infarction is associated with a reduction in cardiovascular complications in the acute phase. However, little is known about it relationship with prognosis after hospitalization (e.g., cardiovascular death and the development of heart failure or ischemic cardiomyopathy). The study included 290 consecutive patients admitted for a first myocardial infarction: 107 (36.9%) had preceding angina while 183 did not. Those with a history of ischemic cardiomyopathy of more than 1 week or structural cardiopathy were excluded. There was no difference in baseline characteristics between the two groups. Moreover, there was no difference in the rates of cardiovascular complications after hospital discharge: cardiovascular death (7% vs. 12.6%; P=.3), heart failure (7.4% vs. 11.6%; P=.2), and myocardial ischemia, including myocardial infarction and unstable angina, requiring hospitalization (41.2% vs. 31.3%; P=.3). The occurrence of angina in the week before a first myocardial infarction did not influence cardiovascular complications after hospital discharge (odds ratio = 0.75 [0.51-1.11]; P=.15).

La maladie de Fabry chez l'adulte: aspects cliniques et progrès thérapeutiques [Fabry disease in adulthood: clinical aspects and therapeutic progress].

INTRODUCTION: Fabry disease is an X-linked recessive abnormality of glycosphingolipid metabolism that is due to deficiency of the lysosomal enzyme alpha-galactosidase A. CURRENT KNOWLEDGE AND KEY POINTS: A majority of hemizygous men develop severe multisystemic disease (classic form), dominated by renal failure, progressive neurological and cardiac involvement. Nevertheless, some affected men retain sufficient enzyme activity and long remain asymptomatic (atypical form); their main manifestation is hypertrophic cardiomyopathy. Female heterozygous carriers are usually asymptomatic; 15% of them, however, have severe involvement of one or several organs. Laboratory, histologic and molecular diagnosis identifies 100% of hemizygous and over 80% of heterozygous subjects. FUTURE PROSPECTS AND PROJECTS: With developments in molecular genetics, it is now possible to produce the human recombinant enzyme alpha-galactosidase A. Two recent studies had proven that this therapeutic approach was able to be clinically and histologically effective in men. In addition, the results of a trial of gene therapy in a Fabry gene knocked-out mouse appear promising.

Experience and intermediate-term results using the Contegra heterograft for right ventricular outflow reconstruction in adults.

OBJECTIVES: The Contegra bioprosthesis (valved heterologous bovine jugular vein) is used for reconstruction of the right ventricular outflow tract (RVOT) in congenital heart malformations and pulmonary valve replacement in different settings. Compared to pulmonary homografts, the Contegra conduit is readily available 'on the shelf'. So far, its use was mainly described in children. The aim of this study is to evaluate the feasibility and the outcome of Contegra graft implantation in the adult. METHODS: Between November 1999 and December 2007, a total of 32 Contegra grafts were implanted in 31 patients (24 men and 7 women), with a mean age of 35.7+/-10.5 years (range 18-54 years). All operations have been completed through median sternotomy with cardiopulmonary bypass. Indications included: Ross procedure for aortic valve disease (n=22); re-operation of corrected Fallot-tetralogy (n=5); isolated pulmonary valve disease (n=2); re-operation of double outlet right ventricle (DORV) (n=1); pulmonary stenosis in congenital dilated cardiomyopathy (DCM) (n=1). Conduit sizes included 22 mm (n=31), 20 mm (n=1). RESULTS: There was no hospital mortality and no valved conduit related early morbidity. In the median follow-up of 38 months (range 1-99 months) of 28 patients there was one late death, not conduit related (total mortality 3.6%). Re-operation for symptomatic graft stenosis was realised in two patients, 7 and 16 months after primo-implantation, corresponding to graft related late morbidity of 7.1%. CONCLUSIONS: In this small review of 32 operations using the Contegra graft for RVOT reconstruction in adult cardiac surgery for different indications, we observed good postoperative mid-term results concerning conduit function. Mean transpulmonary pressure gradients remain low (13.3+/-6.6 mmHg postoperative, 14.5+/-7.9 mmHg at follow-up). The use of the Contegra graft seems to be a good alternative to the homograft with low operative mortality and morbidity. Long-term outcome data are not available and further investigations must be performed to evaluate results.

Duration of untreated psychosis: a proposition regarding treatment definition.

Aim: Duration of untreated psychosis (DUP) refers to the time elapsing between psychosis onset and treatment initiation. Despite a certain degree of consensus regarding the definition of psychosis onset, the definition of treatment commencement varies greatly between studies and DUP may be underestimated due to lack of agreement. In the present study, three sets of criteria to define the end of the untreated period were applied in a first-episode psychosis cohort to assess the impact of the choice of definition on DUP estimation. Methods: The DUP of 117 patients admitted in the Treatment and Early Intervention in Psychosis Program Psychosis in Lausanne was measured using the following sets of criteria to define treatment onset: (i) initiation of antipsychotic medication; (ii) entry into a specialized programme; and (iii) entry into a specialized programme and adequate medication with a good compliance. Results: DUP varied greatly according to definitions, the most restrictive criteria leading to the longest DUP (median DUP1 = 2.2 months, DUP2 = 7.4 months and DUP3 = 13.6 months). A percentage of 19.7 of the patients who did not meet these restrictive criteria had poorer premorbid functioning and were more likely to use cannabis. Longer DUP3 was associated with poorer premorbid functioning and with younger age at onset of psychosis. Conclusion: These results underline the need for a unique and standardized definition of the end of DUP. We suggest that the most restrictive definition of treatment should be used when using the DUP concept in future research.

Extramediastinal surgical problems in heart transplant recipients.

BACKGROUND: As heart transplantation has gained wide acceptance, a growing number of recipients are at risk of experiencing extramediastinal surgical problems. STUDY DESIGN: We retrospectively reviewed our experience in the diagnosis and management of surgical problems occurring in 94 consecutive patients having heart transplantation. During the period of the study, we progressively adopted a policy of low-level immunosuppression, aiming toward monotherapy with cyclosporine. RESULTS: Seventy-four extramediastinal surgical problems developed in 44 of 94 patients (47%). The type of problems were gastrointestinal in 17 of 74 (23%), vascular in 13 of 74 (17.5%), urogenital in 8 of 74 (11%), and neurologic in 4 of 74 (5.5%). There were also 9 of 74 cases of trauma (12%), 9 of 74 skin tumors (12%), and 14 of 74 miscellaneous diseases (19%). Sixty-two surgical diseases occurring in 40 patients required 75 surgical interventions, 11 of them (15%) on an emergency basis. Operations were performed for 12 of 74 neoplasms (16%) and 12 of 74 infectious or potentially infectious diseases (16%). Surgical diseases occurred most commonly within the first 6 months after transplantation (20 of 74; 27%). Complications occurred in 8 of 75 surgical interventions (9%). A high proportion of surgical disease was potentially related to immunosuppressive therapy (37 of 74; 50%) or to transplantation itself (7 of 74; 9%). CONCLUSIONS: Extramediastinal diseases after heart transplantation involve most surgical specialties. Most of them are potentially linked with either the immunosuppressive therapy or the transplantation procedure, supporting our low-level immunosuppression policy. Expectant management is not justified in this population, who withstands operations well both early and late after transplantation.

Can neurally adjusted ventilatory assist (NAVA) improve patient-ventilator interaction? A preliminary study

INTRODUCTION. NAVA is a new spontaneous-assisted ventilatory mode based on thedetection of diaphragmatic electrical activity (Eadi) and its feedback to adjust ventilatorsettings. NAVA uses the Eadi, an expression of the respiratory center's activity, to initiatepressurization, set the level of pressure support and cycle the ventilator into exhalation.Therefore, NAVA should theoretically allow near-perfect synchronization between the patientand the ventilator. However there are few data documenting these effects in intensive carepatients.OBJECTIVES. To determine whether NAVA can improve patient-ventilator synchronycompared to standard pressure support (PS) in intubated intensive care patients.METHODS. Comparative study of patient-ventilator interaction during PS with cliniciandetermined ventilator settings and NAVA with NAVA gain (proportionality factor betweenEadi and the amount of delivered inspiratory pressure) set as to obtain the same peak airwaypressure as the total pressure obtained in PS. A 20 min continuous recording with eachventilatory mode was performed allowing determination of trigger delay (Td), patient neuralinspiratory time (Tin), duration of pressurization by the ventilator (Tiv), excess durationof pressurization (Ti excess = Tiv - Tin/Tin 9 100) and number of asynchrony events byminute: non-triggering breaths, auto-triggering, double triggering, premature and delayedcycling.Results are given in mean ± SD. p is considered significant if\0.05.RESULTS. Preliminary results (mean ± SD): five patients (age 75 ± 12 years, 1 M/4F,BMI 25.7 ± 4.1 kg m-2), two pts with COPD, 1 with restrictive disease, initial settings: PS14.6 ± 1.7 cm H2O, PEEP 6.4 ± 1.5 cm H2O, NAVA gain 2.8 ± 1.3PS NAVA % reduction NAVAversus PSTd (ms) 210.4 ± 63.0 51.8 ± 12.1* 74.5 ± 5.0Ti excess (%) 12.9 ± 19.6 2.2 ± 0.6 70.8 ± 37.8n asynchrony/minute 7.6 ± 6.4 4.1 ± 3.7* 47.5 ± 17.0Respiratory rate (min-1) 16.8 ± 2.6 20.4 ± 4.7 NA* p\0.05CONCLUSION. Compared to standard PS, NAVA improves patient ventilator interaction byreducing Td and the overall incidence of asynchrony events. There is also a strong trend inreducing delayed cycling. This ongoing trial should provide evidence that NAVA can indeedimprove patient-ventilator synchrony in intubated patients undergoing PS.REFERENCE(S). 1. Sinderby C, Navalesi P et al (1995) Neural control of mechanicalventilation in respiratory failure. Nat Med 5(12):1433-1436.2. Colombo D, Cammarota G et al (2008) Physiologic response to varying levels of pressuresupport and neurally adjusted ventilator assist in patients with acute respiratory failure.Intensive Care Med 34(11):2010-2018.

Capacité de travail en cas d'affections pulmonaires

This short review begins by defining some basic medico-legal concepts such as "impairment" and "disability" and gives the corresponding terms in French and German. It is then shown how, in stable obstructive and restrictive respiratory diseases such as COPD and lung fibrosis, the degree of impairment can be assessed on the basis of FEV1 and indices of gas exchange. In the case of bronchial asthma, however, with its typically variable degree of airflow limitation, the amount of reversibility and treatment necessary to achieve optimum bronchodilatation must be taken into account. This can best be done using a score system. Impairment represents a base but in no way equals the final percentage of disability pension or compensation, which are always assessed by the competent administrative authority. However, it is the physician who specifies the amount and type of work an individual patient, with his or her particular degree of disability, can or cannot be expected to do.

The transcriptional repressor REST determines the cell-specific expression of the human MAPK8IP1 gene encoding IB1 (JIP-1).

Islet-brain 1 (IB1) is the human and rat homologue of JIP-1, a scaffold protein interacting with the c-Jun amino-terminal kinase (JNK). IB1 expression is mostly restricted to the endocrine pancreas and to the central nervous system. Herein, we explored the transcriptional mechanism responsible for this preferential islet and neuronal expression of IB1. A 731-bp fragment of the 5' regulatory region of the human MAPK8IP1 gene was isolated from a human BAC library and cloned upstream of a luciferase reporter gene. This construct drove high transcriptional activity in both insulin-secreting and neuron-like cells but not in unrelated cell lines. Sequence analysis of this promoter region revealed the presence of a neuron-restrictive silencer element (NRSE) known to bind repressor zinc finger protein REST. This factor is not expressed in insulin-secreting and neuron-like cells. By mobility shift assay, we confirmed that REST binds to the NRSE present in the IB1 promoter. Once transiently transfected in beta-cell lines, the expression vector encoding REST repressed IB1 transcriptional activity. The introduction of a mutated NRSE in the 5' regulating region of the IB1 gene abolished the repression activity driven by REST in insulin-secreting beta cells and relieved the low transcriptional activity of IB1 observed in unrelated cells. Moreover, transfection in non-beta and nonneuronal cell lines of an expression vector encoding REST lacking its transcriptional repression domain relieved IB1 promoter activity. Last, the REST-mediated repression of IB1 could be abolished by trichostatin A, indicating that deacetylase activity is required to allow REST repression. Taken together, these data establish a critical role for REST in the control of the tissue-specific expression of the human IB1 gene.

Sudden death: ethical and legal problems of post-mortem forensic genetic testing for hereditary cardiac diseases.

Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young. In these cases, genetic testing can be useful and does not require proxy consent if it is carried out at the request of judicial authorities as part of a forensic death investigation. Mutations in several genes are implicated in arrhythmic syndromes, including SCN5A, KCNQ1, KCNH2, RyR2, and genes causing HCM. If the victim's test is positive, this information is important for relatives who might be themselves at risk of carrying the disease-causing mutation. There is no consensus about how professionals should proceed in this context. This article discusses the ethical and legal arguments in favour of and against three options: genetic testing of the deceased victim only; counselling of relatives before testing the victim; counselling restricted to relatives of victims who tested positive for mutations of serious and preventable diseases. Legal cases are mentioned that pertain to the duty of geneticists and other physicians to warn relatives. Although the claim for a legal duty is tenuous, recent publications and guidelines suggest that geneticists and others involved in the multidisciplinary approach of sudden death (SD) cases may, nevertheless, have an ethical duty to inform relatives of SD victims. Several practical problems remain pertaining to the costs of testing, the counselling and to the need to obtain permission of judicial authorities.

The prosecution service function within the spanish criminal justice system

The Spanish judicial system is independent and headed by the Supreme Court. Spain has a civil law system. The criminal procedure is governed by the legality principle--by opposition to the opportunity or expediency principle--which implies that prosecution must take place in all cases in which sufficient evidence exists of guilt. Traditionally, the role of the PPS in Spain has been very limited during the investigative stage of the process. That stage is under the responsibility of the Examining Magistrate (EM). Since the end of the 1980s, a series of modifications has been introduced in order to extend the functions of the PPS. In 1988, the PPS received extended competences which allow them to receive reports of offenses. Upon knowing of an offense (reported or known to have been committed), the PPS can initiate the criminal proceeding. The PPS is also allowed to lead a sort of plea bargain under a series of restrictive conditions and only for some offenses. At the same time, the PPS received extended competences in the juvenile justice criminal proceeding in 2000. With all this said, the role of the PPS has not changed radically and, during the investigative stage of the process, their main role remains the presentation of the accusation, playing a more active role during the trial stage of the proceeding. In this article the national criminal justice system of Spain is described. Special attention is paid to the function of the PPS within this framework and its relationship to police and courts. The article refers to legal provisions and the factual handling of criminal cases.

Image-Derived Input Function from the Vena Cava for 18F-FDG PET Studies in Rats and Mice.

Measurement of arterial input function is a restrictive aspect for quantitative (18)F-FDG PET studies in rodents because of their small total blood volume and the related difficulties in withdrawing blood.

La responsabilité des autorités de surveillance bancaire en Europe : étude comparée du droit suisse et des droits allemand, anglais et français dans le contexte de l'Union européenne

I. Introduction : A. Données du problème : En ce début de XXIe siècle, le nombre d'actions en justice visant à engager la responsabilité des autorités de surveillance des banques, à la suite de faillites bancaires, n'a cessé de croître. Ce contentieux s'inscrit dans une tendance générale de recherche des responsabilités des acteurs chargés du contrôle des entités économiques privées. Les autorités de surveillance bancaire ont-elles l'obligation de répondre, devant la justice, du dommage éventuellement causé dans l'exercice de leur mission et d'en assumer les conséquences financières? C'est ce que tentent d'établir les demandeurs, le plus souvent des déposants lésés, qui, malgré l'existence de mécanismes de garantie des dépôts, n'ont pu recouvrer l'intégralité des sommes déposées auprès de banques défaillantes. Les demandeurs agissent fréquemment en dernier ressort contre l'autorité de surveillance bancaire. Les carences alléguées des autorités de surveillance bancaire constituent les fondements de leurs actions en justice. Plusieurs facteurs peuvent expliquer l'augmentation de ce contentieux : ? La croissance des avoirs financiers. Au sein d'un paysage financier européen caractérisé par l'intégration et l'interdépendance de plus en plus poussées des économies nationales, volume et concentration des avoirs financiers n'ont cessé de croître. ? La formalisation des réglementations prudentielles. La surveillance des banques repose désormais sur un corps de règles détaillé et précis, au niveau national, européen et international. ? Les défaillances bancaires. De telles défaillances ont touché de nombreux Etats ces dernières années: la Bank of Credit and Commerce international (BCCI) dont la faillite a eu des répercussions internationales en 1991, l'établissement Barings au Royaume-Uni en 1995, le Crédit Lyonnais en France en 1992 ou la Spar- und Leihkasse Thun en Suisse en 1991. Cette tendance est cependant paradoxale puisque dans de nombreux Etats européens, comme au Royaume-Uni ou en Allemagne, les autorités de surveillance jouissent d'une protection juridique conférée par la loi, les préservant, théoriquement, de poursuites judiciaires intempestives. Dans d'autres pays, comme en France et en Suisse, c'est le droit général de la responsabilité de l'Etat qui est appliqué de manière restrictive par les juridictions compétentes. Les actions judiciaires devant les juges nationaux comportent également des aspects de droit européen. En effet, depuis 1993 un marché bancaire unique existe en Europe et les demandeurs ont fréquemment invoqué le droit matériel de l'Union européenne à l'appui de leurs prétentions. L'affaire BCCI illustre le type de contentieux auquel doivent faire face le Bundesanstalt für Finanzdienstleistungsaufsicht (BaFin) allemand, la Financial Services Authority (FSA) britannique, la Commission fédérale des banques (CFB) suisse ou la Commission bancaire (CB) française. L'accroissement de ce contentieux prouve que le risque d'engagement de la responsabilité des autorités de surveillance bancaire n'est pas purement théorique.