Rationale and design of a randomized, double-blind, placebo controlled multicenter trial to study efficacy, security, and long term effects of intermittent repeated levosimendan administration in patients with advanced heart failure: LAICA study.

BACKGROUND Advanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation. METHODS The LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo. RESULTS The main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events. CONCLUSIONS The LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.

Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors.

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption.

Accompagnement thérapeutique : le chemin du suivi à long terme [Patient education: the way for long-term follow up]

L'éducation thérapeutique du patient est maintenant parfaitement intégrée dans les soins. Son champ d'application se situe essentiellement dans le domaine des maladies chroniques pour l'acquisition de compétences dans la gestion du traitement, en coopération avec les professionnels. En médecine ambulatoire, patients et soignants se heurtent actuellement aux difficultés du suivi avec sa part d'incertitude, lassitude et de pression économique. La médecine fondée sur les preuves (EBM) et les différents modèles en psychologie de la santé ne nous éclairent que partiellement le chemin. Un nouveau type de démarche réflexive est en train d'émerger. Cette réflexion devrait placer en son centre la notion de relation thérapeutique : entre science et existence. Nous résumons ici ce processus réflexif en cours d'une équipe interdisciplinaire regroupant sciences humaines, art et médecine. Therapeutic education is now perfectly integrated in caring and medicine. Its field of application is primarily in chronic diseases for the acquisition of competences in the management of treatments, in co-operation with health professionals. In ambulatory medicine, patients and health professionals are currently running up against the difficulties of the long-term follow-up with its part of uncertainty, lassitude and economic pressure. EBM and the various models of health psychology light us only partially the way. A new type of reflexive step is emerging. This way of thinking should place in its center the concept of therapeutic relation: between science and being. We summarize here our reflexive process in the course of an interdisciplinary team gathering social sciences, art and medicine

Long-term outcome of patients after a single interruption of antiretroviral therapy: a cohort study.

BACKGROUND To describe the long term outcome of patients who interrupted highly active antiretroviral therapy (HAART) once, identify the variables associated with earlier need to re-start HAART, and the response when therapy was resumed. A retrospective observational cohort of 66 adult patients with HIV-1 infection who interrupted HAART with a CD4+cell count ≥ 350 cells/μL and undetectable viral load (VL) was performed. The pre-established CD4+ cell count for restarting therapy was 300cells/μL. Cox regression was used to analyse the variables associated with earlier HAART reinitiation. RESULTS The median follow-up was 209 weeks (range, 64-395). Rates of HIV-related or possible HIV-related events were 0.37 (one case of acute retroviral syndrome) and 1.49 per 100 patient-years, respectively. Two patients died after re-starting therapy and having reached undetectable VL. Three patients suffered a sexually transmitted disease while off therapy. Fifty patients (76%) resumed therapy after a median of 97 weeks (range, 17-267). Age, a nadir of CD4+ <250 cells/μL, and a mean VL during interruption of >10,000 copies/ml were independent predictors for earlier re-start. The intention-to-treat success rate of the first HAART resumed regimen was 85.4%. There were no differences by regimen used, nor between regimens that were the same as or different from the one that had been interrupted. CONCLUSIONS Our data suggest highly active antiretroviral therapy may be interrupted in selected patients because in these patients, when the HAART is restarted, the viral and clinical response may be achieved.

Tibio-talar arthrodesis with long anterograde nail after complex open fracture-dislocation of the ankle : P17

Introduction: Posttraumatic painful osteoarthritis of the ankle joint after fracture-dislocation often has to be treated with arthrodesis. In the presence of major soft tissue lesions and important bone loss the technique to achieve arthrodesis has to be well chosen in order to prevent hardware failure, infection of bulky implants or non-union. Methods: We present the case of a 53 year-old biker suffering of a fracture-dislocation of the ankle associated with a mayor degloving injury of the heel. After initial immobilization of the lesion by external fixation in Spain the patient was transferred to our hospital for further treatment. The degloving injury of the heel with MRSA infection was initially treated by repeated débridement, changing of the configuration of the Ex Fix and antibiotic therapy with favourable outcome. Because of the bony lesions reconstruction of the ankle-joint was juged not to be an option and arthrodesis was planned. Due to bad soft-tissue situation standard open fixtion with plate and/or screws was not wanted but an option for intramedullary nailing was taken. However the use of a standard retrograde arthrodesis nail comes with two problems: 1) Risk of infection of the heel-part of the calaneus/nail in an unstable soft tissue situation with protruding nail. And 2) talo-calcaneal arthrodesis of an initially healthy subtalar joint. Given the situation of an unstable plantar/heel flap it was decided to perform anklearthrodesis by means of an anterograde nail with static fixation in the talus and in the proximal tibia. Results:This operation was performed with minimal opening at the ankle-site in order to remove the remaining cartilage and improve direct bone to bone contact. Arthrodesis was achieved by means of an anterograde T2 Stryker tibial nail.One year after the anterograde nailing the patient walks without pain for up to 4 hours with a heel of good quality and arthrodesis is achieved. Conclusion: Tibiotalar arthrodesis in the presence of mayor soft tissue lesions and bone loss can be successfully achieved with antegrade nailing.

Minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation.

Long-term outcomes after kidney transplantation remain suboptimal, despite the great achievements observed in recent years with the use of modern immunosuppressive drugs. Currently, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the cornerstones of immunosuppressive regimens in many centers worldwide, regardless of their well described side-effects, including nephrotoxicity. In this article, we review recent CNI-minimization strategies in kidney transplantation, while emphasizing on the importance of long-term follow-up and patient monitoring. Finally, accumulating data indicate that low-dose CNI-based regimens would provide an interesting balance between efficacy and toxicity.

Influence of gender on long-term prognosis of patients with chronic heart failure seen in heart failure clinics.

BACKGROUND Controversy exists concerning the influence of gender in the prognosis of patients with heart failure and no evidence is available from specific heart failure clinics. HYPOTHESIS Women with ambulatory heart failure are managed differently than men, although their prognosis might be better than men. METHODS AND RESULTS We analyzed the clinical characteristics, complementary test results, treatment, and prognosis in 4720 patients with chronic heart failure seen in 62 specialized clinics forming part of a multicenter registry during a mean follow-up of 40 months. The mean age was 65 +/- 12 years and 71% were men. The men were younger than the women and more often had a history of hyperlipidemia and ischemic heart disease. The men had a more advanced heart failure New York Heart Association (NYHA) functional class (III-IV) than the women and a greater frequency of systolic ventricular dysfunction. The men more often received treatment with beta-blockers, vasodilators, and antiplatelet aggregators as well as higher mean doses as compared with the women. The overall survival after the follow-up was similar for both genders, although the women had lower rates of survival free of admission for heart failure. CONCLUSIONS Despite the mortality of women and men with heart failure being similar, the rate of readmission for heart failure is greater in women in specialized heart failure clinics. These results may be associated with the pharmacological treatment differences observed.

Preinfarction angina prior to first myocardial infarction does not influence long-term prognosis: a retrospective study with subgroup analysis in elderly and diabetic patients.

BACKGROUND AND HYPOTHESIS Although prodromal angina occurring shortly before an acute myocardial infarction (MI) has protective effects against in-hospital complications, this effect has not been well documented after initial hospitalization, especially in older or diabetic patients. We examined whether angina 1 week before a first MI provides protection in these patients. METHODS A total of 290 consecutive patients, 143 elderly (>64 years of age) and 147 adults (<65 years of age), 68 of whom were diabetic (23.4%) and 222 nondiabetic (76.6%), were examined to assess the effect of preceding angina on long-term prognosis (56 months) after initial hospitalization for a first MI. RESULTS No significant differences were found in long-term complications after initial hospitalization in these adult and elderly patients according to whether or not they had prodromal angina (44.4% with angina vs 45.4% without in adults; 45.5% vs 58% in elderly, P < 0.2). Nor were differences found according to their diabetic status (61.5% with angina vs 72.7% without in diabetics; 37.3% vs 38.3% in nondiabetics; P = 0.4). CONCLUSION The occurrence of angina 1 week before a first MI does not confer long-term protection against cardiovascular complications after initial hospitalization in adult or elderly patients, whether or not they have diabetes.

Long-term effectiveness of first-line antiretroviral theraphy in a cohort of HIV-1 infected patients.

Eligibility criteria might explain differences in viral response to combined antiretroviral treatment (cART) between clinical trials and routine care setting. Prospective analysis including HIV-1 infected patients starting cART between January 2004 and December 2009, at Hospital Universitari Vall d’Hebron. Effectiveness evaluated as time to treatment failure (TF), defined as virologic failure, loss to follow-up, death or treatment discontinuation whatever the reason other than switching. Effectiveness month 12, 24 and 36 was 82.9%, 78.5% and 76%, respectively. 57 (24.6%) patients presented TF, mainly due to intolerance or toxicity. Higher risk in patients starting before 2006 and those with protease inhibitor based regimen.

Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice

Invariant NKT (iNKT) cells are potent activators of DCs, NK cells, and T cells, and their antitumor activity has been well demonstrated. A single injection of the high-affinity CD1d ligand alpha-galactosylceramide (alphaGalCer) leads to short-lived iNKT cell activation followed, however, by long-term anergy, limiting its therapeutic use. In contrast, we demonstrated here that when alphaGalCer was loaded on a recombinant soluble CD1d molecule (alphaGalCer/sCD1d), repeated injections led to sustained iNKT and NK cell activation associated with IFN-gamma secretion as well as DC maturation in mice. Most importantly, when alphaGalCer/sCD1d was fused to a HER2-specific scFv antibody fragment, potent inhibition of experimental lung metastasis and established s.c. tumors was obtained when systemic treatment was started 2-7 days after the injection of HER2-expressing B16 melanoma cells. In contrast, administration of free alphaGalCer at this time had no effect. The antitumor activity of the CD1d-anti-HER2 fusion protein was associated with HER2-specific tumor localization and accumulation of iNKT, NK, and T cells at the tumor site. Targeting iNKT cells to the tumor site thus may activate a combined innate and adaptive immune response that may prove to be effective in cancer immunotherapy