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

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.

Short- and long-term effects of litter size manipulation in a small wild-derived rodent.

Iteroparous organisms maximize their overall fitness by optimizing their reproductive effort over multiple reproductive events. Hence, changes in reproductive effort are expected to have both short- and long-term consequences on parents and their offspring. In laboratory rodents, manipulation of reproductive efforts during lactation has however revealed few short-term reproductive adjustments, suggesting that female laboratory rodents express maximal rather than optimal levels of reproductive investment as observed in semelparous organisms. Using a litter size manipulation (LSM) experiment in a small wild-derived rodent (the common vole; Microtus arvalis), we show that females altered their reproductive efforts in response to LSM, with females having higher metabolic rates and showing alternative body mass dynamics when rearing an enlarged rather than reduced litter. Those differences in female reproductive effort were nonetheless insufficient to fully match their pups' energy demand, pups being lighter at weaning in enlarged litters. Interestingly, female reproductive effort changes had long-term consequences, with females that had previously reared an enlarged litter being lighter at the birth of their subsequent litter and producing lower quality pups. We discuss the significance of using wild-derived animals in studies of reproductive effort optimization.

Long-term outcome of congenital aortic valve stenosis: predictors of reintervention.

OBJECTIVES: To evaluate long-term outcome of initial aortic valve intervention in a paediatric population with congenital aortic stenosis, and to determine risk factors associated with reintervention. PATIENTS AND METHODS: From 1985 to 2009, 77 patients with congenital aortic stenosis and a mean age of 5.8±5.6 years at diagnosis were followed up in our institution for 14.8±9.1 years. RESULTS: First intervention was successful with 86% of patients having a residual peak aortic gradient 1 regurgitation increased by 7%. Long-term survival after the first procedure was excellent, with 91% survival at 25 years. At a mean interval of 7.6±5.3 years, 30 patients required a reintervention (39%), mainly because of a recurrent aortic stenosis. Freedom from reintervention was 97, 89, 75, 53, and 42% at 1, 10, 15, 20, and 25 years, respectively. Predictors of reintervention were residual peak aortic gradient (p=0.0001), aortic regurgitation post-intervention >1 (p=0.02), prior balloon aortic valvuloplasty (p=0.04), and increased left ventricular posterior wall thickness (p=0.1). CONCLUSIONS: Aortic valve intervention is a safe and effective procedure for congenital aortic stenosis with excellent survival results. However, rate of reintervention is high and influenced by increased left ventricular posterior wall thickness pre-intervention, prior balloon valvuloplasty, higher residual peak systolic valve gradient, and more than mild regurgitation post-intervention. The study highlights that long-term follow-up is recommended for these patients.

Ross procedure: is the root replacement technique superior to the sub-coronary implantation technique? Long-term results.

There is controversy over the use of the Ross procedure with regard to the sub-coronary and root replacement technique and its long-term durability. A systematic review of the literature may provide insight into the outcomes of these two surgical subvariants. A systematic review of reports between 1967 and February 2013 on sub-coronary and root replacement Ross procedures was undertaken. Twenty-four articles were included and divided into (i) sub-coronary technique and (ii) root replacement technique. The 10-year survival rate for a mixed-patient population in the sub-coronary procedure was 87.3% with a 95% confidence interval (CI) of 79.7-93.4 and 89.1% (95% CI, 85.3-92.1) in the root replacement technique category. For adults, it was 94 vs 95.3% (CI, 88.9-98.1) and in the paediatric series it was 90 vs 92.7% (CI, 86.9-96.0), respectively. Freedom from reoperation at 10 years was, in the mixed population, 83.3% (95% CI, 69.9-93.4) and 93.3% (95% CI, 89.4-95.9) for sub-coronary versus root replacement technique, respectively. In adults, it was 98 vs 91.2% (95% CI, 82.4-295.8), and in the paediatric series 93.3 vs 92.0% (95% CI, 86.1-96.5) for sub-coronary versus root replacement technique, respectively. The Ross procedure arguably has satisfactory results over 5 and 10 years for both adults and children. The results do not support the advantages of the sub-coronary technique over the root replacement technique. Root replacement was of benefit to patients undergoing reoperations on neoaorta and for long-term survival in mixed series.

Morphologic and electroretinographic phenotype of SR-BI knockout mice after a long-term atherogenic diet.

PURPOSE: To evaluate functional and ultrastructural changes in the retina of scavenger receptor B1 (SR-BI) knockout (KO) mice consuming a high fat cholate (HFC) diet. METHODS: Three-month-old male KO and wild-type (WT) mice were fed an HFC diet for 30 weeks. After diet supplementation, plasma cholesterol levels and electroretinograms were analyzed. Neutral lipids were detected with oil red O, and immunohistochemistry was performed on cryostat ocular tissue sections. The retina, Bruch's membrane (BM), retinal pigment epithelium (RPE), and choriocapillaris (CC) were analyzed by transmission electron microscopy. RESULTS: Using the WT for reference, ultrastructural changes were recorded in HFC-fed SR-BI KO mice, including lipid inclusions, a patchy disorganization of the photoreceptor outer segment (POS) and the outer nuclear layer (ONL), and BM thickening with sparse sub-RPE deposits. Within the CC, there was abnormal disorganization of collagen fibers localized in ectopic sites with sparse and large vacuolization associated with infiltration of macrophages in the subretinal space, reflecting local inflammation. These lesions were associated with electroretinographic abnormalities, particularly increasing implicit time in a- and b-wave scotopic responses. Abnormal vascular endothelial growth factor (VEGF) staining was detected in the outer nuclear layer. CONCLUSIONS: HFC-fed SR-BI KO mice thus presented sub-RPE lipid-rich deposits and functional and morphologic alterations similar to some features observed in dry AMD. The findings lend further support to the hypothesis that atherosclerosis causes retinal and subretinal damage that increases susceptibility to some forms of AMD.

Prophylaxis of experimental endocarditis with antiplatelet and antithrombin agents : a role for long-term prevention of infective endocarditis in humans?

BACKGROUND: Infective endocarditis (IE) mostly occurs after spontaneous low-grade bacteremia. Thus, IE cannot be prevented by circumstantial antibiotic prophylaxis. Platelet activation following bacterial-fibrinogen interaction or thrombin-mediated fibrinogen-fibrin polymerization is a critical step in vegetation formation. We tested the efficacy of antiplatelet and antithrombin to prevent experimental IE. METHODS: A rat model of experimental IE following prolonged low-grade bacteremia mimicking smoldering bacteremia in humans was used. Prophylaxis with antiplatelets (aspirin, ticlopidine [alone or in combination], eptifibatide, or abciximab) or anticoagulants (antithrombin dabigatran etexilate or anti-vitamin K acenocoumarol) was started 2 days before inoculation with Streptococcus gordonii or Staphylococcus aureus. Valve infection was assessed 24 hours later. RESULTS: Aspirin plus ticlopidine, as well as abciximab, protected 45%-88% of animals against S. gordonii and S. aureus IE (P < .05). Dabigatran etexilate protected 75% of rats against IE due to S. aureus (P < .005) but failed to protect against S. gordonii (<30% protection). Acenocoumarol was ineffective. CONCLUSIONS: Antiplatelet and direct antithrombin agents may be useful in the prophylaxis of IE in humans. In particular, the potential dual benefit of dabigatran etexilate might be reconsidered for patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality.

Inactivation des pathogènes des produits sanguins labiles: entre enjeux financiers et conséquences possibles à long terme [Pathogen reduction of blood components: from financial issues to possible long-term consequences].

Pathogen inactivation of blood products represents a global and major paradigm shift in transfusion medicine. In the next near future, it is likely that most blood products will be inactivated by various physicochemical approaches. The concept of blood safety will be challenged as well as transfusion medicine practice, notably for donor selection or biological qualification. In this context, it seems mandatory to develop analytical economic approaches by assessing costs-benefits ratio of blood transfusion as well as to set up cohorts of patients based on hemovigilance networks allowing rigorous scientific analysis of the benefits and the risks of blood transfusion at short- and long-term.

Antiviral Immunity in HIV-1 infected long term non-progressors (LTNPs).

Now that the acquired immunodeficiency syndrome (AIDS) epidemic is well into its second decade, it has become evident that a small percentage (approximately 5%) of HIV-infected individuals do not experience progression of HIV disease even after several years of being infected with HIV. These individuals have been designated as 'long term non-progressors' (LTNPs). From a virologic standpoint, these LTNPs have low viral burden in mononuclear cells, but persistent virus replication as manifested by chronic and generally low levels of plasma viremia. From an immunologic standpoint, immune functions including CD8(+) T-cell- and CD4(+) T-cell-mediated functions are preserved. In addition, they show a vigorous humoral immune response. More importantly, lymphoid tissue structure and function are preserved in LTNPs. Despite persistent low-level virus replication and chronic stimulation of the immune system, immune activation is qualitatively and quantitatively different in LTNPs compared to that observed in HIV-infected individuals whose HIV disease has progressed.

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma.

We present the long-term results of 18 chemotherapy relapsed indolent (N = 12) or transformed (N = 6) NHL patients of a phase II anti-CD20 (131)I-tositumomab (Bexxar) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with (131)I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, (131)I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46-70 months.