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Objective The underlying pathophysiology of right ventricular (RV) dysfunction in heart failure with preserved ejection fraction (HFpEF) is still debated. The aim of this study is to assess the prognostic significance of echocardiographic right ventricular abnormalities in HFpEF. Methods We enrolled 150 patients with HFpFE in sinus rhythm and no history of chronic lung disease in this observational study. Over a median follow-up of 18 months, 58 patients (38.6%) reached the end point study of hospitalization for heart failure or death (group 1) and 92 remained asymptomatic (group 2). Results While mean ages, sex-ratio, BMI, creatinine level, left ventricular (LV) ejection fraction, LV and RV dimensions were similar between the 2 groups, group 1 patients compared to group 2, had higher ratio of early mitral diastolic inflow velocity E to early diastolic mitral annular velocity e’ (E/e’ ratio: 17 ± 6 vs. 13 ± 7; P Conclusion In HFpEF patients, right ventricular dysfunction progresses with increasing afterload PA pressures, and is associated with worse outcome.

Background Patients with hypertrophic cardiomyopathy (HCM) are prone to develop atrial fibrillation (AF) due to diastolic dysfunction and left atrial (LA) remodeling. According to guidelines, 48-hour ambulatory ECG is recommended every 12–24 months in stable patients and every 6–12 months in case of LA dimension ≥ 45 mm or if new palpitations. Purpose The aim of this study is to investigate the predictive value of LA speckle tracking in detecting paroxysmal atrial fibrillation in HCM patients with enlarged left atrium. Methods We enrolled 62 patients with HCM in sinus rhythm and LA diameter ≥ 45 mm. All patients had previously underwent 24 or 48-hour ambulatory ECG in the last 12 months without detecting any paroxysmal AF. In this study, all our patients underwent standard echocardiographic with left ventricular (LV) and LA speckle tracking examination followed by 7-days long-term ambulatory ECG monitoring. Results Among 62 patients, 19 patients (30.6%) were diagnosed with asymptomatic paroxysmal AF detected by 7-days long-term ambulatory ECG recorder (group1). In the same conditions, no paroxysmal FA was detected in the remaining 43 patients (group2). Group 1 patients showed no differences from group 2 patients with regards to mean ages, BMI, LV dimensions and ejection fraction, E/e’ ratio and even in LA diameter. However, they had significantly impaired left atrial strain indices with significantly lower LA conduit strain 12.15 ± 3.7% vs.17.34 ± 4.08% (P Conclusion Among HCM patients with enlarged LA, those with impaired LA strain indices were prone to higher risk for paroxysmal FA. Thus, LA strain may provide additional functional information for predicting AF susceptibility and may lead in case of impaired indices to propose prolonged ECG monitoring in order to enhance the detection of undiagnosed AF.

Approximately 19 years ago, Terhorst and colleagues ([1][1]) reported the cloning of the gene encoding a small adaptor protein, signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), named by virtue of its binding to the intracellular tail of the cell surface receptor SLAM.

Introduction L’angioplastie coronaire est un challenge quotidien. Depuis son avenement dans les annees 1980, bon nombre de progres a ete realise notamment grâce aux stents actifs, nous permettant d’etendre les indications d’angioplastie. Il demeure certaines limites, mais quel est le meilleur moment pour referer le patient au chirurgien ? Observation Une patiente de 62 ans, hypertendue, diabetique non insulino-requerante, tabagique active et obese, est adressee au service pour coronarographie diagnostique devant une dyspnee d’effort stade 2 de la NYHA et une scintigraphie myocardique positive en apical. La coronarographie realisee par voie radiale droite 6 French, retrouve un reseau de dominance droite, un atherome ectasiant et une lesion monotronculaire de l’IVA moyenne. Il s’agit d’une lesion tres calcifiee de 10 mm de long. Une premiere tentative d’angioplastie est debutee ad hoc. Nous decidons d’arreter la procedure devant la persistance d’une empreinte lors de l’inflation d’un ballon non compliant de 3,5 mm malgre l’utilisation prealable de fraises d’atherectomie rotative de Rotablator de 1,25 et 1,75 mm. La patiente etant parfaitement stable nous programmons, 3 semaines plus tard, une nouvelle tentative d’angioplastie apres avoir commande le materiel adequat. Nous sommes confrontes a un nouvel echec malgre l’utilisation d’un Rotablator de 2 mm et de Cutting Ballons de 3,5 et 4 mm. Nous decidons alors de tenter une troisieme angioplastie apres avoir commande une fraise de Rotablator de 2,5 mm. Nous realisons au prealable un Coroscanner pour comprendre le mecanisme de cette lesion indilatable. Nous mettons alors en evidence un anneau calcaire de l’IVA moyenne dont la lumiere fait 2 mm. Cette procedure a lieu dans notre centre chirurgical referent. Cette fois nous faisons face a un echec de l’utilisation de la fraise de 2,5 mm, qui ne passe pas dans les sondes de 8 French. La solution vient finalement de l’utilisation d’un Cutting ballon le plus court possible (6 mm de long par 3,5 mm de diametre) mene a haute pression (22 atm) lors d’une inflation prolongee (> 1 minute). Discussion L’utilisation de l’atherectomie rotative ne date pas d’hier puisqu’elle a ete mise au point par D. Auth en 1987. La possibilite de mordancage de la plaque calcaire (epargnant le tissu sain) a l’aide d’une fraise en rotation a tres haute vitesse (180 000 tr/min), recouverte de microparticules de diamant, en fait une arme majeure dans l’abord des lesions resistantes. Neanmoins, il est exceptionnel d’utiliser des fraises de diametre superieur a 1,75 mm, il en resulte un challenge technique supplementaire. De nouveaux outils se developpent dans ces indications, tels que les ballons a double paroi capables de supporter de tres hautes pressions (plus de 30 bars), venant etoffer notre arsenal d’angioplastie. Cependant, il ne faut pas oublier le risque lie a de telles procedures et l’angioplastie coronaire ne saurait remplacer la chirurgie de pontage coronaire. Conclusion Nous presentons un cas d’anneau calcaire stenosant de l’IVA moyenne particulierement resistant. L’emploi de Rotablator de 2 mm et de Cutting ballons courts, portes a hautes pressions, lors d’inflations prolongees nous a permis de proposer a cette patiente une alternative au mono-pontage de l’IVA.

Expression of CD40 on cells involved in the inflammatory response has lead to speculation that CD40 ligation could play an important role in the establishment of the inflammatory response. Upon treatment of wild-type CD40 mice with soluble CD40L-CD8 (sCD40L) fusion protein a pulmonary inflammatory response was induced that was not observed in identically treated CD40 knockout mice. This inflammatory response involved polymorphonuclear leukocyte migration into the alveolar space and the accumulation of alveolar macrophages with up-regulated Ia expression. Treatment of wild-type or IFN-gamma knockout mice with sCD40L induced pulmonary responses that were similar except that fewer neutrophils and macrophages accumulated in the lungs of the IFN-gamma knockout mice. This suggested that IFN-gamma plays a role in sCD40L-induced accumulation of inflammatory cells in the lung. The induction of pulmonary inflammation by exogenous sCD40L supports evidence derived in vitro by others that CD40 ligation can result in inflammatory responses and that sCD40L is a potent inflammagen.

In the current study, we examined whether the combination of tumor vasculature-targeted gene therapy with adeno-associated virus bacteriophage-tumor necrosis factor-α (AAVP-TNF-α) and/or the orally administered LCL161, an antagonist of inhibitors of apoptosis proteins (IAPs), enhanced antitumor efficacy without systemic toxicity. M21 human melanoma xenografts were grown subcutaneously in nude mice. Mice were treated according to one of four treatment regimens: AAVP-TNF-α alone (AAVP-TNF-α plus sodium acetate-acetic acid (NaAc) buffer) via tail vein injection; LCL161 alone (phosphate-buffered saline (PBS) plus LCL161) via oral gavage; AAVP-TNF-α plus LCL161; and PBS plus NaAc Buffer as a control group. Tumor volume, survival and toxicity were analyzed. AAVP trafficking and TNF-α production in vivo were detected on days 7 and 21 by real-time PCR, enzyme-linked immunosorbent assay and immunofluorescence. The levels of apoptosis and activation of caspases were assessed on days 7 and 21 by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) and immunofluorescence assays. Our results showed that the combination of AAVP-TNF-α and LCL161 significantly inhibited tumor growth and prolonged survival in mice with melanoma xenografts. The combination of AAVP-TNF-α and LCL161 was also significantly more effective than either agent alone, showing a synergistic effect without systemic toxicity.

We observe that PBMC from most adults (16 of 18 subjects tested) show a small but significant in vitro proliferative response to a 30-amino acid-long peptide (peptide 2, amino acids 34-63) derived from toxic shock syndrome toxin. By contrast, PBMC from newborn blood and thymocytes do not proliferate to this peptide, and furthermore, peptide 2 did not displace the binding of radiolabeled TSST-1 to MHC class II positive cells, nor did it induce IL-1 beta mRNA in monocytes, indicating that this peptide does not behave as a superantigen. Proliferation of PBMC to peptide 2 could be blocked by anti-HLA-DR, but not by anti-HLA-DP or DQ mAb, suggesting that HLA-DR molecules are the restriction elements for the recognition of this peptide by T cells. This premise was further confirmed by demonstrating that mouse L cells transfected with human HLA-DR, but not HLA-DP or DQ molecules, supported the proliferation of purified T cells to peptide 2. Studies with subjects of known HLA-DR types showed that all types tested are capable of responding to this peptide, PBMC from adults exposed to mycobacterial Ag showed significantly better proliferative response to peptide 2 than unexposed adults. Studies with truncations of this peptide suggest that a "core" region of eight amino acids that is conserved between low m.w. heat shock proteins and peptide 2 may be critical to T cell recognition of this peptide. The universal presentation of peptide 2 by HLA-DR molecules may contribute to the widespread natural immunity observed against toxic shock syndrome toxin.

Expression of CD40 on cells involved in the inflammatory response has lead to speculation that CD40 ligation could play an important role in the establishment of the inflammatory response. Upon treatment of wild-type CD40 mice with soluble CD40L-CD8 (sCD40L) fusion protein a pulmonary inflammatory response was induced that was not observed in identically treated CD40 knockout mice. This inflammatory response involved polymorphonuclear leukocyte migration into the alveolar space and the accumulation of alveolar macrophages with up-regulated Ia expression. Treatment of wild-type or IFN-gamma knockout mice with sCD40L induced pulmonary responses that were similar except that fewer neutrophils and macrophages accumulated in the lungs of the IFN-gamma knockout mice. This suggested that IFN-gamma plays a role in sCD40L-induced accumulation of inflammatory cells in the lung. The induction of pulmonary inflammation by exogenous sCD40L supports evidence derived in vitro by others that CD40 ligation can result in inflammatory responses and that sCD40L is a potent inflammagen.

tre lesmodelesmurins deficients en ADAMTS-13 [2]. In vitro, notre equipe a egalement montre que les plasmas de PTT-AI induisent la degranulation des corps de Weibel–Palade endotheliaux par un mecanisme de mobilisation calcique intracellulaire. D’autres auteurs ayant montre in vitro une action proapoptotique des plasmas de PTT sur l’endothelium [3], nous avons voulu etudier le role eventuel de la blessure calcique au cours de la generation de microvesicules et l’apoptose endotheliale induite par les plasmas de PTT-AI. Patients et methodes.– Nous avons teste l’effet de plasmas PTT-AI en phase aigue de la maladie sur des cellules endotheliales cultivees in vitro en mesurant l’apoptose par differentes techniques (cytometrie de flux, activation de caspase 3) et en quantifiant la microvesiculation par cytometrie de flux. Nous avons egalement etudie le role du calcium et des immunoglobulines G (IgG) dans les mecanismes de souffrance endotheliale. Resultats.– Si nous n’avons pas observe de mort endotheliale par apoptose, les pasmas PTT-AI entrainent, en revanche, la production de grandes quantites de microvesicules endotheliales procoagulantes du fait de l’expresssion de la phosphatidyl-serine et proagregantes car exprimant le facteur von Willebrand a leur surface. La microvesiculation apparait entierement dependante d’un flux calcique d’origine extracellulaire inhibe en presence d’EDTA. De plus, les IgG presentes dans le plasma semblent jouer un role determinant puisque leur elimination par colonne d’affinite inhibe presquecompletement lamicrovesiculation induitepar lesplasmas PTT. Conclusion.– Nos resultats confirment l’importance des flux calciques dans l’activation et la souffrance endotheliales presentes au cours du PTT-AI et identifient pour la premiere fois, le role activateur des IgG contenues dans le plasma des patients. L’extrapolation de ces resultats en pathologie suggere que l’epuration des IgG plasmatiques et l’inhibition des flux calciques intra-endotheliaux pourraient etre 2 strategies interessantes dans le traitement du PTT-AI. References [1] Furlan M, et al. N Engl J Med 1998;339:1578. [2] Motto DG, et al. J Clin Invest 2005;115:2752. [3] Laurence J, et al. Blood 1996;87:3245.

Background The medical care of Jehovah’s Witness patients, because they refuse blood transfusion, becomes problematic in cases of severe life-threatening anaemia. Purpose To describe the case of a patient with severe anaemia who received erythropoietin (EPO) treatment as the result of a literature review. Materials and Methods A 77-year old woman was sent to the emergency department with thoracoepigastric pain, blood clots and vomiting for a week. Cardiac examination revealed a coronary syndrome caused by gastrointestinally-induced anaemia at 5.6 g/dl (haematocrit = 18.9%). On day 3 the haemoglobin fell to 4 g/dl (haematocrit = 14.4%) upon which a treatment with EPO beta at 30,000 IU per week (380 IU/kg/week) associated with high intravenous iron supplementation (300 mg/48 hours) was instituted. After 16 days of treatment haemoglobin (8.9 g/dl) and haematocrit (31.6%) had doubled and clinical improvement was observed. The patient was discharged on day 22 of treatment with a total of 4 EPO injections (haemoglobin = 9.6 g/dl). Results Currently in emergency there is no alternative to transfusion and a higher mortality is linked to a low haemoglobin level. In a multicentre study with 148 patients, Georgopoulos et al, showed the efficacy of EPO, used off-label, administered once weekly, to reduce transfusions. Thirteen recent publications reported experiences with the intravenous or subcutaneous administration of EPO in anaemia treatment. The optimal dose of EPO remains unclear: dosage ranges from 200 μg/week darbepoetin alfa (Gutierrez et al), to 130 IU/kg of EPO three times weekly (Walton et al), to 600 Iu/kg/day for 2 days to 300 IU/kg/day (Cothren et al). After starting treatment the haemoglobin level doubled in 19 days (in an average of 4 days–30 days). Conclusions Our weekly EPO protocol is in the lower targets found in the literature but it appears as effective as other protocols. Significant variability without a major difference in efficacy appears when EPO is used for Jehovah’s Witness patients, but EPO may provide an alternative treatment in life-threatening anaemia, when blood transfusions are not accepted. No conflict of interest.

We observe that PBMC from most adults (16 of 18 subjects tested) show a small but significant in vitro proliferative response to a 30-amino acid-long peptide (peptide 2, amino acids 34-63) derived from toxic shock syndrome toxin. By contrast, PBMC from newborn blood and thymocytes do not proliferate to this peptide, and furthermore, peptide 2 did not displace the binding of radiolabeled TSST-1 to MHC class II positive cells, nor did it induce IL-1 beta mRNA in monocytes, indicating that this peptide does not behave as a superantigen. Proliferation of PBMC to peptide 2 could be blocked by anti-HLA-DR, but not by anti-HLA-DP or DQ mAb, suggesting that HLA-DR molecules are the restriction elements for the recognition of this peptide by T cells. This premise was further confirmed by demonstrating that mouse L cells transfected with human HLA-DR, but not HLA-DP or DQ molecules, supported the proliferation of purified T cells to peptide 2. Studies with subjects of known HLA-DR types showed that all types tested are capable of responding to this peptide, PBMC from adults exposed to mycobacterial Ag showed significantly better proliferative response to peptide 2 than unexposed adults. Studies with truncations of this peptide suggest that a "core" region of eight amino acids that is conserved between low m.w. heat shock proteins and peptide 2 may be critical to T cell recognition of this peptide. The universal presentation of peptide 2 by HLA-DR molecules may contribute to the widespread natural immunity observed against toxic shock syndrome toxin.

9016 Background: Liposarcoma (LS) is a heterogeneous group of tumors comprising 5 pathologic subtypes: well-differentiated (WD), dedifferentiated (DD), myxoid (MY), round cell (RC), and pleomorphic...

Severe combined immunodeficiency disease (SCID) is a congenital disorder of severe B- and T-lymphocyte dysfunction in which several pathogenic mechanisms have been identified. The present study describes a female child with SCID who had a primary defect in the ability of T cells to secrete interleukin 2 (IL-2). B- and T-cell numbers were normal, but their functions were severely deficient. Mitogen and antigen-driven lymphoproliferative responses were diminished but were correctable in vitro with recombinant IL-2 (rIL-2). The patient's phytohemagglutinin-stimulated lymphocytes expressed IL-2 receptors normally. Despite the presence of the gene for IL-2, the patient's cells were grossly deficient in messenger RNA for IL-2 and endogenous IL-2 production. Pokeweed mitogen-driven B-cell differentiation was decreased and was not corrected by the addition of normal T cells to the B cells. Two attempts at immune reconstitution by haploidentical bone marrow transplantation failed. Therapy with rIL-2 (30,000 units/kg, given daily i.v.) resulted in marked clinical improvement as well in improved T-cell functions. The child, now 3 yr old, has been on rIL-2 therapy for 2 yr and receives rIL-2 (30,000 units/kg) three times weekly at home. This case study points to a new direction in the treatment of such disorders with rIL-2.

The serum and urine immunoglobulin concentrations of a patient with congenital nephrotic syndrome of the Finnish type (CNS) were studied during an 11 month period. The serum IgG levels were never higher than 25% and most were below 2% of normal infant values. Serum IgM levels rose to three times normal and IgA concentrations varied. The selective protein index (SPI) showed apparent selective proteinuria (SPI less than 0.06). Intravenous gamma-globulin infusions were carried out to raise serum IgG levels. The infused IgG was initially contained within the intravascular space, but within 30 hours 55% was lost in the urine. Compared to the steady state, the renal clearance of IgG showed a 20-fold increase immediately post-infusion. We conclude that children with CNS should be considered essentially agammaglobulinemic throughout the first year of life and perhaps longer. Intravenous IgG infusions provide only hours of sufficient IgG replacement due to rapid urinary losses and may be detrimental.

The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain.