Importance of relative binding of bisphenol A and bisphenol S to plasma proteins for predicting their in vivo potencies.

Many studies suggest that the potential impact of bisphenol S (BPS) as an endocrine disruptor is comparable to that of bisphenol A (BPA). However, in vitro-to-in vivo and from animal to human extrapolations require knowledge of the plasma free fraction of the active endocrine compounds. The present study aimed to characterise BPA and BPS binding to plasma proteins both in humans and different animal species. The plasma protein binding of BPA and BPS was assessed by equilibrium dialysis in plasma from adult female mice, rats, monkeys, early and late pregnant women as well as paired cord blood, early and late pregnant sheep and foetal sheep. The fraction of free BPA was independent of plasma concentrations and ranged between 4% and 7% in adults. This fraction was 2 to 3.5 times lower than that of BPS in all species except sheep, ranging from 3% to 20%. Plasma binding of BPA and BPS was not affected by the stage of pregnancy, BPA and BPS free fractions representing about 4% and 9% during early and late human pregnancy, respectively. These fractions were lower than the free fractions of BPA (7%) and BPS (12%) in cord blood. Our results suggest that similarly to BPA, BPS is extensively bound to proteins, mainly albumin. The higher fraction of free BPS compared to BPA may have implications for human exposure assessment since BPS free plasma concentrations are expected to be 2 to 3.5 times higher than that of BPA for similar plasma concentration.

Grading mitral regurgitation using 4D flow CMR: Comparison to transthoracic echocardiography.

OBJECTIVES: To determine the 4D Flow Cardiac Magnetic Resonance (CMR) thresholds that achieve the best agreement with transthoracic echocardiography (TTE) for grading mitral regurgitation (MR). METHODS: We conducted a single-center prospective study of patients evaluated for chronic primary MR in 2016-2020. MR was evaluated blindly by TTE and 4D Flow CMR, respectively by two cardiologists and two radiologists with decades of experience. MR was graded with both methods as mild, moderate, or severe. 4D Flow CMR measurements included MR regurgitant volume per beat (RV) and mitral anterograde flow per beat (MF). RF was obtained as the ratio RV/MF. Additionally, MF was compared to left ventricular stroke volume (LVSV) by cine-CMR. RESULTS: We included 33 patients in the initial cohort and 33 in the validation cohort. Inter-observer agreement was excellent for 4D Flow CMR ICC = .94 (95% CI, .86-.97, p < 0.0001). Using recommended TTE thresholds (30 ml, 60 ml, 30%, 50%), agreement was moderate for RV and RF. The best agreement between 4D Flow CMR and TTE was obtained with CMR thresholds of 20 and 40 ml for RV (κ = .93; 95% CI, .8-1) and 20% and 37% for RF (κ = .90; 95% CI, .7-.9). In the validation cohort, agreement between TTE and 4D Flow CMR was good with the optimal thresholds (κ = .78; 95% CI, .61-.94). CONCLUSION: We propose CMR thresholds that provide a good agreement between TTE and CMR for grading MR. Further studies are needed to fully validate 4D-Flow CMR accuracy for primary MR quantification.

Clinical Trial Principles and Endpoint Definitions for Paravalvular Leaks in Surgical Prosthesis.

The VARC (Valve Academic Research Consortium) for transcatheter aortic valve replacement set the standard for selecting appropriate clinical endpoints reflecting safety and effectiveness of transcatheter devices, and defining single and composite clinical endpoints for clinical trials. No such standardization exists for circumferentially sutured surgical valve paravalvular leak (PVL) closure. This document seeks to provide core principles, appropriate clinical endpoints, and endpoint definitions to be used in clinical trials of PVL closure devices. The PVL Academic Research Consortium met to review evidence and make recommendations for assessment of disease severity, data collection, and updated endpoint definitions. A 5-class grading scheme to evaluate PVL was developed in concordance with VARC recommendations. Unresolved issues in the field are outlined. The current PVL Academic Research Consortium provides recommendations for assessment of disease severity, data collection, and endpoint definitions. Future research in the field is warranted.

Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.

BACKGROUND: The efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis. OBJECTIVE: We sought to compare the efficacy and tolerance of pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission. STUDY DESIGN: This was a randomized, open-label trial in 36 French centers, comparing pyrimethamine (50 mg qd) + sulfadiazine (1 g tid) with folinic acid vs spiramycin (1 g tid) following toxoplasmosis seroconversion. RESULTS: In all, 143 women were randomized from November 2010 through January 2014. An amniocentesis was later performed in 131 cases, with a positive Toxoplasma gondii polymerase chain reaction in 7/67 (10.4%) in the pyrimethamine + sulfadiazine group vs 13/64 (20.3%) in the spiramycin group. Cerebral ultrasound anomalies appeared in 0/73 fetuses in the pyrimethamine + sulfadiazine group, vs 6/70 in the spiramycin group (P = .01). Two of these pregnancies were terminated. Transmission rates, excluding 18 children with undefined status, were 12/65 in the pyrimethamine + sulfadiazine group (18.5%), vs 18/60 in the spiramycin group (30%, P = .147), equivalent to an odds ratio of 0.53 (95% confidence interval, 0.23-1.22) and which after adjustment tended to be stronger (P = .03 for interaction) when treatment started within 3 weeks of seroconversion (95% confidence interval, 0.00-1.63). Two women had severe rashes, both with pyrimethamine + sulfadiazine. CONCLUSION: There was a trend toward lower transmission with pyrimethamine + sulfadiazine, but it did not reach statistical significance, possibly for lack of statistical power because enrollment was discontinued. There were also no fetal cerebral toxoplasmosis lesions in the pyrimethamine + sulfadiazine group. These promising results encourage further research on chemoprophylaxis to prevent congenital toxoplasmosis.

[THE ROLE OF THE PLANT ARTEMISIA IN SURVIVAL AND INDUCTION OF APOPTOSIS OF B CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)].

BACKGROUND: The cytotoxic effect of plants such as green tea and turmeric (curcumin) on B chronic lymphocytic leukemia (CLL) cells has been established. The plant Artemisia has been used in China for anti-cancer and anti-malaria applications. In Israel, Artemisia absinthium ("the Chiba") is used to release abdominal pain. In attempts to evaluate the cytotoxic effect of this plant in CLL cells, we prepared a decoction of Artemisia leaves and after filtration used it as an inducer of apoptosis of B CLL cells. METHODS: CLL cells were collected from 7 patients in different stages of the disease. Apoptosis was measured using an annexin based flow cytometry assay. RESULTS: First a viability test showed that 100µl/106 cells was the most effective dilution for killing up to 70% cells after 48 hours of incubation. In these conditions Artemisia induced approximately 75% apoptosis in comparison to 32% in the cultures without Artemisia. CONCLUSIONS: We concluded that decoction of Artemisia absinthium is a potent inducer of in vitro apoptosis of CLL cells. Our results provide a laboratory basis for further clinical application.

Interleukin-17-producing decidual CD4+ T cells are not deleterious for human pregnancy when they also produce interleukin-4.

BACKGROUND: Trophoblast expressing paternal HLA-C antigens resemble a semiallograft, and could be rejected by maternal CD4+ T lymphocytes. We examined the possible role in human pregnancy of Th17 cells, known to be involved in allograft rejection and reported for this reason to be responsible for miscarriages. We also studied Th17/Th1 and Th17/Th2 cells never investigated before. We defined for the first time the role of different Th17 subpopulations at the embryo implantation site and the role of HLA-G5, produced by the trophoblast/embryo, on Th17 cell differentiation. METHODS: Cytokine production by CD4+ purified T cell and T clones from decidua of normal pregnancy, unexplained recurrent abortion, and ectopic pregnancy at both embryo implantation site and distant from that site were analyzed for protein and mRNA production. Antigen-specific T cell lines were derived in the presence and in the absence of HLA-G5. RESULTS: We found an associated spontaneous production of IL-17A, IL-17F and IL-4 along with expression of CD161, CCR8 and CCR4 (Th2- and Th17-type markers) in fresh decidua CD4+ T cells during successful pregnancy. There was a prevalence of Th17/Th2 cells (producing IL-17A, IL-17F, IL-22 and IL-4) in the decidua of successful pregnancy, but the exclusive presence of Th17 (producing IL-17A, IL-17F, IL-22) and Th17/Th1 (producing IL-17A, IL-17F, IL-22 and IFN-γ) cells was found in the decidua of unexplained recurrent abortion. More importantly, we observed that Th17/Th2 cells were exclusively present at the embryo implantation site during tubal ectopic pregnancy, and that IL-4, GATA-3, IL-17A, ROR-C mRNA levels increased in tubal biopsies taken from embryo implantation sites, whereas Th17, Th17/Th1 and Th1 cells are exclusively present apart from implantation sites. Moreover, soluble HLA-G5 mediates the development of Th17/Th2 cells by increasing IL-4, IL-17A and IL-17F protein and mRNA production of CD4+ T helper cells. CONCLUSION: No pathogenic role of decidual Th17 cells during pregnancy was observed. Indeed, a beneficial role for these cells was observed when they also produced IL-4. HLA-G5 could be the key feature of the uterine microenvironment responsible for the development of Th17/Th2 cells, which seem to be crucial for successful embryo implantation.

No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception.

BACKGROUND: The efficacy of preventing perinatal transmission (PT) of human immunodeficiency virus type 1 (HIV-1) depends on both viral load (VL) and treatment duration. The objective of this study was to determine whether initiating highly active antiretroviral therapy (ART) before conception has the potential to eliminate PT. METHODS: A total of 8075 HIV-infected mother/infant pairs included from 2000 to 2011 in the national prospective multicenter French Perinatal Cohort (ANRS-EPF) received ART, delivered live-born children with determined HIV infection status, and did not breastfeed. PT was analyzed according to maternal VL at delivery and timing of ART initiation. RESULTS: The overall rate of PT was 0.7% (56 of 8075). No transmission occurred among 2651 infants born to women who were receiving ART before conception, continued ART throughout the pregnancy, and delivered with a plasma VL <50 copies/mL (upper 95% confidence interval [CI], 0.1%). VL and timing of ART initiation were independently associated with PT in logistic regression. Regardless of VL, the PT rate increased from 0.2% (6 of 3505) for women starting ART before conception to 0.4% (3 of 709), 0.9% (24 of 2810), and 2.2% (23 of 1051) for those starting during the first, second, or third trimester (P < .001). Regardless of when ART was initiated, the PT rate was higher for women with VLs of 50-400 copies/mL near delivery than for those with <50 copies/mL (adjusted odds ratio, 4.0; 95% CI, 1.9-8.2). CONCLUSIONS: Perinatal HIV-1 transmission is virtually zero in mothers who start ART before conception and maintain suppression of plasma VL.

Human cytomegalovirus infection elicits new decidual natural killer cell effector functions.

During the first trimester of pregnancy the uterus is massively infiltrated by decidual natural killer cells (dNK). These cells are not killers, but they rather provide a microenvironment that is propitious to healthy placentation. Human cytomegalovirus (HCMV) is the most common cause of intrauterine viral infections and a known cause of severe birth defects or fetal death. The rate of HCMV congenital infection is often low in the first trimester of pregnancy. The mechanisms controlling HCMV spreading during pregnancy are not yet fully revealed, but evidence indicating that the innate immune system plays a role in controlling HCMV infection in healthy adults exists. In this study, we investigated whether dNK cells could be involved in controlling viral spreading and in protecting the fetus against congenital HCMV infection. We found that freshly isolated dNK cells acquire major functional and phenotypic changes when they are exposed to HCMV-infected decidual autologous fibroblasts. Functional studies revealed that dNK cells, which are mainly cytokines and chemokines producers during normal pregnancy, become cytotoxic effectors upon their exposure to HCMV-infected autologous decidual fibroblasts. Both the NKG2D and the CD94/NKG2C or 2E activating receptors are involved in the acquired cytotoxic function. Moreover, we demonstrate that CD56(pos) dNK cells are able to infiltrate HCMV-infected trophoblast organ culture ex-vivo and to co-localize with infected cells in situ in HCMV-infected placenta. Taken together, our results present the first evidence suggesting the involvement of dNK cells in controlling HCMV intrauterine infection and provide insights into the mechanisms through which these cells may operate to limit the spreading of viral infection to fetal tissues.

HLA-G5 induces IL-4 secretion critical for successful pregnancy through differential expression of ILT2 receptor on decidual CD4⁺ T cells and macrophages.

Successful pregnancy in humans has been associated with production of IL-4 by T cells at the feto-maternal interface. Soluble HLA-G5 produced by trophoblasts potentially controls the decidual T cell cytokine profile. We studied the effect of HLA-G5 on the cytokine profile of purified human macrophages and Ag-specific T cells in vitro. We demonstrated that HLA-G5 increased production of IL-12 by purified peripheral blood macrophages. Although IL-12 production by macrophages is known to induce IFN-γ production by CD4(+) T cells, HLA-G5 increased production of IL-4 but not IFN-γ by CD4(+) T cells after Ag presentation by macrophages. We found that this apparent paradox was due to the differential expression of the ILT2 HLA-G5 receptor on activated T cells and macrophages. This receptor was upregulated in the former and downregulated in the latter after Ag presentation and activation of both cell types. This observation was confirmed in situ, where decidual macrophages and T cells are continuously exposed to HLA-G5 produced locally and activated by trophoblast alloantigens. Freshly isolated decidua basalis macrophages expressed lower levels of ILT2 than peripheral blood macrophages from the same pregnant women. They did not spontaneously produce IL-12, whereas freshly isolated decidual CD4(+) T cells expressed high levels of activation markers (CD25, HLA-DR, and CD69) as well as ILT2 and spontaneously produced IL-4 but not IFN-γ. Therefore, HLA-G5 could be responsible, at least in part, via its interaction with ILT2, for decidual T cell IL-4 production, known to be crucial for successful pregnancy.

Multiple Fibroelastoma: Search and You Will Find.

Fibroelastoma is a rare cardiac tumor. Even more rare is multilocalization of these tumors as well as their residence inside the cardiac chambers. Here, the case is reported of a 46-year-old male with three fibroelastomas of which only two were diagnosed preoperatively. The third tumor was discovered during surgery on the endocardium of the left ventricular wall, 2 cm away from the base of the anterolateral papillary muscle after a thorough examination of the ventricle had been instituted. Emphasis must be placed on the importance of performing such an examination during the excision of fibroelastomas, as a failure to address multiple lesions - although their existence is rare - might expose the patient to dangers of future embolization or reoperation.

Pregnancy after kidney transplantation: outcome and anti-human leucocyte antigen alloimmunization risk.

BACKGROUND: Kidney transplantation increases the chances for pregnancy and live birth for women with end-stage kidney disease. The aims of this study were to describe the outcomes of pregnancies in women with a kidney transplant and to evaluate the impact on anti-human leucocyte antigen (HLA) alloimmunization. METHODS: We analysed 61 pregnancies that occurred in 46 patients after having excluded 10 miscarriages during the first trimester and 10 other pregnancies from which important data were missing. Anti-HLA antibodies were screened using the Luminex assay. RESULTS: Overall, the live birth rate was 83% (94% after exclusion of miscarriages during the first trimester). Pre-eclampsia and gestational diabetes occurred in 26 and 21% of cases, respectively. The use of tacrolimus was an independent predictive factor for gestational diabetes. Twenty-four newborns (42%) were premature (<37 weeks). The median birth weight was 2720 (1040-3730) g. Nine newborns (15%) had low birth weights (<2.5 kg). At least one severe complication occurred in 56% of pregnancies. A high glomerular-filtration rate (GFR) before pregnancy was the sole independent protective factor that avoided a severe complication. Death-censored kidney-allograft survival was 80.4% at 6 years. De novo donor-specific anti-HLA antibodies were detected after only 5.9% of pregnancies: for two women, the father had the same HLA antigens as those from the deceased organ donor. The determination of the HLA of the father before pregnancy can better inform the woman about the possible impact of pregnancy on her kidney-allograft function. CONCLUSIONS: Despite many complications, the outcomes for pregnancy and kidney allografts are good. The risk of anti-HLA alloimmunization was low.

Serum immunoglobulin levels at diagnosis have no prognostic significance in stage A chronic lymphocytic leukemia: a study of 1113 cases from the Israeli CLL Study Group.

OBJECTIVES: Hypogammaglobulinemia, commonly encountered in chronic lymphocytic leukemia (CLL), is one of the main causes of morbidity and mortality; however, its prognostic significance in patients diagnosed in early stages of disease remains uncertain. The aim of this study was to evaluate the predictive power of hypogammaglobulinemia at Bonet stage A. METHODS: Using the database of the Israeli CLL Study Group, we analyzed the relationship between low serum levels of IgG, IgA, and IgM; the presence of paraproteinemia, as well as other well-recognized prognostic markers in CLL; and time to first treatment (TTT) and overall survival. A total of 1113 patients consecutively diagnosed during the last 25 yrs with Binet stage A CLL were evaluated, and baseline information on serum immunoglobulin levels was found in 857 of the cases. RESULTS: Overall survival times correlated with age >65 yr, male gender, the presence of lymphadenopathy, high serum beta 2-microglobulin (b2m), CD38 and ZAP-70 expression, but not with low levels of immunoglobulin or the presence of paraproteinemia. By univariate analysis, patients with low IgA levels had a shorter TTT; however, on multivariate analysis, the presence of lymphadenopathy (P 0.02), b2m (P 0.04), CD38 (P < 0.001), and ZAP-70 (P < 0.001) was the only laboratory parameters with prognostic significance. CONCLUSIONS: In our cohort of patients with early-stage CLL, baseline hypogammaglobulinemia and the presence of paraproteinemia were not found to correlate with prognosis.

Pathogenesis, prevalence, and prognostic significance of cytopenias in chronic lymphocytic leukemia (CLL): a retrospective comparative study of 213 patients from a national CLL database of 1,518 cases.

Utilizing the database of the Israeli CLL Study Group, we investigated the prevalence and prognostic significance of anemia and thrombocytopenia in patients with chronic lymphocytic leukemia (CLL). Of 1,477 patients, 113 had anemia and thrombocytopenia associated with "infiltrative" marrow failure, median survival of 41 and 86 months, respectively. Autoimmune cytopenias were diagnosed in 100 patients, autoimmune hemolytic anemia (AIHA) in 80, and immune thrombocytopenia (ITP) in 31, while 11 had both co-existent. Median survival of patients with AIHA and ITP, from CLL diagnosis, was 96 and 137 months, respectively, but 29 and 75 months from onset of cytopenia. Patients with AIHA from the time of CLL diagnosis had a significantly shorter survival than those without anemia (p < .0001). Survival was similar for patients with AIHA or anemia due to "infiltrative" bone marrow failure (p = .44). The presence of positive antiglobulin test even without hemolysis was associated with worse outcome. Overall survival of patients with ITP and those without cytopenias (p = 0.94) were similar. In conclusion, laboratory or clinical evidence of AIHA has a significant negative impact on the survival of patients with CLL. Outcome for cases with ITP and patients without cytopenias was similar.

TCR-independent killing of B cell malignancies by anti-third-party CTLs: the critical role of MHC-CD8 engagement.

We previously demonstrated that anti-third-party CTLs (stimulated under IL-2 deprivation against cells with an MHC class I [MHC-I] background different from that of the host and the donor) are depleted of graft-versus-host reactivity and can eradicate B cell chronic lymphocytic leukemia cells in vitro or in an HU/SCID mouse model. We demonstrated in the current study that human allogeneic or autologous anti-third-party CTLs can also efficiently eradicate primary non-Hodgkin B cell lymphoma by inducing slow apoptosis of the pathological cells. Using MHC-I mutant cell line as target cells, which are unrecognizable by the CTL TCR, we demonstrated directly that this killing is TCR independent. Strikingly, this unique TCR-independent killing is induced through lymphoma MHC-I engagement. We further showed that this killing mechanism begins with durable conjugate formation between the CTLs and the tumor cells, through rapid binding of tumor ICAM-1 to the CTL LFA-1 molecule. This conjugation is followed by a slower second step of MHC-I-dependent apoptosis, requiring the binding of the MHC-I α2/3 C region on tumor cells to the CTL CD8 molecule for killing to ensue. By comparing CTL-mediated killing of Daudi lymphoma cells (lacking surface MHC-I expression) to Daudi cells with reconstituted surface MHC-I, we demonstrated directly for the first time to our knowledge, in vitro and in vivo, a novel role for MHC-I in the induction of lymphoma cell apoptosis by CTLs. Additionally, by using different knockout and transgenic strains, we further showed that mouse anti-third-party CTLs also kill lymphoma cells using similar unique TCR-independence mechanism as human CTLs, while sparing normal naive B cells.

Three-dimensional transoesophageal echocardiography: how to use and when to use-a clinical consensus statement from the European Association of Cardiovascular Imaging of the European Society of Cardiology.

Three-dimensional transoesophageal echocardiography (3D TOE) has been rapidly developed in the last 15 years. Currently, 3D TOE is particularly useful as an additional imaging modality for the cardiac echocardiographers in the echo-lab, for cardiac interventionalists as a tool to guide complex catheter-based procedures cardiac, for surgeons to plan surgical strategies, and for cardiac anaesthesiologists and/or cardiologists, to assess intra-operative results. The authors of this document believe that acquiring 3D data set should become a 'standard part' of the TOE examination. This document provides (i) a basic understanding of the physic of 3D TOE technology which enables the echocardiographer to obtain new skills necessary to acquire, manipulate, and interpret 3D data sets, (ii) a description of valvular pathologies, and (iii) a description of non-valvular pathologies in which 3D TOE has shown to be a diagnostic tool particularly valuable. This document has a new format: instead of figures randomly positioned through the text, it has been organized in tables which include figures. We believe that this arrangement makes easier the lecture by clinical cardiologists and practising echocardiographers.

Cell surface expression of CD25 antigen (surface IL-2 receptor α-chain) is not a prognostic marker in chronic lymphocytic leukemia: results of a retrospective study of 281 patients.

Using the database of the Israeli CLL Study Group, we investigated the incidence and prognostic significance of CD25 expression on the surface of lymphocytic leukemia cells. Strong CD25 expression was found in 46 (16.4 %) of 281 tested cases and was correlated with the presence of splenomegaly (p = 0.04), expression of CD38 antigen (p = 0.001), and FMC-7 (p = 0.04). Age, gender, Binet stage, circulating lymphocyte count, presence of anemia or thrombocytopenia, atypical cell morphology, serum beta 2-microglobulin level, and ZAP-70 expression did not differ in patients with or without cell surface CD25. There was no correlation between CD25 expression and time to first treatment or overall survival. CD25 expression does not appear to be a prognostic factor in CLL.

Insect-bite-like reaction in patients with chronic lymphocytic leukemia: a study from the Israeli Chronic Lymphocytic Leukemia Study Group.

An insect-bite-like reaction is known to occur in patients with chronic lymphocytic leukemia (CLL). Most of the literature, however, consists of isolated case reports or small case series. The aim of this retrospective study was to review the national experience with insect-bite-like reaction in a large group of patients with CLL. The study cohort of patients with these skin reactions consisted of 48 patients (25 males, 23 females) of mean age 64.8 yr (range 33-89) at skin eruption. Data on clinical, histologic, immunophenotypic, and cytogenetic characteristics, treatment, and outcome were collected from the medical files. Mean time between diagnosis of CLL and appearance of the skin lesions was 3.1 yr (range -4 to 14 yr). The eruption was not related to disease activity or the course of the hematological disease. The eruption preceded the diagnosis of CLL in 10 patients (by 0-4 yr); and followed the diagnosis in 36; in 11 patients, it occurred during therapy for CLL and in nine after therapy. Mean duration of the skin findings was 21.5 months (range 0.3-132). The eruption usually presented in summer, although it occurred also at other times of the year, and predominantly affected the upper and lower limbs, although it also appeared on unexposed areas. Treatment included local ointments, antihistaminics, oral steroids, antibiotics, phototherapy, and dapsone with varying responses. Insect-bite-like reactions is a relatively common and disturbing skin reaction in CLL patients, it may be related to the immune dysregulation accompanying CLL and further exacerbated by external factors, including actual insect bites, chemoimmunotherapy, and pyogenic infection.

TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner.

The hallmark of chronic lymphocytic leukemia (CLL) is the relentless accumulation of mature lymphocytes, mostly due to their decreased apoptosis. CD74 was recently shown to serve as a survival receptor on CLL cells. In this study, we show that stimulation of CD74 with its natural ligand, migration inhibitory factor, initiates a signaling cascade that results in upregulation of TAp63, which directly regulates CLL survival. In addition, TAp63 expression elevates the expression of the integrin VLA-4, particularly during the advanced stage of the disease. Blocking of CD74, TAp63, or VLA-4 inhibits the in vivo homing of CLL cells to the bone marrow (BM). Thus, CD74 and its target genes TAp63 and VLA-4 facilitate migration of CLL cells back to the BM, where they interact with the supportive BM environment that rescues them from apoptosis. These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival.

Bicuspidization of a unicuspid valve using sliding plasty of a rudimentary right coronary cusp.

Unicuspid aortic valve repair relies on the principles of bicuspidization by creating a neo-commissure at 180° from the existing commissure, with pericardial patch interposition. We report a case of a 26-year-old patient with cor triatriatum and a severely regurgitating unicuspid valve. The left atrium membrane was resected. Aortic valve repair was performed creating a neo-commissure using a sliding plasty of the rudimentary right coronary cusp and patch reconstruction of the anterior part of the non-coronary cusp, protected by external subvalvular annuloplasty and hemi-root remodelling. We detail a repair technique of a partial autologous reconstruction approach for bicuspidization.