Use of Pre- and Intensified Postprocedural Physiotherapy in Patients with Symptomatic Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement Study (the 4P-TAVR Study).

BACKGROUND: Physiotherapy prior to open-heart surgery lowers the rate of pneumonia and length of the hospital stay. Pneumonia is a major contributor to short-term mortality following transcatheter aortic valve replacement (TAVR). Hence, we hypothesized that pre- and intensified postprocedural physiotherapy in patients undergoing TAVR might impact the net functional and clinical outcome. METHODS AND RESULTS: The 4P-TAVR study was a prospective, monocentric, randomized trial. The study was designed to compare the efficacy and safety of intensified periprocedural physiotherapy including inspiratory muscle training versus standard postprocedural physiotherapy. Patients were randomized in a 1 : 1 fashion. 108 patients were included and followed up for 90 days after TAVR. While patients in group A (control group: 50 patients, age: 81.7 ± 5.0 years, 52% male) did not receive physiotherapy prior to TAVR, group B (intervention group: 58 patients, age: 82.2 ± 5.82 years, 47% male) participated in intensive physiotherapy. Compared to the control group, patients in the interventional group showed a lower incidence of postinterventional pneumonia (10 [20.0%] vs. 3 [5.1%], p=0.016) and had a 3-day shorter mean hospital stay (13.5 ± 6.1 days vs. 10.1 ± 4.7 days, p=0.02). The primary composite endpoint of mortality and rehospitalization was not different between the groups. CONCLUSION: Intensified physiotherapy is safe and has positive effects on clinical outcomes up to 90 days after TAVR but has no impact on the primary combined endpoint of mortality and rehospitalization. Longer follow-up, a multicenter design, and a higher number of subjects are needed to confirm these preliminary results. This trial is registered with DRKS00017239.

JC polyomavirus nephropathy confirmed by using an in-house polymerase chain reaction method.

We report the case of an isolated JC virus (JCV) infection, without co-infection by polyoma BK virus (BKV), associated with nephropathy 4 years after kidney transplantation. Clinical suspicion followed the observation of a decrease in estimated glomerular filtration rate (eGFR) and a renal allograft biopsy revealing polyomavirus-associated tubulointerstitial nephritis and positivity for SV40. An in-house real-time polymerase chain reaction assay, targeting the presence of JCV and the absence of BKV in biopsy tissue, confirmed diagnosis. Thirteen months after diagnosis, and following therapeutic measures, eGFR remains stable.

Prevention of cytomegalovirus disease in renal transplantation: single-center experience.

Cytomegalovirus (CMV) infection and CMV disease remain important issues in renal transplantation. Incidence depends on individual patient risk. There are different possible strategies for CMV prophylaxis. In our center CMV prevention includes prophylaxis with low-dose valganciclovir for all high-risk recipients; for the remaining patients, valganciclovir is only prescribed when there is evidence of CMV replication. All recipients are monitored for viral replication. We evaluated the results of this preventive strategy in all 135 patients who underwent transplantation between 2006 and 2007 in our center. Average follow-up time was 16 months (6-30 months). Fifty-one recipients (38%) received CMV prophylaxis. The median duration of prophylaxis was 84 days. In 37% of the recipients (50 patients) CMV antigenemia became positive, and were given therapeutic doses of valganciclovir. Of these patients, 32% were high-risk recipients undergoing prophylaxis. CMV infection rate was 40% in the group not receiving prophylaxis. No association was observed between CMV infection and prophylaxis duration. However, 50% of patients who suspended prophylaxis before completion of the first 3 months became infected. There were 3 cases of CMV disease (2.2%). Leukopenia was seen in 34% of patients receiving prophylaxis. Valganciclovir prophylaxis for high-risk patients seems to be effective and safe among subjects who complete the full duration of treatment. Despite CMV-positive antigenemia in 40% of patients not undergoing prophylaxis, pre-emptive therapy with valganciclovir was effective to prevent CMV disease, but close monitoring is essential for disease prevention.

The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner.

The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes.

Hypoxia stimulus: An adaptive immune response during dendritic cell maturation.

The 'injury hypothesis' in organ transplantation suggests that ischemia-reperfusion injury is involved in the adaptative alloimmune response. We previously found that a strong immune/inflammatory response was induced by ischemia during kidney transplantation in rats. We show here that immature dendritic cells (DCs) undergo hypoxia-mediated differentiation comparable to allogeneic stimulation. Hypoxia-differentiated DCs overexpress hypoxia inducible factor-1alpha (HIF-1alpha) and its downstream target genes, such as vascular endothelial growth factor or glucose transporter-1. Rapamycin attenuated DC differentiation, HIF-1alpha expression, and its target gene expression in a dose-dependent manner along with downregulated interleukin-10 secretion. Coculture of hypoxia-differentiated DCs with CD3 lymphocytes induced proliferation of lymphocytes, a process also neutralized by rapamycin. Furthermore, in vivo examination of ischemia-reperfusion-injured mouse kidneys showed a clear maturation of resident DCs that was blunted by rapamycin pretreatment. Our results suggest that hypoxia is a central part of the 'injury hypothesis' triggering DC differentiation under hypoxic conditions. Rapamycin attenuates the hypoxic immune-inflammatory response through inhibition of the HIF-1alpha pathway.

Intravenous Immunoglobulin and Rituximab in HLA Highly Sensitized Kidney Transplant Recipients.

INTRODUCTION: HLA-sensitized patients are penalized both in the access to kidney transplantation (KT) and, once transplanted, in the incidence of rejections and long-term allograft survival despite aggressive induction and maintenance therapy. METHODS: This study retrospectively evaluates the impact of combining T- and B-cell-depleting agents and intravenous immunoglobulin for induction therapy in 45 highly sensitized KT patients (anti-panel reactive antibodies >60%, positive flow cytometry crossmatch or donor specific antibodies at the time of transplantation). The outcome data included the occurrence of biopsy-proven acute rejection, new-onset proteinuria, development of leukopenia, incidence of poliomavirus infection (BK or JC virus), fungal or bacterial infection after KT, de novo neoplasia, graft function, graft loss, or death with functioning KT. RESULTS: The average panel reactive antibody was 62.5%; 41 patients (91.1%) had ≥3 HLA mismatches with the donor and 91.1% of patients had class I or II anti-HLA antibodies. Fourteen patients (31.1%) presented pre-KT donor-specific antibodies and 6 patients (13.3%) had a positive flow cytometry cross-match at the time of transplantation. The incidence of acute rejection in the first 6 months was 24.4% and the cumulative incidence was 37.8%. Two patients were diagnosed with leukopenia in the first 6 months after KT. Two patients (4.5%) had cytomegalovirus disease, 17 patients (37.8%) were diagnosed with bacterial infections. Cutaneous neoplasms were identified in 5 patients (11.1%) and solid tumors in 4 (8.9%). The death-censored graft survival was 100% in the first 6 months and 93.5% at the last evaluation. Patient survival in the same periods was 97.8% and 93.3%, respectively. CONCLUSIONS: Induction immunosuppressive therapy with intravenous immunoglobulin and rituximab is effective; outcomes demonstrate an excellent patient and allograft survival and allograft function over the follow-up period.

Hepatitis C Virus Eradication in Kidney Transplant Recipients: A Single-Center Experience in Portugal.

INTRODUCTION: Hepatitis C (HCV) is a major cause of liver impairment post-kidney transplantation (KT). Anti-HCV direct-acting antivirals (DAA) made viral eradication possible. METHODS: We performed a retrospective review of KT patients (n = 23) who received DAA at our hospital. Sustained viral response (SVR) was defined as absence of viral detection 12 weeks after cessation of therapy. RESULTS: From 1985 to September 2017, 1440 patients underwent transplantation at Hospital Santa Cruz. From a total of 32 HCV RNA+ KT recipients on follow-up, we describe the first 23 patients treated with DAA. They were 56.7 ± 9.1 years old; 22 were white, 52.2% were males, they underwent transplantation 18.8 ± 9.0 years ago, and 13 had genotype 1B, 21 were naïve, and 9 had stages F3/F4. All but 2 patients, treated with grazoprevir/elbasvir, received sofosbuvir (18 with ledispasvir, 2 with daclastavir, and 4 with simultaneous ribavirin). Pretreatment, intra-treatment, and post-treatment creatinine clearances were 61.4, 60.6, and 60.7 mL/min/1.73 m2, respectively (not significant [NS]). Cyclosporine A was the basis of immunosuppression in the majority [(n = 14); pretreatment and intra-treatment levels were 79.5 ± 23.0 and 91.8 ± 26.0 ng/mL, respectively (P = .08)]; tacrolimus (n = 8) and mammalian target of rapamycin (mTOR) levels (n = 5) were also similar. One patient interrupted ribavirin after 7 weeks due to anemia; all other patients completed the treatment course without major side effects. Only 3 patients presented positive viral RNA at the fourth week of treatment and SVR was achieved in 100% of the patients 12 weeks after treatment. CONCLUSIONS: DAA therapy was well tolerated and effective in 100% of our treated patients, without significant impact on the renal function or on the immunosuppression.

HCV-infected Renal Transplant Recipients: Our Experience before the Availability of New Antiviral Drugs.

BACKGROUND: Natural history of HCV-infected renal transplant recipients is about to change with the invention of new drugs available for the treatment of HCV. OBJECTIVE: To analyze the evolution of renal transplant recipients infected with HCV in 30 years of activity of a Renal Transplantation Unit. METHODS: We studied 1334 patients who underwent renal transplantation between 1985 and 2015. RESULTS: 189 (14.2%) of these 1334 were found HCV seropositive. 60 were HCV RNA-positive for >6 months. 5 died with a functioning graft; 19 lost their graft and resumed dialysis. Most of the rejections occurred within the first year of the transplantation and none resulted in immediate loss of the graft. In post-transplantation period, 14 patients developed clinical hepatic disease, 10 manifested new-onset diabetes after transplantation, and 4 had de novo neoplasia, none of them had hepatocellular carcinoma. The outcomes of the different variables analyzed were similar between patients with HCV-infection and those with HCV and HBV co-infection. The median survival time was 13.4 (95% CI: 10.7-16.1) years; the median survival time of patients without HCV infection was 14.6 (95% CI: 13.8-15.4) years (p=0.23). CONCLUSION: In the era before the availability of new anti-HCV drugs, our experience with HCV-infected renal transplant recipients revealed similar post-transplantation complications, graft and patient survival as those not infected with HCV.

Kidney Graft Leiomyosarcoma: A Case Report.

BACKGROUND: Kidney transplant (KT) recipients have a higher incidence of malignancy than the general population. Smooth muscle tumors (SMT), including leiomyosarcoma, are rare in kidney transplant recipients, and most cases are associated with Epstein-Barr virus (EBV) infection. CASE REPORT: A 57-year-old man received a deceased donor kidney transplant at the age of 53 years, with 5 human leukocyte antigen (HLA) mismatches. Before the transplantation, the patient was IgG positive for EBV viral capsid antigen (VCA), negative for IgM EBV VCA, and also negative for IgG EBV nuclear antigen (EBNA), suggesting a prior EBV infection. He received immunosuppressive induction with basiliximab, and maintenance with tacrolimus, mycophenolate mofetil, and prednisolone. Two years after transplantation, he had an acute cellular rejection episode treated with methylprednisolone. An increased graft size was found 4 years after transplantation. A computed tomographic scan showed 3 solid tumors involving the renal graft with extension to the perinephric fat; no secondary localizations were found. A nephrectomy of the graft was performed. The histologic diagnosis was a high-grade leiomyosarcoma. In situ hybridization for EBV was negative. Nine months after nephrectomy, local recurrence was diagnosed. The surgical approach was unsuccessful, and the patient died after a brief period. CONCLUSION: Kidney leiomyosarcoma is a very rare clinical condition. Most of these neoplasms that arise in transplanted recipients are associated with EBV in tumor tissue. Only one case of renal graft leiomyosarcoma without EBV RNA in the tumor has been previously reported.

Application of stable carbon isotope analysis to the detection of 17beta-estradiol administration to cattle.

The use of anabolic agents in food producing animals is prohibited within the EU since 1988 (96/22/EC directive). The control of the illegal use of natural steroid hormones in cattle is still an exciting analytical challenge as far as no definitive method and non-ambiguous analytical criteria are available. The ability of gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) to demonstrate the administration of 17beta-estradiol to bovine has been investigated in this paper. By comparison of 13C/12C isotopic ratio of main urinary estradiol metabolite, i.e. 17alpha-estradiol, with two endogenous reference compounds (ERCs), i.e. dehydroepiandrosterone (DHEA) and 5-androstene-3beta,17alpha-diol, the differentiation of estradiol metabolite origin, either endogenous or exogenous, has been proved to be achievable. After treatment, the delta(13)C(VPDB)-values of 17alpha-estradiol reached -27 per thousand to -29 per thousand, whereas delta13CVPDB-values of DHEA remained between -13 per thousand and -20 per thousand depending on the diet, maize and grass, respectively. A significant difference of delta13CVPDB between ERCs and 17alpha-estradiol was measurable over a period of 2 weeks after estradiol ester administration to the animal.

Renal Transplantation in HIV-Infected Patients: The First Portuguese Review.

INTRODUCTION: With the introduction of combination antiretroviral therapy (cART), prognosis of human immunodeficiency virus (HIV) infection has been improved and kidney transplantation (KT) in HIV-positive patients became possible. METHODS: We reviewed the demographic, clinical, laboratory, and therapeutic data of all the HIV-infected patients who underwent KT between 2009 (first KT in Portugal in a HIV-infected patient) and May 2014. Case accrual was through all Portuguese KT centers where a KT in an HIV-infected patient was performed. Patients were transplanted following the American and Spanish guideline recommendations that included maintenance on cART, undetectable plasma HIV RNA copies, and absolute CD4 counts of ≥ 200 cells/µL in the last 6 months. RESULTS: Fourteen KT were performed on men and 3 on women. The mean age of patients at the time of transplantation was 49.9 ± 11.7 years. HIV status was known for 12 ± 5 years. Eight patients had AIDS in the past and all patients received grafts from deceased donors. Twelve patients (64.7%) underwent induction therapy with basiliximab and 2 patients experienced early graft loss. In 2 patients, humoral rejection was diagnosed and in 3 patients, cellular rejection. Two patients died and an additional patient had early graft loss. CONCLUSION: KT is a possible, but challenging, renal replacement therapy in selected HIV-positive patients. Even in those with AIDS criteria in the past, when the disease is controlled, and after the reconstitution of the immune system with cART, KT can be performed. Nevertheless, the risk-benefit ratio for each patient needs to be taken in consideration.

Dedicated immunosensing of the mouse intestinal epithelium facilitated by a pair of genetically coupled lectin-like receptors.

The integrity of the intestinal epithelium is constantly surveyed by a peculiar subset of innate-like T lymphocytes embedded in the epithelial cell layer, hence called intestinal intraepithelial lymphocytes (IELs). IELs are thought to act as "first-line" sentinels sensing the state of adjacent epithelial cells via both T-cell receptors and auxiliary receptors. Auxiliary receptors modulating IEL activity include C-type lectin-like receptors encoded in the natural killer gene complex such as NKG2D. Here, we report that the CTLR Nkrp1g is expressed by a subpopulation of mouse CD103(+) IELs allowing immunosensing of the intestinal epithelium through ligation of the genetically coupled CTLR Clr-f that is almost exclusively expressed on differentiated intestinal epithelial cells (IECs). Most of these Nkrp1g-expressing IELs exhibit a γδTCR(bright)Nkg2a(-) phenotype and are intimately associated with the intestinal epithelium. As Clr-f expression strongly inhibits effector functions of Nkrp1g-expressing cells and is upregulated upon poly(I:C) challenge, Clr-f molecules may quench reactivity of these IELs towards the epithelial barrier that is constantly provoked by microbial and antigenic stimuli. Altogether, we here newly characterize a genetically linked C-type lectin-like receptor/ligand pair with a highly restricted tissue expression that apparently evolved to allow for a dedicated immunosurveillance of the mouse intestinal epithelium.

Body composition and energy expenditure in thyroidectomized patients during short-term hypothyroidism and thyrotropin-suppressive thyroxine therapy.

Thyroid hormone levels are a major determinant of energy balance and are thought to modify body composition by their effects on metabolism of lipids, carbohydrate and protein. The present study evaluates changes of body composition and basal energy expenditure (BEE) in thyroidectomized patients studied during short-term profound hypothyroidism while off all thyroid hormone before diagnostic whole-body (131)I-imaging and while on thyrotropin-suppressive thyroxine therapy. Basal energy expenditure was assessed by indirect calorimetry, and four-point body impedance analysis was used to estimate body composition. Patients were compared with healthy controls matched with respect to sex, age, height and weight. Compared to healthy controls the percentages of body water and body cell mass were significantly lower while the percentage of fat was significantly higher in patients during short-term hypothyroidism. Weight did not change significantly when patients were put on thyroxine treatment, but body fat (-0.95 +/- 2.25 kg, p < 0.01) decreased while body water (+0.94 +/- 1.31 kg, p < 0.01) and body cell mass (+0.9 +/- 2.5 kg, p < 0.05) increased. With thyroxine replacement, body composition was not significantly different between patients and controls. Compared to healthy controls, BEE was significantly lower in patients without thyroxine replacement (5265 +/- 766 kJ/24h vs 6362 +/- 992 kJ/24h; p < 0.001). With thyroxine treatment, BEE increased (6492 +/- 967 kJ/24h) but was not significantly different from the controls (p > 0.05). Neither body composition nor BEE was significantly different in a subgroup of thyroxine-treated patients with free triiodothyronine or thyroxine values above the normal range. In conclusion, both body composition and energy expenditure showed significant changes when patients were deprived of thyroid hormone. However, no evidence of excess metabolic effects of thyroid hormone during thyrotropin-suppressive thyroxine therapy was found.

Uremic bleeding: pathogenesis and therapy.

BACKGROUND: We reviewed current understanding of the pathophysiology of the uremic bleeding diathesis and discuss accepted therapeutic interventions that minimize the risk of bleeding in the uremic patient. METHODS: Computerized literature searches and references from previous publications, including articles describing original research and reviews pertaining to the pathophysiology of and clinical approach to uremic bleeding. RESULTS: The most common hemorrhagic manifestations in uremia are prolonged bleeding from puncture sites; nasal, gastrointestinal and genitourinary bleeding; and subdural hematomas. The most useful clinical laboratory test to assess both bleeding risk and response to therapy is bleeding time. It correlates better with clinical bleeding complications than indices of azotemia (eg, blood urea nitrogen [BUN], creatinine) or in vitro platelet aggregation tests. A low hematocrit is also correlated with increased bleeding risk. Anemia plays an important role in the bleeding diathesis of uremia and its correction with red cell transfusions or human recombinant erythropoietin is critical. Anticoagulation during hemodialysis may transiently exacerbate the bleeding diathesis. Hemodialysis and peritoneal dialysis improve the hemostatic defect and renal transplantation totally corrects it. Cryoprecipitate has been largely replaced by desmopressin acetate, which acts promptly (in less than 1 hour) but has a short duration of action (hours) and exhibits tachyphylaxis. Conjugated estrogens are slower in the onset of action (about 6 hours) but their effect lasts for about 2 weeks. CONCLUSIONS: The pathophysiology of the bleeding diathesis of uremia is complex and incompletely understood but useful clinical tests and therapies have evolved empirically. Broadly available dialysis and the advent of erythropoietin are likely to reduce the magnitude of this problem.

Human herpes virus-8 serology and DNA analysis in recipients of renal allografts showing Kaposi's sarcoma and their respective donors.

Kaposi's sarcoma (KS) developed among 11 of 416 renal allograft recipients transplanted between 1985 and 2000. Only 3 among 364 Caucasian recipients developed KS, while it affected 8 of 52 Black patients, all of whom had been born in African countries (P <.001). All patients had their immunosuppression reduced; two also received daunorubicin and one received electrotherapy. Three patients developed accelerated renal allograft dysfunction, probably due to the reduced immunosuppression. Remission of KS was observed in seven patients, while lesions stabilized or improved partially in the other four. After resuming dialysis 2 of 11 patients died; both were in KS remission. Human herpes virus-8 (HHV-8) serology and DNA analysis was evaluated in sera obtained from seven donors: all were negative. Conversely, among eight sera collected pretransplant from the nine living recipients, HHV-8 IgG was detected in six and DNA was present in one. HHV-8 IgG was expressed in all patients (9/9) at some point posttransplant; DNA was detected in three patients. Therefore, the robust ethnic predisposition to KS was associated with a high pretransplant prevalence of HHV-8 among African recipients. Although some seroconversions were detected posttransplant, there was no evidence for donor-to-recipient transmission.

Identification of IRF1 as critical dual regulator of Smac mimetic-induced apoptosis and inflammatory cytokine response.

Smac (second mitochondria-derived activator of caspase) mimetics are considered as promising anticancer therapeutics and used to induce apoptosis by antagonizing inhibitor of apoptosis proteins, which are often abundantly expressed in cancer cells. Here, we identify interferon regulatory factor 1 (IRF1) as a novel critical regulator of Smac mimetic BV6-induced apoptosis and proinflammatory cytokine secretion with impact on the immune response. IRF1 knockdown rescues cells from BV6-induced apoptosis and attenuates BV6-stimulated upregulation of tumor necrosis factor-α (TNFα), indicating that IRF1 mediates BV6-triggered cell death, at least in part, by inducing TNFα. This notion is supported by data showing that exogenous supply of TNFα restores BV6-induced cell death in IRF-knockdown cells. Interestingly, IRF1 selectively controls the induction of nuclear factor-κB (NF-κB) target genes, as IRF1 depletion attenuates BV6-stimulated upregulation of TNFα and interleukin-8 (IL-8) but not p100 and RelB. Concomitant knockdown of IRF1 and p65 cooperate to inhibit BV6-induced cell death, implying a cooperative interaction of IRF1 and NF-κB. In addition, IRF1 silencing hampers TNFα induction by TNFα itself as an another prototypical NF-κB stimulus. Importantly, IRF1 depletion impedes BV6-stimulated secretion of additional proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IL-6 and monocyte chemoattractant protein-1, and migration of primary monocytes to BV6-treated tumor cells. In conclusion, this identification of IRF1 as a dual regulator of BV6-induced apoptosis and inflammatory cytokine secretion provides novel insights into determinants of sensitivity towards Smac mimetic and possible implications of Smac mimetic treatment on tumor microenvironment and immune response.

The role of TRKA signaling in IL-10 production by apoptotic tumor cell-activated macrophages.

Tumor-associated macrophages (TAMs) are a major supportive component within neoplasms. Mechanisms of macrophage (MΦ) attraction and differentiation to a tumor-promoting phenotype, which is characterized by pronounced interleukin (IL)-10 production, are under investigation. We report that supernatants of dying cancer cells induced substantial IL-10 release from primary human MΦs, dependent on signaling through tyrosine kinase receptor A (TRKA or neurotrophic tyrosine kinase receptor type 1 (NTRK1)). Mechanistically, sphingosine-1-phosphate (S1P) release from apoptotic cancer cells triggered src-dependent shuttling of cytosolic TRKA to the plasma membrane via S1P receptor signaling. Plasma membrane-associated TRKA, which was activated by constitutively autocrine secreted nerve growth factor, used phosphatidylinositol 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase (MAPK) signaling to induce IL-10. Interestingly, TRKA-dependent signaling was required for cytokine production by TAMs isolated from primary murine breast cancer tissue. Besides IL-10, this pathway initiated secretion of IL-6, tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), indicating relevance in cancer-associated inflammation. Our findings highlight a fine-tuned regulatory system including S1P-dependent TRKA trafficking for executing TAM-like cell function in vitro as well as in vivo.

Candida species contamination of preservation fluid-outcome of renal transplantation in 6 patients.

BACKGROUND: Fungal infections are a rare but important cause of morbidity and mortality in kidney transplantation. Fungal contamination of the kidney preservation fluid may, sometimes, be the cause of these infections. However, the clinical consequences of fungal contamination of this fluid are not completely understood and literature on this topic is controversial. The purpose of this study was to determine the incidence of preservation fluid contamination by fungi and its clinical consequences. METHODS: From June 2010 to September 2011, a prospective cohort analysis was conducted at our center, enrolling all patients who received a renal allograft and whose perfusion fluid was analyzed for microbiology sterility. Patients with perfusion fluids positive for fungi were further studied: the patients' status was assessed during regular visits and data were recorded, including clinical characteristics, infections, graft function, immunosuppressive regimen and outcomes. RESULTS: Microbiologic, cultures of 70 kidney perfusion fluids using specific mycologic media, obtained from 74 cadaveric renal transplants (4 fluids were unsuitable for analysis), were evaluated. Six samples were positive for yeasts (8.6%), with 4 isolates of Candida albicans and 2 isolates of Candida glabrata. Four patients had no evidence of fungal infection during the follow-up period (median 321 days); conversely, 2 patients developed severe mycotic vascular complications leading to transplantectomy. CONCLUSIONS: Perfusion fluid contamination by fungi is an elusive situation that can lead either to an unremarkable clinical course or to graft loss life-threatening situations. Routine culture of kidney perfusion fluid is critical for prompt diagnosis and early implementation of appropriate treatment.

New law of renal transplantation in Portugal associated with more acute rejection episodes and higher costs.

The new law implemented in August 2007 changed the criteria to select renal transplantation (RT) candidates in Portugal, favoring hyperimmunized subjects and those on the waiting list for a longer time, making human leukocyte antigen (HLA) compatibilities less important. The authors compared patients who received a deceased donor kidney between 2005 and 2010. Patients were divided in group A who underwent transplantation before August 2007 (n = 132) and group B (n = 125) after that date. We considered a value of P < .05. Overall mean age at RT was 46.6 ± 13.9 years with 58.8% men, 88% on hemodialysis (HD), with a mean dialysis time of 82.8 ± 119 months. Also, 10.5% of patients underwent a previous transplantation. The mean follow-up was 35 ± 17.1 months. Group B showed significant adverse differences, including dialysis time (50.9 vs. 117 months), length of hospitalization (14.4 vs. 23.2 days), need for HD (1 vs. 3.4 days), HLA match (3.3 vs. 1.4 compatibilities), previous sensitization (4.4% vs. 21.7%), acute rejection episodes in the 1st year (23% vs. 37%), greater use of immunosuppressive drugs, higher costs of induction therapy (2790 vs 4360ϵ), and greater costs of drugs during first hospitalization (3456 vs. 7144ϵ). Among the 16 subjects who lost their grafts, 7 were in group A (3 in the first year) and 9 in group B all in the first year. There was a 5.1% decrease in graft survival at 12 months (P = .07). Univariate analysis showed an association of acute rejection episodes with HLA mismatches, hyperimmunized patients, absence of immediate graft function, hospitalization time, longer HD need, and higher creatinine level at months 1, 2, 3, and 6. Multivariate analysis revealed acute rejection episodes to be associated with a lower number of HLA compatibilities (odds ratio = 0.65; 95% confidence interval, [0.46-0.9]). Application of the law has led to a greater number of acute rejection episodes in the first year and increased costs.