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Find video protocols related to scientific articles indexed in Pubmed.
A phase 1/1b study of combined rituximab, bendamustine, and ibrutinib in patients with previously untreated and relapsed/refractory non-Hodgkin's lymphoma.
Blood
PUBLISHED: 10-31-2014
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Ibrutinib has single agent activity of 22-68% in relapsed B-cell non-Hodgkin's lymphoma (NHL). This study evaluated the safety and efficacy of ibrutinib combined with rituximab (R) and bendamustine. Patients received R 375 mg/m(2) day 1, bendamustine 90 mg/m(2) days 1 and 2, and ibrutinib (280 or 560 mg) days 1-28 every 28 days for 6 cycles followed by ibrutinib alone until progression. Forty-eight patients enrolled, including 12 patients with follicular lymphoma (FL), 16 with diffuse large cell lymphoma (DLCL), and 17 with mantle cell lymphoma (MCL). No dose limiting toxicities were observed. Patients received a median of 8 cycles, with 26 completing 6 cycles and continuing ibrutinib alone in cycles 7-34. The overall response rate (ORR) was 72%, with 52% complete responses (CR). By histology, the ORR was 94% (76% CR) in MCL, 37% (31% CR) in DLCL, and 90% (50% CR) in FL. Grade 3-4 toxicities included lymphopenia (77%), neutropenia (33%), thrombocytopenia (19%), and rash (25%). Median progression-free survival has not been reached (95% CI, 8.7 months - not reached). The recommended phase 2 dose of ibrutinib in combination with R-bendamustine in patients with NHL is 560 mg. The combination has promising efficacy, particularly in MCL and FL.
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Differential Complement Activation Pathways Promote C3b Deposition on Native and Acetylated LDL thereby Inducing Lipoprotein Binding to the Complement Receptor 1.
J. Biol. Chem.
PUBLISHED: 10-29-2014
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Lipoproteins can induce complement activation resulting in opsonization and binding of these complexes to complement receptors. We investigated the binding of opsonized native LDL and acetylated LDL (acLDL) to the complement receptor 1 (CR1). Binding of complement factors C3b, IgM, C1q, mannose-binding lectin (MBL) and properdin to LDL and acLDL were investigated by ELISA. Subsequent binding of opsonized LDL and acLDL to CR1 on CR1-transfected Chinese Hamster Ovarian cells (CHO-CR1) was tested by flow cytometry. Both native LDL and acLDL induced complement activation with subsequent C3b opsonization upon incubation with normal human serum. Opsonized LDL and acLDL bound to CR1. Binding to CHO-CR1 was reduced by EDTA, whereas MgEGTA only reduced the binding of opsonized LDL, but not of acLDL suggesting involvement of the alternative pathway in the binding of acLDL to CR1. In vitro incubations showed that LDL bound C1q, whereas acLDL bound to C1q, IgM and properdin. MBL did neither bind to LDL nor to acLDL. The relevance of these findings was demonstrated by the fact that ex vivo upregulation of CR1 on leukocytes was accompanied by a concomitant increased binding of apolipoprotein B containing lipoproteins to leukocytes without changes in LDL-receptor expression. In conclusion, CR1 is able to bind opsonized native LDL and acLDL. Binding of LDL to CR1 is mediated via the classical pathway, whereas binding of acLDL is mediated via both the classical and alternative pathways. Binding of lipoproteins to CR1 may be of clinical relevance due to the ubiquitous cellular distribution of CR1.
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A phase 1 study of vorinostat maintenance after autologous transplant in high-risk lymphoma.
Leuk. Lymphoma
PUBLISHED: 09-13-2014
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Only a minority of patients with high risk lymphoma will be cured with autologous transplant, so maintenance with vorinostat, an oral agent with activity in relapsed lymphoma, was studied starting day + 60 for 21 consecutive days followed by a week off for up to 11 cycles. Twenty-three patients with lymphoma were treated. Ten patients completed the full 11-cycle treatment plan per protocol, four patients were removed due to progressive disease and seven withdrew or were removed from the study due to toxicities. Despite Prevnar vaccine administration every 2 months for three injections, the mean antibody concentration never reached protective levels (> 0.35 ?g/mL). Fatigue and functional well-being measured by Brief Fatigue Inventory and Functional Assessment of Cancer Therapy-General improved significantly from cycle 1 to cycle 7, but depression scores from the Center for Epidemiologic Studies Depression scale did not change. Given the toxicities observed, this broad-spectrum deacetylase inhibitor at this schedule is not optimal for prolonged maintenance therapy.
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Entering the Era of Targeted Therapy for Chronic Lymphocytic Leukemia: Impact on the Practicing Clinician.
J. Clin. Oncol.
PUBLISHED: 07-23-2014
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Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as ibrutinib has the potential to eliminate the role of chemotherapy in the treatment of CLL. How to best incorporate old and new therapies for CLL in this landscape is increasingly complex.
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Purification and functional analysis of human properdin.
Methods Mol. Biol.
PUBLISHED: 06-10-2014
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Properdin is a member of the alternative pathway of complement. It is unique in that it is the only known positive regulator of the complement system. Properdin can stabilize and promote complement activation, but in addition is also capable of initiating the alternative pathway, making it a unique protein. This chapter focuses on the methods required for purifying human properdin and testing its functionality.
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Phagocytosis of apoptotic or necrotic cells differentially regulates the transcriptional expression of IL-12 family members in dendritic cells.
J. Leukoc. Biol.
PUBLISHED: 04-29-2014
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Uptake of apoptotic cells by DCs is considered to contribute to induction and maintenance of immunological tolerance. TolDCs are sought after as cellular therapy in transplantation and autoimmunity and can be generated in vitro using GCs. In this study, we investigated how uptake of dead cells affects the production and expression of different members of the IL-12 family by immature DCs or TolDCs. We show that compared to regular immature DCs, TolDCs display elevated levels of PS-recognizing bridge molecule receptors ?v?5 and CD36, and have enhanced phagocytic abilities with accelerated uptake of apoptotic cells. We confirm that apoptotic cell uptake results in diminished production of IL-12p40 and IL-12p70 by DCs. We now show that this also results in increased expression of IL-12p35 and Ebi3. TolDCs completely lack expression of IL-12p40 yet have enhanced levels of Ebi3 and IL-12p35. Uptake by TolDCs of apoptotic or necrotic cells does not affect the expression of Ebi3/IL-12p35 and also does not increase IL-12p40. This is distinct from the culture of immature DCs with necrotic cells, which is sufficient to induce IL-12p40 secretion. Conversely, ingestion of apoptotic cells by DCs leads to increased expression of IL-12p35 and Ebi3 without affecting IL-12p40. In conclusion, we have shown that uptake of apoptotic versus necrotic cells by DCs differentially regulates members of the IL-12 family. Apoptotic cells favor expression of Ebi3 and IL-12p35, and we propose that differential regulation of the IL-12 family is an additional mechanism in determining the immune response to dying cells.
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Prenatal risk factors for childhood CKD.
J. Am. Soc. Nephrol.
PUBLISHED: 04-17-2014
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Development of CKD may be programmed prenatally. We sought to determine the association of childhood CKD with prenatal risk factors, including birth weight, maternal diabetes mellitus (DM), and maternal overweight/obesity. We conducted a population-based, case-control study with 1994 patients with childhood CKD (<21 years of age at diagnosis) and 20,032 controls in Washington state. We linked maternal and infant characteristics in birth records from 1987 to 2008 to hospital discharge data and used logistic regression analysis to assess the association of prenatal risk factors with childhood CKD. The prevalence of CKD was 126.7 cases per 100,000 births. High birth weight and maternal pregestational DM associated nominally with CKD, with respective crude odds ratios (ORs) of 1.17 (95% confidence interval [95% CI], 1.03 to 1.34) and 1.97 (95% CI, 1.15 to 3.37); however, adjustment for maternal confounders attenuated these associations to 0.97 (95% CI, 0.79 to 1.21) and 1.19 (95% CI, 0.51 to 2.81), respectively. The adjusted ORs for CKD associated with other prenatal factors were 2.88 (95% CI, 2.28 to 3.63) for low birth weight, 1.54 (95% CI, 1.13 to 2.09) for maternal gestational DM, 1.24 (95% CI, 1.05 to 1.48) for maternal overweight, and 1.26 (95% CI, 1.05 to 1.52) for maternal obesity. In subgroup analysis by CKD subtype, low birth weight and maternal pregestational DM associated significantly with increased risk of renal dysplasia/aplasia. Low birth weight, maternal gestational DM, and maternal overweight/obesity associated significantly with obstructive uropathy. These data suggest that prenatal factors may impact the risk of CKD. Future studies should aim to determine if modification of these factors could reduce the risk of childhood CKD.
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Assessment and management of hypertension in patients on dialysis.
J. Am. Soc. Nephrol.
PUBLISHED: 04-03-2014
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Hypertension is common, difficult to diagnose, and poorly controlled among patients with ESRD. However, controversy surrounds the diagnosis and treatment of hypertension. Here, we describe the diagnosis, epidemiology, and management of hypertension in dialysis patients, and examine the data sparking debate over appropriate methods for diagnosing and treating hypertension. Furthermore, we consider the issues uniquely related to hypertension in pediatric dialysis patients. Future clinical trials designed to clarify the controversial results discussed here should lead to the implementation of diagnostic and therapeutic techniques that improve long-term cardiovascular outcomes in patients with ESRD.
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Ocaratuzumab, an Fc-engineered antibody demonstrates enhanced antibody-dependent cell-mediated cytotoxicity in chronic lymphocytic leukemia.
MAbs
PUBLISHED: 03-04-2014
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Chronic lymphocytic leukemia (CLL) is common in both developed and developing nations where the need for inexpensive and convenient administration of therapy is apparent. Ocaratuzumab is a novel Fc-engineered humanized IgG1 anti-CD20 monoclonal antibody (mAb) designed for effective antibody-dependent cell-mediated cytotoxicity (ADCC) at very low concentrations that may facilitate sub-cutaneous (vs. intravenous) dosing. Here, we report ocaratuzumab's potency against CLL cells. In vitro assessment of ocaratuzumab's direct cytotoxicity (DC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and ADCC was performed on CLL cells. Ocaratuzumab induced DC, CDC, and ADCP similarly to rituximab or ofatumumab (anti-CD20 mAbs). However, ocaratuzumab showed an advantage in NK cell-mediated ADCC over these antibodies. In allogeneic ADCC, [E:T (effector:target) ratios = 25:1, 12:1, 6:1], ocaratuzumab (10 µg/mL) improved ADCC by ~3-fold compared with rituximab or ofatumumab (P<0.001 all tested E:T ratios). Notably, the superiority of ocaratuzumab-induced ADCC was observed at low concentrations (0.1-10 ug/ml; P<0.03; allogeneic assays). In extended allogeneic ADCC E:T titration, ocaratuzumab (0.1 µg/mL) demonstrated 19.4% more cytotoxicity than rituximab (E:T = 0.38:1; P = 0.0066) and 21.5% more cytotoxicity than ofatumumab (E:T = 1.5:1; P = 0.0015). In autologous ADCC, ocaratuzumab (10 µg/mL) demonstrated ~1.5-fold increase in cytotoxicity compared with rituximab or ofatumumab at all E:T ratios tested (E:Ts = 25:1,12:1,6:1; all P<0.001). Obinutuzumab, a glyco-engineered anti-CD20 mAb, showed no improvement in ADCC activity compared with ocaratuzumab. The enhanced ADCC of ocaratuzumab suggests that it may be effective at low concentrations. If supported by clinical investigation, this feature could potentially allow for subcutaneous dosing at low doses that could expand the potential of administering chemoimmunotherapy in developing countries.
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Complete response to induction therapy in patients with Myc-positive and double-hit non-Hodgkin lymphoma is associated with prolonged progression-free survival.
Cancer
PUBLISHED: 02-27-2014
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Myc-positive B-cell non-Hodgkin lymphoma (NHL) with or without a B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) rearrangement is associated with inferior progression-free survival (PFS) and overall survival (OS). In this study, the authors reviewed the outcomes of patients with myc-positive and double-hit NHL at The Ohio State University.
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A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia.
Leuk. Res.
PUBLISHED: 02-18-2014
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Adequate dosing of lenalidomide in Chronic Lymphocytic Leukemia (CLL) remains unclear. This study determined maximum tolerated dose (MTD) in relapsed CLL patients (Cohort A) and patients achieving a partial response (PR) or better to recent therapy (Cohort B). Thirty-seven patients were enrolled. MTD was 2.5mg followed by 5.0mg continuous. In Cohort A, tumor flare grade 1-2 occurred in 15 patients (50%) and grade 3 in 1 patient (3%). Cohort A had 19 of 23 evaluable (83%) patients, 4 PR (17%) and 15 (65%) stable disease (SD), Cohort B had 6 of 7 patients (86%) with SD. Despite overall response rate not being high, many patients remained on therapy several months with SD.
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Heart rate and blood pressure variability in children with chronic kidney disease: a report from the CKiD study.
Pediatr. Nephrol.
PUBLISHED: 02-02-2014
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Autonomic nervous system dysfunction and sympathetic nervous system over-activity play important roles in the development of hypertension associated with chronic kidney disease (CKD). In adults, increased blood pressure variability (BPV) appears to be directly related to sympathetic over-activity with increased risk of end-organ damage and cardiovascular events. Decreased heart rate variability (HRV) has been observed in adults with CKD, and is an independent predictor of mortality.
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Adolescent and young adult oncology, version 2.2014.
J Natl Compr Canc Netw
PUBLISHED: 01-24-2014
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The NCCN Guidelines Insights on Adolescent and Young Adult (AYA) Oncology discuss the fertility and endocrine issues that are relevant to the management of AYA patients with cancer. Fertility preservation should be an essential part in the treatment of AYA patients with cancer. The NCCN Guidelines recommend discussion of fertility preservation and contraception before the start of treatment. Oophoropexy and embryo cryopreservation are the 2 established options for fertility preservation in women. Semen cryopreservation before the start of treatment is the most reliable and well-established method of preserving fertility in men. AYA women with cancer also have unique contraception needs, depending on the type of cancer, its treatment, and treatment-related complications. Management of cancer during pregnancy poses significant diagnostic and therapeutic challenges for both the patient and the physician. AYA women diagnosed with cancer during pregnancy require individualized treatment from a multidisciplinary team involving medical, surgical, radiation, and gynecologic oncologists; obstetricians; and perinatologists.
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The effect of abnormal birth history on ambulatory blood pressure and disease progression in children with chronic kidney disease.
J. Pediatr.
PUBLISHED: 01-13-2014
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To examine the associations between abnormal birth history (birth weight <2500 g, gestational age <36 weeks, or small for gestational age), blood pressure (BP), and renal function among 332 participants (97 with abnormal and 235 with normal birth history) in the Chronic Kidney Disease in Children Study, a cohort of children with chronic kidney disease (CKD).
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Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.
Blood
PUBLISHED: 01-10-2014
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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for ? and ? expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.
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Pediatric nephrologists' beliefs regarding randomized controlled trials.
J. Investig. Med.
PUBLISHED: 01-01-2014
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Pediatrics and pediatric nephrology lag behind adult medicine in producing randomized controlled trials (RCTs). Physician attitudes have been shown to play a significant role in RCT enrollment.
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Screening blood pressure measurement in children: are we saving lives?
Pediatr. Nephrol.
PUBLISHED: 11-15-2013
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Blood Pressure screening in children and adolescents is currently recommended by several prominent medical organizations, including the American Heart Association, the National High Blood Pressure Education Program, the National Heart, Lung, and Blood Institute, the European Society of Hypertension, and the American Academy of Pediatrics. This practice was recently subject to intense scientific review by the U.S. Preventive Services Task Force. The conclusion of the Task Force was that "current evidence is insufficient to assess the balance of benefits and harms of screening for primary hypertension in asymptomatic children and adolescents." This commentary provides an alternate interpretation of current evidence for blood pressure screening in children and adolescents and highlights its importance as a part of routine medical care.
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BP Control and Left Ventricular Hypertrophy Regression in Children with CKD.
J. Am. Soc. Nephrol.
PUBLISHED: 09-26-2013
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In adult patients with CKD, hypertension is linked to the development of left ventricular hypertrophy, but whether this association exists in children with CKD has not been determined conclusively. To assess the relationship between BP and left ventricular hypertrophy, we prospectively analyzed data from the Chronic Kidney Disease in Children cohort. In total, 478 subjects were enrolled, and 435, 321, and 142 subjects remained enrolled at years 1, 3, and 5, respectively. Echocardiograms were obtained 1 year after study entry and then every 2 years; BP was measured annually. A linear mixed model was used to assess the effect of BP on left ventricular mass index, which was measured at three different visits, and a mixed logistic model was used to assess left ventricular hypertrophy. These models were part of a joint longitudinal and survival model to adjust for informative dropout. Predictors of left ventricular mass index included systolic BP, anemia, and use of antihypertensive medications other than angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Predictors of left ventricular hypertrophy included systolic BP, female sex, anemia, and use of other antihypertensive medications. Over 4 years, the adjusted prevalence of left ventricular hypertrophy decreased from 15.3% to 12.6% in a systolic BP model and from 15.1% to 12.6% in a diastolic BP model. These results indicate that a decline in BP may predict a decline in left ventricular hypertrophy in children with CKD and suggest additional factors that warrant additional investigation as predictors of left ventricular hypertrophy in these patients.
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Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing.
Blood
PUBLISHED: 09-05-2013
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Membrane antigens are critical to the pathogenesis of chronic lymphocytic leukemia (CLL) as they facilitate microenvironment homing, proliferation, and survival. Targeting the CLL membrane and associated signaling patterns is a current focus of therapeutic development. Many tumor membrane targets are simultaneously targeted by humoral immunity, thus forming recognizable immunoglobulin responses. We sought to use this immune response to identify novel membrane-associated targets for CLL. Using a novel strategy, we interrogated CLL membrane-specific autologous immunoglobulin G reactivity. Our analysis unveiled lymphocyte cytosolic protein 1 (LCP1), a lymphocyte-specific target that is highly expressed in CLL. LCP1 plays a critical role in B-cell biology by crosslinking F-actin filaments, thereby solidifying cytoskeletal structures and providing a scaffold for critical signaling pathways. Small interfering RNA knockdown of LCP1 blocked migration toward CXCL12 in transwell assays and to bone marrow in an in vivo xenotransplant model, confirming a role for LCP1 in leukemia migration. Furthermore, we demonstrate that the Brutons tyrosine kinase inhibitor ibrutinib or the PI3K inhibitor idelalisib block B-cell receptor induced activation of LCP1. Our data demonstrate a novel strategy to identify cancer membrane target antigens using humoral anti-tumor immunity. In addition, we identify LCP1 as a membrane-associated target in CLL with confirmed pathogenic significance. This clinical trial was registered at clinicaltrials.gov; study ID number: OSU-0025 OSU-0156.
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Myeloperoxidase Directs Properdin-Mediated Complement Activation.
J Innate Immun
PUBLISHED: 07-26-2013
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Neutrophils and complement are key members of innate immunity. The alternative pathway (AP) of complement consists of C3, factor B, factor D and properdin, which amplifies AP activation. AP has been implicated in many neutrophil-mediated diseases, such as anti-neutrophil cytoplasmic antibody-associated vasculitis. The exact mechanism by which the AP and neutrophils interact remains largely unstudied. We investigated the ability of the AP to interact with neutrophil components which can be exposed and released upon activation. Our studies focused on neutrophil enzymes, including myeloperoxidase (MPO), proteinase 3 (PR3), azurocidin, elastase, lysozyme and cathepsin G. All enzymes except for azurocidin were able to bind properdin. However, only MPO could induce C3 activation. MPO mediated AP complement activation in the presence of MgEGTA compared to the EDTA control. This activation resulted in C3 deposition and required properdin to occur. Furthermore, we could show that MPO binds properdin directly, which then serves as a focus for AP activation. In summary, properdin can directly interact with neutrophil components. MPO demonstrates the ability to activate the AP which is dependent on properdin. Finally, MPO is capable of inducing properdin-initiated C3 and C5b-9 deposition in vitro. © 2013 S. Karger AG, Basel.
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Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes.
Blood
PUBLISHED: 07-25-2013
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Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
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Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies.
MAbs
PUBLISHED: 06-07-2013
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TRU-016 is a SMIP(TM) (monospecific protein therapeutic) molecule against the tetraspanin transmembrane family protein CD37 that is currently in Phase 2 trials in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). In an attempt to enhance the ADCC function of SMIP-016, the chimeric version of TRU-016, SMIP-016(GV) was engineered with a modification in a glycosylation site in the Fc domain. The wild-type and glycovariant SMIP proteins mediate comparable Type I antibody-like direct cytotoxicity in the presence of anti-human Fc crosslinker and show a similar tyrosine phosphorylation pattern post-treatment. However, NK cells stimulated with the SMIP-016(GV) exhibit enhanced activation and release 3-fold more interferon-? compared with SMIP-016. SMIP-016(GV) shows enhanced ADCC function against cells expressing CD37 with NK cell effectors derived from both normal and CLL-affected individuals. Enhanced ADCC is observed against CLL cells and is sustained at concentrations of SMIP-016(GV) as low at 5E(-6) µg/mL on cells expressing minimal CD37 antigen. In support of the biological relevance of this, SMIP-016(GV) mediates effective ADCC against primary acute lymphoblastic leukemia (ALL) cells with low surface expression of CD37. Collectively, these data suggest potential use of the novel therapeutic agent SMIP-016(GV) with enhanced effector function for B cell malignancies, including CLL and ALL therapy.
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Pilot study on the efficacy of an ondansetron- versus palonosetron-containing antiemetic regimen prior to highly emetogenic chemotherapy.
Support Care Cancer
PUBLISHED: 05-21-2013
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Nausea and vomiting are among the most feared complications of chemotherapy reported by patients. The objective of this study was to establish the overall complete response (CR; no emesis or use of rescue medication 0-120 h after chemotherapy) with either ondansetron- or palonosetron-containing antiemetic regimens in patients receiving highly emetogenic chemotherapy (HEC).
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Effects of obesity and race on left ventricular geometry in hypertensive children.
Pediatr. Nephrol.
PUBLISHED: 04-17-2013
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Like left ventricular hypertrophy (LVH), abnormal left ventricular (LV) geometry increases cardiovascular risk, but little data utilizing age and sex-specific norms are currently available on LV geometry in hypertensive children.
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Identification of endoplasmic reticulum stress-inducing agents by antagonizing autophagy: a new potential strategy for identification of anti-cancer therapeutics in B-cell malignancies.
Leuk. Lymphoma
PUBLISHED: 04-16-2013
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The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress-inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavirs effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveal that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well-known drugs as a combinatorial therapy with anti-cancer properties.
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Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory non-Hodgkins lymphoma.
Am. J. Hematol.
PUBLISHED: 04-07-2013
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Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a Phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkins lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (Cohort 1), mantle cell (Cohort 2), intermediate-grade B-cell including transformed lymphoma (Cohort 3), and T-/NK-cell excluding primary cutaneous disease (Cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common nonhematologic toxicities included diarrhea and fatigue. Biochemical tumor lysis was observed in only two patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m(2) bolus?+?50 mg/m(2) continuous infusion weekly for 4 consecutive weeks of a 6-week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (two mantle cells, three indolent B-cells, and one diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. Am. J. Hematol., 2013. © 2013 Wiley Periodicals, Inc.
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Cyclophosphamide, alvocidib (flavopiridol), and rituximab, a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia.
Leuk. Res.
PUBLISHED: 04-04-2013
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Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.
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KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD.
Am. J. Kidney Dis.
PUBLISHED: 03-27-2013
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In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ?140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ?130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.
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Treatment of obesity-related hypertension in children and adolescents.
Curr. Hypertens. Rep.
PUBLISHED: 03-12-2013
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The obesity epidemic has become a common concern among pediatricians, with an estimated 32 % of US children and adolescents classified as overweight and 18 % as obese. Along with the increase in obesity, a growing body of evidence demonstrates that chronic diseases, such as Type 2 diabetes, primary hypertension, and hyperlipidemia, once thought to be confined solely to adulthood, are commonly seen among the obese in childhood. Following a brief summary of the diagnosis and evaluation of hypertension in obese children and adolescents, this review will highlight recent research on the treatment of obesity-related hypertension. Pharmacologic and non-pharmacologic treatment will be discussed. Additionally, current and emerging therapies for the primary treatment of obesity in children and adolescents, which have been gaining in popularity, will be reviewed.
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Rational use of antihypertensive medications in children.
Pediatr. Nephrol.
PUBLISHED: 02-26-2013
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Hypertension has traditionally been regarded as an uncommon diagnosis in childhood and adolescence; however, there is compelling evidence to suggest that its prevalence is on the rise, particularly in those with obesity. As a result, pediatricians increasingly are asked to evaluate and manage patients with elevated blood pressure. An increased emphasis on conducting drug trials in children over the last 15 years has yielded important advances with respect to evidence-based data regarding the efficacy and safety of antihypertensive medications in children and adolescents. Unfortunately, data to definitively guide selection of initial agents is lacking. This article will present guidelines for the appropriate use of antihypertensive medications in the pediatric population, including the rational approach to selecting an appropriate medication with respect to pathophysiology, putative benefit, and likelihood for side effects.
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Depression and its associated factors in pediatric chronic kidney disease.
Pediatr. Nephrol.
PUBLISHED: 02-10-2013
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Few studies on the occurrence of depression in pediatric patients with chronic kidney disease (CKD) have been conducted and none have identified associated clinical and demographic factors.
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Nephrotic-range proteinuria is strongly associated with poor blood pressure control in pediatric chronic kidney disease.
Kidney Int.
PUBLISHED: 02-08-2013
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Despite the importance of blood pressure (BP) control in chronic kidney disease (CKD), few longitudinal studies on its trends exist for pediatric patients with CKD. Here we longitudinally analyzed casual data in 578 children with CKD and annual BP measurements standardized for age, gender, and height. At baseline, 124 children were normotensive, 211 had elevated BP, and 243 had controlled hypertension. Linear mixed-effects models accounting for informative dropout determined factors associated with BP changes over time and relative sub-hazards (RSH) identified factors associated with the achievement of controlled BP in children with baseline elevated BP. Younger age, black children, higher body mass index, and higher proteinuria at baseline were associated with higher standardized BP levels. Overall average BP decreased during follow-up, but nephrotic-range proteinuria and increased proteinuria and body mass index were risk factors for increasing BP over time. Only 46% of hypertensive patients achieved controlled BP during follow-up; least likely were those with nephrotic-range proteinuria (RSH 0.19), black children (RSH 0.42), and children with baseline glomerular filtration rate under 40?ml/min per 1.73?m(2) (RSH 0.58). Thus, of many coexisting factors, nephrotic-range proteinuria was most strongly associated with poor BP control and worsening BP over time. Future research should focus on strategies to reduce proteinuria, as this may improve BP control and slow the progression of CKD.Kidney International advance online publication, 18 September 2013; doi:10.1038/ki.2013.352.
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Pretreatment of formula or expressed breast milk with sodium polystyrene sulfonate (Kayexalate(®)) as a treatment for hyperkalemia in infants with acute or chronic renal insufficiency.
J Ren Nutr
PUBLISHED: 02-05-2013
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To evaluate the effect on serum potassium of treating infant formula or expressed breast milk (EBM) with sodium polystyrene sulfonate (SPS) before patient consumption.
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Ectopic extramedullary hematopoiesis: evaluation and treatment of a rare and benign paraspinal/epidural tumor.
J Neurosurg Spine
PUBLISHED: 01-18-2013
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Ectopic extramedullary hematopoiesis (EMH), defined as the formation of blood cells outside the bone marrow, usually occurs in a scenario of chronic anemia when, even after conversion of the bony yellow marrow to red marrow, the body is still unable to meet the demand for red blood cells. Ectopic extramedullary hematopoiesis most commonly occurs in the liver and spleen but may, in fact, occur almost anywhere in the body. Although previous reports have documented EMH presenting as paraspinal masses, such lesions have almost always been associated with a predisposing hematological disorder such as hemolytic anemia, myelofibrosis or myelodysplastic syndromes, thalassemia, polycythemia vera, leukemia, or lymphoma. The authors of this report describe the first reported instance of EMH in a patient presenting with a symptomatic epidural and paraspinal cervical lesion arising from the posterior spinal elements and no known predisposing hematological disease. Initial radiographs revealed a bony lesion arising posteriorly from the C2-3 laminae and spinous processes. Subsequent imaging suggested the diagnosis, which was confirmed by CT-guided biopsy, peripheral blood smears, and bone marrow aspirate. Despite epidural compression and slight displacement of the cervical cord and thecal sac, the patients symptoms were limited to pain and diminished cervical range of motion. Therefore, surgery was deferred in favor of nonsurgical therapy. Several alternative modalities for the treatment of EMH have been suggested in the literature, including cytotoxic agents and radiotherapy. The authors opted for an approach utilizing directed low-dose radiotherapy of a total of 25 Gy divided in 2.5-Gy fractions. At the 3-month follow-up, the patient continued to be asymptomatic, and MRI demonstrated a significant reduction in the dimensions of the lesion. Extramedullary hematopoiesis with spinal cord compression in the absence of a preexisting hematological disorder has not been described in the context of clinical neurosurgical practice. Recognizing that EMH may present as an epidural or paraspinal lesion is important since chemotherapy and radiotherapy are effective therapeutic options in the majority of patients who suffer few if any symptoms. Extensive evaluation for underlying hematological disorders is necessary before undertaking directed therapy. Inadvertent resection of these highly vascularized masses may risk catastrophic intraoperative hemorrhage with no proven benefit as compared with medical treatment, which usually provides excellent long-term outcomes.
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Estimation of clinically significant prostate volumes by digital rectal examination: a comparative prospective study.
Can J Urol
PUBLISHED: 12-15-2011
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Reliable quantification of prostate volume is important to correctly select patients with benign prostatic hyperplasia (BPH) most likely to benefit from medical therapy [e.g. 5 alpha-reductase inhibitors (5-ARIs)] and in selecting appropriate surgical approach. We aim to determine the reliability of digital rectal examination (DRE) in estimation of prostate volume which may be helpful in patient selection for 5-ARIs therapy.
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Hypertension in pediatric patients with childhood-onset chronic kidney disease: much to be learned, more to be done.
Kidney Int.
PUBLISHED: 11-02-2011
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Pediatric patients with chronic kidney disease are increasingly recognized as being at increased risk of developing cardiovascular disease as adults. Numerous risk factors contribute, hypertension being one of the most identifiable and potentially modifiable. Despite this, numerous studies have demonstrated that hypertension is common and is frequently underrecognized and/or undertreated in this population. Greater efforts are needed to identify and effectively treat hypertension in these vulnerable patients to reduce the future burden of adult cardiovascular disease.
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Ambulatory blood pressure monitoring in children: imperfect yet essential.
Pediatr. Nephrol.
PUBLISHED: 07-19-2011
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There has been increasing emphasis on hypertension and early cardiovascular disease in the pediatric age group over the past decade as a result of various factors, including the obesity epidemic and publication of new clinical guidelines. A key component of identifying children and adolescents with definite or potential hypertension is proper blood pressure (BP) measurement. While ambulatory blood pressure monitoring (ABPM) offers the potential for improved detection of youths at increased cardiovascular risk, it has not been widely adopted. This commentary highlights the crucial role of ABPM in the context of current trends, while at the same time identifying the current barriers to more widespread application of this technique. Chief among these is the lack of a robust, universally applicable database of pediatric ABPM normative values. Even in the absence of ideal normative data, ABPM can and should be widely applied, and a potential algorithm for such an approach is presented.
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Nucleosomes and C1q bound to glomerular endothelial cells serve as targets for autoantibodies and determine complement activation.
Mol. Immunol.
PUBLISHED: 06-24-2011
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Various studies indicate a role for both anti-nucleosome and anti-C1q autoantibodies in glomerulonephritis in patients with systemic lupus erythematosus. However, a causal relationship between these autoantibodies and the development of lupus nephritis has not been fully established. Since injury of the endothelium is a major target in lupus nephritis we assessed the interaction of C1q and nucleosomes with glomerular endothelial cells in vitro in the presence or absence of autoantibodies against these antigens. We demonstrate a direct and dose-dependent binding of both nucleosomes and C1q to immortalized human glomerular endothelial cells (GEnC) in vitro, which in part is mediated by cell surface heparan sulfate. We demonstrate that nucleosomes and C1q serve as targets for monoclonal and polyclonal antibodies as well as for anti-nuclear autoantibodies from patients with systemic lupus erythematosus. An additive effect of anti-C1q autoantibodies on anti-nucleosome mediated complement activation was observed. Furthermore, we showed that the activation of complement on glomerular endothelial cells is mediated by the classical pathway since the deposition of C3 on GEnC is abrogated by MgEGTA and does not occur in C1q-depleted serum. Taken together, our studies demonstrate a direct binding of both nucleosomes and C1q to glomerular endothelial cells in vitro. The subsequent binding of autoantibodies against nucleosomes in patients with systemic lupus erythematosus is potentially pathogenic and autoantibodies against C1q seem to have an additional effect.
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Casual blood pressure and neurocognitive function in children with chronic kidney disease: a report of the children with chronic kidney disease cohort study.
Clin J Am Soc Nephrol
PUBLISHED: 06-23-2011
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Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on the potential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited. Our objective was to determine whether children with CKD and elevated BP (EBP) had decreased performance on neurocognitive testing compared with children with CKD and normal BP.
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Relationships between renin, aldosterone, and 24-hour ambulatory blood pressure in obese adolescents.
Pediatr. Res.
PUBLISHED: 06-15-2011
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Renin-angiotensin system (RAS) activation and abnormalities of ambulatory blood pressure (ABP) are present in obesity, but relationships between components of the RAS and ABP have not been defined in the young. Anthropometric measurements and 24-h ABP were obtained on 30 obese adolescents with and without type 2 diabetes mellitus. Plasma renin activity (PRA), aldosterone, and other cardiovascular risk factors were measured. Median PRA levels were 2.5 [interquartile range (IQR), 1.7-4.1] ng/mL/h and were higher in the diabetic subjects compared with the nondiabetics. Females had significantly higher PRA than males 3.2 (IQR, 2-4.8) versus 1.8 (IQR, 1.1-2.9) ng/mL/h (p = 0.04) and were more obese. BMI Z score and PRA were significantly correlated (rho = 0.46, p < 0.001). PRA inversely correlated with 24-h systolic ABP (rho = -0.46, p = 0.02) and strongly with 24-h pulse pressure (rho = -0.61, p = 0.001). Aldosterone levels were also correlated with 24-h pulse pressure (rho = -0.46, p = 0.02). In multivariate models, lower PRA was independently associated with 24-h systolic blood pressure. In this study, PRA was positively correlated with BMI, but the relationships between components of the RAS and ABP were inverse. Further studies are needed to define the pathophysiologic relationship between RAS components and blood pressure regulation in obese youth.
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The renin-angiotensin-aldosterone system in 2011: role in hypertension and chronic kidney disease.
Pediatr. Nephrol.
PUBLISHED: 05-24-2011
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Over the past two decades, considerable advances have been made in our understanding of the renin-angiotensin-aldosterone system (RAAS) and its roles in various disease states. In this review, we will discuss the current state of knowledge of the many components of the RAAS, including new data on prorenin and its receptors, and important angiotensin fragments. The roles of these components of the RAAS in the pathogenesis of primary hypertension and the progression of chronic kidney disease (CKD) will also be highlighted. Given the new understanding of the many components and roles of the RAAS, it may be possible to develop improved therapies for hypertension and CKD.
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Reliability of resting blood pressure measurement and classification using an oscillometric device in children with chronic kidney disease.
J. Pediatr.
PUBLISHED: 04-29-2011
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To compare the reliability of blood pressure (BP) readings obtained with an oscillometric device with those obtained by auscultation and assess for differences in BP status classification based on the 2 techniques.
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Enhanced detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide in combination with pokeweed mitogen and phorbol myristate acetate.
Cancer Genet
PUBLISHED: 04-16-2011
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Reproducible cytogenetic analysis in CLL has been limited by the inability to obtain reliable metaphase cells for analysis. CpG oligonucleotide and cytokine stimulation have been shown to improve metaphase analysis of CLL cytogenetic abnormalities, but is limited by variability in the cytokine receptor levels, stability and biological activity of the cytokine in culture conditions and high costs associated with these reagents. We report here use of a novel, stable CpG, GNKG168 along with pokeweed mitogen (PWM) and phorbol 12-myristate 13-acetate (PMA) for conventional cytogenetic assessment in CLL. We demonstrate that the combined use of GNKG168+PWM/PMA increased the sensitivity of detection of chromosomal abnormalities compared to PWM/PMA (n=207, odds ratio=2.2, p=0.0002) and GNKG168 (n=219, odds ratio=1.5, p=0.0452). Further, a significant increase in sensitivity to detect complexity ?3 with GNKG168+PWM/PMA compared to GNKG168 alone (odds ratio 8.0, p=0.0022) or PWM/PMA alone (odds ratio 9.6, p=0.0007) was observed. The trend toward detection of higher complexity was significantly greater with GNKG168+PWM/PMA compared to GNKG168 alone (p=0.0412). The increased sensitivity was mainly attributed to the addition of PWM/PMA with GNKG168 because GNKG168 alone showed no difference in sensitivity for detection of complex abnormalities (p=0.17). Comparison of fluorescence in situ hybridization (FISH) results with karyotypic results showed a high degree of consistency, although some complex karyotypes were present in cases with no adverse FISH abnormality. These studies provide evidence for potential use of GNKG168 in combination with PWM and PMA in karyotypic analysis of CLL patient samples to better identify chromosomal abnormalities for risk stratification.
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Obesity hypertension in adolescents: epidemiology, evaluation, and management.
J Clin Hypertens (Greenwich)
PUBLISHED: 03-30-2011
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The prevalence of hypertension among all adolescents is approximately 3.5%, with somewhat higher rates of prehypertension. Obesity affects approximately 20% of adolescents in the United States, and the prevalence of hypertension is much higher among obese adolescents compared with nonobese adolescents. As in other populations, the evaluation of elevated blood pressure in obese adolescents should begin with a confirmation of the blood pressure elevation, followed by a focused diagnostic work-up to detect possible secondary causes of hypertension. Primary therapy for obesity-related hypertension in adolescents begins with weight loss, and may include antihypertensive medications if target-organ damage or other indications for drug therapy are present. The emphasis of management should be reduction of future cardiovascular risk.
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Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.
Blood
PUBLISHED: 03-21-2011
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B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-?B. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-?), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.
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Predictors of blood pressure and its control in pediatric patients receiving dialysis.
J. Pediatr.
PUBLISHED: 03-11-2011
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To evaluate and characterize the degree of blood pressure (BP) control in children on chronic dialysis and to identify significant predictors of hypertension and BP control in these patients.
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Hypertension, chronic kidney disease, and renal pathology in a child with hermansky-pudlak syndrome.
Int J Nephrol
PUBLISHED: 02-25-2011
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We report a child with Hermansky-Pudlak Syndrome (HPS) and chronic kidney disease (stage II) with histological diagnosis of focal segmental glomerulosclerosis (FSGS). A 15-year-old male of Puerto Rico ancestry with history of HPS, hypertension (HTN), asthma, obesity, and chronic kidney disease (CKD) stage II presented with new-onset proteinuria without edema. His blood pressure had been controlled, serum creatinine had been 0.9-1.4?mg/dL, and first morning urine protein/creatinine ratio (UPC) ranged from 0.2 to 0.38. Due to persistent nonorthostatic proteinuria with CKD, renal biopsy was performed and FSGS (not otherwise specified) with chronic diffuse tubulopathy (tubular cytoplasmic droplets) and acute tubular injury was reported. Ceroid-like material is known to infiltrate tissues (i.e., lungs, colon, and kidney) in HPS, but the reason for the renal insufficiency is unknown. Nonspecific kidney disease and in one adult case IgA nephropathy with ANCA-positive glomerulonephritis have previously been reported in patients with Hermansky-Pudlak syndrome. To our knowledge, we report the first pediatric renal pathology case of HPS associated with CKD. This paper discusses presentation and management of renal disease in HPS.
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Hypertension in infancy: diagnosis, management and outcome.
Pediatr. Nephrol.
PUBLISHED: 01-22-2011
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Advances in the ability to identify, evaluate, and care for infants with hypertension, coupled with advances in the practice of Neonatology, have led to an increased awareness of hypertension in modern neonatal intensive care units. This review will present updated data on blood pressure values in neonates, with a focus on the changes that occur over the first days and weeks of life in both term and preterm infants. Optimal blood pressure measurement techniques as well as the differential diagnosis of hypertension in the neonate and older infants will be discussed. Recommendations for the optimal immediate and long-term evaluation and treatment, including potential treatment parameters, will be presented. We will also review additional information on outcome that has become available over the past decade.
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Management of hypertension in the young: role of antihypertensive medications.
J. Cardiovasc. Pharmacol.
PUBLISHED: 01-19-2011
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Traditionally, antihypertensive medications were used in few children or adolescents, usually just those with underlying renal or other organ system disease. However, with recent data suggesting that the incidence of primary hypertension may be increasing in the young, it is possible that more children and adolescents will be prescribed antihypertensive agents. This article will review currently available pediatric data on the use of calcium channel blockers, agents affecting the renin-angiotensin-aldosterone system and other classes of antihypertensive medications in children, highlighting appropriate indications and safety considerations. Guidelines for use of antihypertensive medications, including choice of initial agent and how to prescribe appropriately, will be presented.
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Neonatal hypertension.
J Med Liban
PUBLISHED: 12-22-2010
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Blood pressure (BP) in neonates depends on a variety of factors, including gestational age, postnatal age and birth weight. The incidence of hypertension in neonates ranges from 0.2 to 3%, and may be higher in premature infants and those who have undergone umbilical arterial catheterization, or who have chronic lung disease. A careful diagnostic evaluation should lead to determination of the underlying cause of hypertension in most infants. Treatment decisions should be tailored to the severity of the hypertension, and may include intravenous and/or oral therapy. Hypertension will resolve in most infants over time, although a small number may have persistent BP elevation throughout childhood. This review will focus on the differential diagnosis of hypertension in the neonate, the optimal diagnostic evaluation, and therapy.
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Isradipine for treatment of acute hypertension in hospitalized children and adolescents.
J Clin Hypertens (Greenwich)
PUBLISHED: 11-09-2010
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Severe acute hypertension in pediatric patients requires prompt and controlled blood pressure (BP) reduction to prevent end-organ damage. The authors aimed to examine the efficacy and safety of isradipine, an orally administered second-generation dihydropyridine calcium channel blocker, for treatment of acute hypertension in hospitalized pediatric patients. A retrospective analysis of 391 doses of isradipine administered to 282 patients (58% boys) with acute hypertension and median age of 12.8 years (range, 0.1-21.9) was performed. Primary diagnoses included renal disease (n=154), malignancy (45), nonrenal transplant (37), neurologic disease (21), and other (25). The decrease in systolic BP was 16.3%±11.6% (mean ± SD) and diastolic BP was 24.2%±17.2%. BPs were significantly lower in all age groups and in all diagnosis categories following isradipine administration. The decrease in BP was the highest in children younger than 2 years. The mean increase in pulse after a dose was 7±17 beats per minute. Forty adverse events were reported in 33 patients, with emesis and nausea being the most common; 5 of these events were hypotension. The authors conclude that isradipine effectively reduces BP in a wide variety of hospitalized children and adolescents with acute hypertension. A lower initial dose of 0.05 mg/kg may be appropriate in children younger than 2 years.
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Racial differences among children with primary hypertension.
Pediatrics
PUBLISHED: 10-18-2010
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Race is a known risk factor for hypertension and cardiovascular disease in adults and influences blood pressure (BP) in children. We sought to determine if there are differences in clinical, laboratory, or echocardiographic characteristics among children with primary hypertension from different racial groups.
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Management of high blood pressure in children and adolescents.
Cardiol Clin
PUBLISHED: 10-13-2010
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Hypertension in childhood is now recognized to be a common and serious problem with a prevalence of 2% to 5%. Large epidemiologic studies have established normative tables for blood pressure beginning in early childhood based on age, gender, and height. Making a diagnosis of hypertension in a child or adolescent identifies an individual at increased risk for early-onset cardiovascular disease who requires specific treatment. Routine blood pressure measurement is recommended at every health care encounter beginning at 3 years of age, but often this is not being accomplished. This measurement is especially important in relation to the obesity epidemic, because approximately one-third of obese children have high blood pressure. Hypertension can be effectively managed with effective lifestyle change and medication when necessary.
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Dyslipidemia in children with chronic kidney disease.
Kidney Int.
PUBLISHED: 08-25-2010
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Dyslipidemia, a known risk factor for atherosclerosis, is frequent among both adults and children with chronic kidney disease. Here, we describe the prevalence and pattern of dyslipidemia from a cross-sectional analysis of 391 children aged 1-16 years, enrolled in the multicenter Chronic Kidney Disease in Children (CKiD) study, with a median glomerular filtration rate (GFR), measured by the plasma disappearance of iohexol, of 43?ml/min per 1.73?m2. Multivariate analysis was applied to adjust for age, gender, body mass index (BMI), GFR, and the urinary protein/creatinine ratio. Proteinuria was in the nephrotic range in 44 and the BMI exceeded the 95th percentile in 57 patients of this cohort. Baseline lipid analysis found a high prevalence of hypertriglyceridemia in 126, increased non-HDL-C in 62, and reduced HDL-C in 83. Overall, 177 children had dyslipidemia, of whom 79 had combined dyslipidemia. Lower GFR was associated with higher triglycerides, lower HDL-C, and higher non-HDL-C. Nephrotic-range proteinuria was significantly associated with dyslipidemia and combined dyslipidemia. Compared with children with a GFR>50, children with a GFR<30 had significantly increased odds ratios for any dyslipidemia or for combined dyslipidemia. Hence, among children with moderate chronic kidney disease, dyslipidemia is common and is associated with lower GFR, nephrotic proteinuria, and non-renal factors including age and obesity.
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Phosphatidylinositol 3-kinase-? inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.
Blood
PUBLISHED: 06-03-2010
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Targeted therapy with imatinib in chronic myeloid leukemia (CML) prompted a new treatment paradigm. Unlike CML, chronic lymphocytic leukemia (CLL) lacks an aberrant fusion protein kinase but instead displays increased phosphatidylinositol 3-kinase (PI3K) activity. To date, PI3K inhibitor development has been limited because of the requirement of this pathway for many essential cellular functions. Identification of the hematopoietic-selective isoform PI3K-? unlocks a new therapeutic potential for B-cell malignancies. Herein, we demonstrate that PI3K has increased enzymatic activity and that PI3K-? is expressed in CLL cells. A PI3K-? selective inhibitor CAL-101 promoted apoptosis in primary CLL cells ex vivo in a dose- and time-dependent fashion that was independent of common prognostic markers. CAL-101-mediated cytotoxicity was caspase dependent and was not diminished by coculture on stromal cells. In addition, CAL-101 abrogated protection from spontaneous apoptosis induced by B cell-activating factors CD40L, TNF-?, and fibronectin. In contrast to malignant cells, CAL-101 does not promote apoptosis in normal T cells or natural killer cells, nor does it diminish antibody-dependent cellular cytotoxicity. However, CAL-101 did decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Collectively, these studies provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell lymphoproliferative disorders.
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Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation.
Br. J. Haematol.
PUBLISHED: 04-29-2010
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Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1-3 cycles of decitabine. Dose-limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m(2) per d days 1-10, consisting of grade 3-4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m(2) per d days 1-10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m(2) per d decitabine days 1-5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3-4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL.
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Second malignancies in B-cell chronic lymphocytic leukaemia: possible association with human papilloma virus.
Br. J. Haematol.
PUBLISHED: 03-08-2010
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Second primary malignancies have long been associated with chronic lymphocytic leukaemia (CLL). We assessed secondary tumour samples from CLL and control patients for the presence of human papilloma virus (HPV). 132 CLL patients with 44 second malignancies were compared to a matched randomly-identified control population of 264 non-CLL patients with 54 solid malignancies. Polymerase chain reaction was performed with the highly conserved MY09/MY11 HPV primer. None of control samples were HPV-positive, while 53% of samples from the CLL group were positive. This report describes preliminary evidence for the presence of HPV in secondary malignancies, in patients with CLL.
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Pediatric hypertension update.
Curr. Opin. Nephrol. Hypertens.
PUBLISHED: 02-19-2010
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The field of childhood hypertension has been changing rapidly since publication of the most recent consensus guidelines contained in the 2004 Fourth Report.
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Dic(17;18)(p11.2;p11.2) is a recurring abnormality in chronic lymphocytic leukaemia associated with aggressive disease.
Br. J. Haematol.
PUBLISHED: 12-16-2009
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Interphase cytogenetics are commonly used to identify clonal abnormalities in chronic lymphocytic leukemia (CLL) patients but fail to identify recurrent translocations that ultimately can direct more focused molecular characterization. Given the importance of del(17p13.1) in CLL outcome, we performed an extensive review of 1213 patients undergoing metaphase cytogenetics at our institution and identified 16 (1.3%) with a recurrent unbalanced translocation between the p arms of chromosomes 17 and 18 that results in a dicentric chromosome with loss of much of 17p and 18p. The dic(17;18)(p11.2;p11.2) was associated with a complex (three or more unrelated cytogenetic abnormalities) karyotype in 12 patients (75%) at the time that the abnormality was first identified, and eventually associated with a complex karyotype in 94% of patients. IGHV mutational analysis was un-mutated in 88% of cases where evaluation was possible. Except for one patient who was diagnosed with CLL incidentally during a workup for metastatic tonsillar cancer, all patients identified with dic(17;18)(p11.2;p11.2) met criteria for disease treatment, with a median time from diagnosis to first treatment of 15 months. Our data demonstrate that dic(17;18)(p11.2;p11.2) is a novel recurrent cytogenetic abnormality in CLL associated with early age at diagnosis and accelerated disease progression. Future efforts to identify genes disrupted by this translocation are warranted and ongoing.
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CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody.
Blood
PUBLISHED: 12-02-2009
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CD19 is a B cell-specific antigen expressed on chronic lymphocytic leukemia (CLL) cells but to date has not been effectively targeted with therapeutic monoclonal antibodies. XmAb5574 is a novel engineered anti-CD19 monoclonal antibody with a modified constant fragment (Fc)-domain designed to enhance binding of FcgammaRIIIa. Herein, we demonstrate that XmAb5574 mediates potent antibody-dependent cellular cytotoxicity (ADCC), modest direct cytotoxicity, and antibody-dependent cellular phagocytosis but not complement-mediated cytotoxicity against CLL cells. Interestingly, XmAb5574 mediates significantly higher ADCC compared with both the humanized anti-CD19 nonengineered antibody it is derived from and also rituximab, a therapeutic antibody widely used in the treatment of CLL. The XmAb5574-dependent ADCC is mediated by natural killer (NK) cells through a granzyme B-dependent mechanism. The NK cell-mediated cytolytic and secretory function with XmAb5574 compared with the nonengineered antibody is associated with enhanced NK-cell activation, interferon production, extracellular signal-regulated kinase phosphorylation downstream of Fcgamma receptor, and no increased NK-cell apoptosis. Notably, enhanced NK cell-mediated ADCC with XmAb5574 was enhanced further by lenalidomide. These findings provide strong support for further clinical development of XmAb5574 as both a monotherapy and in combination with lenalidomide for the therapy of CLL and related CD19(+) B-cell malignancies.
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Treatment of hypertension in children and adolescents.
Pediatr. Nephrol.
PUBLISHED: 11-18-2009
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The treatment of hypertension in children and adolescents has been markedly changed in recent years by several factors, including the publication of new consensus recommendations, the obesity epidemic, and the increased availability of information on efficacy and safety of antihypertensive medications in the young. In this review we present an updated approach to the outpatient management of hypertension in the child or adolescent, utilizing representative cases to illustrate important principles as well as possible controversies.
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Masked hypertension associates with left ventricular hypertrophy in children with CKD.
J. Am. Soc. Nephrol.
PUBLISHED: 11-16-2009
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Left ventricular hypertrophy (LVH) associates with increased risk for cardiovascular disease. Hypertension leads to LVH in adults, but its role in the pathogenesis of LVH in children is not as well established. To examine left ventricular mass and evaluate factors associated with LVH in children with stages 2 through 4 chronic kidney disease (CKD), we analyzed cross-sectional data from children who had baseline echocardiography (n = 366) and underwent ambulatory BP monitoring (n = 226) as a part of the observational Chronic Kidney Disease in Children (CKiD) cohort study. At baseline, 17% of children had LVH (11% eccentric and 6% concentric) and 9% had concentric remodeling of the left ventricle. On the basis of a combination of ambulatory and casual BP assessment (n = 198), 38% of children had masked hypertension (normal casual but elevated ambulatory BP) and 18% had confirmed hypertension (both elevated casual and ambulatory BP). There was no significant association between LVH and kidney function. LVH was more common in children with either confirmed (34%) or masked (20%) hypertension compared with children with normal casual and ambulatory BP (8%). In multivariable analysis, masked (odds ratio 4.1) and confirmed (odds ratio 4.3) hypertension were the strongest independent predictors of LVH. In conclusion, casual BP measurements alone are insufficient to predict the presence of LVH in children with CKD. The high prevalence of masked hypertension and its association with LVH supports early echocardiography and ambulatory BP monitoring to evaluate cardiovascular risk in children with CKD.
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Lymphoma in adolescents and young adults.
Semin. Oncol.
PUBLISHED: 10-20-2009
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Non-Hodgkin (NHL) and Hodgkin (HL) lymphomas are represented prominently in the adolescent and young adult (AYA) population. These diseases represent 11% of total cancer diagnoses in children, 4% in those 40 years of age and older, and 13% in AYA (aged 15-39 years). Although age-adjusted incidence rates of NHL increase with age, the more aggressive lymphomas are seen more commonly in the younger population with a transition to low-grade, indolent subtypes as the population ages. Burkitt lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and anaplastic large cell lymphoma make up the most common subtypes in the AYA population, although within the subgroup age 30-39 years, follicular lymphoma becomes more prominent. As a result, much of the armamentarium in the treatment of aggressive NHL and HL in adults is based on data from pediatric clinical trials. There are obvious limitations to this approach. It is vital that we gain a more thorough understanding of the biology and therapeutic responsiveness of NHL and HL in the AYA population. Thus, we must leverage the large prospective and retrospective trials that have been completed to date and redirect our approaches to cancer care in this unique population. We review the epidemiological data on NHL and HL from the Surveillance, Epidemiology and End Results registries as a cornerstone for a comparative analysis of therapeutic outcomes available in this population.
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Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease.
J. Clin. Oncol.
PUBLISHED: 10-13-2009
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Patients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.
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Severe hypertension in children and adolescents: pathophysiology and treatment.
Pediatr. Nephrol.
PUBLISHED: 09-15-2009
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Severe, symptomatic hypertension occurs uncommonly in children, usually only in those with underlying congenital or acquired renal disease. If such hypertension has been long-standing, then rapid blood pressure reduction may be risky due to altered cerebral hemodynamics. While many drugs are available for the treatment of severe hypertension in adults, few have been studied in children. Despite the lack of scientific studies, some agents, particularly continuous intravenous infusions of nicardipine and labetalol, are preferred in many centers. These agents generally provide the ability to control the magnitude and rapidity of blood pressure reduction and should--in conjunction with careful patient monitoring--allow the safe reduction of blood pressure and the avoidance of complications. This review provides a summary of the underlying causes and pathophysiology of acute severe hypertension in childhood as well as a detailed discussion of drug treatment and the optimal clinical approach to managing children and adolescents with acute severe hypertension.
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Relationship between adiponectin and ambulatory blood pressure in obese adolescents.
Pediatr. Res.
PUBLISHED: 05-12-2009
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Obesity is associated with elevated blood pressure (BP), insulin resistance, and altered plasma adiponectin levels; the relationship between the biochemical features of obesity and 24-h ambulatory blood pressure (24-h ABP) parameters in adolescents remains unknown. Anthropometric measurements and 24-h ABP monitoring were obtained on 41 obese adolescents with and without type 2 diabetes mellitus (T2DM). Serum adiponectin, high sensitivity C-reactive protein (hs-CRP), lipid profile, insulin, fasting glucose, liver enzymes, Hb A1c (HbA1c), and two random urine samples were obtained for creatinine and microalbumin measurements. The determinants of 24-h systolic (SBP) and diastolic (DBP) BP were examined using multivariate linear regression models with BP parameters as outcome variables. Forty-one obese adolescents were studied. Adiponectin levels were reduced and hs-CRP levels were elevated, and were inversely and significantly correlated (rho = -0.3, p = 0.05). ABP showed blunted nocturnal SBP dipping. Twenty-four hour SBP and DBP indexes were significantly (p < 0.05) and inversely correlated with adiponectin (rho = -0.4 and -0.42), respectively. In multivariate models, lower adiponectin level was independently associated with 24-h SBP and DBP. Adiponectin inversely correlate with ABP parameters in obese adolescents. Larger studies are needed to examine the relationship between adiponectin and mechanisms of BP regulation.
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Outcome of dialysis in children with human immunodeficiency virus infection.
Pediatr. Nephrol.
PUBLISHED: 04-17-2009
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Human immunodeficiency virus (HIV) infection accounts for an unknown percentage of children with end-stage kidney disease (ESKD). Our objective was to compare the outcome of renal replacement therapy (RRT) in subjects with ESKD due to HIV and other diagnoses and to examine the prevalence of ESKD due to HIV. We analyzed Kt/V, morbidity, mortality, echocardiography, nutritional, and transplant status in 12 dialysis patients with HIV and 32 without HIV followed at our center between February 2002 and February 2007. Body mass index (BMI) was lower and Kt/V higher in HIV than in non-HIV patients. Shortening fraction was significantly lower in HIV patients. There were six deaths in the HIV group and one in the non-HIV group over the study period. Hemodialysis (HD) is the prevalent mode of RRT in HIV in urban settings, and its adequacy as measured by Kt/V was higher in HIV patients than in non-HIV patients. Decreased BMI and cardiovascular disease may be associated with increased mortality in children with HIV on RRT.
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Evaluation and treatment of hypertension in general pediatric practice.
Clin Pediatr (Phila)
PUBLISHED: 02-07-2009
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Hypertension (HTN) in children and adolescents has become increasingly common. We sought to identify variability in the approach to HTN among general pediatricians as well as obstacles to care of hypertensive youth by surveying pediatricians referring to an urban childrens hospital. Although most pediatricians begin blood pressure measurement at 3 years, there was substantial variability in the initial diagnostic evaluation of hypertensive patients. Just 7% of pediatricians routinely start antihypertensive drug treatment for HTN, whereas 82% refer their hypertensive patients to a specialist; 40% of pediatricians felt uncomfortable evaluating and treating HTN. Pediatricians unfamiliar with The Fourth Report were more likely to be uncomfortable with the care of hypertensive patients than those familiar with it (54% vs 33%, P < .05). Current practice does not appear to follow recent consensus recommendations. Interventions designed to address the issues identified in this survey may lead to improved care for pediatric patients with HTN.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.