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Palestro C.J.,Hofstra North Shore LIJ | Palestro C.J.,North Shore Long Island Jewish Health System | Palestro C.J.,Long Island Jewish Medical Center | Glaudemans A.W.J.M.,University of Groningen | Dierckx R.A.J.O.,University of Groningen
Clinical and Translational Imaging | Year: 2013

Molecular imaging with single photon- and positron-emitting tracers plays an important role in the evaluation of inflammation and infection. Although supplanted by labeled leukocyte imaging for most indications, gallium-67 remains useful for opportunistic infections, pulmonary inflammation and interstitial nephritis and, when [18F]FDG is not available, spinal infection and fever of unknown origin. In vitro labeled leukocyte imaging is the radionuclide procedure of choice for most infections in immunocompetent patients. When performed for musculoskeletal infection, complementary bone marrow imaging usually is necessary. Recent data suggest that dual time point imaging might be an alternative to marrow imaging. Several methods of labeling leukocytes in vivo, with agents including antigranulocyte antibodies and antibody fragments, peptides and cytokines, have been investigated, with variable results. These agents are not widely available and none of them are available in the USA. Radiolabeled antibiotics have been investigated as "infection-specific" tracers, but the results to date have been disappointing. Conversely, radiolabeled antimicrobial peptides do hold promise as infection-specific tracers. The use of positron-emitting tracers for diagnosing inflammation and infection has generated considerable interest. [18F]FDG is useful in fever of unknown origin, spinal osteomyelitis, vasculitis and sarcoidosis. Other positron-emitting tracers that have been investigated include [18F]FDG-labeled leukocytes, copper-64-labeled leukocytes, gallium-68 citrate and iodine-124 FIAU. Although radiolabeled tracers are used primarily for diagnosis, they also offer objective biomarkers for assessing response to therapeutic interventions in inflammatory diseases. They could also potentially be used to target cells and molecules with specific receptor expression for histological characterization, select patients for receptor-targeted therapy and predict response to treatment. © 2013 Italian Association of Nuclear Medicine and Molecular Imaging.


Mebazaa A.,University Paris Diderot | Spiro T.E.,Bayer AG | Haskell L.,Janssen Research and Development LLC | Hu D.,Peking University | And 7 more authors.
Circulation | Year: 2014

Background - Whether heart failure (HF) increases the risk of venous thromboembolism (VTE) is not well established. In the phase III MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) trial, extended-duration rivaroxaban was compared with standard-duration enoxaparin followed by placebo for VTE prevention in 8101 hospitalized acutely ill patients with or without HF. The aim of this analysis was to evaluate the relationship between HF severity and the risk of VTE in MAGELLAN patients. Methods and Results - Hospitalized patients diagnosed with HF were included according to New York Heart Association class III or IV at admission (n=2593). HF severity was determined by N-terminal probrain natriuretic peptide (NT-proBNP) plasma concentrations (median 1904 pg/mL). Baseline plasma D-dimer concentrations ranged from 0.6 to 1.7 μg/L for the less and more severe HF subgroups. Patients with more severe HF had a greater incidence of VTE versus patients with less severe HF, with a significant trend up to Day 10 (4.3% versus 2.2%; P=0.0108) and Day 35 (7.2% versus 4.1%; P=0.0150). Multivariable analysis confirmed that NT-proBNP concentration was associated with VTE risk up to Day 10 (P=0.017) and D-dimer concentration with VTE risk up to Day 35 (P=0.005). The association between VTE risk and HF severity that was observed in the enoxaparin/placebo group was not seen in the extended-duration rivaroxaban group. Conclusions - Patients with more severe HF, as defined by high NT-proBNP plasma concentration, were at increased risk of VTE. NT-proBNP may be useful to identify high short-term risk, whereas elevated D-dimer may be suggestive of high midterm risk. Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT00571649. © 2014 American Heart Association, Inc.


PubMed | Hofstra North Shore LIJ, University of Turku, Garvan Institute of Medical Research, St Vincents Hospital and 3 more.
Type: | Journal: Journal of magnetic resonance imaging : JMRI | Year: 2016

To evaluate in a multi-institutional study whether radiomic features useful for prostate cancer (PCa) detection from 3 Tesla (T) multi-parametric MRI (mpMRI) in the transition zone (TZ) differ from those in the peripheral zone (PZ).3T mpMRI, including T2-weighted (T2w), apparent diffusion coefficient (ADC) maps, and dynamic contrast-enhanced MRI (DCE-MRI), were retrospectively obtained from 80 patients at three institutions. This study was approved by the institutional review board of each participating institution. First-order statistical, co-occurrence, and wavelet features were extracted from T2w MRI and ADC maps, and contrast kinetic features were extracted from DCE-MRI. Feature selection was performed to identify 10 features for PCa detection in the TZ and PZ, respectively. Two logistic regression classifiers used these features to detect PCa and were evaluated by area under the receiver-operating characteristic curve (AUC). Classifier performance was compared with a zone-ignorant classifier.Radiomic features that were identified as useful for PCa detection differed between TZ and PZ. When classification was performed on a per-voxel basis, a PZ-specific classifier detected PZ tumors on an independent test set with significantly higher accuracy (AUC=0.61-0.71) than a zone-ignorant classifier trained to detect cancer throughout the entire prostate (P<0.05). When classifiers were evaluated on MRI data from multiple institutions, statistically similar AUC values (P>0.14) were obtained for all institutions.A zone-aware classifier significantly improves the accuracy of cancer detection in the PZ.3 J. Magn. Reson. Imaging 2016.


Fishbane S.,Hofstra North Shore LIJ | Bolton W.K.,University of Virginia | Winkelmayer W.C.,Stanford University | Strauss W.,AMAG Pharmaceuticals | And 2 more authors.
Clinical Nephrology | Year: 2012

Background: Ferumoxytol is a unique intravenous (i.v.) iron therapy. This report examines factors affecting hemoglobin response to i.v. ferumoxytol, and the relationship between hematologic parameters, concomitant erythropoiesis-stimulating agents (ESA), and adverse events (AEs) in nondialysis CKD patients. Methods: A series of post-hoc efficacy and safety analyses were performed using pooled data from two identically designed Phase III studies in 608 nondialysis CKD patients randomized to receive two 510 mg i.v. injections of ferumoxytol within 5 ± 3 days versus oral iron. Results:Ferumoxytol resulted in a significant increase in hemoglobin in the presence and absence of ESA, and across a range of baseline hemoglobin, transferrin saturation, ferritin, and reticulocyte hemoglobin content levels. Adverse event rates with ferumoxytol were similar across quartiles of change in hemoglobin; there were no trends suggesting an increased rate of cardiovascular AEs with higher maximum achieved hemoglobin or faster rate of hemoglobin rise. There was no meaningful difference in the rate of AEs, serious AEs, and cardiovascular AEs between patients receiving or not receiving ESA. Conclusions: These analyses add to the knowledge of predictors of response and safety outcomes associated with i.v. iron therapy in nondialysis CKD patients. ©2012 Dustri-Verlag Dr. K. Feistle.


Campbell-Thompson M.,University of Florida | Wasserfall C.,University of Florida | Kaddis J.,City of Hope | Albanese-O'Neill A.,University of Florida | And 10 more authors.
Diabetes/Metabolism Research and Reviews | Year: 2012

Background: The Network for Pancreatic Organ Donors with Diabetes (nPOD) was established to recover and characterize pancreata and related organs from cadaveric organ donors with various risk levels for type 1 diabetes (T1D). These biospecimens are available to investigators for collaborative studies aimed at addressing questions related to T1D natural history and pathogenesis. Research design and methods: Organ donors included T1D patients (new onset to long term), non-diabetic autoantibody-positive subjects, non-diabetic controls and individuals with disorders relevant to β-cell function. Pancreas recovery and transport met transplant-grade criteria. Additional samples recovered included serum, whole blood, spleen and pancreatic and non-pancreatic lymph nodes. Biospecimens were processed for cryopreserved cells, fixed paraffin and fresh frozen blocks and snap frozen samples. T1D autoantibodies, C-peptide levels and high-resolution HLA genotyping for risk alleles were also determined. Results: Over 160 donors have been enrolled (ages of 1day to >90years). Standard operating procedures were established along with a quality management system. Donor demographics, laboratory assays and histopathological characterizations were shared through an open online informatics system. Biospecimens were distributed to more than 60 investigators. Conclusions: The nPOD programme provides access to high quality biospecimens without cost to investigators. Collaborations and open data sharing are emphasized to maximize research potential of each donor. On the basis of initial successes, the nPOD programme is expanding to recover additional organs relevant to T1D pathogenesis and complications from European countries (PanFin network). © 2012 John Wiley & Sons, Ltd.


Dulmovits B.M.,Feinstein Institute for Medical Research | Appiah-Kubi A.O.,Feinstein Institute for Medical Research | Papoin J.,Feinstein Institute for Medical Research | Hale J.,New York Blood Center | And 19 more authors.
Blood | Year: 2016

Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably,the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levelsin their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies. (Blood. 2016;127(11):1481-1492) © 2016 by The American Society of Hematology.


Mathew A.T.,Hofstra North Shore LIJ | Strippoli G.F.M.,Diaverum Medical Scientific Office | Strippoli G.F.M.,University of Sydney | Strippoli G.F.M.,University of Bari | And 4 more authors.
Kidney International | Year: 2015

ESKD patients have a large burden of disease, with high rates of readmission to hospital compared with the general population. A readmission after an acute index hospital discharge is either planned or unplanned. A proportion of unplanned readmissions are potentially avoidable, and could have been prevented with optimized transitional care. Readmissions pose financial cost to the health care system and emotional cost to patients and caregivers. In other chronic diseases with high readmission risk, such as congestive heart failure, interventions have improved transitional care and reduced readmission risk. In reviewing the existing literature on readmissions in ESKD, the definition and risk of readmission varied widely by study, with many potentially associated factors including comorbid diseases such as anemia and hypoalbuminemia. An ESKD patient's requisite follow-up in the outpatient dialysis facility provides an opportunity to improve transitional care at the time of discharge. Despite this, our review of existing literature found no studies which have tested interventions to reduce the risk of readmission in ESKD patients. We propose a framework to define the determinants of avoidable readmission in ESKD, and use this framework to define a research agenda. Avoidable readmissions in ESKD patients is a topic prime for in-depth study, given the high-risk nature in this patient population, financial and societal costs, and potential for risk modification through targeted interventions. © 2015 International Society of Nephrology.


Shah K.G.,Hofstra North Shore LIJ | Wu R.,Feinstein Institute for Medical Research | Jacob A.,Feinstein Institute for Medical Research | Molmenti E.P.,Hofstra North Shore LIJ | And 4 more authors.
Intensive Care Medicine | Year: 2012

Purpose: Animal milk fat globule-EGF factor 8 (MFG-E8) has been shown to be beneficial in attenuating the inflammatory response in sepsis. In this study, we examined the effect of recombinant human MFG-E8 (rhMFG-E8) in an animal model of sepsis in an effort to develop it as a potential therapy against sepsis in humans. Methods: Rats were subjected to sepsis by cecal ligation and puncture (CLP), and at 5 h post-CLP, they were given different doses of rhMFG-E8 (20, 40, 80, 160 μg/kg BW) in normal saline. At 20 h post-CLP, samples were collected for further analysis. A 10-day survival study was also performed. Results: At 20 h after CLP, organ injury indicators, serum IL-6 and TNF-α, and plasma HMGB-1 levels were significantly increased as compared to sham-operated animals. Treatment with 20 μg/kg rhMFG-E8 significantly reduced these levels. With higher doses, further reductions in AST and ALT (59-62%), creatinine (65-68%), and lactate (46-57%), and serum IL-6 and TNF-α were obtained. The 160 lg/kg dose produced the greatest reduction in serum TNF-α. With treatment with 20 μg/kg rhMFG-E8, HMGB-1 levels decreased by 80%, returning back to sham values. In a 10-day survival study, vehicle-treated animals produced a 36% survival rate, while rhMFG-E8 significantly improved the survival rate to 68-72%. Treatment with increasing doses of rhMFG-E8 significantly reduced the number of apoptotic cells detected and markedly attenuated the tissue damages observed in the lungs. Conclusions: These data suggest that recombinant human MFG-E8 is beneficial in ameliorating sepsis in an animal model of sepsis. © jointly held by Springer and ESICM 2011.

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