Clinical Blood Flow Quantification with Segmented k-Space Magnetic Resonance Phase Velocity Mapping

To evaluate the accuracy of segmented k-space magnetic resonance phase velocity mapping (PVM) in quantifying aortic blood flow from through-plane velocity measurements. Two segmented PVM schemes were evaluated, one with seven lines per segment (seg-7) and one with nine lines per segment (seg-9), in twenty patients with cardiovascular disease. A non-segmented (non-seg) PVM acquisition was also performed to provide the reference data. There was agreement between the aortic flow curves acquired with segmented and non-segmented PVM. The calculated systolic and total flow volume per cycle from the seg-7 and the seg-9 scans correlated and agreed with the flow volumes from the non-seg scans (differences \u3c 5%). Sign tests showed that there were no statistically significant differences (P-values \u3c 0.05) between the segmented and the non-segmented PVM measurements. Seg-9, which was the fastest among the three sequences, provided adequate spatial and temporal resolution (\u3e 10 phases per cycle)

Cardiac magnetic resonance findings predict increased resource utilization in elective coronary artery bypass grafting

Morbidity following CABG (coronary artery bypass grafting) is difficult to predict and leads to increased healthcare costs. We hypothesized that pre-operative CMR (cardiac magnetic resonance) findings would predict resource utilization in elective CABG. Over a 12-month period, patients requiring elective CABG were invited to undergo CMR 1 day prior to CABG. Gadolinium-enhanced CMR was performed using a trueFISP inversion recovery sequence on a 1.5 tesla scanner (Sonata; Siemens). Clinical data were collected prospectively. Admission costs were quantified based on standardized actual cost/day. Admission cost greater than the median was defined as 'increased'. Of 458 elective CABG cases, 45 (10%) underwent pre-operative CMR. Pre-operative characteristics [mean (S.D.) age, 64 (9) years, mortality (1%) and median (interquartile range) admission duration, 7 (6–8) days] were similar in patients who did or did not undergo CMR. In the patients undergoing CMR, eight (18%) and 11 (24%) patients had reduced LV (left ventricular) systolic function by CMR [LVEF (LV ejection fraction) <55%] and echocardiography respectively. LE (late enhancement) with gadolinium was detected in 17 (38%) patients. The average cost/day was $2723. The median (interquartile range) admission cost was$19059 ($10891–157917). CMR LVEF {OR (odds ratio), 0.93 [95% CI (confidence interval), 0.87–0.99]; P=0.03} and SV (stroke volume) index [OR 1.07 (95% CI, 1.00–1.14); P=0.02] predicted increased admission cost. CMR LVEF (P=0.08) and EuroScore tended to predict actual admission cost (P=0.09), but SV by CMR (P=0.16) and LV function by echocardiography (P=0.95) did not. In conclusion, in this exploratory investigation, pre-operative CMR findings predicted admission duration and increased admission cost in elective CABG surgery. The cost-effectiveness of CMR in risk stratification in elective CABG surgery merits prospective assessment

Chronic non-transmural infarction has a delayed recovery of function following revascularization

<p>Abstract</p> <p>Background</p> <p>The time course of regional functional recovery following revascularization with regards to the presence or absence of infarction is poorly known. We studied the effect of the presence of chronic non-transmural infarction on the time course of recovery of myocardial perfusion and function after elective revascularization.</p> <p>Methods</p> <p>Eighteen patients (mean age 69, range 52-84, 17 men) prospectively underwent cine magnetic resonance imaging (MRI), delayed contrast enhanced MRI and rest/stress 99m-Tc-tetrofosmin single photon emission computed tomography (SPECT) before, one and six months after elective coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).</p> <p>Results</p> <p>Dysfunctional myocardial segments (n = 337/864, 39%) were classified according to the presence (n = 164) or absence (n = 173) of infarction. Infarct transmurality in dysfunctional segments was largely non-transmural (transmurality = 31 ± 22%). Quantitative stress perfusion and wall thickening increased at one month in dysfunctional segments without infarction (p < 0.001), with no further improvement at six months. Despite improvements in stress perfusion at one month (p < 0.001), non-transmural infarction displayed a slower and lesser improvement in wall thickening at one (p < 0.05) and six months (p < 0.001).</p> <p>Conclusions</p> <p>Dysfunctional segments without infarction represent repetitively stunned or hibernating myocardium, and these segments improved both perfusion and function within one month after revascularization with no improvement thereafter. Although dysfunctional segments with non-transmural infarction improved in perfusion at one month, functional recovery was mostly seen between one and six months, possibly reflecting a more severe ischemic burden. These findings may be of value in the clinical assessment of regional functional recovery in the time period after revascularization.</p

Demographic, clinical, diagnostic and therapeutic data of hereditary spherocytosis in our country. A study on 143 cases belonging to 84 families

Introducción. La esferocitosis hereditaria (ESH) es la anemia hemolítica hereditaria más frecuente, pero es muy escasa la información sobre su comportamiento en nuestro país. Objetivos. Comunicar aspectos demográficos, clínicos, diagnósticos y terapéuticos de la enfermedad. Pacientes y métodos. Se revisaron datos de los pacientes estudiados desde 2007, año en que incorporamos al estudio de laboratorio clásico - fragilidad osmótica eritrocitaria (FOE) y autohemólisis (AH) - criohemólisis hipertónica (CH), citometría de flujo con eosina-5’-maleimida (5’EMA-CF) y electroforesis de proteínas de membrana (SDS-PAGE); desde 2009 también incorporamos FOE por citometría de flujo (FOE-CF). Criterios diagnósticos para ESH: visualización de esferocitos en frotis y dos pruebas positivas. Portador sano (PS): familiar con deficiencia de proteína de membrana, pero asintomático y con las otras pruebas negativas. Resultados. Se analizaron 281 individuos, identificando 121 ESH y 22 PS. Porcentajes de positividad de las pruebas: FOE 92,2%, AH 75,7%, SDS-PAGE 72,2%, CH 93,3%, 5’EMA-CF 91,3%, FOE-CF 86,3%. De los 69 casos en que se realizaron las tres nuevas técnicas, todos tuvieron al menos una positiva; 63 (91,3%) presentaron 2 positivas. La SDS-PAGE mostró que las deficiencias más frecuentes fueron ankirina y espectrina. Clasificación por formas clínicas: leves 33,7%, moderadas 44,2%, severas 22,1%. Presentaron manifestaciones en periodo neonatal el 80,9% de los casos, siendo mayor la incidencia en las formas moderadas/ severas que en las leves (p<0,05). No hubo diferencia en el resultado de las pruebas entre los subgrupos de severidad. Se esplenectomizaron 24 pacientes. Todos alcanzaron valores de hemoglobina normales después de la operación, sostenidos en el tiempo. No hubo ningún episodio infeccioso severo. Conclusiones. Las deficiencias más frecuentes en nuestro país son ankirina y espectrina. El uso simultáneo de CH, 5’EMA-CF y FOE-CF permite diagnosticar más del 91% de los casos; la realización de las pruebas convencionales quedaría limitada a casos con fuerte sospecha diagnóstica no confirmados por las mismas. A excepción de mayor incidencia de manifestaciones neonatales, el comportamiento clínico en nuestra población no presentó diferencias con lo informado por la mayoría de los autores. No hubo casos de muerte o sepsis fulminante postesplenectomía.Background. Hereditary spherocytosis (HS) is the most common inherited hemolytic anemia; however, information concerning its behavior in our country is scarce. Aim. To report demographic, clinical, diagnostic, and therapeutic data on the disease. Patients and methods. In 2007 we started performing hypertonic cryohemolysis (HC), 5’EMA flow cytometry (5’EMA-FC), and membrane proteins electrophoresis (SDS-PAGE) in addition to standard tests – osmotic fragility (OF) and autohemolysis (AH) - for evaluation of patients with HS. Since 2009 we added flow cytometric OF (OF-FC). Data from all patients studied from 2007 were analyzed. Diagnostic criteria for HS: spherocytes in blood smear plus two positive tests. Silent carrier (SC): family member with protein deficiency but otherwise asymptomatic and negative for other tests. Results. The study included 281 individuals; 121 HS and 22 SC were identified. Tests positivity rates were: OF 92.2%, AH 75.7%, SDS-PAGE 72.2%, HC 93.3%, 5’EMAFC 91.3%, OF-FC 86.3%. All of the 69 cases in whom the three new procedures were performed had at least one positive test; 63 of them (91.3%) presented two positive tests. The SDS-PAGE showed that the most frequent deficiencies were ankyrin and spectrin. Classification by severity of anemia: mild 33.7%, moderate 44.2%, severe 22.1%. Neonatal manifestations were seen in 80.9% of cases; the incidence was higher in moderate/severe than in mild anemias (p<0.05). Comparison of tests results in relation to severity showed no difference between groups. Splenectomy was performed in 24 patients. All of them reached sustained normal hemoglobin values after the procedure. No life-threatening infection occurred. Conclusions. Most frequent deficiencies in our country are ankyrin and spectrin. The simultaneous use of HC, 5’EMA-FC y OF-FC allows confirming the diagnosis in more than 91% of cases. Except for a higher incidence of neonatal manifestations, the clinical pattern in our population showed no difference with that reported by most authors. No case of death or overwhelming fulminant sepsis post-splenectomy was seen.Fil: Donato, Mariano Humberto. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Crisp, R. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: García, E. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Rapetti, MC. Hospital Nacional Profesor Alejandro Posada; ArgentinaFil: Solari, L. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Vota, Daiana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Chamorro, María Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Schvartzman, G. Hospital Nacional Profesor Alejandro Posada; ArgentinaFil: Miguez, G. Hospital Nacional Profesor Alejandro Posada; ArgentinaFil: Gammela, D. Hospital Nacional Profesor Alejandro Posada; ArgentinaFil: Vittori, Daniela Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Nesse, Alcira Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

Integrated Genomic and Gene Expression Profiling Identifies Two Major Genomic Circuits in Urothelial Carcinoma

Similar to other malignancies, urothelial carcinoma (UC) is characterized by specific recurrent chromosomal aberrations and gene mutations. However, the interconnection between specific genomic alterations, and how patterns of chromosomal alterations adhere to different molecular subgroups of UC, is less clear. We applied tiling resolution array CGH to 146 cases of UC and identified a number of regions harboring recurrent focal genomic amplifications and deletions. Several potential oncogenes were included in the amplified regions, including known oncogenes like E2F3, CCND1, and CCNE1, as well as new candidate genes, such as SETDB1 (1q21), and BCL2L1 (20q11). We next combined genome profiling with global gene expression, gene mutation, and protein expression data and identified two major genomic circuits operating in urothelial carcinoma. The first circuit was characterized by FGFR3 alterations, overexpression of CCND1, and 9q and CDKN2A deletions. The second circuit was defined by E3F3 amplifications and RB1 deletions, as well as gains of 5p, deletions at PTEN and 2q36, 16q, 20q, and elevated CDKN2A levels. TP53/MDM2 alterations were common for advanced tumors within the two circuits. Our data also suggest a possible RAS/RAF circuit. The tumors with worst prognosis showed a gene expression profile that indicated a keratinized phenotype. Taken together, our integrative approach revealed at least two separate networks of genomic alterations linked to the molecular diversity seen in UC, and that these circuits may reflect distinct pathways of tumor development

The Complete Spectrum of Yeast Chromosome Instability Genes Identifies Candidate CIN Cancer Genes and Functional Roles for ASTRA Complex Components

Chromosome instability (CIN) is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ∼2,000 reduction-of-function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2) complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease

Nanotopographical induction of osteogenesis through adhesion, bone morphogenic protein cosignaling, and regulation of microRNAs

It is emerging that nanotopographical information can be used to induce osteogenesis from mesenchymal stromal cells from the bone marrow and it is hoped that this nanoscale bioactivity can be utilized to engineer next generation implants. However, the osteogenic mechanism of surfaces is currently poorly understood. In this report, we investigate mechanism and implicate bone morphogenic protein (BMP) in up-regulation of RUNX2 and show that RUNX2 and its regulatory miRNAs are BMP sensitive. Our data demonstrates that osteogenic nanotopography promotes co-localization of intergrins and BMP2 receptors in order to enhance osteogenic activity and that vitronectin is important in this interface. This provides insight that topographical regulation of adhesion can have effects on signaling cascades outside of cytoskeletal signaling and that adhesions can have roles in augmenting BMP signaling