tbuckley/cabot-search huggingface dataset:
Abstract 5317: Identification and Characterization of a Novel Susceptibility Gene, <i>SCN3B,</i> for Idiopathic Ventricular Fibrillation
Authors: Carmen R Valdivia, Argelia Mereidos-Domingo, Thimothy J Algiers, Michael J Ackerman, Jonathan C Makielski
Journal: Circulation (2008)

Background: Mutations in the Na V 1.5 sodium channel macromolecular complex have been identified in some cases classified as idiopathic ventricular fibrillation (IVF). IVF and Brugada syndrome (BrS) are partially overlapping syndromes. Here, we report a mutation in SCN3B- encoded sodium channel β3 subunit as a novel pathogenic mechanism for IVF. Methods: Comprehensive open reading frame mutational analysis of SCN5A, GPD1L, and the beta subunit genes ( SCN1–4B ) was performed using PCR, DHPLC, and direct DNA sequencing of DNA extracted from a 20-year-old patient diagnosed with IVF. The SCN3B mutation was made by site directed mutagenesis and co-transfected with SCN5A into HEK-293 cells for functional chraracterization using the patch clamp technique. Results: A novel missense mutation, V54G-SCN3B, was identified in a 20-year-old male following collapse and external defibrillation from VF. After recovery, there was no detectable electrocardiographic abnormality. Imaging studies demonstrated a structurally normal heart, and the patient was diagnosed with IVF. The mutation was absent in 800 reference alleles and involved a highly conserved residue in the extracellular domain of the beta 3 subunit. No other mutations were identified in the 5 other genes. HEK cells expressing SCN5A and either WT-, or V54G-SCN3B were studied 24 hours after transfection. Cells expressing V54G-SCN3B showed significant decrease in sodium current density of 60±20 pA/pF compared to 203±35 pA/pF in WT-SCN3B (n=14–19). In addition V54G-SCN3B significantly shifted the activation curve +5 mV without affecting inactivation. Conclusions: This study provides the first molecular and cellular evidence implicating SCN3B in IVF. Given the marked loss-of-function to the sodium channel by V54G-SCN3B and the overlap between IVF and BrS, it will be interesting to determine whether mutations in SCN3B explain some cases of genotype negative Brugada syndrome.
Abstract 434: A New Drug Delivery System Using Fibronectin-vegf Fusion Is More Effective And Harmless Than Vegf Alone For The Therapeutic Neovascularization
Authors: Takahiro inoue, Kensuke Egashira, Tomomi Ide, Takaki Tsutsumi, Yoshiya Monden, Mitsuki Kubo, Takashi Kitajima, Toru Kubota, Kenji Sunagawa
Journal: Circulation (2007)

Background: Recent clinical trials for therapeutic angiogenesis reported limited efficacy. To overcome these limitations, we developed a fusion protein of fibronectin (Fn) and VEGF (Fn-VEGF), with high collagen affinity, binding to extracellular matrix of ischemic area. We hypothesized that controlled delivery of VEGF using this protein is useful for therapeutic angiogenesis. Methods and Results: We examined biological effects of Fn-VEGF on human endothelial cells cultured on collagen coated dishes, and found that a single administration of Fn-VEGF caused sustained proliferation at least for a week. We then produced hindlimb ischemia in mice, and injected PBS, VEGF, Fn, or Fn-VEGF (10 μg/day) into ischemic muscles. Fn-VEGF retained in the injected area for 5 days, whereas VEGF alone rapidly disappeared from the injected area after 3 hours. Moreover, injection of Fn-VEGF enhanced recovery of blood perfusion of ischemic limb, the degrees of which is greater than those afforded by VEGF (Fn-VEGF 94.1 ±12.3 vs VEGF 72.3 ±9.2 %, p&lt;0.01). Importantly, Fn-VEGF enhanced limb salvage rate better than VEGF, and high dose administration of VEGF worsened limb ischemia up to complete amputation, whereas high dose Fn-VEGF (40 μg/day) represented a proper effect (Figure ). Moreover, as well as VEGF, Fn-VEGF has also capacity making mononuclear cells to endothelial progenitor cells, and induced proper degree of angiogenesis from endothelial cells. Conclusions: Injection of Fn-VEGF was more effective and harmless than VEGF, suggesting that controlled delivery of VEGF using this protein may be a clinically useful and feasible strategy for next-generation neovascularization.
Abstract 12390: Association of Plaque Morphology and Tissue Prolapse by OCT with Periprocedural (Type IVa) Myocardial Infarction
Authors: Italo Porto, Luca Di Vito, Francesco Burzotta, Gianpaolo Niccoli, Carlo Trani, Antonio M Leone, Luigi M Biasucci, Rocco Vergallo, Ugo Limbruno, Filippo Crea
Journal: Circulation (2011)

Background: Frequency Domain-Optical Coherence Tomography (FD-OCT) is able to define both pre- and post stenting features of the atherosclerotic plaque. We sought to examine whether FD-OCT-defined ...
Nonlinkage of bipolar illness to tyrosine hydroxylase, tyrosinase, and D2 and D4 dopamine receptor genes on chromosome 11
Authors: A De bruyn, K Mendelbaum, L A Sandkuijl, V Delvenne, D Hirsch, L Staner, J Mendlewicz, C Van Broeckhoven
Journal: American Journal of Psychiatry (1994)

Previous linkage and allelic association studies using DNA polymorphisms, cosegregation of cytogenetic abnormalities with psychiatric illness, and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness. The authors examined linkage in the families of 14 probands with bipolar illness, with the candidate genes tyrosine hydroxylase (TH), D4 dopamine receptor (DRD4) at 11p15, tyrosinase (TYR) at 11q14-q21, and D2 dopamine receptor (DRD2) at 11q22-q23, as well as with the c-Harvey-ras oncogene (HRAS) and insulin gene (INS), both located at 11p15, a region that previously showed linkage to bipolar illness.The genetic data were analyzed with both lod score analysis (parametric) and affected-sib-pair analysis (nonparametric); both narrow and broad definitions of the clinical phenotype were used. Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype.Two-point linkage results excluded close linkage of bipolar illness to each candidate gene; negative results were also obtained when the narrow definition of the clinical phenotype was used. Moreover, multipoint linkage analysis of HRAS and INS excluded the 11p15 region encompassing both DRD4 and TH. In agreement with the negative linkage results, affected-sib-pair analysis did not show preferential sharing of marker alleles at any of the candidate genes.The negative results obtained under different genetic models exclude a frequent role for DRD4, TH, TYR, and DRD2 in the pathogenesis of bipolar illness.
Mental changes associated with hyperparathyroidism
Authors: J W Gatewood, C H Organ, B T Mead
Journal: American Journal of Psychiatry (1975)

To document the point that the hyperparathyroidism should be considered a possible cause of unexplained neurological and psychiatric symptoms, the authors present five case reports of confirmed primary hyperparathyroidism in which the patients initially appeared with problems that seemed mainly psychiatric. The presenting symptoms in these cases consisted of varying degrees of depression, catatonia, confusion, disorientation, fatigue, and lethargy; there was no associated bone or renal pathology in four of the cases. The authors include a review of the pertinent literature and a discussion of the effect of calcium and magnesium bivalent ions on the central nervous system associated with hyperparathyroidism. They conclude that more investigation of the role of magnesium in this disease seems warranted.
Abstract 3358: Resistance to Endogenous Erythropoietin Predicts Survival in Anemic Heart Failure Patients
Authors: Peter Van Der Meer, Dirk J Lok, Erik Lipsic, Jan Van Wijngaarden, Pieta W Brugginnk, Adriaan A Voors, Wiek H Van Gilst, Dirk J Van Veldhuisen
Journal: Circulation (2007)

Background In response to hypoxia the kidney produces erythropoietin (EPO). Elevated levels of EPO are observed in patients with chronic heart failure (CHF) and are related to an impaired outcome. However it is unknown whether these EPO-levels are adequate for the degree of anemia and how the adequacy of EPO levels relates to prognosis. Methods Therefore, we studied 240 CHF patients (96% were in NYHA functional class III). The adequacy of EPO levels was assessed by an observed-predicted ratio. A value &lt;0.9 indicates inadequate low EPO levels (=blunted EPO-response), whereas &gt;1.1 indicates inappropriate high EPO levels (=EPO resistance). Group comparisons were therefore made between low EPO responders n = 30 normal EPO responders n = 25 EPO-resistance n = 22. Anemia was defined according to the WHO definition (males and postmenopausal females Hemoglobin (Hb) &lt; 3.0 g/dL and premenopausal females Hb &lt; 12.0 g/dL). The primary endpoint was mortality. Results During a median follow up of 3.8 years, 98 patients died (41.4% mortality rate). EPO levels were an independent predictor of mortality, also adjusted for hemoglobin levels (HR 1.013, 95%CI [1.007–1.018], p=0.001). Anemia was present in 77 (32%) patients. Inadequate low EPO levels were observed in 30 anemic patients (39%) and related to renal failure (glomerular filtration rate &lt; 30 ml/min/1.73m2 (p&lt;0.009). EPO resistance was present in 22 anemic patients (29%) and was associated with a significant higher mortality rate compared to patients with a normal EPO response and a low EPO response, 72.7% vs 34.8% and 40.0% respectively (p=0.012 and p=0.021, respectively). EPO resistance was an independent predictor of an increased mortality risk in Cox regression analyses adjusted for variables with p&lt;0.10 in the univariate analysis including age, sex and high sensitive CRP; HR 2.63 95%CI [1.12– 6.17], p=0.026, whereas a low EPO response was not associated with an impaired outcome; HR 1.12 95% CI [0.45–2.79], p=0.81, compared to normal EPO responders. Conclusion EPO resistance is common in CHF patients and is associated with a high mortality.
Abstract 17078: Soluble Flt-1 Deficiency Plays a Significant Role in the Exacerbation of Cardiac Hypertrophy and Heart Failure
Authors: Ayako Seno, Yukiji Takeda, Masaru Matsui, Yasuki Nakada, Tomoya Ueda, Aya Okuda, Bart Jonckx, Hitoshi Nakagawa, Kenji Onoue, Makoto Watanabe, Hiroyuki Kawata, Rika Kawakami, Shiro Uemura, Yoshihiko Saito
Journal: Circulation (2014)

Background:  Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease including heart failure, cardiac hypertrophy, and atherosclerosis which is called cardio-renal syndrome (CRS), however, its underling molecular mechanism is not fully understood. In our previous data, soluble Flt-1 (sFlt-1), which is endogenous inhibitor of PLGF (placental growth factor), can be a key molecule of CRS. Soluble Flt-1 production was decreased with the progression of renal diseases, and sFlt-1 deficiency results in progression of atherosclerosis using double knock-out mice (sFlt-1-/-ApoE-/-). In this study, we examined the role of PLGF/Flt-1 system in heart failure and cardiac hypertrophy using sFlt-1-/- mice which mimics CKD condition.   Methods and Results:  Soluble Flt-1 deficient mice and their wild type littermates (WT) were subjected to transverse aortic constriction (TAC), and evaluated after 7 days. Almost half of sFlt-1-/- died within 1 week after TAC, though 85% of WT survived. sFlt-1 deficiency aggravated cardiomegaly and lung-weight to body-weight ratios compared with WT after TAC, which indicates sFlt-1-/- is susceptible to heart failure by pressure-overload. LV wall thickening was significantly increased and ejection fraction was decreased in sFlt-1-/- compared to WT by echocardiography. Histological analysis showed that myocardial fibrosis and macrophage infiltration were significantly increased in sFlt-1 KO compared to WT. Anti-PLGF neutralizing antibody (αPLGF: ThromboGenics, Heverlee, Belgium) prevented pressure-overloaded cardiac hypertrophy and cardiac dysfunction after TAC in sFlt-1-/-. Furthermore, αPLGF prevented not only macrophage accumulation but myocardial fibrosis in sFlt-1-/-, which implies PLGF signal is the main cause of cardiac hypertrophy and cardiac dysfunction in sFlt-1-/-. Moreover, recombinant sFlt-1 protein administration prevented the deterioration of cardiac hypertrophy and LV systolic dysfunction following pressure overload in sFlt-1-/-.   Conclusions:  The present study demonstrated that sFlt-1 can be a novel therapeutic target for CRS including cardiac hypertrophy and heart failure.
Abstract B08: The role of periostin in pancreatic carcinogenesis and metastatic spread
Authors: Simone Hausmann, Ivonne Regel, Anna Federlein, Pawel K. Mazur, Katja Steiger, Christoph W. Michalski, Mert Erkan, Jörg Kleeff
Journal: Cancer Research (2015)

Abstract Background: Excessive desmoplasia is a typical feature of pancreatic ductal adenocarcinoma (PDAC) and is highly associated with an aggressive tumor phenotype. The main cell population contributing to the stromal response consists of pancreatic stellate cells (PSCs). Periostin, an extracellular matrix protein (ECM), produced by activated PSCs has been shown to have anti-apoptotic and growth-stimulatory effects on pancreatic tumor cells as well as the ability to create a metastatic niche in the secondary target organ. The main signaling route by which periostin mediates its effects is the integrin signaling pathway. Through binding to different integrin subunits the focal adhesion kinase (FAK) gets phosphorylated and downstream signaling pathways such as RAS/ERK/MEK become additionally activated. Aim: Analyzing the function of periostin in early pancreatic carcinogenesis as well as metastatic spread. Methods: A conditional tumor mouse model, expressing oncogenic KrasG12D under the control of a pancreas specific Ptf1a promoter was crossbred with Postn global knockout mice (p48Cre/+;LSL-KrasG12D/+;Postn-/-) and early tumor development was analyzed at two, three and six months of age. In a second approach, a tumor-promoting inflammatory stromal reaction was induced by cerulein injections in p48Cre/+;LSL-KrasG12D/+ mice whereby one group of mice was additionally treated with a daily dose (30mg/kg) of FAK inhibitor. All mice were sacrificed after 7 days and HE staining was performed. Thirdly, to study metastasis formation, murine pancreatic tumor cells were injected into the tail vein of wild type, Postn+/- and Postn-/- mice. After 6 weeks target organs were collected for subsequent analyses. Results: In the early phases, p48Cre/+;LSL-KrasG12D/+;Postn-/- mice displayed less PanIN lesions, fewer atypical ductal structures and reduced proliferating cells. The inhibition of FAK-signaling blocked pancreatic tumorigenesis and absence of periostin abrogated metastatic spread. Conclusion: Periostin produced by the pancreatic stellate cell is necessary both for early carcinogenesis and metastatic spread. The effects of periostin can be antagonized by blocking its downstream pathway using FAK inhibitors. Citation Format: Simone Hausmann, Ivonne Regel, Anna Federlein, Pawel K. Mazur, Katja Steiger, Christoph W. Michalski, Mert Erkan, Jörg Kleeff. The role of periostin in pancreatic carcinogenesis and metastatic spread. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B08.
Different toxicity profile of sorafenib across various types of cancer.
Authors: F. Sclafani, F. De Vincenzo, P. Zucali, L. Rimassa, L. Giordano, A. Bertuzzi, T. Pressiani, E. M. Stroppa, S. Secondino, A. Santoro
Journal: Journal of Clinical Oncology (2010)

e13565 Background: Sorafenib (S) is an oral multitarget drug inhibiting tumor proliferation, reducing tumor vasculature, and promoting apoptosis. S is a standard treatment in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) and is extensively studied in other tumor types. However, the toxicity profile of S is not fully elucidated. The aim of this study was to compare the safety of S across different types of cancer. Methods: This is a retrospective analysis of toxicity data from 411 patients (pts) treated with S, of which 296 (72%) pts for HCC, 89 (21.7%) pts for soft tissue sarcoma (STS) and 26 (6.3%) pts for RCC. Data for HCC and STS pts were collected prospectively within clinical trials conducted at our institution, whereas data for RCC pts were collected from pts treated in our institution as per routine clinical practice according to the approved indications. Toxicity was evaluated according to NCI-CTC version 3.0 criteria. Data were evaluated by using χ2-test, Fisher exact test, Manthel-Hanzel and Cochrane Manthel-Hanzel test with respect to frequencies and data distribution. Statistical significance p value was set at 0.05. Results: The adverse events (AEs) reported more frequently in HCC compared to STS and RCC were constitutional events (65% vs 44% vs. 23%; p<.001) and pain (40% vs. 9% vs. 0%; p<0.001). Gastrointestinal (anorexia, nausea, stomatitis, diarrhea) and neurologic events were documented more often in HCC than STS (73% vs. 44%; p<.001 and 8% vs. 0%; p=0.004, respectively). The AEs observed more frequently in RCC compared to HCC and STS were infection events (23% vs. 9% vs. 5%; p<0.03). Hand-foot skin reaction occurred more frequently in RCC than STS (65% vs. 33%; p=0.003), whereas rash/desquamation was observed more often in STS than RCC (30% vs 8%; p=.021) (statistical significance not reached for comparison with HCC). Conclusions: The different toxicity profile of S in the three analyzed cancer populations suggests an influence by the type of cancer. Indeed, different underlying disease characteristics might influence the safety of S. However, the reasons and possible mechanisms have still to be defined and more studies to confirm and explain these results are needed. No significant financial relationships to disclose.
Pars planitis
Authors: Sharath C Raja, Douglas A Jabs, J.P Dunn, Sharon Fekrat, Carol H Machan, Marta J Marsh, Neil M Bressler
Journal: Ophthalmology (1999)

ObjectiveTo describe a cohort of patients with pars planitis followed at a single tertiary care institution, determine the frequency of multiple sclerosis and/or optic neuritis in patients with this disorder, and calculate gene frequencies of human leukocyte antigen (HLA) class II alleles in these patients.DesignFifty-three patients with the diagnosis of pars planitis underwent clinical record review or telephone interview for follow-up or both; 32 of these underwent phlebotomy for analysis of HLA class II alleles.Main outcome measuresOutcomes included visual acuity, occurrence of multiple sclerosis and/or optic neuritis, and HLA class II gene frequencies.ResultsWith a mean follow-up of 2 years, approximately 90% of patients maintained a visual acuity better than 20/40 in at least one eye. The most frequently encountered ophthalmic complications included cystoid macular edema, cataract, and epiretinal membrane formation. Of 37 patients with pars planitis who had medical or neurologic follow-up evaluations, 6 (16.2%) developed multiple sclerosis. The HLA-DR15 allele, coding for one of the two HLA-DR2 subtypes, was associated with pars planitis (odds ratio = 2.86, 95% confidence interval = 1.42–5.78, P = 0.004).ConclusionsA common immunogenetic predisposition to multiple sclerosis and pars planitis may be associated with the HLA-DR15 allele. This association may represent genetic linkage to the HLA-DR locus or a role for the HLA-DR15 gene product in the pathogenesis of both of these diseases.
Abstract 9383: Galectin-3 and Long-term Mortality in Patients with Acute Heart Failure
Authors: Ravi V Shah, Anju Bhardwaj, Roland D van Kimmenade, James L Januzzi
Journal: Circulation (2010)

Background:Galectin-3 (gal-3), a β-galactoside-binding lectin macrophage product, is upregulated in models of cardiac hypertrophy, before the onset of HF and promotes fibrosis. We have shown that g...
Conflicts of Interest: How Money Clouds Objectivity
Authors: Richard Smith
Journal: Journal of the Royal Society of Medicine (2006)

Richard Smith was editor of the BMJ and chief executive of the BMJ Publishing Group for 13 years. In his last year at the journal he retreated to a 15th century palazzo in Venice to write a book. This is a much shortened chapter from the author's book provisionally entitled The Trouble With Medical Journals that the RSM Press will publish in the autumn [ www.rsmpress.co.uk ], and this is the third in a series of extracts that will be published in the JRSM.
Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor
Authors: Jason Boyang Wu, Changhong Shi, Gina Chia-Yi Chu, Qijin Xu, Yi Zhang, Qinlong Li, John S. Yu, Haiyen E. Zhau, Leland W.K. Chung
Journal: Biomaterials (2015)
Malaria in Greece, 1975 to 2010
Authors: A Vakali, E Patsoula, G Spanakos, K Danis, E Vassalou, N Tegos, A Economopoulou, A Baka, A Pavli, C Koutis, C Hadjichristodoulou, T Kremastinou
Journal: Eurosurveillance (2012)

Malaria, which was endemic in Greece in the past, was officially eliminated in 1974. Since that time and up to 2010, a number of imported cases (ranging from 19 to 76) have been annually reported. The total number of reported laboratory-confirmed cases between 1975 and 2010 was 1,419. Plasmodium falciparum was identified in 628 (44%) of these cases, while P. vivax was found in 524 (37%). Of the total cases, 1,123 (79%) were male (ratio males vs. females: 3.78). Age was only available for 490 cases, of which 352 (72%) belonged to the 18-40 year-age group. Of the 382 malaria cases reported from 1999 to 2010 for which the region/country of acquisition was known, 210 (55%) were from Africa and 142 (37%) from Asia. The massive introduction of economic migrants, in the period from 1990 to 1991 and from 2006 onwards, mainly from countries where malaria is endemic, resulted in the appearance of introduced sporadic cases. In Peloponnese, Central and East Macedonia, Thrace and East Attica, mosquitoes of the genus Anopheles (e.g. Anopheles sacharovi, A. superpictus and A. maculipenis) that can act as plasmodia vectors are abundant and during the summer of 2011, 27 P. vivax cases were reported in Greek citizens residing in the agricultural area of Evrotas in Lakonia and without travel history. As further P. vivax malaria cases occurred in the Lakonia and East Attica areas in 2012, it is becoming urgent to strengthen surveillance and perform integrated mosquito control that will help eliminate the potential risk of malaria reintroduction and reestablishment.