tbuckley/cabot-search huggingface dataset:
Acceleration of functional reentry by rapid pacing in anisotropic cardiac monolayers: Formation of multi-wave functional reentries
Authors: N BURSAC, L TUNG
Journal: Cardiovascular Research (2005)

Attempts to cardiovert tachycardia by rapid point pacing can sometimes result in transient or stable increase of the heart rate (acceleration), changed ECG morphology, and/or fibrillation. The goal of this study was to investigate the effect of rapid pacing on the dynamics of functional reentry in monolayer cultures of cardiac cells.Fully confluent, uniformly anisotropic monolayers of neonatal rat ventricular myocytes were prepared using methods of microabrasion. Cells were paced by a point electrode at rest and during functional reentry, and membrane voltages were optically mapped.Point pacing readily induced single loop anisotropic functional reentry with monomorphic optical pseudo-ECG (pECG) and average rotation period of 193+/-52 ms (n=71 monolayers). Attempts to cardiovert reentry by rapid pacing at rates 10-50% faster than the reentry rate were successful in 57/71 monolayers. In 14/71 monolayers, the number of rotating waves was stably increased by 1 to 4, yielding a 10-70% acceleration of pECG rate and change to a different monomorphic or polymorphic pECG. The resulting multi-wave functional reentries were classified based on the number and direction of their rotating waves. The higher the number of waves in the multi-wave reentry, the more accelerated was the rate of cell firing in the monolayer. Importantly, stable acceleration was only inducible in monolayers with relatively deep and broad conduction velocity restitution relationships. Reapplication of point pacing further accelerated, decelerated, or eventually terminated the reentrant activity.These results suggest that stable multiplication of rotating waves in conjunction with a deep and broad conduction velocity restitution relationship is a possible mechanism for stable acceleration of functional reentry by rapid pacing.
Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study
Authors: A Hochhaus, G Rosti, N C P Cross, J L Steegmann, P le Coutre, G Ossenkoppele, L Petrov, T Masszi, A Hellmann, L Griskevicius, W Wiktor-Jedrzejczak, D Rea, D Coriu, T H Brümmendorf, K Porkka, G Saglio, G Gastl, M C Müller, P Schuld, P Di Matteo, A Pellegrino, L Dezzani, F-X Mahon, M Baccarani, F J Giles
Journal: Leukemia (2015)

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR4 (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10 000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR4 at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.
Adiposity, serum lipid levels, and allergic sensitization in Chinese men and women
Authors: Fengxiu Ouyang, Rajesh Kumar, Jacqueline Pongracic, Rachel E. Story, Xin Liu, Binyan Wang, Houxun Xing, Xue Liu, Zhiping Li, Wenbin Zhang, Yaping Fang, Shanchun Zhang, Xiping Xu, Xiaobin Wang
Journal: Journal of Allergy and Clinical Immunology (2009)
THE DEMISE OF THE PHILADELPHIA MEDICAL JOURNAL.
Authors: James Hendrie Lloyd
Journal: JAMA (1903)

Philadelphia, June 15, 1903. <h3>To the Editor:</h3> —The<i>Philadelphia Medical Journal</i>was sold out last week by the majority stockholders. As this deal closes an extraordinary chapter in the history of medical journalism in this country, it is desirable that the medical public should learn something about it. As the writer was one of the minority stockholders who were opposed to this deal, and as, moreover, he had been the editor-in-chief of the journal for more than two years, he feels himself qualified to comment on it. The great bulk of the stock of the<i>Philadelphia Medical Journal</i>was held by laymen. In fact the journal from its very inception had owed very much to laymen, among whom were men of the highest character, who had supplied money with the unselfish desire to found a medical journal in Philadelphia that should be permanent and representative. That this scheme has failed
Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis
Authors: Jeong-Hae Kie, Matthias H. Kapturczak, Amie Traylor, Anupam Agarwal, Nathalie Hill-Kapturczak
Journal: Journal of the American Society of Nephrology (2008)

Induction of heme oxygenase-1 (HO-1) is associated with potential antifibrogenic effects. The effects of HO-1 expression on epithelial-mesenchymal transition (EMT), which plays a critical role in the development of renal fibrosis, are unknown. In this study, HO-1(-/-) mice demonstrated significantly more fibrosis after 7 d of unilateral ureteral obstruction compared with wild-type mice, despite similar degrees of hydronephrosis. The obstructed kidneys of HO-1(-/-) mice also had greater macrophage infiltration and renal tubular TGF-beta1 expression than wild-type mice. In addition, the degree of EMT was more extensive in obstructed HO-1(-/-) kidneys, as assessed by alpha-smooth muscle actin and expression of S100A4 in proximal tubular epithelial cells. In vitro studies using proximal tubular cells isolated from HO-1(-/-) and wild-type kidneys confirmed these observations. In conclusion, HO-1 deficiency is associated with increased fibrosis, tubular TGF-beta1 expression, inflammation, and enhanced EMT in obstructive kidney disease. Modulation of the HO-1 pathway may provide a new therapeutic approach to progressive renal diseases.
How bad are the symptoms and bowel dysfunction of patients with the irritable bowel syndrome? A prospective, controlled study with emphasis on stool form.
Authors: K W Heaton, S Ghosh, F E Braddon
Journal: Gut (1991)

Since it is not known whether the symptoms and bowel function of patients with the irritable bowel syndrome are truly abnormal we used diaries and frequent telephone interviews over a 31 day period to assess symptoms, defecation, and stool types in 26 unselected female hospital patients with the irritable bowel syndrome, 27 women who admitted to recurrent colonic pain but had not consulted a doctor (non-complainers), and 27 healthy control subjects. Unexpectedly, abdominal pain and bloating occurred in most of the control subjects. Pain, however, was six times more frequent in the patients and was more often considered severe. Bloating occurred three times more often. Defecation was more frequent, more erratic in timing and stool form, and more likely to produce stools of extreme forms, indicating rapid fluctuations in intestinal transit time. Urgency was four times more prevalent in patients than control subjects. Straining to finish defecating was nine times more prevalent and was often accompanied by feelings of incomplete evacuation--a combination which could lead to the misdiagnosis of constipation. The normal relation between stool form and the above symptoms was distorted, possibly due to rectal irritability. Non-complainers were intermediate between patients and control subjects in almost every parameter but were closer to control subjects than to patients. Patients with the irritable bowel syndrome have real cause for complaint and their bowel function is truly abnormal.
Proteinase 3–dependent caspase-3 cleavage modulates neutrophil death and inflammation
Authors: Fabien Loison, Haiyan Zhu, Kutay Karatepe, Anongnard Kasorn, Peng Liu, Keqiang Ye, Jiaxi Zhou, Shannan Cao, Haiyan Gong, Dieter E. Jenne, Eileen Remold-O’Donnell, Yuanfu Xu, Hongbo R. Luo
Journal: Journal of Clinical Investigation (2014)

Caspase-3–mediated spontaneous death in neutrophils is a prototype of programmed cell death and is critical for modulating physiopathological inflammatory responses; however, the underlying regulatory pathways remain ill defined. Here we determined that in aging neutrophils, the cleavage and activation of caspase-3 is independent of the canonical caspase-8– or caspase-9–mediated pathway. Instead, caspase-3 activation was mediated by serine protease proteinase 3 (PR3), which is present in the cytosol of aging neutrophils. Specifically, PR3 cleaved procaspase-3 at a site upstream of the canonical caspase-9 cleavage site. In mature neutrophils, PR3 was sequestered in granules and released during aging via lysosomal membrane permeabilization (LMP), leading to procaspase-3 cleavage and apoptosis. Pharmacological inhibition or knockdown of PR3 delayed neutrophil death in vitro and consistently delayed neutrophil death and augmented neutrophil accumulation at sites of inflammation in a murine model of peritonitis. Adoptive transfer of both WT and PR3-deficient neutrophils revealed that the delayed death of neutrophils lacking PR3 is due to an altered intrinsic apoptosis/survival pathway, rather than the inflammatory microenvironment. The presence of the suicide protease inhibitor SERPINB1 counterbalanced the protease activity of PR3 in aging neutrophils, and deletion of Serpinb1 accelerated neutrophil death. Taken together, our results reveal that PR3-mediated caspase-3 activation controls neutrophil spontaneous death.
QT interval and antidepressant use: a cross sectional study of electronic health records
Authors: V. M. Castro, C. C. Clements, S. N. Murphy, V. S. Gainer, M. Fava, J. B. Weilburg, J. L. Erb, S. E. Churchill, I. S. Kohane, D. V. Iosifescu, J. W. Smoller, R. H. Perlis
Journal: BMJ (2013)

<b>Objective</b> To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population. <b>Design</b> A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity. <b>Setting</b> A large New England healthcare system comprising two academic medical centres and outpatient clinics. <b>Participants</b> 38 397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011. <b>Main outcome measures</b> Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined. <b>Results</b> Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P&lt;0.01), escitalopram (adjusted beta 0.58 (0.15), P&lt;0.001), and amitriptyline (adjusted beta 0.11 (0.03), P&lt;0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P&lt;0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P&lt;0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P&lt;0.01). <b>Conclusions</b> This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments.
Increase in myocardial oxygenation with propranolol
Authors: A. J. Moss, J. Johnson, J. Sentman
Journal: Cardiovascular Research (1970)

Intravenous propranolol, 0·25 mg/kg, significantly increased intramyocardial oxygen tension by 3 mm Hg (from 9 to 12 mm Hg) at a time when there was no change in coronary venous pO2. Propranolol appears to augment myocardial oxygen availability by decreasing the metabolic oxygen requirement of the heart in association with a reduction in cardiac work. It is concluded that propranolol has a rational physiological basis for use in the treatment of angina pectoris.
Altered Ca2+ homeostasis in polymorphonuclear leukocytes from chronic myeloid leukaemia patients
Authors: Chetana M Revankar, Suresh H Advani, Nishigandha R Naik
Journal: Molecular Cancer (2006)

Abstract Background In polymorphonuclear leukocytes (PMNL), mobilization of calcium ions is one of the early events triggered by binding of chemoattractant to its receptors. Besides chemotaxis, a variety of other functional responses are dependent on calcium ion mobilization. PMNL from chronic myeloid leukaemia (CML) patients that were morphologically indistinguishable from normal PMNL were found to be defective in various functions stimulated by a chemoattractant – fMLP. To study the mechanism underlying defective functions in CML PMNL, we studied calcium mobilization in CML PMNL in response to two different classical chemoattractants, fMLP and C5a. Results Release of calcium estimated by flow cytometry and spectrofluorimetry using fluo-3 as an indicator showed that the [Ca 2+ ] i levels were lower in CML PMNL as compared to those in normal PMNL. But, both normal and CML PMNL showed maximum [Ca 2+ ] i in response to fMLP and C5a at 10 sec and 30 sec, respectively. Spectrofluorimetric analysis of the total calcium release in chemoattractant treated PMNL indicated more and faster efflux of [Ca 2+ ] i in CML PMNL as compared to normal PMNL. Conclusion Fine-tuning of Ca 2+ homeostasis was altered in CML PMNL. The altered Ca 2+ homeostasis may contribute to the defective functions of CML PMNL.
The impact of traffic air pollution on bronchiolitis obliterans syndrome and mortality after lung transplantation
Authors: T. S. Nawrot, R. Vos, L. Jacobs, S. E. Verleden, S. Wauters, V. Mertens, C. Dooms, P. H. Hoet, D. E. Van Raemdonck, C. Faes, L. J. Dupont, B. Nemery, G. M. Verleden, B. M. Vanaudenaerde
Journal: Thorax (2011)

<h3>Objective</h3> Cortactin acts as a prominent substrate of histone deacetylases (HDACs) and plays important roles in tumour progression in several human cancers. However, the clinical significance of its expression in human prostate cancer (PCa) has not been determined. We aimed to identify the potential role of cortactin expression in tumour progression and prognosis in PCa and the association with HDACs. <h3>Methods</h3> 256 foci with distinctive lesions in 110 prostate specimens were collected to identify the status of among cortactin, SIRT2, histone deacetylase 6 (HDAC6) by immunohistochemistry and its relationship with clinicopathological and follow-up data were analysed. <h3>Results</h3> The results showed that cortactin expression was significantly higher (79.1%), and SIRT2 expression was lower (37.3%) in PCa foci, when it was compared with high-grade prostatic intraepithelial neoplasia foci and benign foci, respectively. HDAC6 expression was low and had no statistical significance in PCa. High intensity of cortactin staining was significantly and independently associated with a high prostate-specific antigen (PSA) level, high Gleason score, clinical stage progression and shortened survival time in patients with PCa. High intensity of SIRT2 staining was significantly and independently associated with a high PSA level, old age, high Gleason score and clinical stage progression. Multivariable Cox regression analysis showed cortactin expression was a significant prognostic factor for survival of patients with PCa (β, 0.736; 95% CI 1.371 to 3.181; p=0.001). <h3>Conclusions</h3> The results suggested that cortactin seems to be a satisfactory marker to predict tumour progression and survival in cases of PCa. And it may be SIRT2 rather than HADAC6 is responsible for tumour occurrence and the progression of PCa.
Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C
Authors: A K P Lim
Journal: Gut (2004)

<b>Background and aims:</b> A reliable non-invasive assessment of the severity of diffuse liver disease is much needed. We investigated the utility of hepatic vein transit times (HVTT) for grading and staging diffuse liver disease in a cohort of patients with hepatitis C virus (HCV) infection using an ultrasound microbubble contrast agent as a tracer. <b>Materials and methods:</b> Eighty five untreated patients with biopsy proven HCV induced liver disease were studied prospectively. All were HCV RNA positive on polymerase chain reaction testing. Based on their histological fibrosis (F) and necroinflammatory (NI) scores, untreated patients were divided into mild hepatitis (F ⩽2/6, NI ⩽3/18), moderate/severe hepatitis (3 ⩽F &lt;6 or NI ⩾4), and cirrhosis (F = 6/6) groups. In addition, 20 age matched healthy volunteers were studied. After an overnight fast, a bolus of contrast agent (Levovist) was injected into an antecubital vein and spectral Doppler signals were recorded from both the right and middle hepatic veins for analysis. HVTTs were calculated as the time from injection to a sustained rise in Doppler signal &gt;10% above baseline. The Doppler signals from the carotid artery were also measured in 60 patients and carotid delay times (CDT) calculated as the difference between carotid and hepatic vein arrival times. The earliest HVTT in each patient was used for analysis. <b>Results:</b> Mean (SEM) HVTT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis groups showed a monotonic decrease of 38.1 (2.8), 38.8 (2.4), 26.0 (2.4), and 15.8 (0.8) seconds, respectively. Mean (SEM) CDT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis patients again showed progressive shortening of 30.3 (2.6), 25.9 (2.6), 14.8 (2.1), and 5.6 (1.2) seconds, respectively. There were significant differences between the groups for HVTT (ANOVA, p&lt;0.001) and CDT (ANOVA, p&lt;0.001). There was 100% sensitivity and 80% specificity for diagnosing cirrhosis and 95% sensitivity and 86% specificity for differentiating mild hepatitis from more severe liver disease. <b>Conclusion:</b> We have shown, for the first time, that HVTT using an ultrasound microbubble contrast agent can assess HCV related liver disease with clear differentiation between mild hepatitis and cirrhosis. There were significant differences between these two groups and the moderate/severe hepatitis group. CDT offers no additional benefit or greater differentiation than HVTT and can be omitted, thus simplifying this technique. HVTT may complement liver biopsy and may also be a useful alternative for assessment of liver disease in patients who have contraindications to biopsy.
Zebrafish: A New Companion for Translational Research in Oncology
Authors: Jorge Barriuso, Raghavendar Nagaraju, Adam Hurlstone
Journal: Clinical Cancer Research (2015)

In an era of high-throughput "omic" technologies, the unprecedented amount of data that can be generated presents a significant opportunity but simultaneously an even greater challenge for oncologists trying to provide personalized treatment. Classically, preclinical testing of new targets and identification of active compounds against those targets have entailed the extensive use of established human cell lines, as well as genetically modified mouse tumor models. Patient-derived xenografts in zebrafish may in the near future provide a platform for selecting an appropriate personalized therapy and together with zebrafish transgenic tumor models represent an alternative vehicle for drug development. The zebrafish is readily genetically modified. The transparency of zebrafish embryos and the recent development of pigment-deficient zebrafish afford researchers the valuable capacity to observe directly cancer formation and progression in a live vertebrate host. The zebrafish is amenable to transplantation assays that test the serial passage of fluorescently labeled tumor cells as well as their capacity to disseminate and/or metastasize. Progress achieved to date in genetic engineering and xenotransplantation will establish the zebrafish as one of the most versatile animal models for cancer research. A model organism that can be used in transgenesis, transplantation assays, single-cell functional assays, and in vivo imaging studies make zebrafish a natural companion for mice in translational oncology research.
Clinical Assessment of Stereoscopic Optic Disc Photographs for Glaucoma: The European Optic Disc Assessment Trial
Authors: Nicolaas J. Reus, Hans G. Lemij, David F. Garway-Heath, P. Juhani Airaksinen, Alfonso Anton, Alain M. Bron, Christoph Faschinger, Gábor Holló, Michele Iester, Jost B. Jonas, Andrea Mistlberger, Fotis Topouzis, Thierry G. Zeyen
Journal: Ophthalmology (2010)
The Cytoskeleton Regulatory Protein hMena (ENAH) Is Overexpressed in Human Benign Breast Lesions with High Risk of Transformation and Human Epidermal Growth Factor Receptor-2–Positive/Hormonal Receptor–Negative Tumors
Authors: Francesca Di Modugno, Marcella Mottolese, Anna Di Benedetto, Andrea Conidi, Flavia Novelli, Letizia Perracchio, Irene Venturo, Claudio Botti, Elke Jager, Angela Santoni, Pier Giorgio Natali, Paola Nisticò
Journal: Clinical Cancer Research (2006)

Abstract Purpose: hMena (ENAH), a cytoskeleton regulatory protein involved in the regulation of cell motility and adhesion, is overexpressed in breast cancer. The aim of this study was to define at what stage of breast carcinogenesis hMena is overexpressed and to correlate hMena overexpression with established prognostic factors in breast cancer, focusing on human epidermal growth factor receptor-2 (HER-2). Experimental Design: hMena expression was assessed immunohistochemically in a prospective cohort of cases (n = 360) encompassing a highly representative spectrum of benign breast diseases associated with different risk of transformation, in situ, invasive, and metastatic tumors. Correlations with conventional pathologic and prognostic variables, such as proliferation index, hormonal receptor status, and HER-2 overexpression, were also evaluated. In vitro experiments were done to study the effect of neuregulin-1 and Herceptin treatments on hMena expression. Results: hMena protein is undetectable in normal breast and is weakly expressed in a small percentage of low-risk benign diseases (9%), but displays a progressive and significant increase of positivity in benign lesions at higher risk of transformation (slightly increased risk 43%; moderate increased risk 67%), in in situ (72%), invasive (93%), and metastatic breast cancer (91%). A significant direct correlation with tumor size (P = 0.04), proliferation index (P &amp;lt; 0.0001), and HER-2 overexpression (P &amp;lt; 0.0001) and an inverse relationship with estrogen (P = 0.036) and progesterone receptors (P = 0.001) are found in invasive carcinomas. In vitro experiments show that neuregulin-1 up-regulates, whereas Herceptin down-regulates, hMena expression. Conclusions: Our data provide new insights into the relevance of actin-binding proteins in human breast carcinogenesis and indicate hMena overexpression as a surrogate indicator in breast disease management.