tbuckley/cabot-search huggingface dataset:
Effects of Rapid Atrial Pacing on the Arrhythmogenic Activity of Single Cardiomyocytes From Pulmonary Veins
Authors: Yi-Jen Chen, Shih-Ann Chen, Yao-Chang Chen, Hung-I Yeh, Paul Chan, Mau-Song Chang, Cheng-I Lin
Journal: Circulation (2001)

Pulmonary veins (PVs) are important sources of paroxysmal atrial fibrillation. Long-term rapid atrial pacing (RAP) changes atrial electrophysiology and facilitates the maintenance of atrial fibrillation. It is not clear whether RAP alters the arrhythmogenic activity of PVs. The purpose of this study was to isolate single PV cardiomyocytes from control and RAP dogs and evaluate their electrophysiological characteristics.The action potential and ionic currents were investigated in PV cardiomyocytes from control and long-term (6 to 8 weeks) RAP (780 bpm) dogs by use of the whole-cell clamp technique. Dissociation of PVs yielded rod-shaped single cardiomyocytes without (n=91, 60%) or with (n=60, 40%) pacemaker activity. Compared with the control group, the RAP dog PV cardiomyocytes had faster beating rates (0.86+/-0.28 versus 0.45+/-0.07 Hz, P<0.05) and shorter action potential duration. The RAP dog PV cardiomyocytes with pacemaker activity have a higher incidence of delayed (59% versus 7%, P<0.001) or early (24% versus 0%, P<0.005) after depolarization. The RAP dog PV cardiomyocytes with pacemaker activity had smaller slow inward and transient outward but larger transient inward (0.017+/-0.004 versus 0.009+/-0.002 pA/pF, P<0.05) and pacemaker (0.111+/-0.019 versus 0.028+/-0.008 pA/pF, P<0.001) currents. The RAP dog PV cardiomyocytes without pacemaker activity had only smaller slow inward and transient outward and larger pacemaker currents.PVs contain multiple cardiomyocytes with distinct electrophysiological characteristics. RAP changes the electrophysiological characteristics and arrhythmogenic activity of PVs.
Quantitating Therapeutic Disruption of Tumor Blood Flow with Intravital Video Microscopy
Authors: Arthur M. Iga, Sandip Sarkar, Kevin M. Sales, Marc C. Winslet, Alexander M. Seifalian
Journal: Cancer Research (2006)

Vascular-disrupting agents (VDA) kill tumor cells by selectively disrupting blood circulation in tumors. In vivo analysis of this intensely studied class of anticancer agents is invaluable for preclinical assessment of pharmacodynamic end points and effective therapeutic windows. In this review, we consider the role of intravital video microscopy in measuring tumor vascular response to VDAs, the potential of which lies in the opportunity to quantitate specific variables and to obtain real-time information on how VDAs affect tumor microcirculation.
Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature
Authors: G. Umberto Meduri, Paul E. Marik, George P. Chrousos, Stephen M. Pastores, Wiebke Arlt, Albertus Beishuizen, Faran Bokhari, Gary Zaloga, Djillali Annane
Journal: Intensive Care Medicine (2007)
Amelioration of Sardinian 0 thalassemia by genetic modifiers
Authors: R. Galanello, S. Sanna, L. Perseu, M. C. Sollaino, S. Satta, M. E. Lai, S. Barella, M. Uda, G. Usala, G. R. Abecasis, A. Cao
Journal: Blood (2009)
The patient U wave
Authors: C CONRATH, T OPTHOF
Journal: Cardiovascular Research (2005)

See also article by Ritsema van Eck et al.  [7]  (pages 256–262) in this issue. 

After having described the electrocardiogram in 1895 [1], Einthoven extended our notion of the ECG by mentioning the U wave in a later paper in the Lancet in 1912 [2]. Sandwiched between a paper on paratyphoid fever following meat poisoning and a paper on a ruptured kidney, Einthoven's seminal paper ended in two brief sentences: “The method of electrocardiography is still a young plant. We may reasonably expect that it will continue to bear good fruit” [2]. Einthoven died in 1927 after having earned the Noble Prize in 1924, and he could not foresee that, almost one century later, we still do not fully understand the relationship between cardiac repolarization and the T wave in the ECG, let alone the significance of the U wave…

Einthoven described the U wave as being of “considerable height” in pathological cases, but as present also in normal hearts, albeit of small amplitude. Lewis had estimated that the U wave was present in 75% of all ECGs and Einthoven agreed that it was present in more than 50% of all persons [2]. The source of the U wave remained obscure at that time, but Einthoven made two other important observations. First, he noted that the U wave was “not of equal height in all heart beats. This wave must be regarded as an inconstant one.” Second, we quote the following: “The end of the U wave lies after the second (heart) sound, so that there is no doubt that wave U falls wholly or partly in that phase of the cardiac cycle which follows the closing of the semilunar valves. The heart is in diastole after the closing of these valves. But the heart muscle, … 

*Corresponding author. Experimental and Molecular Cardiology Groups, Academic Medical Center, M0-107, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 566 3265; fax: +31 20 697 5458. Email address: t.opthof{at}med.uu.nl
Genomic heterogeneity of hepatitis B virus (HBV) and outcome of perinatal HBV infection
Authors: Irene Cacciola, Giovanni Cerenzia, Teresa Pollicino, Giovanni Squadrito, Stefania Castellaneta, Alessando R. Zanetti, Giorgina Mieli-Vergani, Giovanni Raimondo
Journal: Journal of Hepatology (2002)
Voluntary Running Prevents Progressive Memory Decline and Increases Adult Hippocampal Neurogenesis and Growth Factor Expression after Whole-Brain Irradiation
Authors: Sarah J.E. Wong-Goodrich, Madeline L. Pfau, Catherine T. Flores, Jennifer A. Fraser, Christina L. Williams, Lee W. Jones
Journal: Cancer Research (2010)

Abstract Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention. Cancer Res; 70(22); 9329–38. ©2010 AACR.
Treatment of stage I seminoma: is it time to change your practice?
Authors: Darren R Feldman, George J Bosl
Journal: Journal of Hematology & Oncology (2008)

At the plenary session of the 2008 annual meeting of the American Society of Clinical Oncology, updated results were presented from a large randomized phase III trial comparing adjuvant radiation therapy (RT) and one cycle of Carboplatin for the adjuvant treatment of Stage I seminoma. Results of this Medical Research Council (MRC) trial led its investigators to conclude that one cycle of carboplatin was equivalent in safety and efficacy and less toxic than RT. In this editorial, the trial's design, statistics, toxicity, and length of follow-up are discussed within the context of historical treatments of this disease. With a 1.3% increase in relapse rate (5.3% with carboplatin vs. 4.0% with radiation), a 3% or greater increase in relapse rate could not be excluded, the primary endpoint of the study. A decrease in second testicular germ cell tumors was observed, but was equivalent to the increase in relapse rate. Acute toxicity was generally less with carboplatin. However, the extent of late toxicity, including late second neoplasms, cannot be evaluated because of the short median follow-up. Carboplatin is not yet a standard of care. Surveillance-based strategies, including risk-adapted policies that limit RT to patients with the greatest likelihood of relapse remain prudent at this time.
Cardiovascular Autonomic Neuropathy Is Associated With Microalbuminuria in Older Patients With Type 2 Diabetes
Authors: Andrew Moran, Walter Palmas, Lesley Field, Jyoti Bhattarai, Joseph E. Schwartz, Ruth S. Weinstock, Steven Shea
Journal: Diabetes Care (2004)

OBJECTIVE—Cardiovascular autonomic neuropathy is associated with microalbuminuria in young and middle-aged patients with type 2 diabetes. We examined this relationship and the potential mediating role of blood pressure in older patients. RESEARCH DESIGN AND METHODS—At least two of three components of cardiovascular autonomic testing were completed by 132 patients (mean age 70 ± 5.6 years). Relative rankings on each of the components were averaged to create a summary heart rate variability (HRV) measure. The urine microalbumin-to-creatinine ratio (milligrams albumin/grams creatinine) was calculated. Blood pressure was measured at rest and by 24-h ambulatory recording. RESULTS—Urine microalbumin-to-creatinine ratio was higher in those with lower HRV (mean urine microalbumin-to-creatinine ratio 28, 56, and 191 mg/g from the highest to lowest tertile of HRV; P &amp;lt; 0.0001). Resting and ambulatory blood pressure levels were negatively correlated with HRV and positively correlated with urine microalbumin-to-creatinine ratio. In multivariate analysis adjusting for age, duration of diabetes, HbA1c, and HDL cholesterol, HRV and blood pressure were both independently associated with urine microalbumin-to-creatinine ratio, with no evidence that either mediates the effect of the other. CONCLUSIONS—Cardiovascular autonomic neuropathy and blood pressure are independently associated with microalbuminuria in older patients with type 2 diabetes.
Gene therapy for cystic fibrosis: what message for the recipient?
Authors: J A DODGE
Journal: Thorax (1998)

The notion that genetic diseases might be cured by correcting or replacing the abnormal gene in the affected tissues is an attractive one, and probably reflects the average educated layman’s concept of gene therapy. In the case of severe combined immunodeficiency due to adenosine deaminase deficiency, such curative gene therapy has in fact been achieved by correction of autologous bone marrow cells ex vivo before returning the marrow stem cells to the patient. There are understandable professional and public fears about gene therapy which might introduce additional “corrected” genes into the germ tissue of individuals and thereby potentially into the permanent human gene pool, and for that reason germ line gene therapy is regarded as unethical throughout the world. The limitation which this places on the treatment of a multisystem disease whose clinical effects begin in fetal life is therefore obvious, and expectations of a cure for cystic fibrosis by gene therapy are intrinsically unrealistic.

An alternative strategy is to look for control, rather than cure, of a disease such as cystic fibrosis by repeated delivery of the normal gene to the target tissue for as long as the patient lives. This is the approach which has been taken by teams on both sides of the Atlantic, and an update on progress is …
Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ.
Authors: K Inaba, J P Metlay, M T Crowley, R M Steinman
Journal: The Journal of Experimental Medicine (1990)

T cells recognize peptides that are bound to MHC molecules on the surface of different types of antigen-presenting cells (APC). Antigen presentation most often is studied using T cells that have undergone priming in situ, or cell lines that have been chronically stimulated in vitro. The use of primed cells provides sufficient numbers of antigen-reactive lymphocytes for experimental study. A more complete understanding of immunogenicity, however, requires that one develop systems for studying the onset of a T cell response from unprimed lymphocytes, especially in situ. Here it is shown that mouse T cells can be reliably primed in situ using dendritic cells as APC. The dendritic cells were isolated from spleen, pulsed with protein antigens, and then administered to naive mice. Antigen-responsive T cells developed in the draining lymphoid tissue, and these T cells only recognized protein when presented on cells bearing the same MHC products as the original priming dendritic cells. In contrast, little or no priming was seen if antigen-pulsed spleen cells or peritoneal cells were injected. Since very small amounts of the foreign protein were visualized within endocytic vacuoles of antigen-pulsed dendritic cells, it is suggested that dendritic cells have a small but relevant vacuolar system for presenting antigens over a several day period in situ.
K <sub>ATP</sub> Channels and Cardiovascular Disease
Authors: Colin G. Nichols, Gautam K. Singh, Dorothy K. Grange
Journal: Circulation Research (2013)

ATP-sensitive potassium (KATP) channels were first discovered in the heart 30 years ago. Reconstitution of KATP channel activity by coexpression of members of the pore-forming inward rectifier gene family (Kir6.1, KCNJ8, and Kir6.2 KCNJ11) with sulfonylurea receptors (SUR1, ABCC8, and SUR2, ABCC9) of the ABCC protein subfamily has led to the elucidation of many details of channel gating and pore properties. In addition, the essential roles of Kir6.x and SURx subunits in generating cardiac and vascular KATP(2) and the detrimental consequences of genetic deletions or mutations in mice have been recognized. However, despite this extensive body of knowledge, there has been a paucity of defined roles of KATP subunits in human cardiovascular diseases, although there are reports of association of a single Kir6.1 variant with the J-wave syndrome in the ECG, and 2 isolated studies have reported association of loss of function mutations in SUR2 with atrial fibrillation and heart failure. Two new studies convincingly demonstrate that mutations in the SUR2 gene are associated with Cantu syndrome, a complex multi-organ disorder characterized by hypertrichosis, craniofacial dysmorphology, osteochondrodysplasia, patent ductus arteriosus, cardiomegaly, pericardial effusion, and lymphoedema. This realization of previously unconsidered consequences provides significant insight into the roles of the KATP channel in the cardiovascular system and suggests novel therapeutic possibilities.
CT features of pulmonary arterial hypertension and its major subtypes: a systematic CT evaluation of 292 patients from the ASPIRE Registry
Authors: S. Rajaram, A. J. Swift, R. Condliffe, C. Johns, C. A. Elliot, C. Hill, C. Davies, J. Hurdman, I. Sabroe, J. M. Wild, D. G. Kiely
Journal: Thorax (2014)

We evaluated the prevalence and prognostic value of CT-pulmonary angiographic (CTPA) measures in 292 treatment naive patients with pulmonary arterial hypertension (PAH). Pulmonary artery calcification (13%) and thrombus (10%) were exclusively seen in PAH-congenital heart disease. Oesophageal dilation (46%) was most frequent in PAH-systemic sclerosis. Ground glass opacification (GGO) (41%), pericardial effusion (38%), lymphadenopathy (19%) and pleural effusion (11%) were common. On multivariate analysis, inferior vena caval area, the presence of pleural effusion and septal lines predicted outcome. In PAH, CTPA provides diagnostic and prognostic information. In addition, the presence of GGO on a CT performed for unexplained breathlessness should alert the physician to the possibility of PAH.
Human immunodeficiency virus infection as risk factor for mother-to-child hepatitis C virus transmission; Persistence of anti–hepatitis C virus in children is associated with the mother's anti–hepatitis C virus immunoblotting pattern
Authors: Paola Manzini, Giorgio Saracco, Antonella Cerchier, Caterina Riva, Alberto Musso, Emanuela Ricotti, Elvia Palomba, Carlo Scolfaro, Giorgio Verme, Ferruccio Bonino, Pier Angelo Tovo
Journal: Hepatology (1995)

To determine the rate of vertical transmission of hepatitis C virus (HCV), we prospectively studied 45 babies born to anti-HCV-positive women with or without concomitant infection with the human immunodeficiency virus (HIV). We performed a second-generation recombinant immunoblotting assay, alanine transaminase (ALT) evaluation, and HCV-RNA testing on sera from 27 infants of HCV+, HIV- mothers and 18 babies of HCV+, HIV+ women, at birth and thereafter. After birth, HCV antibodies progressively disappeared within 12 months in all children but one, whose mother was HCV+, HIV+; this child was the only one who showed detectable levels of HCV-RNA and abnormal ALT values throughout the follow-up (range, 12 to 27 months). Viremia was persistently negative, and ALT levels were continuously normal in the remaining infants, showing that "seronegative" infection with HCV was absent in both groups. Clearance of passively acquired anti-HCV antibodies was found to be slower among babies born to HIV+ mothers (22.3% vs. 3.8% at 12 months, P = .03) and children whose mothers showed three or four anti-HCV reactivities by immunoblotting maintained anti-HCV for longer periods compared with babies born to mothers with one or two anti-HCV reactivities (P = .0001). Seventeen of 27 babies born to HCV+, HIV- mothers were breast-fed, and none of them was infected, confirming the apparent safety for HCV of breast milk. In summary, according to our study, vertical transmission of HCV is an infrequent event, and the presence of HIV in the mother is not an important co-factor for transmission of HCV infection.
Management of Squamous Cancer Metastatic to Cervical Nodes With an Unknown Primary Site
Authors: Thomas J. Galloway, John A. Ridge
Journal: Journal of Clinical Oncology (2015)

Squamous cell carcinoma of an unknown primary (SCCUP) of the head and neck is a rare disease. As a diagnosis of exclusion, the manner in which it is assigned merits consideration. Despite the development and refinement of several techniques designed to locate an occult tumor, including cross-sectional anatomic imaging, functional imaging, and transoral surgical techniques, delineating SCCUP remains an active clinical problem. Its relative rarity has prevented prospective study of the entity. Hence, investigators must rely on retrospective analyses to understand the disease and its appropriate treatment. The current understanding of SCCUP differs substantially from when it was initially described decades ago. The most common site of a small primary tumor initially thought to represent SCCUP is the tonsil or base of the tongue, and an increasing percentage are associated with human papilloma virus. Modern treatment of SCCUP by neck dissection alone, neck dissection followed by radiation with or without concurrent chemotherapy, or primary chemoradiation according to initial nodal disease burden produces extraordinarily low recurrence rates. Whether the potential mucosal primary site and/or the contralateral neck should be electively treated is controversial. Efficacy data seem to be similar; therefore, an evaluation of the toxicity of both treatment paradigms is warranted.
Retinoblastoma and Phosphate and Tensin Homolog Tumor Suppressors: Impact on Ductal Carcinoma In Situ Progression
Authors: Erik S. Knudsen, Thomas F. Pajak, Maria Qeenan, A. Kathleen McClendon, Benjamin D. Armon, Gordon F. Schwartz, Agnieszka K. Witkiewicz
Journal: JNCI Journal of the National Cancer Institute (2012)

A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease.The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided.Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR = 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties.These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of beneﬁt.
Identification of an endogenous membrane anchor-cleaving enzyme for group A streptococcal M protein. Its implication for the attachment of surface proteins in gram-positive bacteria.
Authors: V Pancholi, V A Fischetti
Journal: The Journal of Experimental Medicine (1989)

How streptococcal M protein or other surface proteins of gram-positive bacteria are anchored to the cell is poorly understood. Previously, we reported that M protein released after cell wall removal with a muralytic enzyme lacked the COOH terminal hydrophobic amino acids and charged tail predicted from DNA sequence. An endogenous membrane anchor-cleaving enzyme has now been identified with the ability to release M protein from isolated streptococcal protoplasts. At pH 5.5 in the presence of 30% raffinose, the streptococcal cell wall may be removed with a muralytic enzyme without releasing M protein from the resulting protoplasts indicating that the M molecule is attached through the bacterial cytoplasmic membrane. Release of M molecules occurs when the M protein-charged protoplasts are placed in raffinose buffer at pH 7.4. Although Zn2+, Cd2+, Ca2+, PHMB, and pHMPS inhibit the activity of the releasing enzyme, the blocking activity of Zn2+, Cd2+, and Ca2+ are reversible while PHMB and pHMPS are irreversible. PHMB-treated protoplasts are unable to release M protein at pH 7.4. However, M protein is liberated from these protoplasts when mixed with those prepared from M- streptococci serving as an enzyme source. The supernatant from M- protoplasts is unable to release M protein from PHMB-inactivated M+ protoplasts, confirming that the anchor-cleaving enzyme is membrane bound. Thus, the M protein releasing activity appears to be the result of a thiol-dependent anchor-cleaving enzyme. Streptococcal membranes treated with sodium carbonate and Triton X-114 still retain the M protein verifying that it is an integral membrane molecule. Evidence also is presented indicating significant sequence similarity between M protein and certain GPI-anchored proteins in the region responsible for protein anchoring.