tbuckley/cabot-search huggingface dataset:
Local Overexpression of Thrombomodulin for In Vivo Prevention of Arterial Thrombosis in a Rabbit Model
Authors: J. M. Waugh, E. Yuksel, J. Li, M. D. Kuo, M. Kattash, R. Saxena, R. Geske, S. N. Thung, S. M. Shenaq, S. L. C. Woo
Journal: Circulation Research (1999)

Abstract —Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form, a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi. By histological analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52±3.72% of available lumen, while viral controls reached 86.85±2.82% thrombotic occlusion; in contrast, Adv/RSV-THM reduced thrombosis to 28.61±3.31% of lumen in cross section. No significant intima-to-media ratio was observed in the thrombomodulin group relative to controls. Local infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery, without the inflammatory damage that has limited many other adenoviral applications.
Measuring the damage--ethanol and the liver.
Authors: R P Thompson
Journal: Gut (1986)

Leading articleMeasuring the damage-ethanol and the liver Acute or chronic administration of large amounts of ethanol causes morphological damage not only to the liver but also to many other organs, together with various metabolic changes, such as accumulation of triglycerides in the liver. - It is not known if ethanol is the primary toxin, or only indirectly toxic through the damaging effects of its metabolites, nor whether alcoholics are genetically more susceptible to tissue damage by ethanol than others who drink seemingly with impunity.'46 These two problems are addressed in this issue of Gut by MIvlatteliwso el'ti,7 who combine measurement of hepatic enzyme activities in vitro with the blood concentrations of acetaldehyde after an ethanol load.After rapid absorption from the stomach and small intestine ethanol not bound to plasma proteins is distributed in body water and efficiently removed from blood almost solelv by the liver.More than 60% of ethanol is rapidly oxidised in hepatocytes to acetate and thence to carbon dioxide and water: the accompanying obligatory reduction of NAD to NADH alters the hepatic intracellular redox state, which can adversely affect many other metabolic reactions in the liver. - These biochemical changes may contribute to the hepatotoxicity of ethanol.Acetaldehyde, the first metabolite of alcohol is, however, itself toxic and may augment the widespread tissue damage that follows ethanol
Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl.
Authors: N Carlesso, D A Frank, J D Griffin
Journal: The Journal of Experimental Medicine (1996)

Bcr/Abl is a chimeric oncogene that can cause both acute and chronic human leukemias. Bcr/Abl-encoded proteins exhibit elevated kinase activity compared to c-Abl, but the mechanisms of transformation are largely unknown. Some of the biological effects of Bcr/Abl overlap with those of hematopoietic cytokines, particularly interleukin 3 (IL-3). Such effects include mitogenesis, enhanced survival, and enhanced basophilic differentiation. Therefore, it has been suggested that p210Bcr/Abl and the IL-3 receptor may activate some common signal transduction pathways. An important pathway for IL-3 signaling involves activation of the Janus family kinases (JAKs) and subsequent tyrosyl phosphorylation of STAT proteins (signal transducers and activators of transcription). This pathway directly links growth factor receptors to gene transcription. We analyzed JAK activation, STAT protein phosphorylation, and the formation of specific DNA-binding complexes containing STAT proteins, in a series of leukemia cell lines transformed by Bcr/Abl or other oncogenes. We also examined these events in cell lines transformed by a temperature sensitive (ts) mutant of Bcr/Abl, where the kinase activity of Abl could be regulated. STAT1 and STAT5 were found to be constitutively phosphorylated in 32D, Ba/F3, and TF-1 cells transformed by Bcr/Abl, but not in the untransformed parental cell lines in the absence of IL-3. Phosphorylation of STAT1 and STAT5 was also observed in the human leukemia cell lines K562 and BV173, which express the Bcr/Abl oncogene, but not in several Bcr/Abl-negative leukemia cell lines. Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant. DNA-STAT complexes were detected in all Bcr/Abl-transformed cell lines and they were supershifted by antibodies against STAT1 and STAT5. DNA-STAT complexes in 32Dp210Bcr/Abl cells were similar, but not identical, to those formed after IL-3 stimulation. It is interesting to note that JAK kinases (JAK1, JAK2, JAK3, and Tyk2) were not consistently activated in Bcr/Abl-positive cells. These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. Overall, our results suggest a novel mechanism that could contribute to some of the major biological effects of Bcr/Abl transformation.
Atresia of the Left Atrioventricular Orifice Associated with a Holmes Heart
Authors: MANUEL QUERO
Journal: Circulation (1970)

The first well-documented case of Holmes heart associated with an atretic left atrioventricular orifice is reported. The Holmes heart may be considered as a single ventricle in which the main chamber has the morphologic characteristics of a left ventricle, the infundibular chamber is not inverted, and the great arteries are normally arranged. The importance of this report is greater than its simple description since it definitely establishes that coexistence of a true single ventricle and atresia of the atrioventricular orifice is possible.
The effects of adding non-invasive positive pressure ventilation to supplemental oxygen during exercise training in severe COPD: A randomized controlled study
Authors: Senay Tuncel, Alev Gurgun, Hale Karapolat, Hatice Uluer
Journal: European Respiratory Journal (2014)

Aims and Objectives  We evaluated the effects of Non-Invasive Positive Pressure Ventilation and supplemental oxygen (PR+NIPPV+O 2 , supplemental oxygen during PR (PR+O 2 ) in comparison with only Pulmonary Rehabilitation (PR) on lung functions, blood gases, lactate levels, respiratory muscle pressures, dyspnea, walking distances, quality of life and depression in patients with severe COPD.  Methods  Thirty-five patients (mean±SD age, 65.4±6.5 y) with a mean FEV1 of 39.4±7% predicted, undergoing an 8 week outpatient PR were randomized to either PR+NIPPV+O 2  or PR+O 2  or PR groups. The patients were assessed at baseline and after the intervention.  Results  The average inspiratory and expiratory pressures were 12.0±1.5 cmH 2 0 and 5.1±0.8 cmH 2 0, respectively. In PR+NIPPV+O 2  group, RV and TLC decreased (-305.0±489.1 and -325.0±524.8, both p=0.05, respectively). Although there was an increase in FVC in PR group, no significant change was found in PR+O 2  patients. The increases in P imax  were (13.5±12.1 cmH 2 0, p=0.003) in PR+NIPPV+O 2 and (8.7±9.8 cmH 2 0, p=0.02) in PR group. There was no decrease in lactate levels. The increases in walking tests were greater in PR+NIPPV+O 2  group (69.8±53.2 m in 6MWT and 66.6±65.2 m in ISWT, p=0.001 and p=0.005, respectively) than PR+O 2  group (42.5+55.5 m in 6MWT and 53.5+70.2 m in ISWT, p=0.01 each, respectively). Dyspnea and depression improvement was achieved only in PR+NIPPV+O 2  and the total score of SGRQ improved in PR+O 2  patients.  Conclusion  NIPPV added to supplemental oxygen during PR was associated with better physiological adaptations than other modalities.
Long-Term Complications Related to Biventricular Defibrillator Implantation
Authors: Maurizio Landolina, Maurizio Gasparini, Maurizio Lunati, Saverio Iacopino, Giuseppe Boriani, Carlo Bonanno, Antonello Vado, Alessandro Proclemer, Alessandro Capucci, Chantal Zucchiatti, Sergio Valsecchi, Renato P. Ricci, Massimo Santini
Journal: Circulation (2011)

Background— Long-term data on device-related untoward events in patients receiving defibrillators for resynchronization therapy (CRT-D) are lacking. We quantified the frequency of repeat invasive procedures and the nature of long-term complications in current clinical practice and examined possible predictors of device-related events and their association with long-term patient outcome. Methods and Results— We analyzed data from 3253 patients who underwent de novo successful implantation of CRT-D and were followed up for a median of 18 months (25th to 75th percentiles: 9 to 30) in 117 Italian centers. Device-related events were reported in 416 patients, and, specifically, surgical interventions for system revision were described in 390 patients. Four years after the implantation procedure, 50% of patients underwent surgical revision for battery depletion and 14% for unanticipated events. For comparison, at 4 years battery depletion occurred in 10% and 13% of patients who received single- and dual-chamber defibrillators at the study centers, and unanticipated events were reported as 4% and 9%, respectively. In CRT-D, infections occurred at a rate of 1.0%/y, and the risk of infections increased after device replacement procedures (hazard ratio, 2.04; 95% confidence interval, 1.01 to 4.09; P =0.045). Left ventricular lead dislodgements were reported at a rate of 2.3%/y and were predicted by longer fluoroscopy time and higher pacing threshold on implantation. Device-related events were not associated with a worse clinical outcome; indeed, the risk of death was similar in patients with and without surgical revision (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.47; P =0.682). Conclusions— In current clinical practice device-related events are more frequent in CRT-D than in single- or dual-chamber defibrillators, and are frequently managed by surgical intervention for system revision. However, a worse clinical outcome is not associated with these events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01007474.
Association Between a Functional Variant of the <i>KLOTHO</i> Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity
Authors: Dan E. Arking, Gil Atzmon, Albert Arking, Nir Barzilai, Harry C. Dietz
Journal: Circulation Research (2005)

We previously identified a functional variant of KLOTHO , termed KL-VS, that is associated with human aging and early-onset occult coronary artery disease. Here, we determine whether the KL-VS allele influences cardiovascular disease risk factors, cardiovascular events, and ultimately, mortality. A total of 525 Ashkenazi Jews composed of 216 probands (age ≥95 years) and 309 unrelated individuals (ages 51 to 94) were genotyped for the KL-VS allele. In concordance with our previous data in Czech individuals (age ≥79; P &lt;0.01), a heterozygous advantage for longevity was observed for individuals ≥79 years of age ( P &lt;0.004). Combined analysis indicates a 1.57-fold (95% CI, 1.23 to 1.98) increased odds ratio (OR) for 5-year survival in two independent populations ( P &lt;0.0002). Cardiovascular disease risk factors were assessed through multivariate regression analysis, demonstrating that high-density lipoprotein cholesterol (HDL-C; P &lt;0.05) and systolic blood pressure (SBP; P &lt;0.008) are associated with KL-VS genotype. History of vascular events was analyzed using logistic regression, indicating that after adjustment for traditional risk factors, heterozygous individuals were at significantly lower risk for stroke than wild-type individuals (OR, 5.88; 95% CI, 1.18 to 29.41), whereas homozygous KL-VS individuals had the highest risk (OR, 30.65; 95% CI, 2.55 to 368.00). Similarly, prospective analysis of mortality in probands using Cox regression indicates that wild-type individuals have a 2.15-fold (95% CI, 1.18 to 3.91) and homozygous KL-VS individuals a 4.49-fold (95% CI, 1.35 to 14.97) increase in relative risk for mortality after adjusting for potential confounders. Thus, cross-sectional and prospective studies confirm a genetic model in which the KL-VS allele confers a heterozygous advantage in conjunction with a marked homozygous disadvantage for HDL-C levels, SBP, stroke, and longevity.
Abstract 3578: Local Atherosclerotic Plaques Hide Information That Is Predictive For The Occurrence Of Adverse Cardiovascular Events And Will Help To Identify The Vulnerable Patient: A Prospective Cohort Study In 667 Patients.
Authors: Gerard Pasterkamp, Willem E Hellings, Domique De kleijn, Jean-Paul de Vries, Cees A Seldenrijk, Peter De Bruin, Evelyn Velema, Frans L Moll
Journal: Circulation (2007)

Introduction Atherosclerosis is a systemic disease and the risk for ischemic events in any vascular bed increases when one arterial bed has been affected. It could be speculated that atherosclerotic lesions within the vascular bed share common denominators that destabilize multiple atherosclerotic lesions and increase risk for a subsequent cardiovascular event. We hypothesized that atherosclerotic plaques hide a cellular and molecular fingerprint that is shared by many plaques within the same individual, and that some of these characteristics would be predictive for the occurrence of clinical events due to progression of atherosclerotic disease. Methods Atherosclerotic specimens were collected after carotid endarterectomy and patients underwent clinical follow-up for the duration of 3 years. This first report summarizes the results of a study which investigated the predictive value of histological examination atherosclerotic plaques (macrophage and smooth muscle cell infiltration, collagen, calcifications, thrombus and lipid core) for the occurrence of future adverse cardiovascular events. Results A total of 164 (24.7%) of 667 patients reached the composite primary endpoint of myocardial infarction [n=11], PCI [n=14], CABG [n=6] cardiovascular death [n=12], stroke [n=24], cerebral bleeding [n=14], aneurysm surgery [n=8], peripheral artery surgery [n=64], non cardiovascular death [n=11]. The extent of macrophage or smooth muscle cell infiltration, collagen, calcification and lipid core size within the plaque did not predict systemic adverse cardiovascular events during follow up [p&gt;0.20]. However, the presence of thrombus in the dissected plaque was strongly positively associated with reaching the primary endpoint [Cox Regression: Hazard ratio = 1.6; 95% Confidence interval = 1.1 – 2.5]. Conclusion This atherosclerotic biobank with a longitudinal study design allows identifying local plaque markers related with progression of atherosclerotic disease in the entire vascular system. For the first time we show proof of concept that local plaques hide information that may help to identify the vulnerable patient who is likely to suffer a cardiovascular event.
Hyperbaric Oxygen in Cardiovascular Disease
Authors: HERBERT A. SALTZMAN
Journal: Circulation (1965)

In summary, hyperbaric oxygenation produces remarkable physiologic increases in oxygen transport to body tissues. However, potential benefit from hyperoxygenation in the treatment of ischemic disease appears dependent upon the presence of a partially intact capillary circulation. Improved means for prevention of oxygen toxicity and better technics of oxygen delivery to specific sites are required, if hyperbaric oxygenation is to fulfill present hopes for therapeutic application.
Potential transmission of BSE via medicinal products
Authors: E A. Wickham
Journal: BMJ (1996)

The identification of 10 cases of Creutzfeldt-Jakob disease, which seem to represent a new variant,1 and the announcement by the Spongiform Encephalopathy Advisory Committee (SEAC) on 20 March that these cases could be linked to exposure to bovine spongiform encephalopathy, have caused great concern. Patients are worried about the risks of developing Creutzfeldt-Jakob disease not only from eating beef but also from medicinal products of bovine origin and are looking to doctors, pharmacists, and pharmaceutical companies for reassurance.

The risk of transmission of bovine spongiform encephalopathy via medicinal products depends on whether the infective agent is a human pathogen and on the level of exposure to the agent. To date, no epidemiological link has been made between any spongiform encephalopathy that is transmissible in animals and human disease, despite exposure of humans to the scrapie agent for at least 200 years. This suggests that the risk of transmission to humans is small.2

Measures aimed at minimising exposure to transmissible spongiform encephalopathies via medicinal products were introduced soon after the report of the …
A Randomized Double-Blind Trial of Iseganan in Prevention of Ventilator-associated Pneumonia
Authors: Marin Kollef, Didier Pittet, Miguel Sánchez García, Jean Chastre, Jean-Yves Fagon, Marc Bonten, Robert Hyzy, Thomas R. Fleming, Henry Fuchs, Lisa Bellm, Alain Mercat, Rafael Mañez, Antonio Martínez, Philippe Eggimann, Martín Daguerre
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Iseganan, an antimicrobial peptide, is active against aerobic and anaerobic gram-positive and gram-negative bacteria as well as fungi and yeasts. The drug has shown little resistance in vitro and to be safe and well tolerated in 800 patients with cancer treated for up to 6 wk.To determine the efficacy of iseganan for the prevention of ventilator-associated pneumonia (VAP).Mechanically ventilated patients in the United States and Europe were randomized to oral topical iseganan or placebo (1:1) and treated six times per day while intubated for up to 14 d. Patients were eligible if randomized within 24 h of intubation and estimated to survive and remain mechanically ventilated for 48 h or more. The primary efficacy endpoint of the study was VAP measured among survivors at Day 14.A total of 709 patients were randomized and received at least one dose of study drug. The two groups were comparable at baseline except iseganan-treated patients were, on average, 3 yr older. The rate of VAP among survivors at Day 14 was 16% (45/282) in patients treated with iseganan and 20% (57/284) in those treated with placebo (p = 0.145). Mortality at Day 14 was 22.1% (80/362) in the iseganan group compared with 18.2% (63/347) in the placebo group (p = 0.206). No pattern of excess adverse events in the iseganan group compared with placebo was observed.Iseganan is not effective in improving outcome in patients on prolonged mechanical ventilation.
Genetic Movement Disorders in Patients of Jewish Ancestry
Authors: Rivka Inzelberg, Sharon Hassin-Baer, Joseph Jankovic
Journal: JAMA Neurology (2014)

Genetic diseases often cluster in different ethnic groups and may present with recognizable unique clinical manifestations.To summarize current knowledge about movement disorders overrepresented among patients of Jewish ancestry.We searched PubMed and the OMIM and Israeli National Genetic Databases for articles published from 1969 through March 31, 2014, using the search terms Parkinson's disease,movement disorders, ataxia, dystonia, chorea, and Creutzfeldt-Jakob with and Jewish. The final reference list was generated by giving priority to articles directly related to the topic, articles with the latest information, and comprehensive but relevant reviews.About one-third of patients with sporadic Parkinson disease (PD) and more than 40% of patients with familial PD of Ashkenazi Jewish descent likely carry the G2019S mutation in the LRRK2 gene, a mutation in the glucocerebrosidase (GBA) gene, or both. This finding contrasts with only a 10% frequency of these mutations in patients with PD who are of non-Jewish ancestry. A dystonia due to a TOR1A gene mutation is responsible for most early-onset autosomal dominant dystonia, and 90% of Ashkenazi Jews who develop early-onset disease have TOR1A-related dystonia. Familial Creutzfeldt-Jakob disease and cerebrotendinous xanthomatosis tend to cluster among Jews of North African descent, and Machado-Joseph disease is particularly frequent in Yemenite Jews.Genetic forms of PD are much more common in patients of Ashkenazi Jewish ancestry with sporadic and familial PD than in the non-Jewish population. The recognition of the particular movement disorder phenotype, coupled with information about the ethnic origin of the patients, may point to specific genetic testing and lead to early and correct diagnosis.
Haematopoietic stem cell transplantation (HSCT) in a patient with Sjogren's syndrome and lung malt lymphoma cured lymphoma not the autoimmune disease
Authors: G FERRACCIOLI
Journal: Annals of the Rheumatic Diseases (2001)

Haematopoietic stem cell transplantation (HSCT) has been used in an attempt to control autoimmune diseases that respond poorly to conventional treatment, or as a way of readjusting the immunological balance.1 As far as we know, only one case of primary Sjogren's (SS) has been reported,2 with an unfavourable outcome. Another patient received an allogeneic bone marrow transplant and also had an unfavourable outcome.3 We describe here a further patient with primary SS who underwent HSCT for a non-Hodgkin's lymphoma affecting the lung (large cell, mucosa associated lymphoid tissue (MALT) lymphoma) and review the literature on the effects of HSCT on the autoimmune features and histopathological changes in primary SS.

### Case report

A white woman, aged 42, developed recurrent parotid swelling and symptomatic sicca syndrome, with a Schirmer's test I of 5 mm in the right eye and 4 mm in the left eye. Break up time was 6 s and sialometry was <1 ml.

She had periodic relapses of her parotid swelling. In August 1994 (aged 57) lung x rays …
Electrical assessment of functional lactase activity in conscious man.
Authors: N W Read, R J Davies, C D Holdsworth, R J Levin
Journal: Gut (1977)

Using an electrical technique for measuring transjejunal potential differences (PDs) in conscious man, we have estimated the electrogenic absorption of the hexoses liberated by hydrolysis of lactose which was infused into the jejunum of one normal control and 21 patients with diarrhoea. The results were compared with jejunal lactase levels determined from biopsy specimens taken from the recording site immediately after infusion. The PD evoked by 100 mM lactose was very significantly lower in patients with lactase levels below 4 units (lactase deficient) compared with subjects with normal lactase levels. There was also a significant correlation (r = 0.87, P less than 0.005) between the magnitude of the lactose potential (expressed as the ratio of the maximum glucose transfer potential) and the mucosal lactase level in the hypolactasic subjects but not in patients with normal lactase levels. Thus, in the subjects with lactase deficiency, the electrogenic transfer of hexose is clearly limited by the rate of lactose hydrolysis. Unlike other assessments of functional lactase activity, the electrical test provides a specific index of jejunal function and, moreover, can be adapted to investigate the possible disorders of small intestinal motility and secretion associated with hypolactasia.