tbuckley/cabot-search huggingface dataset:
Chronic obstructive pulmonary disease in 1-antitrypsin PI MZ heterozygotes: a meta-analysis
Authors: C P Hersh
Journal: Thorax (2004)

Severe alpha(1)-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial.A search of MEDLINE from January 1966 to May 2003 identified studies that examined the risk of COPD in PI MZ individuals and studies that measured forced expiratory volume in 1 second (FEV(1)) in heterozygotes.In 16 studies that reported COPD as a categorical outcome, the combined odds ratio (OR) for PI MZ versus PI MM (normal genotype) was 2.31 (95% CI 1.60 to 3.35). The summary OR was higher in case-control studies (OR 2.97; 95% CI 2.08 to 4.26) than in cross sectional studies (OR 1.50; 95% CI 0.97 to 2.31) and was attenuated in studies that adjusted for cigarette smoking (OR 1.61; 95% CI 0.92 to 2.81). In seven studies that reported FEV(1) as a continuous outcome there was no difference in mean FEV(1) between PI MM and PI MZ individuals.Case-control studies showed increased odds of COPD in PI MZ individuals, but this finding was not confirmed in cross sectional studies. Variability in study design and quality limits the interpretation. These results are consistent with a small increase in risk of COPD in all PI MZ individuals or a larger risk in a subset. Future studies that adjust for smoking and include other COPD related phenotypes are required to conclusively determine the risk of COPD in PI MZ heterozygotes.
Passive Containment and Reverse Remodeling by a Novel Textile Cardiac Support Device
Authors: W F Konertz, J E Shapland, H Hotz, S Dushe, J P Braun, K Stantke, F X Kleber
Journal: Circulation (2001)

Progressive remodeling and dilation of cardiac chambers is responsible in part for myocardial dysfunction in chronic heart failure. Preclinical studies with suitable animal models indicate that a passive cardiac constraint device can promote reverse remodeling, with improvement in cardiac function. We hypothesize that such a device could provide benefit for stable heart failure patients in New York Heart Association (NYHA) class II and III.From April 1999 to March 2000, 27 patients received Acorn's Cardiac Support Device (CSD) during an initial safety/feasibility study. In 11 patients, the only surgical measure was CSD placement. Most patients suffered from idiopathic cardiomyopathy; 4 were in NYHA class II, one was in class II/III, and 6 were in class III. All were stable on intensive medical treatment. The CSD, a textile polyester device, was fitted snugly around the heart during surgery. All patients survived surgery and recovered smoothly. Three months after surgery, 56% of patients were in NYHA class I, 33% were in class II, and 11% were in class II/III. Echocardiography showed an improvement in left ventricular ejection fraction from an average of 22% to 28% and 33% at 3 and 6 months, respectively. Simultaneously, the left ventricular end-diastolic dimension decreased from 74 mm to 68 mm and 65 mm, respectively. Mitral valve regurgitation (on a scale of 0 to 4+) decreased from 1.3 to 0.7 by 3 months. Quality-of-life indices correlated with the apparent reversal of ventricular remodeling. Preoperative cardiac medications remained virtually unchanged after implant.In the short- and intermediate-term, CSD implantation seems to ameliorate symptoms and improve cardiac and functional performance in heart failure patients. Worldwide randomized trials are currently underway.
Vascular Endothelial Growth Factor Is Essential for Hyperglycemia-Induced Structural and Functional Alterations of the Peritoneal Membrane
Authors: AN S. DE VRIESE, RONALD G. TILTON, CLIFFORD C. STEPHAN, NORBERT H. LAMEIRE
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Long-term peritoneal dialysis is associated with the development of functional and structural alterations of the peritoneal membrane. Long-term exposure to the high glucose concentrations in conventional peritoneal dialysate has been implicated in the pathogenesis of peritoneal hyperpermeability and neoangiogenesis. Vascular endothelial growth factor (VEGF) is an endothelial-specific growth factor that potently stimulates microvascular permeability and proliferation. High glucose exposure upregulates VEGF expression in various cell types and tissues. This study investigated whether VEGF plays a pathogenetic role in hyperglycemia-induced microvascular dysfunction in the peritoneal membrane. The peritoneal microcirculation of streptozotocin-induced diabetic rats and age-matched controls was studied in vivo with a combination of functional and morphologic techniques. The diabetic microcirculation was characterized by an elevated transport of small solutes, indicating the presence of an increased effective vascular surface area. The leakage of FITC-albumin was more rapid in diabetic vessels, suggesting hyperpermeability for macromolecules. Structurally, an increased vascular density with focal areas of irregular capillary budding was found in the diabetic peritoneum. The hyperglycemia-induced structural and functional microvascular alterations were prevented by long-term treatment with neutralizing anti-VEGF monoclonal antibodies, whereas treatment with isotype-matched control antibodies had no effect. VEGF blockade did not influence microvascular density or macromolecular leakage in control rats, demonstrating specificity for the hyperglycemia-induced alterations. The present results thus support an causative link among high glucose exposure, upregulation of VEGF, and peritoneal microvascular dysfunction.
A phosphorus-31 nuclear magnetic resonance study of the metabolic, contractile, and ionic consequences of induced calcium alterations in the isovolumic rat heart.
Authors: J A Hoerter, M V Miceli, D G Renlund, W E Jacobus, G Gerstenblith, E G Lakatta
Journal: Circulation Research (1986)

Isolated adult rat hearts perfused in an isovolumic mode were used to study the effects of sodium-potassium pump inhibition and sodium-calcium exchange alterations on the tissue content of adenosine triphosphate, phosphocreatine, inorganic phosphate, and intracellular pH, all measured by phosphorus-31 nuclear magnetic resonance spectroscopy. Rates of oxygen consumption, contractile function, and the cell contents of calcium, sodium, and potassium also were determined. The inhibition of sodium-potassium adenosine triphosphatase, either by the reduction in perfusate potassium from 5.9 to 1 millimolar or less, or by the addition of 10(-4) molar ouabain, transiently increased systolic pressure. This was followed by a decrease in systolic pressure, an increase in diastolic pressure, and eventual inexcitability. This contractile profile was accompanied by a persistent increase in oxygen consumption, a monotonic decline in cellular adenosine triphosphate and phosphocreatine content, the development of marked intracellular acidosis, a gain in cell sodium and calcium content, and a reduction in cell potassium. Quite similar metabolic changes were also observed when cell calcium was increased after a reduction in perfusate sodium. These metabolic and contractile effects could be prevented or reversed by decreasing perfusate calcium. The results emphasize the profound role of calcium in modulating cell oxygen consumption, energy balance, pH, excitability, and force production. These data are discussed in light of changes in the myocardial energy supply/demand balance, as well as from the viewpoint of the known competition between mechanisms for mitochondrial calcium transport vs. high-energy phosphate production.
Absorption and Transport of Cobalamin (Vitamin B<sub>12</sub>)
Authors: Bellur Seetharam, David H. Alpers
Journal: Annual Review of Nutrition (1982)

This review apprises the reader of recent advances in cobalamin absorption and transport since 1970. This field has been of interest to gastroenterologists, hematologists, and biochemists as well as nutritionists. Clinical conditions leading to cobalamin deficiency present especially to the first two of these specialties. Many recent advances involve biochemical definition of the specific transport proteins themselves. Full understanding of the multiple clinical conditions associated with cobalamin deficiency requires some knowledge of these proteins. We do not discuss every paper in the field, especially the early literature (see 47, 61, 150). Despite rapid strides in understanding the mechanism of absorption and transport of cobalamin both in prokaryotic and eukaryotic cells, the complete sequence of events during cellular absorption at the plasma membrane level and events in the cells that mediate intracellular movement of cobalamin have not been elucidated completely. Here we emphasize the current state of knowledge about cobalamin absorption and transport in man and other mammalian systems, particularly the physiological role and biochemical nature of proteins involved (intrinsic factor, intrinsic factor-cobalamin receptor, transcobalamins).
Recruitment and Derecruitment During Acute Respiratory Failure
Authors: PAOLO PELOSI, MARI GOLDNER, ANDREW McKIBBEN, ALEX ADAMS, GIUDITTA ECCHER, PIETRO CAIRONI, SABINA LOSAPPIO, LUCIANO GATTINONI, JOHN J. MARINI
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

We aimed to elucidate the relationships between pleural (Ppl), esophageal (Pes), and superimposed gravitational pressures in acute lung injury, and to understand the mechanisms of recruitment and derecruitment. In six dogs with oleic acid respiratory failure, we measured Pes and Ppl in the uppermost, middle, and most dependent lung regions. Each dog was studied at positive end-expiratory pressure (PEEP) of 5 and 15 cm H2O and three levels of tidal volume (Vt; low, medium, and high). For each PEEP–Vt combination, we obtained a computed tomographic (CT) scan at end-inspiration and end-expiration. The variations of Ppl and Pes pressures were correlated (r = 0.86 ± 0.07, p < 0.0001), as was the vertical gradient of transpulmonary (Pl) and superimposed pressure (r = 0.92, p < 0.0001). Recruitment proceeded continuously along the entire volume–pressure curve. Estimated threshold opening pressures were normally distributed (mode = 20 to 25 cm H2O). The amount of end-expiratory collapse at the same PEEP and Pl was significantly lower when ventilation was performed at high Vt. End-inspiratory and end-expiratory collapse were highly correlated (r = 0.86, p < 0.0001), suggesting that as more tissue is recruited at end-inspiration, more remains recruited at end-expiration. When superimposed pressure exceeded applied airway pressure (Paw), collapse significantly increased.Keywords: ALI/ARDS; oleic acid; mechanical ventilation; computed tomography; volume pressure curve
A practical treatment of agoraphobia.
Authors: C Weekes
Journal: BMJ (1973)

Agoraphobia?the condition in which a patient suffers in capacitating anxiety in public places or anywhere outside his own home?is a common syndrome affecting thousands of people in Britain. Optimism in treating it is contrary to much current opinion. However, after many years of practice with a special interest in the anxiety state of which agoraphobia has often been a major symptom, and especially after the results of my last 10 years' experience concerned almost exclusively with treating agoraphobic people, an opti mistic approach is in my opinion justified. A brief outline is offered here of my method of treating agoraphobia. The special difficulty of treating the disorder is that inability to travel to the doctor's surgery is often so much part of the agoraphobic's illness that he may rarely, perhaps never, succeed in making the journey. In these cir cumstances, offering a satisfactory programme of treatment and in addition giving the frequent encouragement and re assurance the agoraphobic patient needs present special diffi culties; while to treat a patient adequately at home is surely asking too much from a busy practitioner. The treatment described here overcomes these difficulties. It does not require the personal presence of the doctor. It is available when needed (which may be many times during one day) either at home, or away from home when the patient's agoraphobic fears are at their worst. In addition, the cost is negligible. Treatment is in the form of two books,12 two long playing (L.P.) recordings,3 quarterly magazines sent to 1,800 agorapho bic men and women in Great Britain and Ireland during the four years 1969-72, and a cassette4 for a small portable tape recorder. This remote control (perhaps direction would be a more accurate word) has made it possible to treat people living not only in distant parts of Great Britain but also in other countries. The books are available in most libraries, the L.P. record ings and cassette are in the library of the British Medical As sociation, and the quarterly magazines (1969-72) have recently been published in book form.2 In psychiatric clinics in Great Britain where the recordings are used patients are encouraged to bring their tape recorders and make copies, and no objec tions are raised. The condition is explained to the patients in the following way.
SkM1 and Cx32 improve conduction in canine myocardial infarcts yet only SkM1 is antiarrhythmic
Authors: Gerard J.J. Boink, David H. Lau, Iryna N. Shlapakova, Eugene A. Sosunov, Evgeny P. Anyukhovsky, Helen E. Driessen, Wen Dun, Ming Chen, Peter Danilo, Tove S. Rosen, Nazira Őzgen, Heather S. Duffy, Yelena Kryukova, Penelope A Boyden, Richard B. Robinson, Peter R. Brink, Ira S. Cohen, Michael R. Rosen
Journal: Cardiovascular Research (2012)

Reentry accounts for most life-threatening arrhythmias, complicating myocardial infarction, and therapies that consistently prevent reentry from occurring are lacking. In this study, we compare antiarrhythmic effects of gene transfer of green fluorescent protein (GFP; sham), the skeletal muscle sodium channel (SkM1), the liver-specific connexin (Cx32), and SkM1/Cx32 in the subacute canine infarct. Immediately after ligation of the left anterior descending artery, viral constructs were implanted in the epicardial border zone (EBZ). Five to 7 days later, efficient restoration of impulse propagation (narrow QRS and local electrogram duration) occurred in SkM1, Cx32, and SkM1/Cx32 groups (P< 0.05 vs. GFP). Programmed electrical stimulation from the EBZ induced sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) in 15/22 GFP dogs vs. 2/12 SkM1, 6/14 Cx32, and 8/10 SkM1/Cx32 (P< 0.05 SkM1 vs. GFP). GFP, SkM1, and SkM1/Cx32 had predominantly polymorphic VT/VF, whereas in Cx32 dogs, monomorphic VT predominated (P< 0.05 for Cx32 vs. GFP). Tetrazolium red staining showed significantly larger infarcts in Cx32- vs. GFP-treated animals (P< 0.05). Whereas SkM1 gene transfer reduces the incidence of inducible VT/VF, Cx32 therapy to improve gap junctional conductance results in larger infarct size, a different VT morphology, and no antiarrhythmic efficacy.
Mouse Modeling in Oncologic Preclinical and Translational Research
Authors: Brett S. Carver, Pier P. Pandolfi
Journal: Clinical Cancer Research (2006)

Abstract Through scientific and technological advancements, our ability to manipulate the mouse genome has allowed us to evaluate the effect of specific genetic alterations on in vivo tumorigenesis. This has allowed and will allow us to define molecular pathways describing the processes of tumor initiation, invasion, and progression to metastatic disease. Additionally, these models may serve as an excellent platform for the identification of novel molecular targets for therapy as well as to evaluate the efficacy of targeted therapies. Ultimately this will translate from preclinical mouse model trials to the development of clinical trials and protocols for cancer patients. Here we review the usefulness of mouse modeling in oncologic translational research.
Evolutionary conservation of domain-domain interactions.
Authors: Zohar Itzhaki, Eyal Akiva, Yael Altuvia, Hanah Margalit
Journal: Genome biology (2006)

Abstract Background Recently, there has been much interest in relating domain-domain interactions (DDIs) to protein-protein interactions (PPIs) and vice versa , in an attempt to understand the molecular basis of PPIs. Results Here we map structurally derived DDIs onto the cellular PPI networks of different organisms and demonstrate that there is a catalog of domain pairs that is used to mediate various interactions in the cell. We show that these DDIs occur frequently in protein complexes and that homotypic interactions (of a domain with itself) are abundant. A comparison of the repertoires of DDIs in the networks of Escherichia coli , Saccharomyces cerevisiae , Caenorhabditis elegans , Drosophila melanogaster , and Homo sapiens shows that many DDIs are evolutionarily conserved. Conclusion Our results indicate that different organisms use the same 'building blocks' for PPIs, suggesting that the functionality of many domain pairs in mediating protein interactions is maintained in evolution.
II. INDUCED ALTERATIONS IN THE PERMEABILITY OF THE LYMPHATIC CAPILLARY
Authors: Philip D. McMaster, Stephen Hudack
Journal: The Journal of Experimental Medicine (1932)

A standardized solution of a vital dye which escapes with some difficulty from the lymphatics of the ear of the mouse has been utilized in tests of the permeability of the lymphatic wall under various conditions. It has been found that this permeability is subject to great change. The slight pressure that suffices to prevent lymph flow from the ear,-an organ in which such flow goes on normally,-soon results in increased permeability of the obstructed lymphatics without as yet any perceptible dilatation of these vessels. Mechanical stimulation as for example a stroke with a blunt wire, or scratching so light as not to break the epidermis, results in a practically immediate, great increase in lymphatic permeability, which is sharply localized to the region pressed upon. This increase in permeability, though so great that even hemoglobin is let pass by the lymphatics, endures but a few hours. Warming the ear to 43 degrees C. or exposure to mild sunlight increases permeability considerably. Slight chemical irritation increases it greatly, though not so much that particulate matter is let pass. The edema developing as result of lymphatic obstruction or mechanical, thermal, or chemical stimulation is preceded by and associated with a large increase in lymphatic permeability. The facts are discussed in relation to their bearing upon fluid accumulation within the tissue. It is plain that influences within the realm of the normal suffice to increase lymphatic permeability and that those which lead to edema cause a very great increase in it. In proportion as this increase occurs the lymphatics cease to be channels demarcated by a semipermeable membrane. It seems certain that the changes must be in some part responsible for the local accumulation of fluid. There exist possibilities, on the other hand, of a correlation between the functionings of the blood and lymph vessels under certain pathological conditions, as during the resorption of edema.
Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction
Authors: David D. Waters, Gregory G. Schwartz, Anders G. Olsson, Andreas Zeiher, Michael F. Oliver, Peter Ganz, Michael Ezekowitz, Bernard R. Chaitman, Sally J. Leslie, Theresa Stern
Journal: Circulation (2002)

This report describes the effect of intensive cholesterol lowering with atorvastatin on the incidence of nonfatal stroke, a secondary end point, in a randomized, placebo-controlled trial of patients with unstable angina or non-Q-wave myocardial infarction. The primary end point, a composite of death, nonfatal myocardial infarction, resuscitated cardiac arrest, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization, was reduced from 17.4% in the placebo group to 14.8% in the atorvastatin group over the 16 weeks of the trial (P=0.048).Strokes were adjudicated by a blinded end-point committee using standard clinical and imaging criteria. The outcomes of nonfatal stroke and fatal plus nonfatal stroke were analyzed by time to first occurrence during the 16-week trial. Of 38 events (in 36 patients) adjudicated as fatal or nonfatal strokes, 3 were classified as hemorrhagic, one as embolic, and 29 as thrombotic or embolic; 5 could not be categorized. Nonfatal stroke occurred in 9 patients in the atorvastatin group and 22 in the placebo group (relative risk, 0.40; 95% confidence intervals, 0.19 to 0.88; P=0.02). Fatal or nonfatal stroke occurred in 12 atorvastatin patients and 24 placebo patients (relative risk, 0.49; 95% confidence intervals, 0.24 to 0.98; P=0.04). All 3 hemorrhagic strokes occurred in the placebo group.Intensive cholesterol lowering with atorvastatin over 16 weeks in patients with acute coronary syndromes reduced the overall stroke rate by half and did not cause hemorrhagic stroke. These findings need to be confirmed in future trials.
Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease
Authors: Nico H.J. Pijls, William F. Fearon, Pim A.L. Tonino, Uwe Siebert, Fumiaki Ikeno, Bernhard Bornschein, Marcel van't Veer, Volker Klauss, Ganesh Manoharan, Thomas Engstrøm, Keith G. Oldroyd, Peter N. Ver Lee, Philip A. MacCarthy, Bernard De Bruyne
Journal: Journal of the American College of Cardiology (2010)
Id4 dependent acetylation restores mutant-p53 transcriptional activity
Authors: Ashley E Knowell, Divya Patel, Derrick J Morton, Pankaj Sharma, Shanora Glymph, Jaideep Chaudhary
Journal: Molecular Cancer (2013)

Abstract Background The mechanisms that can restore biological activity of mutant p53 are an area of high interest given that mutant p53 expression is observed in one third of prostate cancer. Here we demonstrate that Id4, an HLH transcriptional regulator and a tumor suppressor, can restore the mutant p53 transcriptional activity in prostate cancer cells. Methods Id4 was over-expressed in prostate cancer cell line DU145 harboring mutant p53 (P223L and V274F) and silenced in LNCaP cells with wild type p53. The cells were used to quantitate apoptosis, p53 localization, p53 DNA binding and transcriptional activity. Immuno-precipitation/-blot studies were performed to demonstrate interactions between Id4, p53 and CBP/p300 and acetylation of specific lysine residues within p53. Results Ectopic expression of Id4 in DU145 cells resulted in increased apoptosis and expression of BAX, PUMA and p21, the transcriptional targets of p53. Mutant p53 gained DNA binding and transcriptional activity in the presence of Id4 in DU145 cells. Conversely, loss of Id4 in LNCaP cells abrogated wild type p53 DNA binding and transactivation potential. Gain of Id4 resulted in increased acetylation of mutant p53 whereas loss of Id4 lead to decreased acetylation in DU145 and LNCaP cells respectively. Id4 dependent acetylation of p53 was in part due to a physical interaction between Id4, p53 and acetyl-transferase CBP/p300. Conclusions Taken together, our results suggest that Id4 regulates the activity of wild type and mutant p53. Id4 promoted the assembly of a macromolecular complex involving CBP/P300 that resulted in acetylation of p53 at K373, a critical post-translational modification required for its biological activity.