tbuckley/cabot-search huggingface dataset:
Discoidal bilayer structure of nascent high density lipoproteins from perfused rat liver.
Authors: R L Hamilton, M C Williams, C J Fielding, R J Havel
Journal: Journal of Clinical Investigation (1976)

Rat livers were perfused for 6 h without added plasma proteins using washed erythrocytes and buffer in a recirculating system. An inhibitor to the enzyme lecithin-cholesterol acyltransferase (5,5'-dithionitrobenzoic acid) was added in some experiments to prevent modification of substrate-lipids contained in secreted lipoproteins. The inhibitor did not detectably alter hepatic ultrastructure or gas exchange, but it inhibited the secreted lecithin-cholesterol acyltransferase by more than 85%. Very low density lipoproteins in perfusate were unaltered but the high density lipoproteins obtained from livers perfused with the inhibitor appeared disk-shaped in negative stain by electron microscopy with a mean edge thickness of 46 +/- 5 A and a mean diameter of 190 +/- 25 A. The high density lipoproteins were composed predominantly of polar lipids and protein with only small amounts of cholesteryl esters and triglycerides. The major apoprotein of these discoidal fractions had the same electrophoretic mobility as the arginine-rich apoprotein, whereas plasma high density lipoproteins contained mainly the A-I approtein. In all these respects the discoidal perfusate high density lipoproteins closely resemble those found in human plasma which is deficient in lecithin-cholesterol acyltransferase. Perfusate high density lipoproteins obtained in the absence of the enzyme inhibitor more closely resembled plasma high density lipoproteins in chemical composition (content of cholesteryl esters and apoproteins) and in electron microscopic appearance. Purified lecithin-cholesterol acyltransferase synthesized cholesteryl esters at a substantially faster rate from substrate lipids of perfusate high density lipoproteins than those from plasma. The discoidal high density lipoproteins were the best substrate for this reaction. Thin sections of plasma high density lipoproteins indicated a spherical particle whereas discoidal high density lipoproteins stained with the characteristic trilaminar image of membranes. These observations suggest that the liver secretes disk-shaped lipid bilayer particles which represent both the nascent form of high density lipoproteins and preferred substrate for lecithin-cholesterol acyltransferase.
Exacerbations in non-COPD patients: truth or myth—authors’ response
Authors: Wan C Tan, Jean Bourbeau, Shawn Aaron, J Mark FitzGerald, Paul Hernandez, Robert Cowie, Kenneth R Chapman, Darcy Marciniuk, Francois Maltais, Sonia Buist, Denis O'Donnell, Don D Sin
Journal: Thorax (2014)

Exacerbations in non-COPD patients: truth or mythauthors' response Dear Sir, We are grateful to Dr Khurana and Dr Aggarwal for their interest 1 in our paper. 2n their first point, we agree that we should be careful about terminology.We evaluated a random sample of individuals representative of the general population rather than patients, so the findings that episodes of respiratory events occurred in these subjects would likely reflect real events in the general population.Furthermore, our study definition for exacerbations was the same standard questionnaire criteria for exacerbations used in clinical trials of selected patients with COPD. 3 On the second point on aetiologies for non-COPD subgroup in this study, we would like to emphasise that 'non-COPD' was defined by the absence of chronic airflow limitation using the standard, although arbitrary spirometric criteria.We excluded those individuals with selfreported chronic obstructive lung diseases, namely, COPD, chronic bronchitis, emphysema and asthma and evaluated bronchodilator reversibility but did not perform bronchoprovocation test.Thus, residual confounding by undiagnosed asthma or bronchiectasis remains.We could not address other specific aetiologies in this study, and further data would require linkage to administrative databases and longitudinal follow-up of the cohort.On the third point of aetiologies for exacerbations, we do not have aetiologies for the exacerbation-like events.However, to be fair, do we really know the aetiologies for exacerbations among patients with COPD?We assume most of the causes are viral or bacterial infections, but data on causality are lacking.This is an area that requires further exploration.Our study could only address this point indirectly.
Prognostic Value of the Admission Electrocardiogram in Acute Coronary Syndromes
Authors: Stefano Savonitto
Journal: JAMA (1999)

ContextThe presence of ischemic changes on electrocardiogram (ECG) correlates with poorer outcomes in patients with acute chest pain.ObjectiveTo determine the prognostic value of various ECG presentations of acute myocardial ischemia.DesignRetrospective analysis of the presenting ECGs of patients enrolled in Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb).SettingThree hundred seventy-three hospitals in 13 countries in North America, Europe, Australia, and New Zealand.PatientsA total of 12,142 patients who reported symptoms of cardiac ischemia at rest within 12 hours of admission and had signs of myocardial ischemia confirmed by ECG. On presenting ECG, 22% of patients had T-wave inversion, 28% had ST-segment elevation, 35% had ST-segment depression, and 15% had a combination of ST-segment elevation and depression.Main Outcome MeasureAbility of presenting ECG to predict death or myocardial reinfarction during the first 30 days of follow-up.ResultsThe 30-day incidence of death or myocardial reinfarction was 5.5% in patients with T-wave inversion, 9.4% in those with ST-segment elevation, 10.5% in those with ST-segment depression, and 12.4% in those with ST-segment elevation and depression (P<.001). After adjusting for factors associated with an increased risk of 30-day death or reinfarction, compared with those who had T-wave inversion only, the odds of 30-day death or reinfarction were 1.68 (95% confidence interval [CI], 1.36-2.08) in those with ST-segment elevation, 1.62 (95% CI, 1.32-1.98) for those with ST-segment depression, and 2.27 (95% CI, 1.80-2.86) for those with combined elevation and depression. An elevated creatine kinase level at admission correlated with a higher risk of death (odds ratio [OR], 2.36; 95% CI, 1.92-2.91) and death or reinfarction (OR, 1.56; 95% CI, 1.32-1.85). The ECG category and creatine kinase level at admission remained highly predictive of death and myocardial infarction after multivariate adjustment for the significant baseline predictors of events.ConclusionsThe ECG at presentation allows immediate risk stratification across the spectrum of acute coronary syndromes. An elevated creatine kinase level at admission is associated with worse outcomes.
Risk Factors for the Incidence of Second Cancers in Survivors of Retinoblastoma With a Family History
Authors: Annette C. Moll, Charlotte J. Dommering, Machteld I. Bosscha, Pim de Graaf, W. Arjenne Kors, Flora E. van Leeuwen
Journal: Journal of Clinical Oncology (2012)

TO THE EDITOR: Kleinerman et al recently published an article concerning variations in second cancer risk by family history of retinoblastoma among long-term survivors of retinoblastoma. They concluded that retinoblastoma survivors with bilateral disease and an inherited germline mutation are at slightly higher risk of a second cancer (in particular, melanoma) compared with those with a de novo germline mutation, perhaps because of shared genetic alterations. As Kleinerman et al stated in the Patients and Methods section of their article, genetic testing data were not available for all of the survivors in their study; therefore, they used laterality and family history as asurrogateforthepresenceofaninheritedordenovogermlinemutation. It is possible that between 6% and 10% of survivors of retinoblastoma with a de novo mutation are in fact mosaic for the mutation. Kaye and Harbour reported that in survivors of sporadic hereditary retinoblastoma with the mosaic form, the risk of a second cancer may be elevated to a lesser extent, given that not all cells carry the RB1 mutation and thus not all tissues are at risk for a second cancer. This could explain the difference in risk of second cancers between sporadic and familial retinoblastoma as reported by Kleinerman et al, because for the patients with familial retinoblastoma, mosaicism is excluded and all tissues are at risk for second cancers. Kleinerman et al are to be complimented for their interesting study. However, we believe that the slightly higher risk of a second cancer in survivors of bilateral retinoblastoma and an inherited germline mutation (47%) compared with those with a de novo germline mutation (38%) could also be explained by mosaicism.
Endometrial Glandular Dysplasia with Frequent p53 Gene Mutation: A Genetic Evidence Supporting Its Precancer Nature for Endometrial Serous Carcinoma
Authors: Lin Jia, Yongjuan Liu, Xiaofang Yi, Alexander Miron, Christopher P. Crum, Beihua Kong, Wenxin Zheng
Journal: Clinical Cancer Research (2008)

Endometrial glandular dysplasia (EmGD) has been recently proposed to be a putative precursor to endometrial serous carcinoma (ESC). The purpose of this study is to determine if EmGD is genetically linked to ESC and if it can be used for early detection.The tumor suppressor p53 gene was sequenced from serial samples of benign and neoplastic endometria with serous differentiation. The study group contained 15 neoplastic uteri and the control group had 12 age-matched benign uteri. A total of 139 informative samples were obtained, including 55 resting endometrium, 37 EmGD, 25 serous endometrial intraepithelial carcinoma (EIC), and 22 ESC. At least one representative section from each uterus was used for p53 immunohistochemical staining to correlate p53 overexpression with gene mutation status.The mutations of p53 were detected in 0%, 43%, 72%, and 96% in resting endometrium, EmGD, serous EIC, and ESC, respectively. More than 50% of the neoplastic uteri showed at least one identical p53 gene mutant among lesions of EmGD, serous EIC, and/or ESC. The majority of lesions showed overexpression of p53 protein, which was significantly correlated with p53 gene mutation (P < 0.01).This genetic evidence strongly supports that EmGD represents the precancer of ESC or serous EIC. Mutation of p53 gene is probably one of the most important factors to initiate the endometrial serous carcinogenesis. Correct identification of EmGD will provide us an opportunity of early diagnosis and a potentially effective therapeutic modality to control ESC.
Tackling social factors is key in reducing cardiovascular disease, say US heart doctors
Authors: Michael McCarthy
Journal: BMJ (2015)

Dealing with the social determinants of health offers the greatest opportunities for reducing death and disability from cardiovascular disease (CVD) in the United States, says a policy statement by the American Heart Association released on 3 August.1

After three decades of decline the prevalence of CVD in the US is expected to rise by 10% from 2010 to 2030, partly driven by an ageing population but also by rising rates of obesity, hypertension, and physical inactivity, the statement said.

“Although there is no consensus on the precise causes of …
Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis
Authors: Gianluca Moroncini, Antonella Grieco, Giulia Nacci, Chiara Paolini, Cecilia Tonnini, Katarzyna N. Pozniak, Massimiliano Cuccioloni, Matteo Mozzicafreddo, Silvia Svegliati, Mauro Angeletti, Andrius Kazlauskas, Enrico V. Avvedimento, Ada Funaro, Armando Gabrielli
Journal: Arthritis & Rheumatology (2015)

To identify the epitopes recognized by autoantibodies targeting platelet-derived growth factor receptor α (PDGFRα) in systemic sclerosis (SSc) and develop novel assays for detection of serum anti-PDGFRα autoantibodies. Epstein-Barr virus-immortalized B cells from 1 patient with SSc (designated PAM) were screened for expression of IgG binding to PDGFRα and induction of reactive oxygen species in fibroblasts. The variable regions of anti-PDGFRα IgG were cloned into an IgG expression vector to generate distinct recombinant human monoclonal autoantibodies (mAb), which were characterized by binding and functional assays. The epitopes of anti-PDGFRα recombinant human mAb were defined by molecular docking, surface plasmon resonance binding assays, screening of a conformational peptide library spanning the PDGFRα extracellular domains, and expression analyses of alanine-scanned PDGFRα mutants. Direct or competitive enzyme-linked immunosorbent assays were established to detect all serum anti-PDGFRα autoantibodies or, selectively, the agonistic ones. Three types of anti-PDGFRα recombinant human mAb, with the same VH but distinct VL chains, were generated. Nonagonistic VH PAM-Vκ 13B8 recognized 1 linear epitope, whereas agonistic VH PAM-Vλ 16F4 and VH PAM-Vκ 16F4 recognized 2 distinct conformational epitopes. Serum anti-PDGFRα antibodies were detected in 66 of 70 patients with SSc, 63 of 130 healthy controls, 11 of 26 patients with primary Raynaud's phenomenon (RP), and 13 of 29 patients with systemic lupus erythematosus (SLE). Serum VH PAM-Vκ 16F4-like antibodies were found in 24 of 34 patients with SSc, but not in healthy controls, patients with primary RP, or patients with SLE. Peptides composing the VH PAM-Vκ 16F4 epitope inhibited PDGFRα signaling triggered by serum IgG from SSc patients. Agonistic anti-PDGFRα autoantibodies are enriched in SSc sera and recognize specific conformational epitopes that can be used to discriminate agonistic from nonagonistic antibodies and block PDGFRα signaling in patients with SSc.
Diagnosis of obstructive sleep apnea using a portable transducer catheter.
Authors: M Tvinnereim, S Mateika, P Cole, J Haight, V Hoffstein
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

As an initial step in simplifying the diagnosis of sleep apnea with a view toward using portable equipment in the home setting, we examined the efficacy of a portable transducer catheter that measures intrathoracic pressure. This catheter, connected to a miniature data-logger, can be introduced nasally into the airway, and the data so collected can be acquired, stored, and analyzed off-line. We tested this catheter against standard nocturnal polysomnography in 10 patients suffering from obstructive sleep apnea. We found that by using a combination of the raw pressure signal and an envelope pressure signal, we accurately identified apneas and hypopneas, and classified them as obstructive, central, and mixed. For the 10 subjects studied, the polysomnographic apnea/hypopnea index was 34 + 30, versus 32 + 28 obtained by analysis of the pressure tracings. Analysis of 200 respiratory events identified one-by-one from polysomnograms and pressure tracings revealed close correspondence between the two methods. The average duration of apneas was 22.1 + 6.7 s as measured by polysomnography, versus 21.9 + 6.6 s as measured from pressure tracings. Furthermore, there was excellent agreement between the two methods (kappa = 0.89, 95% confidence limits = 0.84 to 0.94). We conclude that our technique for identifying apnea based on measurements of intrathoracic pressure using a thin, portable transducer catheter is a promising method for simplifying the diagnosis of this disorder.
Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome
Authors: Kiichi Nakahira, Jeffrey Adam Haspel, Vijay A K Rathinam, Seon-Jin Lee, Tamas Dolinay, Hilaire C Lam, Joshua A Englert, Marlene Rabinovitch, Manuela Cernadas, Hong Pyo Kim, Katherine A Fitzgerald, Stefan W Ryter, Augustine M K Choi
Journal: Nature Immunology (2010)
Margaret McCartney: The false god of appraisal
Authors: Margaret McCartney
Journal: BMJ (2015)

Twenty three minutes on a train. Until a couple of years ago I used the time spent on this regular journey thinking about things I’d like to write about, or the best birthday presents for friends, the colour of the trees rushing by, the enticing smell of other people’s fish and chips. That time was mine. It was aimless but gloriously, fruitfully productive.

This has stopped. Appraisal now means that I use those 23 minutes writing down my “learning activities” from the week before. Appraisal means that I must keep collecting evidence of professional development. It is a sacrifice to the god of revalidation—because only when written down is something proved to have happened.

Like everyone else, I look up things …
Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial
Authors: Vincent JJ Odekerken, Teus van Laar, Michiel J Staal, Arne Mosch, Carel FE Hoffmann, Peter CG Nijssen, Guus N Beute, Jeroen PP van Vugt, Mathieu WPM Lenders, M Fiorella Contarino, Marieke SJ Mink, Lo J Bour, Pepijn van den Munckhof, Ben A Schmand, Rob J de Haan, P Richard Schuurman, Rob MA de Bie
Journal: The Lancet Neurology (2012)
Bone Marrow Stroma–Secreted Cytokines Protect JAK2V617F-Mutated Cells from the Effects of a JAK2 Inhibitor
Authors: Taghi Manshouri, Zeev Estrov, Alfonso Quintás-Cardama, Jan Burger, Ying Zhang, Ana Livun, Liza Knez, David Harris, Chad J. Creighton, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Cancer Research (2011)

Signals emanating from the bone marrow microenvironment, such as stromal cells, are thought to support the survival and proliferation of the malignant cells in patients with myeloproliferative neoplasms (MPN). To examine this hypothesis, we established a coculture platform [cells cocultured directly (cell-on-cell) or indirectly (separated by micropore membrane)] designed to interrogate the interplay between Janus activated kinase 2-V617F (JAK2(V617F))-positive cells and the stromal cells. Treatment with atiprimod, a potent JAK2 inhibitor, caused marked growth inhibition and apoptosis of human (SET-2) and mouse (FDCP-EpoR) JAK2(V617F)-positive cells as well as primary blood or bone marrow mononuclear cells from patients with polycythemia vera; however, these effects were attenuated when any of these cell types were cocultured (cell-on-cell) with human marrow stromal cell lines (e.g., HS5, NK.tert, TM-R1). Coculture with stromal cells hampered the ability of atiprimod to inhibit phosphorylation of JAK2 and the downstream STAT3 and STAT5 pathways. This protective effect was maintained in noncontact coculture assays (JAK2(V617F)-positive cells separated by 0.4-μm-thick micropore membranes from stromal cells), indicating a paracrine effect. Cytokine profiling of supernatants from noncontact coculture assays detected distinctly high levels of interleukin 6 (IL-6), fibroblast growth factor (FGF), and chemokine C-X-C-motif ligand 10 (CXCL-10)/IFN-γ-inducible 10-kD protein (IP-10). Anti-IL-6, -FGF, or -CXCL-10/IP-10 neutralizing antibodies ablated the protective effect of stromal cells and restored atiprimod-induced apoptosis of JAK2(V617F)-positive cells. Therefore, our results indicate that humoral factors secreted by stromal cells protect MPN clones from JAK2 inhibitor therapy, thus underscoring the importance of targeting the marrow niche in MPN for therapeutic purposes.
Hormone interactions in the isolated rabbit heart. Synthesis and coronary vasomotor effects of prostaglandins, angiotensin, and bradykinin.
Authors: P Needleman, G R Marshall, B E Sobel
Journal: Circulation Research (1975)

In the present study, the synthesis and degradation of several potent vasoactive substances influencing coronary resistance were characterized in the isolated perfused rabbit heart. Prostaglandin synthetase activity, angiotensin converting enzyme activity, and bradykininase activity (without angiotensinase) were observed. A prostaglandin E2-like substance appeared to be the ednogenous mediator of the coronary vasodilation produced by bradykinin and angiotensin II (AII). (1) The concentration of this prostaglandinlike substance in the coronary venous effluent was directly proportional to the concentration of the coronary vasocilator stimulus (bradykinin or AII). (2) The prostaglandinlike substance released and the coronary dilation produced by the agonists correlated temporally and quantitatively. (3). Abolition of cardiac biosynthesis of the prostaglandinlike substance by indomethacin also abolished the decrease in coronary resistance produced by the agonists. AII, the most potent naturally occurring vasoconstrictor substance, produced a paradoxical coronary vasodilation because it stimulated cardiac prostaglandin biosynthesis, but the direct coronary vasoconstrictor action of AII could be readily unmasked by indomethacin, which blocks prostaglandin synthesis. The nonapeptide SQ-20881 blocked cardiac biosynthesis of AII (from angiotensin I) and enhanced the coronary vascular effects of bradykinin by interfering with bradykininase activity. Similarly, the AII-receptor antagonist, 1-Sar-8-Ile-AII, blocked the coronary vascular effect of AII.
Catheter Ablation of Ventricular Fibrillation in Rabbit Ventricles Treated With β-Blockers
Authors: Hui-Nam Pak, Yong-Seog Oh, Yen-Bin Liu, Tsu-Juey Wu, Hrayr S. Karagueuzian, Shien-Fong Lin, Peng-Sheng Chen
Journal: Circulation (2003)

A therapeutic implication of the focal-source hypothesis of ventricular fibrillation (VF) is that VF can be terminated by focal ablation. We hypothesize that beta-adrenergic receptor blockade converts multiple-wavelet VF to focal-source VF and that this focal source is located near the papillary muscle (PM).We used optical mapping techniques to study the effects of propranolol (0.3 mg/L) on VF dynamics in Langendorff-perfused rabbit hearts. The left ventricular (LV) anterior wall was mapped and optical action potential duration restitution (APDR) was determined at 25 epicardial sites. We performed ablation during VF of the left anterior PM in hearts with (N=6) or without (N=6) cytochalasin infusion, the LV lateral epicardium (Epi group, N=3), and the LV endocardium (Endo group, N=3). The PM was also ablated in 3 hearts without propranolol (control group). Propranolol converted multiple-wavelet VF to slow VF with reentry localized to the PM. Propranolol decreased the maximal slope of the APDR curve (P<0.001) as well as its spatial heterogeneity (P<0.01) and conduction velocity (P=0.01) while increasing the VF cycle length (P<0.001). PM ablation terminated VF during propropranolol infusion with (6 of 6, 100%) or without (4 of 6, 67%) cytochalasin D and significantly reduced inducibility. VF did not terminate in the Epi, Endo, and control groups (P<0.001).Propranolol flattens the APDR curve and reduces conduction velocity, converting multiple-wavelet VF into VF with a focal source anchored to the PM. Ablation of this focal source may terminate VF.