tbuckley/cabot-search huggingface dataset:
Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak
Authors: J J Y Sung
Journal: Thorax (2004)

The outcome is reported of a prospective uncontrolled study based on a stepwise treatment protocol during an outbreak of severe acute respiratory syndrome (SARS) in Hong Kong.One hundred and thirty eight patients were treated with broad spectrum antibiotics, a combination of ribavirin and low dose corticosteroid, and then intravenous high dose methylprednisolone according to responses. Sustained response to treatment was defined as (1) defervescence for > or =4 consecutive days, (2) resolution of lung consolidation by >25%, and (3) oxygen independence by the fourth day without fever. Patients with defervescence who achieved either criterion 2 or 3 were classified as partial responders. Patients who fell short of criteria 2 and 3 were non-responders.Laboratory confirmation of SARS coronavirus infection was established in 132 (95.7%). None responded to antibiotics but 25 (18.1%) responded to ribavirin + low dose corticosteroid. Methylprednisolone was used in 107 patients, of whom 95 (88.8%) responded favourably. Evidence of haemolytic anaemia was observed in 49 (36%). A high level of C-reactive protein at presentation was the only independent predictor for use of methylprednisolone (odds ratio 2.18 per 10 mg/dl increase, 95% confidence interval 1.12 to 4.25, p = 0.02). Thirty seven patients (26.8%) required admission to the intensive care unit and 21 (15.2%) required invasive mechanical ventilation. There were 15 deaths (mortality rate 10.9%), most with significant co-morbidities, whereas 122 (88.4%) had been discharged home 4 months after the outbreak onset.The use of high dose pulse methylprednisolone during the clinical course of a SARS outbreak was associated with clinical improvement, but randomised controlled trials are needed to ascertain its efficacy in this condition.
Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau
Authors: Yang Hong-Qi, Sun Zhi-Kun, Chen Sheng-Di
Journal: Translational Neurodegeneration (2012)

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mainly the memory and cognitive function in elderly. Extracellular beta amyloid deposition and intracellular tau hyperphosphorylation are the two pathological events that are thought to cause neuronal dysfunction in AD. Since the detailed mechanisms that underlie the pathogenesis of AD are still not clear, the current treatments are those drugs that can alleviate the symptoms of AD patients. Recent studies have indicated that these symptom-reliving drugs also have the ability of regulating amyloid precursor protein processing and tau phosphorylation. Thus the pharmacological mechanism of these drugs may be too simply-evaluated. This review summarizes the current status of AD therapy and some potential preclinical considerations that target beta amyloid and tau protein are also discussed.
The role of natriuretic peptides in cardioprotection
Authors: T NISHIKIMI, N MAEDA, H MATSUOKA
Journal: Cardiovascular Research (2005)

Atrial natriuretic peptide (ANP) and brain (B-type) natriuretic peptide (BNP) are circulating hormones of cardiac origin that play an important role in the regulation of intravascular blood volume and vascular tone. The plasma concentrations of ANP and BNP are elevated in heart failure, and they are considered to compensate for heart failure because of their diuretic, natriuretic, and vasodilating actions and inhibitory effects on renin and aldosterone secretion. Evidence is also accumulating from recent work that ANP and BNP exert their cardioprotective functions not only as circulating hormones but also as local autocrine and/or paracrine factors. In studies using cultured neonatal myocytes and fibroblasts, exogenous administration of both ANP and ANP antagonists demonstrated that ANP has antihypertrophic and antifibrotic functions. Corroborating these in vitro results, mice lacking natriuretic receptor-A (NPR-A), the receptor for ANP and BNP, develop cardiac hypertrophy and fibrosis independent of their blood pressure. Recent studies also suggest that the intracardiac natriuretic peptides/cGMP system plays a counter-regulatory role against the intracardiac renin–angiotensin–aldosterone system and TGF-beta mediated pathway. In a clinical setting, human recombinant ANP and BNP may be used for a therapy of heart failure; however, further evaluation is required in the future.
Whole-Genome Duplications Spurred the Functional Diversification of the Globin Gene Superfamily in Vertebrates
Authors: Federico G. Hoffmann, Juan C. Opazo, Jay F. Storz
Journal: Molecular Biology and Evolution (2011)

It has been hypothesized that two successive rounds of whole-genome duplication (WGD) in the stem lineage of vertebrates provided genetic raw materials for the evolutionary innovation of many vertebrate-specific features. However, it has seldom been possible to trace such innovations to specific functional differences between paralogous gene products that derive from a WGD event. Here, we report genomic evidence for a direct link between WGD and key physiological innovations in the vertebrate oxygen transport system. Specifically, we demonstrate that key globin proteins that evolved specialized functions in different aspects of oxidative metabolism (hemoglobin, myoglobin, and cytoglobin) represent paralogous products of two WGD events in the vertebrate common ancestor. Analysis of conserved macrosynteny between the genomes of vertebrates and amphioxus (subphylum Cephalochordata) revealed that homologous chromosomal segments defined by myoglobin + globin-E, cytoglobin, and the α-globin gene cluster each descend from the same linkage group in the reconstructed proto-karyotype of the chordate common ancestor. The physiological division of labor between the oxygen transport function of hemoglobin and the oxygen storage function of myoglobin played a pivotal role in the evolution of aerobic energy metabolism, supporting the hypothesis that WGDs helped fuel key innovations in vertebrate evolution.
Stroke in Patients With Acute Coronary Syndromes
Authors: Kenneth W. Mahaffey, Robert A. Harrington, Maarten L. Simoons, Christopher B. Granger, Carmelo Graffagnino, Mark J. Alberts, Daniel T. Laskowitz, Julie M. Miller, Michael A. Sloan, Lisa G. Berdan, Cynthia M. MacAulay, A. Michael Lincoff, Jaap Deckers, Eric J. Topol, Robert M. Califf
Journal: Circulation (1999)

Background —The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates. Methods and Results —We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke. Conclusions —Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population.
Distribution, surface density, and membrane area of diadic junctional contacts between plasma membrane and terminal cisterns in mammalian ventricle.
Authors: E Page, M Surdyk-Droske
Journal: Circulation Research (1979)

The surface density of diadic junctional complexes (DJC) between plasmalemma and terminal cisternal membrane, as well as the areas of plasmalemmal and cisternal membrane involved in DJC, have been determined morphometrically in external plasmalemmal envelope and T-system of rabbit, rat, and mouse ventricular heart muscle. In all three species, both the surface density and the plasmalemmal area of DJC are 4- to 6-fold greater in the T-system than in the external plasmalemmal envelope. The surface density and DJC membrane area per unit cell volume and per unit myofibrillar volume increase in the order rabbit less than rat congruent to mouse and are not related simply to basal heart rate or intraventricular pressure. The results show that if Ca2+ release is a function of terminal cisterns, then, in ventricular heart muscle, most of the Ca2+ thus released for myofibrillar activation must originate from cisterns associated with the T-system. They make it necessary to consider the possibility that the 20--50% of plasmalemma in the T-system that is involved in excitation-contraction coupling may be unavailable for other processes; and they show that interspecies differences in surface density and membrane area of DJC/unit cellular and myofibrillar volume correlate with differences in Ca2+- activated Ca2+ release in skinned fibers and with differences in rate of tension development described for intact rat and rabbit ventricular muscle.
SOX10 Ablation Arrests Cell Cycle, Induces Senescence, and Suppresses Melanomagenesis
Authors: Julia C. Cronin, Dawn E. Watkins-Chow, Art Incao, Joanne H. Hasskamp, Nicola Schönewolf, Lauren G. Aoude, Nicholas K. Hayward, Boris C. Bastian, Reinhard Dummer, Stacie K. Loftus, William J. Pavan
Journal: Cancer Research (2013)

The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1(Tg)) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced expression of the melanocyte determining factor microphthalmia-associated transcription factor, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB, and reduced levels of its binding partner E2F1. As cell-cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma.
A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus.
Authors: I Z Zador, G D Deshmukh, R Kunkel, K Johnson, N S Radin, J A Shayman
Journal: Journal of Clinical Investigation (1993)

Glucosylceramide (GlcCer) and related glycosphingolipids have been implicated as causal elements in both the growth of cells and in the regulation of hormonal signaling. We therefore studied whether the renal hypertrophy induced by diabetes was associated with enhanced synthesis of glycosphingolipids. 16 d after the induction of diabetes, increases in renal size and concentration of glucocerebroside and ganglioside GM3 were observed paralleling an increase in UDP-Glc concentration. GlcCer synthase and beta-glucosidase-specific activities were no different between control and diabetic kidneys. The apparent Km of the GlcCer synthase with respect to UDP-Glc was 250 microM and was unchanged in the diabetic kidneys. The observed concentrations of UDP-Glc were 149 and 237 microM in control and diabetic kidneys, respectively. The UDP-Glc level is thus rate limiting with regard to GlcCer synthesis. To determine whether the changes in glycolipid content were functionally significant, diabetic and control groups were treated with the GlcCer synthase inhibitor, D-threo-1-phenyl-2-decanoyl-amino-3-morpholino-1- propanol, 2 wk after the induction of diabetes. Kidney weights in the diabetic rats treated with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol were no different than the control groups. Morphometric analysis of glomerular volumes paralleled changes in renal growth. Glycosphingolipid formation may therefore represent a significant pathway for glucose utilization in early diabetic nephropathy.
Should an athlete eat straight after training?--A study of intestinal transit time and its relationship to prior exercise.
Authors: D Scott, B Scott
Journal: British Journal of Sports Medicine (1994)

The mouth-to-caecum transit time of food was measured using the rise in breath hydrogen after a standard breakfast of baked beans on two occasions in seven healthy volunteers. The first occasion was after resting and the second after moderate exercise on a bicycle ergometer. There was no significant difference between the transit times with or without prior exercise. It is concluded that moderate exercise taken before food does not interfere with transit time and therefore should not in that way interfere with nutrition.
Systems biology of SLE: biochemical characterisation of subgroups within sle for improved diagnosis and treatment
Authors: Helena Idborg, Ganna Oliynyk, Stefan Rännar, Jenny Forshed, Rui Mamede Branca, Magdalena Donten, Johanna Gustafsson, Anna Vikerfors, Iva Gunnarsson, Johan Trygg, Janne Lehtiö, Torbjörn Lundstedt, Elisabet Svenungsson, Per-Johan Jakobsson
Journal: Annals of the Rheumatic Diseases (2012)

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with symptoms ranging from skin related problems to more severe cardiovascular effects. The heterogenous representation of the disease might be the reason for the lack of efficient treatment. The authors hypothesise that subgroups of SLE can be characterised by different biochemical pathways and that specific biomarkers along these pathways can be identified. In this study, the authors have utilised the Karolinska lupus cohort that consists of 320 SLE patients and 320 age-matched controls. Two main subgroups were defined: One group was defined as having SSA and SSB antibodies and a negative lupus anticoagulant test (LAC), that is, a 'Sjögren-like' group. The other group was defined as being negative for SSA and SSB antibodies but positive in the LAC test. According to previous studies these patients are at increased risk for cardiovascular events as compared to the 'Sjörgren-like' group. A pilot study was designed and EDTA-plasma from selected patients in these two groups and controls were analysed using a proteomic and metabolomic approach. Pathway analysis was then performed on the obtained data. The pilot study showed that it was possible to differentiate the two subgroups of SLE based on the proteomic profile. From the proteins found to be significantly different between the groups, several proteins known to be involved in SLE were detected, for example, Apolipoprotein A1 and complement factor 3. In addition, proteins that to our knowledge have not been reported earlier to correlate with SLE, for example, Apolipoprotein M, were detected and are subject for further investigations. Apolipoprotein E was one of the proteins that was found to be significantly different between the two subgroups of SLE and will be investigated in the entire cohort. Preliminary data from metabolomics demonstrate that it is possible to separate patients from controls and the authors found for example that tryptophan levels were lower in SLE patients. Pathway analyses of proteomics and metabolomics data strongly predict that the changes in SLE patients compared to controls are associated with inflammation and immunity related pathways. This project will provide new knowledge about SLE taking several complex systems into account simultaneously. Using selected biomarkers it will be possible to identify more homogenous patient populations for clinical trials and thereby increase the efficacy. The systems biology approach is likely to identify pathways that may lead to better understanding of the disease, identification of novel drug targets and biomarkers supporting improved diagnosis of SLE.
Antigen-driven C–C Chemokine-mediated HIV-1 Suppression by CD4+ T Cells from Exposed Uninfected Individuals Expressing the Wild-type CCR-5 Allele
Authors: Lucinda Furci, Gabriella Scarlatti, Samuele Burastero, Giuseppe Tambussi, Claudia Colognesi, Caroline Quillent, Renato Longhi, Patrizia Loverro, Barbara Borgonovo, Davide Gaffi, Emily Carrow, Mauro Malnati, Paolo Lusso, Antonio G. Siccardi, Adriano Lazzarin, Alberto Beretta
Journal: The Journal of Experimental Medicine (1997)

Despite repeated exposure to HIV-1, certain individuals remain persistently uninfected. Such exposed uninfected (EU) people show evidence of HIV-1–specific T cell immunity and, in rare cases, selective resistance to infection by macrophage-tropic strains of HIV-1. The latter has been associated with a 32–base pair deletion in the C–C chemokine receptor gene CCR-5, the major coreceptor of macrophage-tropic strains of HIV-1. We have undertaken an analysis of the HIV-specific T cell responses in 12 EU individuals who were either homozygous for the wild-type CCR-5 allele or heterozygous for the deletion allele (CCR-5Δ32). We have found evidence of an oligoclonal T cell response mediated by helper T cells specific for a conserved region of the HIV-1 envelope. These cells produce very high levels of C–C chemokines when stimulated by the specific antigen and suppress selectively the replication of macrophage-tropic, but not T cell–tropic, strains of HIV-1. These chemokine-producing helper cells may be part of a protective immune response that could be potentially exploited for vaccine development.
Investigation of Molecular Characteristics of Aspirin Exacerbated Respiratory Disease
Authors: Whitney W. Stevens, Christopher J. Ocampo, James E. Norton, Roderick G. Carter, Lydia Suh, Leslie C. Grammer, Kathryn E. Hulse, Anju T. Peters, Rakesh K. Chandra, David B. Conley, Robert C. Kern, Bruce K. Tan, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2015)
On T2* Magnetic Resonance and Cardiac Iron
Authors: John-Paul Carpenter, Taigang He, Paul Kirk, Michael Roughton, Lisa J. Anderson, Sofia V. de Noronha, Mary N. Sheppard, John B. Porter, J. Malcolm Walker, John C. Wood, Renzo Galanello, Gianluca Forni, Gualtiero Catani, Gildo Matta, Suthat Fucharoen, Adam Fleming, Michael J. House, Greg Black, David N. Firmin, Timothy G. St. Pierre, Dudley J. Pennell
Journal: Circulation (2011)

Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance relaxation parameter R2* (assessed clinically via its reciprocal, T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans are limited.Twelve human hearts were studied from transfusion-dependent patients after either death (heart failure, n=7; stroke, n=1) or transplantation for end-stage heart failure (n=4). After cardiovascular magnetic resonance R2* measurement, tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean ± SD global myocardial iron causing severe heart failure in 10 patients was 5.98 ± 2.42 mg/g dry weight (range, 3.19 to 9.50 mg/g), but in 1 outlier case of heart failure was 25.9 mg/g dry weight. Myocardial ln[R2*] was strongly linearly correlated with ln[Fe] (R²=0.910, P<0.001), leading to [Fe]=45.0×(T2*)⁻¹·²² for the clinical calibration equation with [Fe] in milligrams per gram dry weight and T2* in milliseconds. Midventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron.These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration. The iron values are of considerable interest in terms of the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in vivo by cardiovascular magnetic resonance of the midseptum.
Facial Emotion Recognition in Schizophrenia: Intensity Effects and Error Pattern
Authors: Christian G. Kohler, Travis H. Turner, Warren B. Bilker, Colleen M. Brensinger, Steven J. Siegel, Stephen J. Kanes, Raquel E. Gur, Ruben C. Gur
Journal: American Journal of Psychiatry (2003)

The authors used color photographs of emotional and neutral expressions to investigate recognition patterns of five universal emotions in schizophrenia.Twenty-eight stable outpatients with schizophrenia (19 men and nine women) and 61 healthy subjects (29 men and 32 women) completed an emotion discrimination test that presented mild and extreme intensities of happy, sad, angry, fearful, disgusted, and neutral faces, balanced for gender and ethnicity. Analyses evaluated accuracy of identifying emotions as a function of intensity, diagnosis, and gender of poser and rater.Patients performed worse than comparison subjects on recognition of all emotions and neutral faces combined, including mild and extreme expressions. For specific emotions, patients performed worse on recognition of fearful, disgusted, and neutral expressions. For all emotions except disgust, recognition of extreme intensity was better than recognition of mild intensity. However, patients showed less benefit from increased intensity for all emotions combined, and the difference was most pronounced for fear. Thus, patients were more impaired than healthy comparison subjects in identifying high-intensity expressions, even though this was an easier task than identifying low-intensity expressions. In the comparison of patterns of errors, patients and healthy subjects differed only in misattributions of neutral expressions; patients overattributed disgusted expressions and underattributed happy expressions.Patients with schizophrenia were impaired in overall emotion recognition, particularly fear and disgust, and did not benefit from increased emotional intensity. Error patterns indicate that patients misidentified neutral cues as negatively valenced.