tbuckley/cabot-search huggingface dataset:
Accuracy of transpulmonary thermodilution cardiac output measurement (PiCCO) in patients with right heart failure (RHF) due to precapillary pulmonary hypertension (PH)
Authors: Elise Artaud-Macari, Marion Gilbert, Romain Persichini, Raed Rifai, Sven Gunther, Xavier Jais, David Montani, Patrick Assayag, Marc Humbert, Gérald Simonneau, Olivier Sitbon, Laurent Savale
Journal: European Respiratory Journal (2013)

The main cause of death in patients with precapillary PH is RHF. Except right heart cath (RHC), no reliable hemodynamic method has been evaluated to monitor patients with RHF. The aim of our study is to describe the hemodynamic profile of PH patients with RHF requiring vasoactive drugs and to evaluate relevance of PiCCO monitoring.  Methods: Data of 15 patients (8 F, 60 y-o) with PH and RHF were prospectively analysed. Baseline clinical, biological and PiCCO data were collected at admission in ICU (d0) and after 5 days. RHC was performed in 7/15 patients within 24 hours after d0. Bland-Altman analyses evaluated the agreement between RHC and PiCCO measurements  Results: At d0, median PiCCO values were: mean arterial pressure (MAP) 93 mmHg, central venous pressure (CVP) 16 mmHg, cardiac index (CI) 1.99 L/min/m2, cardiac function index (CFI) 2.5 min-1. Median value of central venous O2 saturation (ScvO2) was 55%, BNP 1135 ng/mL, creatinin 123 µM. The bias for PiCCO estimates of CI was 0.08 L/min/m2 with 95% limits of agreement (LA) 0.11 to 0.26 L/min/m2. The bias for CVP was -0.2 mmHg with 95% LA -4.2 to 3.8 mmHg. At d5, all patients received dobutamine 5 µg/kg/min and 3 additional norepinephrine. Assessment by PiCCO at d5 showed significantly improved CI (2.59L/min/m2; p=0.04), CFI (3.9 min-1; p=0.01) and CVP (11 mmHg; p=0.005). In contrast, MAP measurement, and BNP and creatinin levels did not change significantly  Conclusion: PiCCO monitoring in PH patients with RHF seems to be relevant to assess and follow up CI and volemia with a minimal invasive device. This data need to be confirmed in a larger cohort.
Ancient DNA Analyses Reveal High Mitochondrial DNA Sequence Diversity and Parallel Morphological Evolution of Late Pleistocene Cave Bears
Authors: Michael Hofreiter, Cristian Capelli, Matthias Krings, Lisette Waits, Nicholas Conard, Susanne Münzel, Gernot Rabeder, Doris Nagel, Maja Paunovic, Gordana Jambresić, Sonja Meyer, Gunter Weiss, Svante Pääbo
Journal: Molecular Biology and Evolution (2002)

Cave bears (Ursus spelaeus) existed in Europe and western Asia until the end of the last glaciation some 10,000 years ago. To investigate the genetic diversity, population history, and relationship among different cave bear populations, we have determined mitochondrial DNA sequences from 12 cave bears that range in age from about 26,500 to at least 49,000 years and originate from nine caves. The samples include one individual from the type specimen population, as well as two small-sized high-Alpine bears. The results show that about 49,000 years ago, the mtDNA diversity among cave bears was about 1.8-fold lower than the current species-wide diversity of brown bears (Ursus arctos). However, the current brown bear mtDNA gene pool consists of three clades, and cave bear mtDNA diversity is similar to the diversity observed within each of these clades. The results also show that geographically separated populations of the high-Alpine cave bear form were polyphyletic with respect to their mtDNA. This suggests that small size may have been an ancestral trait in cave bears and that large size evolved at least twice independently.
Atherosclerosis: Basic Mechanisms
Authors: Judith A. Berliner, Mohamad Navab, Alan M. Fogelman, Joy S. Frank, Linda L. Demer, Peter A. Edwards, Andrew D. Watson, Aldons J. Lusis
Journal: Circulation (1995)

Abstract The clinical events resulting from atherosclerosis are directly related to the oxidation of lipids in LDLs that become trapped in the extracellular matrix of the subendothelial space. These oxidized lipids activate an NFκB-like transcription factor and induce the expression of genes containing NFκB binding sites. The protein products of these genes initiate an inflammatory response that initially leads to the development of the fatty streak. The progression of the lesion is associated with the activation of genes that induce arterial calcification, which changes the mechanical characteristics of the artery wall and predisposes to plaque rupture at sites of monocytic infiltration. Plaque rupture exposes the flowing blood to tissue factor in the lesion, and this induces thrombosis, which is the proximate cause of the clinical event. There appear to be potent genetically determined systems for preventing lipid oxidation, inactivating biologically important oxidized lipids, and/or modulating the inflammatory response to oxidized lipids that may explain the differing susceptibility of individuals and populations to the development of atherosclerosis. Enzymes associated with HDL may play an important role in protecting against lipid oxidation in the artery wall and may account in part for the inverse relation between HDL and risk for atherosclerotic clinical events.
Effect of dietary nucleotides on small intestinal repair after diarrhoea. Histological and ultrastructural changes.
Authors: J Bueno, M Torres, A Almendros, R Carmona, M C Nunez, A Rios, A Gil
Journal: Gut (1994)

The effects of specific nutrients on intestinal maturation and repair after injury are practically unknown. The purpose of this work was to study the effects of dietary nucleotides on the repair of the intestinal mucosa after chronic diarrhoea induced by a lactose enriched diet in the weanling rat. One group of weanling rats was fed with a standard semipurified diet (control group), and another group was fed with the same diet containing lactose as the only soluble carbohydrate (lactose group). After 14 days the lactose group was allowed to recover for four weeks with the control diet (lactose-control group) or with the control diet supplemented with AMP, GMP, IMP, CMP, and UMP 50 mg/100 g each (lactose-nucleotide group). The control group was divided into two subgroups, which were fed with the control diet and the nucleotide supplemented diet for the same period (control-control group and control-nucleotide group). The lactose diet induced diarrhoea after 24 hours of feeding. Two weeks later there were changes in intestinal structure with loss of enterocyte microvillar surface, significant lymphocyte infiltration, supranuclear cytoplasmic vesiculation, decreased number of goblet cells, and enlarged mitochondria with low density and few cristae. After recovery from diarrhoea, animals fed the nucleotide enriched diet showed an intestinal histology and ultrastructure closer to that of the normal control group. Mitochondrial ultrastructure was closer to normal in comparison with the lactose-control diet group. In this second group the number of goblet cells as well as the villous height/crypt depth ratio was reduced and the number of intraepithelial lymphocytes increased compared with the nucleotide supplemented group. These results suggest that dietary nucleotides may be important nutrients for intestinal repair.
Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery
Authors: Claes Held, Nils Åsenblad, Jean Pierre Bassand, Richard C. Becker, Christopher P. Cannon, Marc J. Claeys, Robert A. Harrington, Jay Horrow, Steen Husted, Stefan K. James, Kenneth W. Mahaffey, José C. Nicolau, Benjamin M. Scirica, Robert F. Storey, Marius Vintila, Joseph Ycas, Lars Wallentin
Journal: Journal of the American College of Cardiology (2010)
Analysis of the response of B cells from CBA/N-defective mice to nonspecific T cell help.
Authors: J L Greenstein, E Lord, J W Kappler, P C Marrack
Journal: The Journal of Experimental Medicine (1981)

We have investigated the induction of antibody responses to erythrocyte (RBC)-bound antigens in the (CBA/N x B10)F1 mouse. Male B cells, which express the CBA/N defect, were shown to be unresponsive to RBC antigens when the delivered T cell helper activity was solely nonspecific. Thus we demonstrated that defective B cells did not respond to concanavalin A supernatants or bystander helper activity, in spite of the fact that CBA/N-defective mice could produce these T cell activities. The defective B cell did not respond to RBC-bound antigen in the presence of RBC-primed T cells, although the magnitude of this response was usually twofold less than normal controls. The insensitivity of CBA/N defective B cells to nonspecific T cell helper activities seemed to involve at least the inability of RBC antigens to activate defective B cells in the absence of antigen-specific T cell help.
From monkey-like action recognition to human language: An evolutionary framework for neurolinguistics
Authors: Michael A. Arbib
Journal: Behavioral and Brain Sciences (2005)

The article analyzes the neural and functional grounding of language skills as well as their emergence in hominid evolution, hypothesizing stages leading from abilities known to exist in monkeys and apes and presumed to exist in our hominid ancestors right through to modern spoken and signed languages. The starting point is the observation that both premotor area F5 in monkeys and Broca's area in humans contain a "mirror system" active for both execution and observation of manual actions, and that F5 and Broca's area are homologous brain regions. This grounded the mirror system hypothesis of Rizzolatti and Arbib (1998) which offers the mirror system for grasping as a key neural "missing link" between the abilities of our nonhuman ancestors of 20 million years ago and modern human language, with manual gestures rather than a system for vocal communication providing the initial seed for this evolutionary process. The present article, however, goes "beyond the mirror" to offer hypotheses on evolutionary changes within and outside the mirror systems which may have occurred to equip Homo sapiens with a language-ready brain. Crucial to the early stages of this progression is the mirror system for grasping and its extension to permit imitation. Imitation is seen as evolving via a so-called simple system such as that found in chimpanzees (which allows imitation of complex "object-oriented" sequences but only as the result of extensive practice) to a so-called complex system found in humans (which allows rapid imitation even of complex sequences, under appropriate conditions) which supports pantomime. This is hypothesized to have provided the substrate for the development of protosign, a combinatorially open repertoire of manual gestures, which then provides the scaffolding for the emergence of protospeech (which thus owes little to nonhuman vocalizations), with protosign and protospeech then developing in an expanding spiral. It is argued that these stages involve biological evolution of both brain and body. By contrast, it is argued that the progression from protosign and protospeech to languages with full-blown syntax and compositional semantics was a historical phenomenon in the development of Homo sapiens, involving few if any further biological changes.
Phylogenetic Analysis of the Teneurins: Conserved Features and Premetazoan Ancestry
Authors: R. P. Tucker, J. Beckmann, N. T. Leachman, J. Scholer, R. Chiquet-Ehrismann
Journal: Molecular Biology and Evolution (2011)

Teneurins are type II transmembrane proteins expressed during pattern formation and neurogenesis with an intracellular domain that can be transported to the nucleus and an extracellular domain that can be shed into the extracellular milieu. In Drosophila melanogaster, Caenorhabditis elegans, and mouse the knockdown or knockout of teneurin expression can lead to abnormal patterning, defasciculation, and abnormal pathfinding of neurites, and the disruption of basement membranes. Here, we have identified and analyzed teneurins from a broad range of metazoan genomes for nuclear localization sequences, protein interaction domains, and furin cleavage sites and have cloned and sequenced the intracellular domains of human and avian teneurins to analyze alternative splicing. The basic organization of teneurins is highly conserved in Bilateria: all teneurins have epidermal growth factor (EGF) repeats, a cysteine-rich domain, and a large region identical in organization to the carboxy-half of prokaryotic YD-repeat proteins. Teneurins were not found in the genomes of sponges, cnidarians, or placozoa, but the choanoflagellate Monosiga brevicollis has a gene encoding a predicted teneurin with a transmembrane domain, EGF repeats, a cysteine-rich domain, and a region homologous to YD-repeat proteins. Further examination revealed that most of the extracellular domain of the M. brevicollis teneurin is encoded on a single huge 6,829-bp exon and that the cysteine-rich domain is similar to sequences found in an enzyme expressed by the diatom Phaeodactylum tricornutum. This leads us to suggest that teneurins are complex hybrid fusion proteins that evolved in a choanoflagellate via horizontal gene transfer from both a prokaryotic gene and a diatom or algal gene, perhaps to improve the capacity of the choanoflagellate to bind to its prokaryotic prey. As choanoflagellates are considered to be the closest living relatives of animals, the expression of a primitive teneurin by an ancestral choanoflagellate may have facilitated the evolution of multicellularity and complex histogenesis in metazoa.
Pharmacokinetics of Insulin Aspart in Pregnant Women With Type 1 Diabetes: Every Day Is Different
Authors: Robert J.B. Goudie, David Lunn, Roman Hovorka, Helen R. Murphy
Journal: Diabetes Care (2014)

Rapid-acting insulin analogs are increasingly used during type 1 diabetic pregnancy. They may assist women to safely optimize glucose control (1,2), but little is known about their pharmacokinetics and reproducibility in pregnancy. Using a unique data set of 1,300 plasma insulin samples collected under strictly observed experimental conditions, we explored the relationship between aspart pharmacokinetics and clinical and demographic factors. We also assessed reproducibility both within and between pregnant women using continuous subcutaneous insulin infusion (CSII).

In study 1 (ISRCTN62568875), 10 women were studied on two occasions under sedentary conditions with prandial boluses administered before standardized evening and breakfast meals in early (12–16 weeks) and in late (28–32 weeks) gestation (3). In study 2 (ISRCTN50385583), 12 women were studied on two occasions in midgestation (19 and 23 weeks) (4). The boluses were administered before standardized evening and breakfast meals (60-g carbohydrate dinner, 50-g carbohydrate breakfast). Physical activity was encouraged with postprandial walking (20 min after each meal) with 50 min of brisk treadmill walking (3.9 km/h) after breakfast (4). Ethics approval was obtained from Suffolk, Norfolk, and Cambridgeshire (study 1) …
DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility
Authors: Daniel J. Urban, Bryan L. Roth
Journal: The Annual Review of Pharmacology and Toxicology (2014)

In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein–coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.
Impact of Controlled Pericardial Drainage on Critical Cardiac Tamponade With Acute Type A Aortic Dissection
Authors: Taro Hayashi, Takuro Tsukube, Teruo Yamashita, Tomonori Haraguchi, Ritsu Matsukawa, Shuichi Kozawa, Kyoichi Ogawa, Yutaka Okita
Journal: Circulation (2012)

Background— Cardiac tamponade is associated with fatal outcomes for patients with acute type A aortic dissection, and the presence of cardiac tamponade should prompt urgent aortic repair. However, treatment of the patient with critical cardiac tamponade who cannot survive until surgery remains unclear. We analyzed our experience of controlled pericardial drainage (CPD) managing critical cardiac tamponade. Methods and Results— Between September 2003 and May 2011, 175 patients with acute type A aortic dissection were treated surgically, including 43 (24.6%) who presented with cardiac tamponade on arrival. Eighteen patients, who did not respond to intravenous volume resuscitation, underwent CPD in the emergency department. An 8F pigtail drainage catheter was inserted percutaneously, and drainage volume was controlled by means of several cycles of intermittent drainage to maintain blood pressure at ≈90 mm Hg. After CPD, all of the patients were transferred to the operating room, and immediate aortic repair was performed. Systolic blood pressure before CPD was 64.3±8.2 mm Hg and elevated significantly in all of the cases after CPD. Systolic blood pressure after CPD was 94.8±10.5 mm Hg, and increase in systolic pressure was 30.5±11.7 mm Hg. Total volume of aspirated pericardial effusion was 40.1±30.6 mL, and 10 patients required only ≤30-mL aspiration volume. All of the patients underwent aortic repair successfully. In-hospital mortality was 16.7%; however, there was no complications or mortality related to CPD. Conclusions— Preoperative pericardial drainage with control of volume is a safe and effective procedure for acute type A aortic dissection complicated by critical cardiac tamponade. In our patient population, timely controlled pericardial drainage is warranted.
Hypertension and Diabetes
Authors: Roland E. Schmieder
Journal: Diabetes Care (2009)

In recent years, the British Medical Journal published several papers apropos the “parachute approach evidence-based medicine” (1). In the original profound article, Smith and Pell argued that the parachute use to prevent death and major trauma due to capital challenge is clearly obvious, and there is no need for randomized controlled trials (2). Although this argument may hold true in medicine for only few situations, waiting for the results of randomized end point trials of therapeutic interventions can cost hundred of lives under certain circumstances. If the science is good, we should act before trials are performed using intermediate end points or “surrogates” as therapeutic targets. Indeed, surrogate parameters have emerged as most helpful tools for an evidence-based approach for therapeutic decisions in cardiovascular medicine. The ensuing article outlines the pro arguments that surrogates are most acceptable targets for treating patients with hypertension and diabetes.

According to Merriam Webster's dictionary, the meaning of surrogate is “one appointed to act in place of another” and “one that serves as a substitute.” In the 2007 European Society of Hypertension Guidelines (3), the word “surrogate” is replaced by the wording “intermediate end point,” thereby pointing to the fact that, in hypertensive disease, a surrogate in general reflects early structural or functional changes of the vascular, renal, or cardiac tissue due to the presence of cardiovascular risk factors. More specifically, certain requirements for clinical use of organ damage measures should be fulfilled before a clinical parameter is considered an intermediate end point or surrogate for fatal or nonfatal cardiovascular complications. These eligibility criteria are as follows: the surrogate must be a sensitive and common marker of early damage in cardiovascular disease, should ideally be measured noninvasively, should have a high reproducibility (low between/within-observer variability), the assessment must be (worldwide) standardized, and evidence of prognostic …
Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: a randomised controlled trial
Authors: Nynke Smidt, Daniëlle AWM van der Windt, Willem JJ Assendelft, Walter LJM Devillé, Ingeborg BC Korthals-de Bos, Lex M Bouter
Journal: The Lancet (2002)
The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) Enhances the Radiation Responsiveness of Lung and Colorectal Tumor Xenografts
Authors: Aoife M. Shannon, Brian A. Telfer, Paul D. Smith, Muhammed Babur, Armelle Logie, Robert W. Wilkinson, Camille Debray, Ian J. Stratford, Kaye J. Williams, Stephen R. Wedge
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Novel molecularly targeted agents, given in combination with radiotherapy, have the potential to increase tumor response rates and the survival of patients with lung cancer. AZD6244 is a potent and selective inhibitor of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2), a critical enzyme within the MAPK/extracellular signal-regulated kinase (ERK) signaling pathway that regulates the proliferation and survival of tumor cells. Experimental Design: This study examined the potential benefit of combining AZD6244 with fractionated radiotherapy using human lung and colon carcinoma xenograft models. Results: AZD6244 reduced ERK phosphorylation in Calu-6 lung cancer cells in vitro. Administration of AZD6244 for 10 days (25 mg/kg twice daily p.o.) inhibited the tumor growth of Calu-6 xenografts, with regrowth occurring on cessation of drug treatment. When fractionated tumor-localized radiotherapy (5 × 2 Gy) was combined with AZD6244 treatment, the tumor growth delay was enhanced significantly when compared with either modality alone, and this effect was also seen in a colon tumor model. We examined the effect of inhibiting MEK1/2 on the molecular responses to hypoxia, a potential interaction that could contribute to radioresponsiveness. AZD6244 reduced hypoxia-inducible factor–specific transactivation in vivo, shown using Calu-6 dual clone cells that stably express a Firefly luciferase gene under the control of a hypoxia-driven promoter. Furthermore, hypoxia-inducible factor-1α, GLUT-1, and vascular endothelial growth factor levels were reduced by AZD6244, and there was a significant decrease in vascular perfusion in the tumors given combination treatment when compared with the other treatment groups. Conclusions: These data provide support for the clinical development of AZD6244 in combination with radiotherapy and indicate a potential role for AZD6244 in inhibiting the tumor hypoxia response. (Clin Cancer Res 2009;15(21):6619–29)