tbuckley/cabot-search huggingface dataset:
Adenosine metabolism in canine myocardial reactive hyperemia.
Authors: R A Olsson, J A Snow, M K Gentry
Journal: Circulation Research (1978)

In pentobrabital-anesthetized open chest dogs, myocardial adenosine content is elevated by 5 or 15 seconds of left coronary artery occlusion and falls exponentially to control levels during reactive hyperemia. The rate constants for adenosine dissipation are (mean +/- SEM): -0.08 +/- 0.01 and -0.034 +/- 0.007 sec-1 after 5- and 15-second occlusion, respectively. Kinetic analysis of the reactive hyperemia flow curves (Circ Res 14/15 (suppl I): 81-85, 1963) predicts rates of -0.069 +/- 0.009 sec-1 and -0.04 +/- 0.009 sec-1, indicating that changes in adenosine levels can account for the way coronary flow changes during this response. The log (dose-) response curve relating reactive hyperemia flow to tissue adenosine concentration has a steeper slope and is half-maximal at a lower adenosine concentration than the dose-response curve obtained by intracoronary infusions of adenosine in oxygenated hearts, indicating that the coronary vasoactivity of adenosine is enhanced during reactive hyperemia. This could explain why theophylline antagonizes the coronary vasocilatory effect of adenosine in oxygenated hearts but has relatively little effect on reactive hyperemia.
Effects of Selective α <sub>1</sub> - and α <sub>2</sub> -Adrenergic Blockade on Coronary Flow Reserve After Coronary Stenting
Authors: Luisa Gregorini, Jean Marco, Bruno Farah, Monique Bernies, Carlo Palombo, Michaela Kozàkovà, Irene M. Bossi, Bernard Cassagneau, Jean Fajadet, Carlo Di Mario, Remo Albiero, Massimo Cugno, Adalberto Grossi, Gerd Heusch
Journal: Circulation (2002)

Coronary flow reserve (CFR) is not normalized shortly after coronary stenting. We hypothesized that alpha-adrenergic coronary vasoconstriction acts to limit CFR.We assessed flow velocity by Doppler wires and cross-sectional area by angiography in 46 patients undergoing coronary culprit lesion stenting (81+/-4% stenosis). Hyperemia was induced by adenosine (24 micro g IC or 140 micro g/kg per minute IV) before and after stenting. Finally, either the alpha(1)-antagonist urapidil (10 mg IC) or the alpha(2)-antagonist yohimbine (3 mg IC) was randomly combined with adenosine. In 8 subjects with angiographically normal coronary arteries, CFR was increased from 3.21+/-0.30 to 3.74+/-0.43 by yohimbine and to 4.58+/-0.65 by urapidil, respectively (P=0.0001). Patients were divided according to the cutoff of CFR > or =3.0 (n=18) or <2.5 (n=28). Revascularization per se did not change CFR. However, 15 minutes after stenting, CFR decreased to 2.05+/-0.55 from CFR 3.64+/-0.58, whereas in patients with CFR 2.39+/-0.51, it remained unchanged. Yohimbine improved CFR to 3.26+/-0.42 and to 3.41+/-0.58 in patients with >3.0 and <2.05+/-0.55 baseline CFR, respectively. Urapidil improved CFR to 3.52+/-0.30 and 3.98+/-1.07, respectively.Urapidil and yohimbine attenuated the CFR impairment occurring after revascularization by increasing both the epicardial vasodilator effect of adenosine and the blood flow velocity, thus suggesting that the adrenergic system plays an important role in limiting the capacity of the coronary circulation to dilate.
Interleukin-1 Gene Cluster Polymorphisms in Sarcoidosis and Idiopathic Pulmonary Fibrosis
Authors: BEÁTA HUTYROVÁ, PANAGIOTIS PANTELIDIS, JIŘÍ DRÁBEK, MONIKA ŽŮRKOVÁ, VÍTĚZSLAV KOLEK, KAREL LENHART, KENNETH I. WELSH, ROLAND M. DU BOIS, MARTIN PETŘEK
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Members of the interleukin-1 (IL-1) family are implicated in the pathogenesis of sarcoidosis and idiopathic pulmonary fibrosis (IPF). We have, therefore, performed a case–control study to investigate a plausible association between sarcoidosis and the polymorphisms in the IL-1 α , IL-1 β , and IL-1 receptor antagonist (IL-1Ra) genes. Further, as a separate question, we explored whether the aforementioned genes of the IL-1 cluster are associated with IPF. Using PCR with sequence-specific primers, IL-1 α − 889, IL-1 β − 511, IL-1 β + 3953, and IL-1Ra intron 2 VNTR polymorphisms were determined in 348 white subjects of West Slavonic ancestry (95 patients with sarcoidosis, 54 patients with IPF, and 199 healthy control subjects). The IL-1 α − 889 1.1 genotype was significantly overrepresented in patients with sarcoidosis in comparison with control subjects (60.0 versus 44.2%, p = 0.012, pcorr = 0.047). The distribution of IL-1 β − 511, IL-1 β + 3953, and IL-1Ra VNTR genotypes and alleles did not significantly differ between the cases and controls. No association between IPF and the investigated polymorphisms was found. Strong linkage disequilibrium between pairs of polymorphic loci was observed. Further population studies are warranted to confirm the observed association between sarcoidosis and the IL-1 α polymorphism and also to explore mechanisms of IL-1 α − 889 participation in aberrant immune response in sarcoidosis.
A shopping list of doctors
Authors: C. J. Scott
Journal: BMJ (2010)

The season of dietary indulgence seems a good time to celebrate doctors whose names have become linked with items of food and drink. From antiquity to the present, doctors have attempted to influence the diet of their patients. Some have developed foods that became so popular that they have achieved lasting commercial success. Although many are forgotten as doctors, their names remain well known to the public, becoming famous brand names and trademarks.



Doctors played a major role in the development of the Australian wine industry, and two remain as popular brands today: Penfolds and Lindeman’s.

Christopher Rawson Penfold1 studied medicine at St Bartholomew’s Hospital, London, graduating in 1838. For six years he practised medicine in Brighton, before emigrating to Australia in 1844 and settling close to Adelaide. He believed in the medicinal power of wine, particularly for the treatment of anaemia, and before he left Britain had obtained vine cuttings from France. In Australia he developed a successful medical practice and began to make wine. Originally this was intended for medicinal use, but demand understandably grew and soon his wine was being sold throughout the country. Although he reduced his clinical work as demands of the vineyards increased, he continued to practise some medicine until the year of his death. After his death, his wife, who had been involved in wine production from the beginning, took over the business. It has now become internationally successful.

Henry John Lindeman2 graduated from St Bartholomew’s Hospital in 1834 and became a naval surgeon. Dissatisfied with his prospects in the navy, he …
The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Authors: Luc Friboulet, Nanxin Li, Ryohei Katayama, Christian C. Lee, Justin F. Gainor, Adam S. Crystal, Pierre-Yves Michellys, Mark M. Awad, Noriko Yanagitani, Sungjoon Kim, AnneMarie C. Pferdekamper, Jie Li, Shailaja Kasibhatla, Frank Sun, Xiuying Sun, Su Hua, Peter McNamara, Sidra Mahmood, Elizabeth L. Lockerman, Naoya Fujita, Makoto Nishio, Jennifer L. Harris, Alice T. Shaw, Jeffrey A. Engelman
Journal: Cancer Discovery (2014)

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease. Cancer Discov; 4(6); 662-73. ©2014 AACR. See related commentary by Ramalingam and Khuri, p. 634 This article is highlighted in the In This Issue feature, p. 621.
Trauma, PTSD, and Substance Use Disorders: Findings From the Australian National Survey of Mental Health and Well-Being
Authors: Katherine L. Mills, Maree Teesson, Joanne Ross, Lorna Peters
Journal: American Journal of Psychiatry (2006)

Objective: The aim of the present study was to examine the association between trauma and posttraumatic stress disorder (PTSD) and substance use disorders and to examine the correlates of substance use disorder plus PTSD comorbidity in the Australian general population. Method: Data were collected from a stratified sample of 10,641 participants as part of the Australian National Survey of Mental Health and Well-Being. A modified version of the Composite International Diagnostic Interview was used to determine the presence of DSM-IV anxiety, affective, and substance use disorders and ICD-10 personality disorders. Results: Substance use disorder plus PTSD was experienced by a significant minority of the Australian general population (0.5%). Among those with PTSD, the most common substance use disorder was an alcohol use disorder (24.1%), whereas among those with a substance use disorder, PTSD was most common among individuals with an opioid use disorder (33.2%). Consistent with U.S. clinical literature, individuals with substance use disorder plus PTSD experience significantly poorer physical and mental health and greater disability than those with substance use disorder alone. In contrast, individuals with PTSD alone and those with substance use disorder plus PTSD shared a remarkably similar clinical profile. Conclusions: It is important that individuals entering treatment for substance use disorder or PTSD be assessed for this comorbidity. The addition of either disorder may present complications that need to be considered for the provision of appropriate treatment. Further research is necessary to ascertain which treatments are most effective in treating comorbid substance use disorder plus PTSD.
Structure of the Homer EVH1 Domain-Peptide Complex Reveals a New Twist in Polyproline Recognition
Authors: Jutta Beneken, Jian Cheng Tu, Bo Xiao, Mutsuo Nuriya, Joseph P. Yuan, Paul F. Worley, Daniel J. Leahy
Journal: Neuron (2000)

Homer EVH1 (Ena/VASP Homology 1) domains interact with proline-rich motifs in the cytoplasmic regions of group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-trisphosphate receptors (IP3Rs), and Shank proteins. We have determined the crystal structure of the Homer EVH1 domain complexed with a peptide from mGluR (TPPSPF). In contrast to other EVH1 domains, the bound mGluR ligand assumes an unusual conformation in which the side chains of the Ser–Pro tandem are oriented away from the Homer surface, and the Phe forms a unique contact. This unusual binding mode rationalizes conserved features of both Homer and Homer ligands that are not shared by other EVH1 domains. Site-directed mutagenesis confirms the importance of specific Homer residues for ligand binding. These results establish a molecular basis for understanding the biological properties of Homer-ligand complexes.
The neurological junction between the appendix and ascending colon
Authors: J. L. Emery, J. Underwood
Journal: Gut (1970)

The junction between gut wall having the intramural plexus distribution characteristic of large bowel and that of appendix does not occur at the anatomical junction of the caecum and the appendix but at a level proximal to this and just distal to the ileocaecal valve.
Increased Plasma Aldosterone Concentration In Response to Hemodialysis In Nephrectomized Man
Authors: Robert E. McCaa, Connie S. McCaa, Dale G. Read, John D. Bower, Arthur C. Guyton
Journal: Circulation Research (1972)

The nephrectomized patient maintained on intermittent hemodialysis while awaiting renal transplantation provides an excellent model for studying the influence of factors other than the renal renin-angiotensin system that play a role in the regulation of plasma aldosterone concentration. Peripheral plasma aldosterone concentrations were determined using a sensitive radioimmunoassay method in nine anephric patients in the recumbent position immediately before and after hemodialysis. Average patient weight fell 1.5 kg following 12 hours of dialysis on the Kiil dialyzer. Plasma sodium concentration decreased from 137 ± 1 (SE) to 132 ± 1 mEq/liter, plasma potassium concentration decreased from 4.8 ± 0.3 to 3.2 ± 0.1 mEq/liter, and the ratio of sodium to potassium increased from 31.3 ± 1.9 to 41.7 ± 0.9. Plasma aldosterone concentration increased from 9.7 ± 1.6 ng/100 ml plasma before dialysis to 17.9 ± 2.1 ng/100 ml plasma after dialysis despite the lack of kidneys to produce renin. Plasma cortisol concentration did not change significantly (17.5 ± 2.0 µg/100 ml plasma to 14.8 ± 1.9 µg/100 ml plasma). These results show that plasma aldosterone concentration increased in anephric patients in response to hemodialysis. This increase occurred without a concomitant increase in plasma cortisol levels, suggesting absence of an adrenocorticotropic hormone response, and was independent of the renal reninangiotensin system.
Aorto–Right Ventricular Tunnel Causing Functional Tricuspid Atresia
Authors: Barbara E.U. Burkhardt, Raoul Arnold, Christian Schlensak, Regina Bökenkamp, Brigitte Stiller
Journal: Circulation (2012)

A girl with symmetrical intrauterine growth retardation and a birth weight of 2240 g was delivered at term by primary cesarean section to a 27-year-old primiparous woman.Fetal echocardiography had shown a nearly atretic tricuspid valve.Postnatally, the child stabilized rapidly but showed signs of heart failure with tachypnea and general weakness, as well as cyanosis (transcutaneous oxygen saturation, 85%).The presence of an aorto-right ventricular (RV) tunnel (ARVT) was confirmed by transthoracic echocardiography,
Transferrin-Conjugated Liposome Targeting of Photosensitizer AlPcS4 to Rat Bladder Carcinoma Cells
Authors: A. S. L. Derycke, A. Kamuhabwa, A. Gijsens, T. Roskams, D. De Vos, A. Kasran, J. Huwyler, L. Missiaen, P. A. M. de Witte
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: The efficacy and safety of photodynamic therapy for superficial bladder cancer depend on tumor-selective accumulation of the photosensitizer. Bladder transitional-cell carcinoma cells overexpress the transferrin receptor on their surface. We examined whether transferrin-mediated liposomal targeting of the photosensitizer aluminum phthalocyanine tetrasulfonate (AlPcS 4 ) is an effective strategy to attain tumor-selective accumulation of this compound when applied intravesically. Methods: AlPcS 4 was stably encapsulated in unconjugated liposomes (Lip-AlPcS 4 ) or transferrin-conjugated liposomes (Tf-Lip–AlPcS 4 ). The accumulation of free AlPcS4, Lip-AlPcS 4 , and Tf-Lip–AlPcS 4 in human AY-27 transitional-cell carcinoma cells and in an orthotopic rat bladder tumor model was visualized by fluorescence microscopy. In vitro AlPcS 4 accumulation was quantified by fluorescence measurements following drug extraction, and the photodynamic efficacy of AlPcS 4 was measured in a clonogenic assay. All statistical tests were two-sided. Results: AY-27 cells incubated with Tf-Lip–AlPcS 4 had much higher intracellular AlPcS 4 levels than AY-27 cells incubated with Lip-AlPcS 4 (384.1 versus 3.7 μM; difference = 380.4 μM, 95% CI = 219.4 to 541.3; P = .0095). Among rats bearing AY-27 cell–derived bladder tumors, intravesical instillation with Tf-Lip–AlPcS 4 resulted in mean AlPcS 4 fluorescence in tumoral tissue, normal urothelium, and submucosa/muscle of 77.9 fluorescence units (fu) (95% CI = 69.1 to 86.8 fu), 4.3 fu (95% CI = 4.0 to 4.5 fu), and 1.0 (95% CI = 0.1 to 1.9 fu), respectively, whereas instillation of free AlPcS 4 resulted in nonselective accumulation throughout the whole bladder wall, and Lip-AlPcS 4 instillation resulted in no tissue accumulation. Photodynamic therapy of AY-27 cells incubated with Lip-AlPcS 4 resulted in cell viabilities greater than 90% for all concentrations and incubation times tested; photodynamic therapy of cells incubated with 1 μM Tf-Lip–AlPcS 4 or AlPcS 4 resulted in cell viabilities of 0.19% (95% CI = 0.02% to 0.36%) and 1.32% (95% CI = 0.46% to 2.19%), respectively. Higher concentrations of either AlPcS 4 or Tf-Lip–AlPcS 4 resulted in cell kills of more than 3 logs. Conclusions: Transferrin-mediated liposomal targeting of photosensitizing drugs is a promising potential tool for photodynamic therapy of superficial bladder tumors.
Prospective Neurocognitive Function Over 5 Years After Allogeneic Hematopoietic Cell Transplantation for Cancer Survivors Compared With Matched Controls at 5 Years
Authors: Karen L. Syrjala, Samantha B. Artherholt, Brenda F. Kurland, Shelby L. Langer, Sari Roth-Roemer, JoAnn Broeckel Elrod, Sureyya Dikmen
Journal: Journal of Clinical Oncology (2011)

Research has documented cognitive deficits both before and after high-dose treatment followed by allogeneic hematopoietic cell transplantation (HCT), with partial recovery by 1 year. This study prospectively examined the trajectory and extent of long-term cognitive dysfunction, with a focus on 1 to 5 years after treatment.Allogeneic HCT recipients completed standardized neuropsychological tests including information processing speed (Trail Making A and Digit Symbol Substitution Test), verbal memory (Hopkins Verbal Learning Test-Revised), executive function (Controlled Oral Word Association Test and Trail Making B), and motor dexterity and speed (Grooved Pegboard). Survivors (n = 92) were retested after 80 days and 1 and 5 years after transplantation. Case-matched controls (n = 66) received testing at the 5-year time point. A Global Deficit Score (GDS) summarized overall impairment. Response profiles were analyzed using linear mixed effects models.Survivors recovered significant cognitive function from post-transplantation (80 days) to 5 years in all tests (P < .0001) except verbal recall (P > .06). Between 1 and 5 years, verbal fluency improved (P = .0002), as did executive function (P < .01), but motor dexterity did not (P > .15), remaining below controls (P < .0001) and more than 0.5 standard deviation below population norms. In GDS, 41.5% of survivors and 19.7% of controls had mild or greater deficits (NcNemar test = 7.04, P = .007).Although neurocognitive function improved from 1 to 5 years after HCT, deficits remained for more than 40% of survivors. Risk factors, mechanisms and rehabilitation strategies need to be identified for these residual deficits.
Effect of Glucose Degradation Products on Human Peritoneal Mesothelial Cell Function
Authors: JANUSZ WITOWSKI, KATARZYNA KORYBALSKA, JUSTYNA WISNIEWSKA, ANDRZEJ BREBOROWICZ, GERHARD M. GAHL, ULRICH FREI, JUTTA PASSLICK-DEETJEN, ACHIM JÖRRES
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Bioincompatibility of conventional glucose-based peritoneal dialysis fluids (PDF) has been partially attributed to the presence of glucose degradation products (GDP) generated during heat sterilization of PDF. Most previous studies on GDP toxicity were performed on animal and/or transformed cell lines, and the impact of GDP on peritoneal cells remains obscure. The short-term effects of six identified GDP on human peritoneal mesothelial cell (HPMC) functions were examined in comparison to murine L929 fibroblasts. Exposure of HPMC to acetaldehyde, formaldehyde, glyoxal, methylglyoxal, furaldehyde, but not to 5-hydroxymethyl-furfural, resulted in dose-dependent inhibition of cell growth, viability, and interleukin-1 β (IL-1 β)-stimulated IL-6 release; for several GDP, this suppression was significantly greater compared with L929 cells. Although the addition of GDP to culture medium at concentrations found in PDF had no major impact on HPMC function, the exposure of HPMC to filter-sterilized PDF led to a significantly smaller suppression of HPMC proliferation compared to that induced by heat-sterilized PDF. The growth inhibition mediated by filter-sterilized PDF could be increased after the addition of clinically relevant doses of GDP. These effects were equally evident in L929 cells. In conclusion, GDP reveal a significant cytotoxic potential toward HPMC that may be underestimated in test systems using L929 cells. GDP-related toxicity appears to be particularly evident in experimental systems using proliferating cells and the milieu of dialysis fluids. Thus, these observations may bear biologic relevance in vivo where HPMC are repeatedly exposed to GDP-containing PDF for extended periods of time.
Unitary consciousness requires distributed comparators and global mappings
Authors: George N. Reeke
Journal: Behavioral and Brain Sciences (1995)

Abstract Gray, like other recent authors, seeks a scientific approach to consciousness, but fails to provide a biologically convincing description, partly because he implicitly bases his model on a computationalist foundation that embeds the contents of thought in irreducible symbolic representations. When patterns of neural activity instantiating conscious thought are shorn of homuncular observers, it appears most likely that these patterns and the circuitry that compares them with memories and plans should be found distributed over large regions of neocortex.
Cerebral Oxygen, Glucose, Lactate, and Pyruvate Metabolism in Stroke
Authors: JOHN S. MEYER, T. SAWADA, A. KITAMURA, M. TOYODA
Journal: Circulation (1968)

Cerebral blood flow, oxygen, glucose, lactate, and pyruvate metabolism were measured in 13 subjects with completed stroke. Cerebral blood flow and oxygen consumption were reduced, glucose consumption and pyruvate production were normal, and lactate production was increased, suggesting a shift from aerobic to anaerobic cerebral glycolysis. To test this hypothesis, cerebral blood flow and oxygen delivery were decreased by hyperventilation and increased by inhalation of 5% CO 2 in air. Hyperventilation decreased cerebral oxygen consumption (CMRO 2 ) and increased cerebral lactate production. Inhalation of 5% CO 2 in air increased cerebral blood flow and oxygen delivery and increased both glucose and oxygen consumption. Relationships between reduction in PaCO 2 and cerebral venous PO 2 and increased cerebral lactate production were found. Increasing cerebral blood flow by 5% CO 2 inhalation improved circulation and oxygen delivery to ischemic cerebral areas and improved oxygen and glucose metabolism in the majority of cases since these procedures do not alter CMRO 2 in normal persons. Intravenous injection of glucose increased cerebral glucose uptake but insulin did not.