tbuckley/cabot-search huggingface dataset:
PULMONARY VASOCONSTRICTION IN RESPONSE TO PRECAPILLARY HYPOXEMIA*
Authors: Edward H. Bergofsky, Berl G. Bass, Ricardo Ferretti, Alfred P. Fishman
Journal: Journal of Clinical Investigation (1963)

The pulmonary arterial pressor response to acute hypoxia is generally attributed to pulmo- nary vasoconstriction (1).Moreover, the dem- onstration that the pulmonary pressor response can occur without the intervention of either the autonomic nervous system (2-4) or known neurohumoral mediators (5, 6) has led to the popular view that the pulmonary vasoconstric- tion is a consequence of local effects of acute hypoxia on the vascular wall (7).There is much less unanimity concerning the particular vascular segment (or segments) af- fected by hypoxia.On the premise that the pul- monary capillaries cannot constrict, the bulk of the evidence has been interpreted as indicating that acute hypoxia elicits postcapillary vasoconstriction (7, 8).These experiments, however, which have involved either the breathing of hy- poxic inspired mixtures either by both lungs (9) or by one lung (10), have rarely excluded the possibility that the precapillary vessels may also be involved in the pressor response (11).Fur- thermore, while experiments on isolated lungs and artificial preparations (12) have shown that acute hypoxia is capable of changing the caliber of the precapillary vessels, they have not settled the nature of this response: vasoconstriction or vasodilatation (12, 13), active or passive (14, 15).
Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness
Authors: Bryan C. Batch, Svati H. Shah, Christopher B. Newgard, Christy B. Turer, Carol Haynes, James R. Bain, Michael Muehlbauer, Mahesh J. Patel, Robert D. Stevens, Lawrence J. Appel, L. Kristin Newby, Laura P. Svetkey
Journal: Metabolism (2013)
Connexin-26 mutations in sporadic and inherited sensorineural deafness
Authors: Xavier Estivill, Paolo Fortina, Saul Surrey, Raquel Rabionet, Salvatore Melchionda, Leonardo D'Agruma, Elaine Mansfield, Eric Rappaport, Nancy Govea, Montse Milà, Leopoldo Zelante, Paolo Gasparini
Journal: The Lancet (1998)
Effects of Antidepressant Treatment on Neuroactive Steroids in Major Depression
Authors: Elena Romeo, Andreas Ströhle, Gianfranco Spalletta, Flavia di Michele, Bettina Hermann, Florian Holsboer, Augusto Pasini, Rainer Rupprecht
Journal: American Journal of Psychiatry (1998)

There is evidence from animal studies that fluoxetine may enhance the concentrations of neuroactive steroids. Therefore, the authors investigated whether clinically effective treatment with antidepressants may alter the concentrations of neuroactive steroids in patients suffering from a major depressive episode.In the first study, eight drug-naive outpatients with major depression were studied during treatment with fluoxetine. In a complementary study, 11 inpatients with major depression were studied during a severe depressive episode and after recovery following treatment with different antidepressants. Plasma samples were quantified for neuroactive steroids by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis.During depression, there was a significant decrease in 3 alpha, 5 alpha-tetrahydroprogesterone (3 alpha, 5 alpha-THP) and 3 alpha, 5 beta-THP concentrations, both of which are positive modulators of the gamma-aminobutyric acidA receptor, and a concomitant increase in 3 beta, 5 alpha-THP levels. This dysequilibrium of neuroactive steroids could be corrected by treatment with different antidepressants.These results provide the first clinical evidence of a possible role of neuroactive steroids in successful antidepressant therapy.
Anticardiolipin antibody, recurrent thrombosis, and warfarin withdrawal.
Authors: R A Asherson, J K Chan, E N Harris, A E Gharavi, G R Hughes
Journal: Annals of the Rheumatic Diseases (1985)

Antibodies to cardiolipin, closely related to the 9lupus anticoagulant9, are strongly implicated in the pathogenesis of thrombosis. We record six patients, all with high titres of these antibodies (greater than SD) in serum, who developed recurrent vascular occlusions six to 12 weeks after warfarin withdrawal. Five of the six had deep vein thrombosis, while the sixth suffered a myocardial infarction. To minimise the risk of 9recurrent9 thrombosis it is strongly suggested that such patients remain on long-term anticoagulation, pending the reduction of high antibody levels.
Thrombin-activatable fibrinolysis inhibitor and its relation with inflammation in rheumatoid arthritis
Authors: M J L Peters, M T Nurmohamed, I C van Eijk, C J N Verkleij, P F Marx
Journal: Annals of the Rheumatic Diseases (2009)

Rheumatoid arthritis (RA) is associated with an excessive risk of cardiovascular morbidity and mortality, and inflammation appears to be the missing link explaining this markedly elevated risk.1 Inflammation is a potent inducer of coagulation and fibrinolysis and may contribute to atherosclerotic and thrombotic components of cardiovascular events.2 Thrombin-activatable fibrinolysis inhibitor (TAFI), a procarboxypeptidase in plasma, is a regulatory protein of the coagulation/fibrinolysis balance as well as inflammation. TAFIa, the activated form of TAFI, acts by removing C-terminal arginine and lysine residues from substrates such as fibrin degradation products, bradykinin and the anaphylatoxins C3a and C5a. Elevated TAFI levels may reflect an enhanced risk of developing cardiovascular …
The Nosocomial Spread of Respiratory Syncytial Viral Infections
Authors: C B Hall
Journal: Annual Review of Medicine (1983)

Respiratory syncytial virus is a regular winter visitor that is highly contagious among persons of all ages. It is the major nosocomial pathogen on infant and toddler wards, and has recently been recognized as also causing appreciable nosocomial illness in the elderly. Control of the spread of this virus has been difficult, but transmission appears to require close contact via large-particle aerosols or via fomites. Environmental conditions affect the survival of the virus on varying surfaces and skin, but self-inoculation after touching contaminated surfaces appears to be an important mode of transmission.
Autonomic Denervation With Magnetic Nanoparticles
Authors: Lilei Yu, Benjamin J. Scherlag, Kenneth Dormer, Kytai T. Nguyen, Carey Pope, Kar-Ming Fung, Sunny S. Po
Journal: Circulation (2010)

prior studies indicated that ablation of the 4 major atrial ganglionated plexi (GP) suppressed atrial fibrillation.superparamagnetic nanoparticles (MNPs) made of Fe(3)O(4) (core), thermoresponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacrylamide monomer [NIPA-M]) were synthesized. In 23 dogs, a right thoracotomy exposed the anterior right GP (ARGP) and inferior right GP (IRGP). The sinus rate and ventricular rate slowing responses to high-frequency stimulation (20 Hz, 0.1 ms) were used as the surrogate for the ARGP and IRGP functions, respectively. In 6 dogs, MNPs carrying 0.4 mg NIPA-M were injected into the ARGP. In 4 other dogs, a cylindrical magnet (2600 G) was placed epicardially on the IRGP. MNPs carrying 0.8 mg NIPA-M were then infused into the circumflex artery supplying the IRGP. The hydrogel shell reliably contracted in vitro at temperatures ≥ 37°C, releasing NIPA-M. MNPs injected into the ARGP suppressed high-frequency stimulation-induced sinus rate slowing response (40 ± 8% at baseline; 21 ± 9% at 2 hours; P=0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.9 ± 0.8 V (baseline) to 10.2 ± 0.9 V (2 hours; P=0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing: 57 ± 8% at baseline, 20 ± 8% at 2 hours; P=0.002; sinus rate slowing: 31 ± 7% at baseline, 33 ± 8 % at 2 hours; P=0.604). Prussian Blue staining revealed MNP aggregates only in the IRGP, not the ARGP.intravascularly administered MNPs carrying NIPA-M can be magnetically targeted to the IRGP and reduce GP activity presumably by the subsequent release of NIPA-M. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.
Does This Child Have Acute Otitis Media?
Authors: R. Rothman
Journal: JAMA (2003)

Acute otitis media (AOM) is one of the most common problems in pediatrics. An accurate diagnosis of AOM can guide proper treatment and follow-up.To systematically review the literature regarding precision and accuracy of history taking and physical examination in diagnosing AOM in children.We searched MEDLINE for English-language articles published from 1966 through May 2002. Bibliographies of retrieved articles and textbooks were also searched.We located studies with original data on the precision or accuracy of history or physical examination for AOM in children. Of 397 references initially identified, 6 met inclusion criteria for analysis.Two authors independently reviewed and abstracted data to calculate likelihood ratios (LRs) for symptoms and signs.Four studies of symptoms used clinical diagnosis as the criterion standard and were limited by incorporation bias. Ear pain is the most useful symptom (positive LRs, 3.0-7.3); fever, upper respiratory tract symptoms, and irritability are less useful. One study of clinical signs used tympanocentesis as the criterion standard, and we adjusted the results to correct for verification bias. A cloudy (adjusted LR, 34; 95% confidence interval [CI], 28-42), bulging (adjusted LR, 51; 95% CI, 36-73), or distinctly immobile (adjusted LR, 31; 95% CI, 26-37) tympanic membrane on pneumatic otoscopy are the most useful signs for detecting AOM. A distinctly red tympanic membrane is also helpful (adjusted LR, 8.4; 95% CI, 6.7-11) whereas a normal color makes AOM much less likely (adjusted LR, 0.2; 95% CI, 0.19-0.21).Although many of the studies included in this analysis are limited by bias, a cloudy, bulging, or clearly immobile tympanic membrane is most helpful for detecting AOM. The degree of erythema may also be useful since a normal color makes otitis media unlikely whereas a distinctly red tympanic membrane increases the likelihood significantly.
Microelectrode Study of Alternating Responses to Repetitive Premature Excitation in Canine Purkinje Fibers
Authors: JACK P. BANDURA, DANIEL A. BRODY
Journal: Circulation Research (1974)

Microelectrode studies were performed to produce alternation of coupled beats in the specialized conduction system of the heart and to determine the underlying mechanisms of their production. A typical preparation consisted of a superfused Y-shaped bifurcating segment of canine Purkinje tissue, in which the two branches of the Y were approximately symmetrical and terminated in a functionally communicating bridge of myocardium. Transmembrane potentials were recorded simultaneously from a proximal and a distal location in one branch of the Y. Stimulating the stem of the preparation with 60 pulse pairs/min at a critical coupling interval produced alternation of the coupled beats. Alternate reversal of the proximl-to-distal sequence of activation was observed under these circumstances. This finding probably resulted from alternate antegrade block of the instrumental branch accompanied by retrograde conduction through the accessory pathway offered by the other branch and the common myocardial bridge. The validity of this inference was confirmed by microelectrode exploration and by transection of the retrograde pathway. Analysis of the results demonstrated further that alternating block was also intimately related to the alternation of preceding cycle lengths.
CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer.
Authors: Peilin Zhang, Jie Wang, Weiyi Gao, Bao-Zhu Yuan, John Rogers, Eddie Reed
Journal: Molecular Cancer (2004)

CHK2 kinase is a tumor suppressor that plays important role in DNA damage signaling, cell cycle regulation and DNA damage induced apoptosis. CHK2 kinase expression was known to be ubiquitous in mammalian cells. CHK2-/- cells were remarkably resistant to DNA damage induced apoptosis, mimicking the clinical behavior of non-small cell lung cancer to conventional chemo and radiation therapy. We reported that the CHK2 expression is diminished or absent in both non-small cell lung cancer (NSCLC) cell lines and clinical lung cancer tumor specimens. The absent CHK2 expression in NSCLC was due to hypermethylation of the CHK2 gene promoter, preventing from binding of a transcriptional factor, leading to silence of the CHK2 gene transcription. Since the CHK2 null mice showed a remarkable radioresistance, which bear significant similarity to clinical behavior of NSCLC, down-regulation of CHK2 kinase expression by CHK2 gene silencing and methylation in non-small cell lung cancer suggest a critical role of CHK2 kinase in DNA damage induced apoptosis and a novel mechanism of the resistance of NSCLC to DNA damage based therapy.
Antisense transcripts with rice full-length cDNAs
Authors: Naoki Osato, Hitomi Yamada, Kouji Satoh, Hisako Ooka, Makoto Yamamoto, Kohji Suzuki, Jun Kawai, Piero Carninci, Yasuhiro Ohtomo, Kazuo Murakami, Kenichi Matsubara, Shoshi Kikuchi, Yoshihide Hayashizaki
Journal: Genome biology (2003)

Natural antisense transcripts control gene expression through post-transcriptional gene silencing by annealing to the complementary sequence of the sense transcript. Because many genome and mRNA sequences have become available recently, genome-wide searches for sense-antisense transcripts have been reported, but few plant sense-antisense transcript pairs have been studied. The Rice Full-Length cDNA Sequencing Project has enabled computational searching of a large number of plant sense-antisense transcript pairs.We identified sense-antisense transcript pairs from 32,127 full-length rice cDNA sequences produced by this project and public rice mRNA sequences by aligning the cDNA sequences with rice genome sequences. We discovered 687 bidirectional transcript pairs in rice, including sense-antisense transcript pairs. Both sense and antisense strands of 342 pairs (50%) showed homology to at least one expressed sequence tag other than that of the pair. Microarray analysis showed 82 pairs (32%) out of 258 pairs on the microarray were more highly expressed than the median expression intensity of 21,938 rice transcriptional units. Both sense and antisense strands of 594 pairs (86%) had coding potential.The large number of plant sense-antisense transcript pairs suggests that gene regulation by antisense transcripts occurs in plants and not only in animals. On the basis of our results, experiments should be carried out to analyze the function of plant antisense transcripts.
Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro
Authors: Carlo Pirazzi, Martin Adiels, Maria Antonella Burza, Rosellina Margherita Mancina, Malin Levin, Marcus Ståhlman, Marja-Riitta Taskinen, Marju Orho-Melander, Jeanna Perman, Arturo Pujia, Linda Andersson, Cristina Maglio, Tiziana Montalcini, Olov Wiklund, Jan Borén, Stefano Romeo
Journal: Journal of Hepatology (2012)
Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction
Authors: Larry J. Schaaf, Lisa A. Hammond, Stuart J. Tipping, Richard M. Goldberg, Rakesh Goel, John G. Kuhn, Langdon L. Miller, Linda D. Compton, Laura A. Cisar, Gary L. Elfring, Gabriela Gruia, J. Patrick McGovren, Nicoletta Pirotta, Donghua Yin, Amarnath Sharma, Barbara A. Duncan, Mace L. Rothenberg
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 × institutional upper limit of normal (IULN) and ALT/AST ≤5.0 × IULN; Group 2 (n = 7): total bilirubin 3.1 to 5.0 × IULN and ALT/AST ≤5.0 × IULN; Group 3 (n = 6): total bilirubin ≤1.5 × IULN and ALT/AST 5.1 to 20.0 × IULN; Group 4 (n = 10): total bilirubin 1.5 to 3.0 × IULN and ALT/AST 5.1 to 20.0 × IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m2. After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups. Results: Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m2 were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m2. Conclusions: Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m2 for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.
Self major histocompatibility complex class I antigens expressed solely in lymphoid cells do not induce tolerance in the CD4+ T cell compartment.
Authors: R Schulz, A L Mellor
Journal: The Journal of Experimental Medicine (1996)

Transgenic mice expressing self major histocompatibility complex (MHC) class I (H-2Kb) antigen solely in lymphoid cell lineages do not acquire tolerance to H-2Kb expressed on skin grafts. H-2Kb-specific cytotoxic T cell responses were completely abrogated in these mice, even after they had rejected skin grafts. Moreover, thymocytes expressing T cell receptors that confer H-2Kb reactivity on cytotoxic CD8+ T cells were eliminated. The ability to reject grafts correlated with the presence of a novel population of H-2Kb-reactive CD4+ T cells. At least some of these CD4+ T cells recognize peptides derived from H-2Kb by processing. We conclude that self MHC I antigens induce tolerance in the CD8 T cell compartment via negative selection when expressed exclusively by lymphoid cells. In contrast, tolerance to MHC class II-restricted self peptides derived by processing of such MHC I antigens is not induced in the CD4 T cell compartment. This suggests that effective transfer of self antigens from lymphoid cells to MHC II-positive cells that can process and present them as self peptides to thymocytes or CD4+ T cells does not take place in vivo. Thus, sequestration of self antigens and MHC II molecules in distinct cell types in the thymic microenvironment allows potentially autoreactive and functionally competent CD4+ T cells that recognize cryptic MHC II-restricted self peptides to mature into the peripheral T cell repertoire under normal physiological circumstances.
N<scp>OTCH AND</scp>P<scp>RESENILIN</scp>: Regulated Intramembrane Proteolysis Links Development and Degeneration
Authors: Dennis Selkoe, Raphael Kopan
Journal: Annual Review of Neuroscience (2003)

▪ Abstract Intensive studies of three proteins—Presenilin, Notch, and the amyloid precursor protein (APP)—have led to the recognition of a direct intersection between early development and late-life neurodegeneration. Notch signaling mediates many different intercellular communication events that are essential for determining the fates of neural and nonneural cells during development and in the adult. The Notch receptor acts in a core pathway as a membrane-bound transcription factor that is released to the nucleus by a two-step cleavage mechanism called regulated intramembrane proteolysis (RIP). The second cleavage is effected by Presenilin, an unusual polytopic aspartyl protease that apparently cleaves Notch and numerous other single-transmembrane substrates within the lipid bilayer. Another Presenilin substrate, APP, releases the amyloid ß-protein that can accumulate over time in limbic and association cortices and help initiate Alzheimer's disease. Elucidating the detailed mechanism of Presenilin processing of membrane proteins is important for understanding diverse signal transduction pathways and potentially for treating and preventing Alzheimer's disease.
Phase I Trial of ALT-801, an Interleukin-2/T-Cell Receptor Fusion Protein Targeting p53 (aa264–272)/HLA-A*0201 Complex, in Patients with Advanced Malignancies
Authors: Mayer N. Fishman, John A. Thompson, Gregory K. Pennock, Rene Gonzalez, Luz M. Diez, Adil I. Daud, Jeffery S. Weber, Bee Y. Huang, Shamay Tang, Peter R. Rhode, Hing C. Wong
Journal: Clinical Cancer Research (2011)

ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T-cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics, and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies.p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of four daily 15-minute intravenous infusions, then 10 days rest and four more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose.Four, 16, and 6 patients were treated at the 0.015, 0.04, and 0.08 mg/kg cohorts, respectively. Two dose-limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced toxicities similar to those associated with high-dose IL-2 but of lesser severity. The serum half-life of ALT-801 was 4 hours and ALT-801 serum recovery was as expected based on the dose administered. ALT-801 treatment induced an increase of serum IFN-γ but not TNF-α. Response assessment showed 10 subjects with stable disease at at least 11 weeks, and in one who had melanoma metastasis, there is an ongoing complete absence of identifiable disease after resection of radiographically identified lesions.This first-in-man study defines an ALT-801 regimen that can be administered safely and is associated with immunologic changes of potential antitumor relevance.