tbuckley/cabot-search huggingface dataset:
A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection
Authors: Andrew J. Muir, Sanjeev Arora, Gregory Everson, Robert Flisiak, Jacob George, Reem Ghalib, Stuart C. Gordon, Todd Gray, Susan Greenbloom, Tarek Hassanein, Jan Hillson, Maria Arantxa Horga, Ira M. Jacobson, Lennox Jeffers, Kris V. Kowdley, Eric Lawitz, Stefan Lueth, Maribel Rodriguez-Torres, Vinod Rustgi, Lynn Shemanski, Mitchell L. Shiffman, Subasree Srinivasan, Hugo E. Vargas, John M. Vierling, Dong Xu, Juan C. Lopez-Talavera, Stefan Zeuzem
Journal: Journal of Hepatology (2014)
Metronidazole and Hepatic Abscess
Authors: James G. Kane
Journal: JAMA (1976)

METRONIDAZOLE is a nitroheterocyclic compound with established efficacy in the treatment of trichomaniasis since 1959. Evaluation of metronidazole for use in the treatment of intestinal amebiasis followed its discovery, and the first successful trials were reported in 1966. Since then it has been shown to be effective in the treatment of all forms of amebiasis. Recently, its efficacy and low incidence of side effects compared to alternate drugs has led to its designation as the drug of choice for moderate to severe intestinal amebic disease and amebic hepatic abscess. In fact, recent literature has stressed the usefulness of a therapeutic trial of metronidazole in distinguishing between pyogenic and amebic liver abscess. We wish to report a falsepositive response as a caveat to its use in this regard. <h3>Report of a Case</h3> A 46-year-old butcher was admitted to the Veterans Administration Hospital forexamination. He had fever, chills, weight loss, diarrhea, and
Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans.
Authors: M A Hussain, O Schmitz, A Mengel, Y Glatz, J S Christiansen, J Zapf, E R Froesch
Journal: Journal of Clinical Investigation (1994)

Insulin-like growth factor-I (IGF-I) is considered to be the mediator of the growth-promoting effects of growth hormone (GH). The metabolic effects of these two hormones, however, are different. Whereas GH treatment leads to elevated insulin and glucose levels, reduced insulin sensitivity, and impaired glucose tolerance, IGF-I treatment leads to reduced insulin and GH levels and enhanced insulin sensitivity. IGF-I may, therefore, not only be the mediator of the growth-promoting effects of GH but also a modulator of the effects of GH on insulin action and glucose metabolism. To study the influence of GH and IGF-I on substrate metabolism and insulin sensitivity (assessed by euglycemic, hyperinsulinemic clamping combined with indirect calorimetry and glucose tracer infusion), we have treated eight GH-deficient adults with GH (2 IU/m2 daily subcutaneously [s.c.]), IGF-I (10 micrograms/kg.h s.c.), or both hormones together for 7 d, respectively, and compared the effects of these treatment regimens with a control phase. Our findings suggest that (a) both GH and IGF-I promote lipolysis and lipid oxidation, albeit by different mechanisms; (b) treatment with either hormone is followed by enhanced energy expenditure and reduced protein oxidation; and (c) IGF-I reverses the insulin resistance induced by GH.
Hypoxia-inducible Factor 1 Mediates Nasal Polypogenesis by Inducing Epithelial-to-Mesenchymal Transition
Authors: Hyun-Woo Shin, Kumsun Cho, Dae Woo Kim, Doo Hee Han, Roza Khalmuratova, Sang-Wook Kim, Sea-Yuong Jeon, Yang-Gi Min, Chul Hee Lee, Chae-Seo Rhee, Jong-Wan Park
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Nasal polyposis implies a refractory clinical course in case of chronic rhinosinusitis (CRS). Although hypoxia is believed to be associated with nasal polyposis, little is known about the mechanism underlying polypogenesis.To determine if hypoxia drives nasal polyposis by epithelial-to-mesenchymal transition (EMT).Immunoblotting, immunofluorescence, flow cytometry, and real-time polymerase chain reaction were performed to evaluate EMT and hypoxic markers in human nasal epithelial cells (hNECs) and in sinonasal tissues from patients with CRS with or without polyps. In addition, the effects of hypoxia-inducible factor (HIF)-1α inhibitors on nasal polypogenesis were investigated in a murine model.E-cadherin and α-smooth muscle actin (α-SMA) were down-regulated and up-regulated, respectively, in patients with polyps as compared with patients without polyps. Under hypoxia, hNECs transformed to a mesenchymal shape, and demonstrated representative changes in EMT markers; that is, mesenchymal markers (α-SMA, vimentin, and twist) increased but epithelial markers (E-cadherin and β-catenin) decreased. Mechanistically, E-cadherin level was recovered in hypoxia by silencing HIF-1α and decreased in normoxia by expressing HIF-1α. Furthermore, hypoxia was found to down-regulate PP2Ac phosphatase and up-regulate pSmad3, which led to α-SMA induction. In CRS sinonasal specimens, HIF-1α expression was found to correlate with E-cadherin loss and α-SMA expression. Finally, HIF-1α inhibitors suppressed nasal polypogenesis in a murine model.hNECs undergo EMT during hypoxia and this process is critically mediated by HIF-1α and pSmad3. This study shows that hypoxia-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that HIF-1α be viewed as a therapeutic target for nasal polyposis.
Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss
Authors: John B. Dixon, Prithi S. Bhathal, Norman R. Hughes, Paul E. O'Brien
Journal: Hepatology (2004)

The effect of significant weight loss on nonalcoholic fatty liver disease remains unclear. In this case series of 36 selected obese patients, we examined the effect of weight loss on nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. These 36 patients (11 males, 25 females) had paired liver biopsies, the first at the time of laparoscopic adjustable gastric band placement and the second after weight loss. Second biopsies were obtained from two groups: those requiring a subsequent laparoscopic procedure (n = 19) and those with index biopsy score of 2 or greater for zone 3-centric hepatic fibrosis (n = 17). All biopsies were scored, blinded to the patient's identity and clinical condition, for individual histological features and for NASH stage and grade. Initial biopsies demonstrated NASH in 23 patients and steatosis in 12 patients. Repeat biopsies were taken at 25.6 ± 10 months (range, 9-51 months) after band placement. Mean weight loss was 34.0 ± 17 kg, and percentage of excess weight loss was 52 ± 17%. There were major improvements in lobular steatosis, necroinflammatory changes, and fibrosis at the second biopsy ( P &lt; .001 for all). Portal abnormalities remained unchanged. Only four of the repeat biopsies fulfilled the criteria for NASH. There were 18 patients with an initial fibrosis score of 2 or more compared with 3 patients at follow-up ( P &lt; .001). Those with the metabolic syndrome (n = 23) had more extensive changes before surgery and greater improvement with weight loss. In conclusion , weight loss after surgery provides major improvement or resolution of obesity and metabolic syndrome-associated abnormal liver histological features in severely obese subjects. (Hepatology 2004;39:1647-1654.)
TCT-619 Prognostic Implications Of Percutaneous Coronary Interventions Performed According To The Appropriate Use Criteria For Coronary Revascularization
Authors: Israel Barbash, Danny Dvir, Rebecca Torguson, Salem Badr, Joshua Loh, Lowell Satler, Augusto Pichard, Ron Waksman
Journal: Journal of the American College of Cardiology (2012)
Nanoparticle-mediated Gene Silencing Confers Radioprotection to Salivary Glands In Vivo
Authors: Szilvia Arany, Danielle SW Benoit, Stephen Dewhurst, Catherine E Ovitt
Journal: Molecular Therapy (2013)

Radiation treatment of head and neck cancers causes irreversible damage of the salivary glands (SG). Here, we introduce a preclinical mouse model for small-interfering RNA (siRNA)-based gene silencing to provide protection of SG from radiation-induced apoptosis. Novel, pH-responsive nanoparticles complexed with siRNAs were introduced into mouse submandibular glands (SMG) by retroductal injection to modulate gene expression in vivo. To validate this approach, we first targeted Nkcc1, an ion transporter that is essential for saliva secretion. Nkcc1 siRNA delivery resulted in efficient knockdown, as quantified at the mRNA and the protein levels, and the functional result of Nkcc1 knockdown phenocopied the severe decrease in saliva secretion, characteristic of the systemic Nkcc1 gene knockout. To establish a strategy to prevent apoptotic cell loss due to radiation damage, siRNAs targeting the proapoptotic Pkcδ gene were administered into SMG before ionizing radiation. Knockdown of Pkcδ not only reduced the number of apoptotic cells during the acute phase of radiation damage, but also markedly improved saliva secretion at 3 months in irradiated animals, indicating that this treatment confers protection from hyposalivation. These results demonstrate that nanoparticle delivery of siRNAs targeting a proapoptotic gene is a localized, nonviral, and effective means of conferring radioprotection to the SGs.
ORAL TIUSORALEN THERAPY IN VITILIGO
Authors: RODNEY P. R. DAWBER
Journal: British Journal of Dermatology (1970)

SUMMARY.– Seven patients with vitiligo have been treated with oral Trisoralen followed by u.v. radiation exposure. Two patients were cosmetically improved; 3 patients showed repigmentation of affected parts with no overall cosmetic improvement; all patients showed darkening of normal skin of exposed parts. It is concluded that Trisoralen may have a place in the treatment of vitiligo in some patients.
Charles Dickens and the Art of Medicine
Authors: HOWARD MARKEL
Journal: Annals of Internal Medicine (1984)

Charles Dickens, the novelist, humanist, and social reformer, was a keen observer of all the characteristics of the people in his novels. Dickens observed physicians and visited hospitals so that he could record various illnesses and diseases of people he met during his life. Dickens also worked for many public health reforms in Victorian England. The author used his observations of sick people in many of his novels and produced several accurate descriptions of disease, including Ménière's disorder and acute leukemia.
Intraductal Papillary Neoplasms of the Pancreas: Diagnosis by Endoscopic Pancreatic Biopsy
Authors: T. Obara, H. Maguchi, Y. Saitoh, M. Sohma, K. Tsuji, Y. Koike, K. Takemura, H. Ura, M. Namiki
Journal: Endoscopy (1993)

Intraductal papillary neoplasms of the pancreas (IPN) are rare tumors, distinct from other pancreatic duct cell carcinomas both in terms of papillary polyp formation in the main pancreatic duct and their favorable prognosis. In the present study, endoscopic pancreatic biopsy (EPB) under fluoroscopic control was employed in three cases of IPN to obtain a tissue diagnosis prior to surgery. There were no complications and all biopsy specimens were adequate for histopathological evaluation. In our experience, EPB is a simple, safe and effective method, yielding sufficient material for preoperative tissue diagnosis of pancreatic tumors, especially in the case of IPN.
Aetiology of community acquired pneumonia in Valencia, Spain: a multicentre prospective study.
Authors: J Blanquer, R Blanquer, R Borras, D Nauffal, P Morales, R Menendez, I Subias, L Herrero, J Redon, J Pascual
Journal: Thorax (1991)

A year long multicentre prospective study was carried out in the Valencia region of Spain, to determine the cause of community acquired pneumonia. The study was based on 510 of 833 patients with pneumonia. Of these, 462 were admitted to hospital, where 31 patients died. A cause was established in only 281 cases--208 of bacterial, 60 of viral, and 13 of mixed infection. The most common microorganisms were Streptococcus pneumoniae (14.5%), Legionella sp (14%), Influenza virus (8%), and Mycoplasma pneumoniae (4%). There was a higher incidence of Legionella sp than in other studies.
486 QUANTIFICATION OF HEPATITIS B SURFACE ANTIGEN AS A PREDICTOR OF OFF-TREATMENT SUSTAINED VIROLOGICAL RESPONSE IN CHRONIC HEPATITIS B PATIENTS TREATED WITH ORAL NUCLEOS(T)IDE ANALOGUE
Authors: S.J. Suh, J.E. Yeon, E.L. Yoon, H.J. Lee, S.J. Lee, S.H. Kang, K. Kang, J.H. Kim, H.J. Yim, K.S. Byun
Journal: Journal of Hepatology (2012)
Abstract 3253: Novel oxindole inhibitors of Aurora A kinase: Structure based hit-to-lead approach
Authors: Roberta Pireddu, Harshani R. Lawrence, Mathew P. Martin, Stephane Betzi, Richard Yip, Hua Yang, Nan N. Sun, Jin Q. Cheng, Ernst Schonbrunn, Said M. Sebti, Nicholas J. Lawrence
Journal: Cancer Research (2011)

Abstract The M-phase of cell division is controlled by phosphorylation events performed by several mitotic serine/threonine kinases. For example, the three human isoforms of Aurora kinase (A, B, and C) have been amply investigated as they are essential for the execution of numerous mitotic events and required for genome integrity and stability. Studies have shown that Aurora A and B are frequently over-expressed in various cancer cells. Aurora A also acts as an oncogene inducing malignant transformation when over-expressed. Since the discovery of the Aurora kinases and their association with cancer, there has been great interest in developing small molecule inhibitors of Aurora kinases as potential anticancer drugs.In-house screening campaign directed toward the discovery of novel Aurora A inhibitors, led to the identification of a new and potent class of oxindole derivatives as inhibitors of Aurora-A kinase. The initial hit HL1-058-1 was identified as an inhibitor of histone H3-Ser10 phosphorylation (IC50 1-5 μM). By using a Z’-lyte kinase assay kit, the inhibitory effect of HL1-058-1 was shown to be the direct consequence of the Aurora kinase inhibition (IC50 of 2.7 ± 0.3 µM). Based on the preliminary data, HL1-058-1 was selected for further study. Synthesis of a focused library of analogs based on this hit revealed RPM305 and RPM304 as potent inhibitors of Aurora A (IC50 0.020 ± 0.005 μM, and 0.038 ± 0.018 μM, respectively). Interestingly, compound RPM304 showed 26 fold selectivity over Aurora B (IC50 0.99 ± 0.08 μM). A coupled enzyme assay was also used to carry out further structure activity relationship studies of the most potent analogs. One of the lead compounds was co-crystallized with the kinase domain of Aurora A. The design and synthesis of further focused libraries of oxindoles, based on this X-ray structure will be described. Details of the cell activity of this class of compound to inhibit Aurora A activity and tumor cell growth will be described. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3253. doi:10.1158/1538-7445.AM2011-3253
Effects of inhibition of nitric oxide formation on regional blood flow in experimental myocardial infarction.
Authors: H Drexler, E Hablawetz, W Lu, U Riede, A Christes
Journal: Circulation (1992)

BACKGROUND Large myocardial infarction is associated with reactive hypertrophy and dilation of the left ventricle, depressed coronary flow reserve, and the development of heart failure including systemic vasoconstriction. We hypothetized that changes in endothelial function, e.g., in the synthesis or action of nitric oxide in the coronary and peripheral vasculatures, might be involved in the depressed coronary flow reserve and increased systemic vascular resistance observed in postinfarction myocardial hypertrophy and failure. METHODS AND RESULTS The regional blood flow changes that occur as a result of inhibiting the basal release of nitric oxide with NG-monomethyl-L-arginine (L-NMMA) and how this regional pattern may be altered in large MI (infarct size, 30-51% of left ventricle) were examined. Measurements were made 24 hours and 8 weeks after myocardial infarction or sham operation in conscious rats. The left ventricular end-diastolic pressure and effects of L-NMMA on left ventricular end-diastolic pressure was similar 24 hours and 8 weeks after myocardial infarction. The effects of L-NMMA (30 mg/kg i.v.) on heart rate and blood pressure were similar in infarcted and sham animals. L-NMMA exerted a marked vasoconstriction in the renal, splanchnic, cutaneous, and cerebral circulations of similar magnitude in sham-operated rats and animals with myocardial infarction. The coronary vasoconstrictor effect of L-NMMA was attenuated significantly in the hypertrophied right and noninfarcted left ventricle of 8-week-old infarcted rats (p less than 0.01 versus sham-operated animals) but not 24 hours after induction of myocardial infarction when cardiac hypertrophy has not yet developed. The increase in left ventricular coronary resistance in 8-week-old infarcted animals was inversely related to infarct size (r = -0.787, p = 0.012, n = 9). Nitroglycerin exerted similar increases in coronary blood flow in rats with chronic myocardial infarction and sham-operated animals, arguing against a reduced vascular responsiveness to nitric oxide. Transmission electron microscopy of coronary resistance vessels in 8-week-old infarcted animals did not reveal endothelial abnormalities. CONCLUSIONS These data suggest that the basal release of nitric oxide in the renal, intestinal, and cutaneous circulations is not affected adversely in this model of myocardial infarction and failure. However, the blunted coronary vasoconstrictor effect of L-NMMA late after large myocardial infarction supports the view that the basal release of nitric oxide is impaired in postinfarction reactive cardiac hypertrophy.
Novel Assessment of Acute Lung Injury by <i>In Vivo</i>Near-Infrared Spectroscopy
Authors: SATOSHI SHIBATA, HIDEKI OHDAN, TOSHIO NORIYUKI, SHINKICHIRO YOSHIOKA, TOSHIMASA ASAHARA, KIYOHIKO DOHI
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We investigated the feasibility and validity of near-infrared (NIR) spectroscopy for evaluation of acute lung injury (ALI). In an in vitro model simulating the spectrophotometric characteristics of the lung, NIR spectroscopy could precisely detect changes in water volume, suggesting its ability to assess the extent of pulmonary edema caused by ALI. The different grades of ALI were induced in rats by administering oleic acid and varying the pulmonary ventilation conditions, and NIR spectroscopy was employed to determine lung water content and hemoglobin (Hb) oxygenation of the lungs. NIR spectroscopy detected increased water content even in histologically mild ALI. The changes in lung water content measured by NIR spectroscopy were significantly correlated with gravimetric lung water content (r = 0.877, p < 0.0001). Deoxy-Hb measured by NIR spectroscopy consistently reflected the histological changes in the lungs, and the deoxy-Hb levels correlated with changes in SaO2 (r = − 0.798, p < 0.0001). These findings demonstrate that NIR spectroscopy can evaluate lung water content and Hb oxygenation quantitatively, and may be a useful tool for assessing pathological status in ALI.
Abstract B36: Glutathione S-transferase pi modulates DNA damage responses
Authors: Bong-su Kang, Beom Jun Lee, Jong-Soo Kim
Journal: Cancer Research (2011)

Abstract Glutathione S-transferase pi (GSTP1 in human) has been considered to be a marker for cancer development, because of high levels of expression in variety of cancers and preneoplastic lesions, because in most normal tissues, its expression is very low. High level of GSTP1 expression and its nuclear localization have been shown to correlate with drug resistance and also with tumor increased tumor grade. To demonstrate the function of GST-pi in DNA damage response, using the GST-pi over expressing stable cells ((HEK293-GST-pi) we examined protein interactions We found that phosphorylation levels of p53 at Ser-15 induce by non-lethal concentration of hydrogen peroxide (0.25∼0.5mM) were lower in HEK293-GST-pi cells than those in wild-type cells. p53 is phosphorylated at Ser-15 in response to cellular stress, DNA damage, by ATM (ataxia-telangiectasia mutated), ATR (ataxia-telangiectasia mutated and Rad3-related), and DNA-PK (DNA-dependent protein kinase). On the other hand, elevated nuclear Mre11 (DNA double strand break sensor) level was observed following exposure to hydrogen peroxide in HEKk293-GST-pi cells compared with wild-type cells, whereas the expression level of Mre11 in HEK293-GST-pi cells was similar to or even lower than that of wild-type cells in the absence of hydrogen peroxide treatment. In HEK293-GST-pi cells, hydrogen peroxide treatment induced predominant translocation of nuclear GST-pi to cytoplasm. Similar results were obtained in UV irradiated experiments. Since p53 and Mre11/Rad50/NBS1 complex are downstream regulators of ATM/ATR, GST-pi may play a role in modulating ATM/ATR signaling in cellular stress condition. Further observations are undergoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B36.
Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients
Authors: Philippe Joly, Marie‐Claude Gagnieu, Claire Bardel, Alain Francina, Corinne Pondarre, Cyril Martin
Journal: American Journal of Hematology (2012)

Because no frequency data are available for the main opiate-related polymorphisms in sickle-cell disease (SCD) populations, we decided to perform such a genotyping in a cohort of 139 individuals. For pharmacodynamics,the OPRM1 A118G and the COMT G322A single nucleotide polymorphisms (SNPs) were chosen for their negative effects on the m receptors [1,2]. For pharmacokinetics [3], important SNPs for the CYP2D6 gene (codeine to morphine conversion) and for three genes involved in morphine elimination (namely CYP3A, UGT2B7, and ABCB1) were genotyped. The allelic frequencies of the OPRM1 and COMT SNPs appeared very low (0.01 to 0.05-no double mutant homozygous),as well as the proportion of CYP2D6 poor metabolizers (1.4%)and CYP3A wild-type (17.9%) which are associated with a low morphine exposure. On the contrary, up to 35% of SCD patients may have unfavorable ABCB1 and UGT2B7 genotypes for a good morphine exposure.Obviously, pharmacokinetic studies with precise phenotype/genotype correlations are required to draw definitive conclusions.