tbuckley/cabot-search huggingface dataset:
Abstract 1379: Angiotensin II Inhibits the Na+-K+ pump via PKC-dependent Activation of NAD(P)H Oxidase
Authors: Gemma A Figtree, Caroline N White, Chia Chi Liu, Alvaro Garcia, Elisha J Hamilton, Karin K Chia, Helge H Rasmussen
Journal: Circulation (2008)

Background: The sarcolemmal Na + -K + pump, essentially the only export route for Na + and pivotal for cardiac myocyte function, is inhibited by angiotensin II (Ang II). Since Ang II activates NAD(P)H oxidase we tested the hypothesis that NAD(P)H oxidase mediates Ang II-induced pump inhibition. This is important for our understanding of pathophysiology and treatment of heart failure, a condition with increases in circulating Ang II levels; intracellular myocyte Na + ; NAD(PH oxidase activity; and myocardial oxidative stress. The raised myocyte Na + is believed to contribute to the electro-mechanical phenotype of contractile abnormalities and cardiac arrhythmias. Methods and results: Exposure to 100 nmol/L Ang II increased fluorescence of isolated rabbit ventricular myocytes loaded with a superoxide-sensitive dye. The increase was abolished by pegylated superoxide dismutase (SOD), by the NAD(P)H oxidase inhibitor apocynin and by myristolated inhibitory peptide to ϵ -protein kinase C ( ϵ PKC), previously implicated in Ang II-induced Na + -K + pump inhibition. Exposure of voltage-clamped myocytes to Ang II decreased electrogenic Na + -K + pump current, I p , from 0.48 ± 0.02 pA/pF, N = 11 to 0.36 ± 0.03 pA/pF, N = 11 (P &lt; 0.05). The decrease was abolished (P &lt; 0.05) by inclusion in pipette solution of: SOD, the gp91ds inhibitory peptide that blocks assembly and activation of NAD(P)H oxidase and by ϵ PKC inhibitory peptide. Since co-localization should facilitate NAD(P)H-oxidase dependent regulation of the Na + -K + pump we examined if there is physical association between the pump and NAD(P)H oxidase. Cell lysate was immunoprecipitated with antibody to the α 1 pump subunit. Immunoblotting demonstrated co-immunoprecipitation of the α 1 subunit with caveolin 3 and with membrane-associated p22 phox and cytosolic p47 phox NAD(P)H oxidase subunits at baseline. Ang II had no effect on α 1 /caveolin3 or α 1 /p22 phox interaction, but increased α 1 /p47 phox co-immunoprecipitation. Conclusion: Ang II is known to induce PKC-dependent phosphorylation and translocation of p47 phox resulting in activation of NAD(P)H oxidase, and we propose this activation occurs in a caveolar microdomain and that it mediates the inhibition of the Na + -K + pump by Ang II.
High correspondence between EGFR mutations in tissue and in circulating DNA form non-small-cell lung cancer (NSCLC) patients (p) with poor performance status (PS)
Authors: Cristina Queralt, Clara Mayo, Ana Pradas, Miguel Angel Molina, Noemi Reguart, Jose Luis Ramirez, Fernanda Salazar, Itziar de Aguirre, Miquel Taron, Rafael Rosell
Journal: Cancer Research (2007)

5676  EGFR mutations are associated with sensitivity to erlotinib and gefitinib in NSCLC. The aim of this study was to evaluate the correspondence between EGFR mutations in NSCLC tissue and matched serum DNA and the value of EGFR mutations as a serological marker. 121 Spanish stage IV NSCLC p received customized first- or second-line erlotinib monotherapy based on the presence of EGFR mutations in the tumor tissue. Serum genomic DNA was obtained from all p prior to erlotinib administration. EGFR exon 19 deletions were studied by length analysis of fluorescently labeled PCR products and the exon 21 L858R mutation by a PCR Taqman assay. The EGFR mutation status in the serum was consistent with that in the tumor tissue of 82/121 p (68%) and of 15/16 p (93.8%) with PS 2 had mutations. Overall, 64.3% of p had an exon 19 deletion and 35.7% had L858R. 78% of mutations were found in females (P=0.01) and 77.6% in never-smokers (P=0.07). Response rate was 88% in p with mutations only in the tumor and 87% in p with mutations in tumor and serum. Complete responses were observed in 20% of p with mutations in tumor and serum vs 4% of p with mutations only in tumor (P=0.09). With a median follow-up of 6.8 months (m) (range, 1.2-17.6), time to progression and median survival have not been reached. A trend to better outcome was seen in p without serum EGFR mutations. TTP was longer for p with EGFR exon 19 deletions (not reached) than for p with L858R (7.7 m) (P=0.02). TTP for p with PS 2 with exon 19 deletions was not reached, while it was 2.7 m for p with L858R (P=0.17). The high detection rate of EGFR mutations in serum DNA in p with poor PS could be due to the very elevated serum DNA concentrations resulting from the tumor burden. EGFR mutations in serum could be a non-invasive source of information on the genotype of the original tumor cells and could be a useful tool to predict p response to erlotinib, especially in p with poor PS, where a dramatic differential effect of erlotinib was observed between p with EGFR deletions and those with L858R.
Parent-reported recurrent wheeze after RSV lower respiratory tract infection versus non-RSV lower respiratory tract infection
Authors: Saskia Tamminga, Loes Nibbelke, Maarten Blanken, Louis Bont
Journal: European Respiratory Journal (2013)

BACKGROUND Respiratory syncytial virus accounts for fifty to eighty percent of the hospitalizations for lower respiratory tract infection (LRTI) hospitalizations. In term infants, RSV LRTI has a more severe course than non-RSV LRTI, while both types are associated with recurrent wheeze. Differences in recurrent wheeze after RSV LRTI versus non-RSV LRTI are not known in otherwise healthy late preterm infants.  OBJECTIVES The aim of this study was to compare the incidence of parent reported recurrent wheezing in the first year of life in late preterms after hospitalization for RSV LRTI versus non-RSV LRTI.  METHODS This prospective study included 3104 infants born between 33-35 weeks of gestation at 41 participating hospitals across the Netherlands. A parental questionnaire about clinical and demographic characteristics of the infant was completed at birth and at the age of one year. In case of admission for LRTI, clinical details were obtained.  RESULTS We found that 196 infants were hospitalized for LRTI (RSV, n=138; non-RSV, n=44, unknown, n=14). RSV LRTI was associated with longer duration of hospitalization (5 versus 3 days, p  CONCLUSION Although RSV LRTI has a more severe course than non-RSV LRTI in late preterms, the incidence of subsequent recurrent wheezing during the first year of life is similar in both types. This suggests distinct mechanisms of disease severity and reactive airway disease following viral LRTI during the first year of life in late preterms.
Comprehensive Respiratory Care--A Learning System
Journal: Thorax (1986)

incision, especially after osteotomy of the second rib.'0In view of this a posterolateral approach was preferred for our patient and first rib resection was carried out via this approach without difficulty.Postoperative recovery was uneventful and the cosmetic result was also satisfactory.Payne-James, Walesby Our case illustrates the problems of management of a potentially malignant lesion in a rare and relatively inacces- sible site.We would suggest that the treatment of choice for tuinour of a first rib would be excision via a posterolateral approach.
THE WATERHOUSE-FRIDERICHSEN SYNDROME: REPORT OF A CASE IN AN ADULT
Authors: A. T. Kwedar
Journal: Annals of Internal Medicine (1942)

Case Reports1 April 1942THE WATERHOUSE-FRIDERICHSEN SYNDROME: REPORT OF A CASE IN AN ADULTA. T. KWEDAR, M.D.A. T. KWEDAR, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-16-4-787 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe presence of purpuric or petechial spots on the skin, associated with a massive hemorrhagic destruction of both adrenals and the presence of a fulminating septicemia, is recognized as the Waterhouse-Friderichsen syndrome.1Seventy per cent of all cases reported are in children under the age of two years. This may be owing to the susceptibility and lack of immunity of children to the meningococcus. In Aegerter's2review of the literature he found only six cases of Waterhouse-Friderichsen syndrome occurring in adults, only three of whom were over 50 years of age. Foucar,3in 1936, reported one case in a 20...References1. SACHS MS: Fulminating septicemia associated with purpura and bilateral adrenal hemorrhage—Waterhouse-Friderichsen syndrome: report of two cases with review of the literature, ANN. INT. MED., 1937, x, 1105-1114. Google Scholar2. AEGERTER EE: The Waterhouse-Friderichsen syndrome. A review of the literature and a report of two cases, Jr. Am. Med. Assoc., 1936, cvi, 1715-1719. CrossrefGoogle Scholar3. FOUCAR FH: Acute fulminating meningococcus infection with bilateral capillary hemorrhage of the adrenals as the most striking gross pathologic lesion; a case report, ANN. INT. MED., 1936, ix, 1736-1746. Google Scholar4. KUNSTADTER RH: The Waterhouse-Friderichsen syndrome, Arch. Pediat., 1939, lvi, 489-507. Google Scholar5. LEVINSON SA: The Waterhouse-Friderichsen syndrome, Jr. Pediat., 1939, xiv, 506-516. CrossrefGoogle Scholar6. MCNAMARACONNELL FPWJ: The Waterhouse-Friderichsen syndrome, Jr. Iowa State Med. Soc., 1938, xxviii, 197-199. Google Scholar7. MCLEANCAFFEY SJ: Endemic purpuric meningococcus bacteremia in early life: diagnostic values of smears from purpuric lesions, Am. Jr. Dis. Child., 1931, xlii, 1053-1074. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Springfield, Illinois*Received for publication August 6, 1940. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byRapid and Definitive Diagnosis of Infectious Diseases Using Peripheral Blood Smears 1 April 1942Volume 16, Issue 4Page: 787-791KeywordsChildrenImmunityNeisseria meningitidisSepsis ePublished: 1 December 2008 Issue Published: 1 April 1942 PDF downloadLoading ...
20. Directed Evolution of AAV2 Yields Novel Capsid Variants
Authors: Narendra Maheshri, Brian Kaspar, David V. Schaffer
Journal: Molecular Therapy (2004)

Adeno-associated virus (AAV) is a highly promising gene delivery vehicle, though gene transfer barriers can in cases limit its efficiency. These barriers arise at every step of delivery: the transit of the vector from injection to a cell surface, receptor binding and uptake, intracellular trafficking, and nuclear steps. The AAV gene transfer properties at each of these steps are determined by its capsid structure. Previous capsid modifications that alter AAV tropism, as well as the existence of multiple AAV serotypes, suggest that the structure-function relationships of the AAV capsid are reasonably plastic. We have taken advantage of this remarkable capsid plasticity to generate a large random mutant AAV library (1e6) and select for mutant AAV virions that can overcome several barriers to infection. Specifically, we have selected the AAV2 library for infectious particles with altered heparan sulfate (HS) affinity and for the ability to evade an AAV2 immune response. First, we have generated mutants with both lower and higher affinity to heparin, which could prove valuable in controlling the therapeutic zone of an AAV vector in tissues where ECM HS hinders AAV2 diffusion. Furthermore, we have generated vector variants that have greater than 100-fold improved resistance to human serum that neutralizes wild type AAV2, yet retain AAV2 gene delivery efficiency. These vectors may enable high gene delivery efficiency even in patients with pre-existing immunity, and the locations of point mutations on the capsid surface suggest new regions of functional importance to the virus. These AAV libraries therefore both provide useful variants for gene therapy applications as well as offer new avenues to dissect basic AAV biology.
Medicinal Chemistry Based Approaches and Nanotechnology‐Based Systems to Improve <scp>CNS</scp> Drug Targeting and Delivery
Authors: Patrick Vlieghe, Michel Khrestchatisky
Journal: Medicinal Research Reviews (2012)

Abstract The central nervous system ( CNS ) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood–brain barrier ( BBB ), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug‐targeting approaches and targeted nanotechnology‐based systems, two promising strategies for BBB targeting and delivery of drugs to the brain.
Abstract 1810: PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity
Authors: Said M. Sebti, Aslamuzzaman Kazi, Sevil Ozcan, Awet G. Tecleab, Ying Sun, Harshani Lawrence
Journal: Cancer Research (2014)

Abstract Non-covalent proteasome inhibitors that are less toxic and more effective against solid tumors than currently used proteasome inhibitors are desirable. Through HTS and hit-to-lead optimization efforts we have identified PI-1840, a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nM) over T-L and PGPH (IC50 values &amp;gt;100 µM) activities of the proteasome. Furthermore, PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Dialysis and mass spectrometry studies demonstrate that PI-1840 is a non-covalent and rapidly reversible CT-L inhibitor. PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax and IκB-α, inhibits survival pathways and proliferation, and induces apoptosis in human cancer cells. The mdm2/p53 disruptor, nutlin, sensitizes cancer cells to PI-1840 in a p53-dependent manner. Furthermore, the pan Bcl-2 antagonist BH3-M6 also sensitizes cancer cells to PI-1840. Finally, in vivo, PI-1840 but not Bortezomib (clinically used proteasome inhibitor) suppresses the growth in nude mice of human breast xenografts. These results warrant further evaluation of non-covalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors. Citation Format: Said M. Sebti, Aslamuzzaman Kazi, Sevil Ozcan, Awet G. Tecleab, Ying Sun, Harshani Lawrence. PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1810. doi:10.1158/1538-7445.AM2014-1810
Comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach
Authors: Nariman Battulin, Veniamin S Fishman, Alexander M Mazur, Mikhail Pomaznoy, Anna A Khabarova, Dmitry A Afonnikov, Egor B Prokhortchouk, Oleg L Serov
Journal: Genome biology (2015)

The three-dimensional organization of the genome is tightly connected to its biological function. The Hi-C approach was recently introduced as a method that can be used to identify higher-order chromatin interactions genome-wide. The aim of this study was to determine genome-wide chromatin interaction frequencies using the Hi-C approach in mouse sperm cells and embryonic fibroblasts. The obtained data demonstrate that the three-dimensional genome organizations of sperm and fibroblast cells show a high degree of similarity both with each other and with the previously described mouse embryonic stem cells. Both A- and B-compartments and topologically associated domains are present in spermatozoa and fibroblasts. Nevertheless, sperm cells and fibroblasts exhibit statistically significant differences between each other in the contact probabilities of defined loci. Tight packaging of the sperm genome results in an enrichment of long-range contacts compared with the fibroblasts. However, only 30% of the differences in the number of contacts are based on differences in the densities of their genome packages; the main source of the differences is the gain or loss of contacts that are specific for defined genome regions. We find that the dependence of the contact probability on genomic distance for sperm is close to the dependence predicted for the fractal globular folding of chromatin. Overall, we can conclude that the three-dimensional structure of the genome is passed through generations without being dramatically changed in sperm cells.
Interleukin-4 (IL-4) is an endogenous inhibitor of neutrophil influx and subsequent glomerular pathology in acute antibody-mediated murine nephritis
Authors: S. Saleem, Z.H. Dai, B.T. Konieczny, K.J.M. Assmann, F.K. Baddoura, F.G. Lakkis
Journal: Journal of the American Society of Nephrology (1997)
APPENDICITIS AND UPPER RESPIRATORY INFECTION: A REPORT OF 18 CASES AT SEA
Authors: George L. Calvy
Journal: Annals of Internal Medicine (1948)

Article1 May 1948APPENDICITIS AND UPPER RESPIRATORY INFECTION: A REPORT OF 18 CASES AT SEAGEORGE L. CALVYGEORGE L. CALVYAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-28-5-998 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptA naval escort carrier was engaged in shuttle operations between mainland and Southwest Pacific ports, carrying passengers, and following the Great Circle Route in its crossings.Three epidemic waves of virus type "colds" were encountered in a three month period, synchronous with the appearance of an abdominal syndrome clinically indistinguishable from acute appendicitis. There were three distinct groups totaling five, four, and six cases respectively, whose periodicity corresponded with each upturn in incidence of upper respiratory infection. Three additional cases, occurring singly, were also admitted and are included in the series.This was a curious experience, because, during an antecedent...Bibliography1. BUNTING CH: Variations in lymphoid resistance, Trans. Assoc. Am. Phys., 1926, xli, 30-33. Google Scholar2. GRAYHEIFETZ SHCJ: Lymphoid hyperplasia of the appendix with a special note on its role in acute appendicitis, Arch. Surg., 1937, xxxv, 887-900. CrossrefGoogle Scholar3. BOHROD MG: The pathogenesis of acute appendicitis, Am. Jr. Clin. Path., 1946, xvi, 752-760. CrossrefGoogle Scholar4. WANGENSTEENBOWERS OHWF: Significance of obstructive factor in genesis of acute appendicitis; experimental study, Arch. Surg., 1937, xxxiv, 496-526. CrossrefGoogle Scholar5. EVANS JS: Epidemiology of acute appendicitis in relation to acute nasal and tonsillar infections, Wisconsin Med. Jr., 1918, xvii, 91-93. Google Scholar6. DAWSON GR: Appendicitis following tonsillitis and respiratory infections, Mil. Surg., 1937, lxxx, 447-455. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: *Received for publication July 14, 1947.Opinions expressed herein are those of the writer and do not necessarily represent the views of the Bureau of Medicine and Surgery, Navy Department. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byDer Verdauungstrakt und die großen DrüsenDie Krankheiten des Darmes 1 May 1948Volume 28, Issue 5Page: 998-1002KeywordsAppendicitisSurgeryUpper respiratory tract infections ePublished: 1 December 2008 Issue Published: 1 May 1948 PDF downloadLoading ...
Canadian government pours money into provincial health budgets
Authors: David Spurgeon
Journal: BMJ (2000)

Pressured by public fears about a failing healthcare system and the anger of provincial premiers, Canada's prime minister, Jean Chretien, has announced a substantial increase in funding for provincial health budgets.

The increase, of $C23.4bn (£11bn; $15.6bn) over five years in new federal health and social transfer funds, is intended to go some way to restore the cuts in funding for Medicare, the system that gives comprehensive coverage of approved medical and hospital services for every Canadian. It represents an increase of about 35%.

The money includes $C2.2bn for “early childhood development,” $C1bn for medical equipment such as magnet resonance imaging scanners, $C500m …
Can we keep the “academic” in academic medicine?
Authors: Nancy C. Andrews
Journal: Journal of Clinical Investigation (2009)

This article is adapted from a presentation at the ASCI/AAP Joint Meeting, April 25, 2009, in Chicago, Illinois, USA.



Citation for this article: J. Clin. Invest. 120:390–393 (2010). doi:10.1172/JCI41934.
Fluticasone propionate/formoterol fumarate combination therapy has comparable efficacy to its individual components administered concurrently
Authors: Anna Bodzenta-Lukaszyk, Jan A. van Noord, Winfried G. Schröder-Babo, Kirsten McAulay, Tammy McIver
Journal: European Respiratory Journal (2011)

Background: A combination of fluticasone propionate and formoterol fumarate (FLUT/FORM; flutiform ®) in a single aerosol inhaler has been developed. This study investigated the efficacy and safety of the combination compared to its individual components administered concurrently (FLUT+FORM).

Methods: Patients aged 12 years or over (N=210) with mild to moderate-severe persistent, reversible asthma were randomized in a 1:1 ratio to 12 weeks of twice daily treatment with one of two doses of FLUT/FORM or FLUT+FORM in an open-label, parallel group, multicentre study in Europe. Total daily doses were FLUT/FORM: 200/20μg or 500/20μg; FLUT+FORM: 200/24μg or 500/24μg. The primary objective was to show non-inferiority of FLUT/FORM compared to FLUT+FORM based on post-dose forced expiratory volume in 1 second (FEV1) on Day 84.

Results: FLUT/FORM had comparable efficacy to FLUT+FORM in the treatment of asthma with mean FEV1 30 to 60 minutes post-dose on Day 84 of 2.6L in both groups (per protocol groups; least squares mean difference: -0.03 L; 95%CI: -0.148, 0.081; p=0.004). The lower limit of the 95% CI was above the pre-defined non-inferiority threshold of ≥-0.2L. Analysis of other pulmonary function tests, patient reported outcomes, rescue medication use, asthma exacerbations and quality of life questionnaires were also comparable. The safety profiles of the two study groups were similar overall.

Conclusions: Fluticasone/formoterol combination therapy has comparable efficacy to its individual components administered concurrently. The safety and tolerability profile of fluticasone/formoterol combination therapy is similar to that of its individual components.
Type 2M von Willebrand Disease: F606I and I662F Mutations in the Glycoprotein Ib Binding Domain Selectively Impair Ristocetin- but not Botrocetin-Mediated Binding of von Willebrand Factor to Platelets
Authors: Cheryl A. Hillery, David J. Mancuso, J. Evan Sadler, Jay W. Ponder, Mary A. Jozwiak, Pamela A. Christopherson, Joan Cox Gill, J. Paul Scott, Robert R. Montgomery
Journal: Blood (1998)