tbuckley/cabot-search huggingface dataset:
Impaired expression and function of toll-like receptor 7 in hepatitis C virus infection in human hepatoma cells
Authors: Serena Chang, Karen Kodys, Gyongyi Szabo
Journal: Hepatology (2009)

Hepatitis C virus (HCV) interferes with interferon (IFN)-mediated innate immune defenses. Toll-like receptor (TLR) 7 agonists robustly inhibit HCV infection. We hypothesize that HCV infection may interfere with the expression and/or function of TLR7, a sensor of single-stranded RNA. We identified reduced TLR7 RNA and protein levels in hepatoma cells expressing HCV (full-length, BB7-subgenomic, and JFH-1 clone) compared with control HCV-naïve cells. The biological relevance of this finding was confirmed by the observation of decreased TLR7 RNA in livers of HCV-infected patients compared with controls. HCV clearance, by IFN-α treatment or restrictive culture conditions, restored the decreased TLR7 expression. Treatment with RNA polymerase inhibitors revealed a shorter TLR7 half-life in HCV-replicating cells compared with controls. Downstream of TLR7, an increased baseline IRF7 nuclear translocation was observed in HCV-positive cells compared with controls. Stimulation with the TLR7 ligand R837 resulted in significant IRF7 nuclear translocation in control cells. In contrast, HCV-replicating cells showed attenuated TLR7 ligand-induced IRF7 activation. Conclusion: Reduced TLR7 expression, due to RNA instability, directly correlates with HCV replication and alters TLR7-induced IRF7-mediated cell activation. These results suggest a role for TLR7 in HCV-mediated evasion of host immune surveillance. (Hepatology 2009.)
The Muscular Dystrophies and Related Disorders
Authors: Tetsuo Furukawa
Journal: JAMA (1978)

BETWEEN the middle and the end of the 19th century, muscular dystrophies were established as clinical and pathological entities distinct from neurogenic muscular atrophies. However, keen eyes of excellent clinicians have never overlooked unusual signs occasionally observed in muscular dystrophy patients. Landouzy and Déjèrine<sup>1</sup>observed fasciculations in one of their patients with facioscapulohumeral (FSH) dystrophy and stated, "Fibrillary contractions of muscle favor myelopathy." Some cases of atypical muscular dystrophies with fasciculations have been described. As early as 1886 Penzoldt<sup>2</sup>recognized such a disease and considered it a transitional form between muscular dystrophy and spinal muscular atrophy. Erb<sup>3</sup>in 1910 emphasized the difficulty in diagnosing muscular dystrophy because of the presence of such a transitional form. However, little attention was paid such atypical muscular dystrophies. Recently, biochemical, electron microscopic, and electrophysiological studies have shown the presence of several new diseases, some of which are clinically difficult to differentiate
CD68 expression is a discriminative feature of indolent cutaneous CD8-positive lymphoid proliferation and distinguishes this lymphoma subtype from other CD8-positive cutaneous lymphomas
Authors: M. Wobser, S. Roth, T. Reinartz, A. Rosenwald, M. Goebeler, E. Geissinger
Journal: British Journal of Dermatology (2014)

Indolent cutaneous CD8+ lymphoid proliferation is a recently described rare entity among cutaneous T-cell lymphomas that typically presents with solitary skin lesions at acral sites. Separation from otherwise aggressive T-cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental to avoid unnecessary harmful treatment. However, up to now, no reliable discriminative marker has been identified.Motivated by these diagnostic quandaries, we have analyzed a large series of archived formalin-fixed paraffin-embedded (FFPE) specimens of atypical CD8+ cutaneous infiltrates with clear-cut diagnosis and clinical follow-up (n = 44) including five cases of indolent CD8+ lymphoid proliferation by using immunohistochemistry with the aim of obtaining markers predictive of subtype assignment.We identified exclusive expression of CD68 by lymphoma cells within the subgroup of indolent CD8+ lymphoid proliferation (5/5 cases). Specific CD68 expression in this entity was confirmed by the application of several monoclonal antibodies (KP1, PG-M1, KiM1P) against the CD68 molecule available for FFPE tissue. In contrast, none of the infiltrates of the other CD8+ cutaneous lymphoma entities stained positive for CD68 (0/39).Based on these observations, we suggest CD68 as a new discriminative marker which is helpful in distinguishing indolent CD8+ lymphoid proliferation from other CD8+ cutaneous lymphomas in ambiguous cases.
CAN TYPHOID FEVER BE ABORTED?Read before the Mississippi Valley Medical Association, October, 1893
Authors: J. E. WOODBRIDGE
Journal: JAMA (1894)

The answer echoed and reëchoed from the great thinkers of the profession we all love and practice, from all over the civilized world, is one prolonged and emphatic negative, nowhere more emphatically spoken than in the great representative body of American physicians—theAMERICAN MEDICAL ASSOCIATION. At its last meeting in the city of Milwaukee the original papers, the discussions on them, and the editorial comments in the Society'sJOURNALclearly indicate this, and that the medical profession is not at all agreed on its treatment. The most divergent methods were advised; some condemned what others strongly advocated, these again advising different methods, only to be condemned again, and all were finally disposed of by the editor of theASSOCIATION JOURNAL, who under the caption, "The Treatment of Typhoid Fever," says: "In the topic which heads this editorial the medical profession is certainly as much interested as it is in the
Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia
Authors: Nancy B Ray, Lakshmi Durairaj, Bill B Chen, Bryan J McVerry, Alan J Ryan, Michael Donahoe, Alisa K Waltenbaugh, Christopher P O'Donnell, Florita C Henderson, Christopher A Etscheidt, Diann M McCoy, Marianna Agassandian, Emily C Hayes-Rowan, Tiffany A Coon, Phillip L Butler, Lokesh Gakhar, Satya N Mathur, Jessica C Sieren, Yulia Y Tyurina, Valerian E Kagan, Geoffrey McLennan, Rama K Mallampalli
Journal: Nature Medicine (2010)
EXFOLIATIVE DERMATITIS FOLLOWING INGESTION OF PHENYLBUTAZONE (BUTAZOLIDIN)
Authors: Harold C. Fishman
Journal: JAMA (1953)

Phenylbutazone (Butazolidin) is the pyrazole derivative 4-butyl-l,2-diphenyl-3,5-pyrazolidinedione sodium. It is being used extensively in the treatment of rheumatoid arthritis, ankylosing spondylitis, arthritis with psoriasis, degenerative joint disease, acute peritendinitis, and gout. Over 10% of patients have been reported unable to tolerate the drug. Reported toxic manifestations include morbilliform rash, edema, nausea, activation of peptic ulcer, vertigo, stomatitis, insomnia, nervousness, thrombocytopenia, and agranulocytosis. It has been said that a rash occurs in only 3 to 4% of patients, that it subsides rapidly on discontinuance of medication, and that desensitization with minute doses of phenylbutazone has made possible continuation of therapy in some of those who show rashes.  As we were unable to find any reference in the literature to exfoliative dermatitis attributable to the drug and as we feel that our case indicates that continued use of the drug may be definitely dangerous and absolutely contraindicated after a rash has been
Guanylyl Cyclase C Prevents Colon Cancer Metastasis by Regulating Tumor Epithelial Cell Matrix Metalloproteinase-9
Authors: Wilhelm J. Lubbe, David S. Zuzga, Zengyi Zhou, Weili Fu, Joshua Pelta-Heller, Ruth J. Muschel, Scott A. Waldman, Giovanni M. Pitari
Journal: Cancer Research (2009)

Matrix metalloproteinase-9 (MMP-9) produced by colorectal cancer cells is a critical determinant of metastatic disease progression and an attractive target for antimetastatic strategies to reduce colon cancer mortality. Cellular signaling by cyclic GMP (cGMP) regulates MMP-9 dynamics in various cell systems, and the bacterial enterotoxin receptor guanylyl cyclase C (GCC), the principle source of cGMP in colonocytes, which is overexpressed in colorectal cancers, inhibits tumor initiation and progression in the intestine. Here, we show that ligand-dependent GCC signaling through cGMP induces functional remodeling of cancer cell MMP-9 reflected by a compartmental redistribution of this gelatinase, in which intracellular retention resulted in reciprocal extracellular depletion. Functional remodeling of MMP-9 by GCC signaling reduced the ability of colon cancer cells to degrade matrix components, organize the actin cytoskeleton to form locomotory organelles and spread, and hematogenously seed distant organs. Of significance, GCC effects on cancer cell MMP-9 prevented establishment of metastatic colonies by colorectal cancer cells in the mouse peritoneum in vivo. Because endogenous hormones for GCC are uniformly deficient in intestinal tumors, reactivation of dormant GCC signaling with exogenous administration of GCC agonists may represent a specific intervention to target MMP-9 functions in colon cancer cells. The notion that GCC-mediated regulation of cancer cell MMP-9 disrupts metastasis, in turn, underscores the unexplored utility of GCC hormone replacement therapy in the chemoprevention of colorectal cancer progression.
Effect of Medroxyprogesterone Acetate on Endothelium-Dependent Vasodilation in Postmenopausal Women Receiving Estrogen
Authors: Akihiko Wakatsuki, Yuji Okatani, Nobuo Ikenoue, Takao Fukaya
Journal: Circulation (2001)

Background Estrogen increases endothelium-dependent vasodilation in postmenopausal women. However, use of progestins in combination with estrogen may counter beneficial effects of estrogen on endothelium. We investigated the effect of medroxyprogesterone acetate (MPA) on estrogen-induced increase in endothelium-dependent vasodilation in postmenopausal women. Methods and Results Postmenopausal women were treated daily with conjugated equine estrogen (CEE) 0.625 mg (n=14), CEE 0.625 mg and MPA 2.5 mg (n=15) or CEE 0.625 mg and MPA 5.0 mg (n=16) for 3 months. Plasma lipids and hormones were measured before and after treatment. Vasodilatory responses of the brachial artery were evaluated by measuring flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation by use of high-resolution ultrasonography. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO 4 while kinetics of conjugated diene formation was monitored. Plasma total and LDL cholesterol concentrations were decreased significantly in all groups. CEE increased FMD significantly, from 4.5±1.7% to 8.5±2.8% ( P &lt;0.001). Addition of MPA reversed this effect in a concentration-dependent manner (for MPA 2.5 mg, from 5.0±3.2% to 6.2±3.1%; for MPA 5.0 mg, from 4.9±3.4% to 3.6±3.7%; P =NS for each). No treatment significantly altered nitroglycerin-induced dilation. Lag time for conjugated diene formation was prolonged significantly in all groups, and the oxidation rate was significantly reduced. Conclusions Concurrent MPA administration may offset favorable effects of estrogen on endothelial function in postmenopausal women. Because MPA did not diminish LDL-lowering and antioxidant effects of estrogen, MPA-induced inhibition of endothelium-dependent vasodilation may be independent of changes in oxidative susceptibility and plasma concentration of LDL.
Abstract 4680: DNA dependent protein kinase as a new molecular target for treatment of non-small cell lung cancer
Authors: Naoko Aragane, Akemi Sato, Kentaro Iwanaga, Naomi Kobayash, Shinya Kimura, Eisaburo Sueoka
Journal: Cancer Research (2012)

Abstract Prognosis with non-small cell lung cancer (NSCLC) has improved with the recent introduction of molecular targeted therapy. However, it is limited to patients with epidermal growth factor receptor (EGFR) mutations, who benefit from EGFR tyrosine kinase inhibitors (EGFR-TKI). A new molecular target is needed with other NSCLC patients. In general, chemotherapeutic agents cause DNA double-strand breaks (DNA DSB), leading to apoptosis of cancer cells; DNA repair reverses their effect, resulting in resistance to chemotherapy. DNA DSB repair can be mediated via two major pathways: homologous recombination (HR) and non-homologous end-joining (NHEJ). More than 90% of DSBs in mammalian cells are repaired by NHEJ, which is accomplished by core protein components including Ku70/Ku86, DNA-dependent protein kinase (DNA-PK), XRCC4, DNA ligase IV, Artemis, and Cernunnos-XLF. We recently reported that NK314, a dual inhibitor of topoisomerase IIα (Top2β) and DNA-PK, evidences a potent anti-tumor effect in adult T-cell leukemia-lymphoma (ATL). NK314 induced DNA DSBs and inhibited DNA repair mediated through degradation of the DNA-PK catalytic subunit (DNA-PKcs). In the present study, we examined the effect of NK314 in NSCLC cell lines and assessed DNA-PK as a possible molecular target for NSCLC. Twenty separate NSCLC cell lines were used, with IC50 varying from 46-193 nM. Levels of DNA-PKcs protein varied among the cell lines, whereas those of Ku70 and Ku86 did not. The inhibitory effect of cell growth was closely related to level of DNA-PKcs protein, but not to levels of other DNA-damage-activated protein kinases such as ATM or ATR. Establishment of predictive markers concomitantly with the development of a novel molecular target is indispensable for clinical application. Because detection of DNA-PKcs in peripheral blood is difficult, we investigated an alternative marker for predicting DNA-PKcs inhibitor. We previously found that heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1), an RNA binding protein, interacts with DNA-PK, and we established a system for detecting hnRNP B1 mRNA in peripheral blood. We therefore examined the suitability of hnRNP B1 as an alternative biomarker for DNA-PK inhibitors. Close correlation between levels of DNA-PKcs and hnRNP B1 proteins was established using Western blot analysis with NSCLC cell lines (p=0.995). These results suggest that DNA-PK is a novel molecular target for NSCLC, and detection of hnRNP B1 might serve as an alternative molecular marker for the amount of DNA-PK inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4680. doi:1538-7445.AM2012-4680
Increasing incidence of ectopic pregnancy
Authors: P. J. Aselton
Journal: JAMA (1984)

To the Editor.—  Recently, an increased incidence of ectopic pregnancies in New York State from 1971 to 1979 1 and in the United States from 1970 to 1978 2 was reported inThe Journal. This prompted us to examine the experience of 35,297 pregnant women who were members of Group Health Cooperative (GHC) of Puget Sound in Seattle from Jan 1, 1972, through Dec 31, 1982.  All women with a diagnosis of ectopic or tubal pregnancy were identified at GHC, and incidence rates per year were calculated. The total number of pregnancies or conceptions per year was obtained by adding together the number of live births, spontaneous or induced abortions, and ectopic pregnancies.  There was a significant increase in the incidence of ectopic pregnancy during this 11-year period (x 2 [df=9] for trend, 42.6; P
Nitric oxide inactivates rat hepatic methionine adenosyltransferasein vivo byS-nitrosylation
Authors: F�lix Ruiz, Fernando J. Corrales, Carmen Miqueo, Jos� M. Mato
Journal: Hepatology (1998)

We investigated the mechanism of nitric oxide (NO) action on hepatic methionine adenosyltransferase (MAT) activity using S-nitrosoglutathione (GSNO) as NO donor. Hepatic MAT plays an essential role in the metabolism of methionine, converting this amino acid into S-adenosylmethionine. Hepatic MAT exists in two oligomeric states: as a tetramer (MAT I) and as a dimer (MAT III) of the same subunit. This subunit contains 10 cysteine residues. In MAT I, S-nitrosylation of 1 thiol residue per subunit was associated with a marked inactivation of the enzyme (about 70%) that was reversed by glutathione (GSH). In MAT III, S-nitrosylation of 3 thiol residues per subunit led to a similar inactivation of the enzyme, which was also reversed by GSH. Incubation of isolated rat hepatocytes with S-nitrosoglutathione monoethyl ester (EGSNO), a NO donor permeable through the cellular membrane, induced a dose-dependent inactivation of MAT that was reversed by removing the NO donor from the cell suspension. MAT, purified from isolated rat hepatocytes, contained S-nitrosothiol groups and the addition of increasing concentrations of EGSNO to the hepatocyte suspension led to a progressive S-nitrosylation of the enzyme. Removal of the NO donor from the incubation media resulted in loss of most NO groups associated to the enzyme. Finally, induction in rats of the production of NO, by the administration of bacterial lipopolysaccharide (LPS), induced a fivefold increase in the S-nitrosylation of hepatic MAT, which led to a marked inactivation of the enzyme. Thus, the activity of liver MAT appears to be regulated in vivo by S-nitrosylation
Manual of Ambulatory Surgery
Authors: George W. Machiedo
Journal: JAMA (1984)

In the modern world of ever-increasing medical care costs, there have been many attempts at cost containment. One which has achieved some success is the concept of ambulatory or same-day surgery. In this volume, one of the<i>Comprehensive Manuals of Surgical Specialties</i>, Kassity and his coauthors do an outstanding job of presenting the rationale behind ambulatory surgery, including a detailed analysis of the cost advantages. It must be emphasized that ambulatory surgery, as described in this volume, is not to be confused with minor surgery. Many of the procedures are performed under general anesthesia and the authors point out that only 10% of the patients operated on in their facility are given local anesthesia without an anesthesiologist in attendance. The initial section of the book is devoted to problems in development of an ambulatory surgical center (including floor plans), staffing patterns, and relationships—both physical and functional—to the "parent" hospital. Anesthetic
Toxicity of Local Anesthetics
Authors: Milton H. Alper
Journal: New England Journal of Medicine (1976)

Local anesthetics comprise one of the most widely used classes of drugs in medicine and dentistry, with their remarkable ability to block, quickly and reversibly, the traffic of impulses through both sensory and motor nerves. Historically, the demonstration of the general anesthetic properties of diethyl ether in 1846 antedated by 38 years Koller's finding of the topical anesthetic properties of cocaine. Some of the earliest descriptions of its use mention Central-nervous-system excitation and convulsions as a feared complication. Subsequently, the synthesis of procaine in 1904 permitted the attainment of regional anesthesia by an injectable agent with an appropriate margin of . . .
Development of Macrovascular Diseases in NIDDM Patients in Northern Taiwan: A 4-yr follow-up study
Authors: Chen-Chung Fu, Chih-Jen Chang, Chin-Hsiao Tseng, Muh-Shy Chen, Chie-Shung Kao, Ta-Jen Wu, Huey-Peir Wu, Lee-Ming Chuang, Chien-Jen Chen, Tong-Yuan Tai
Journal: Diabetes Care (1993)

Objective— To assess the development of macrovascular diseases and explore major associative factors in NIDDM. Research Design and Methods— A total of 479 NIDDM patients ≥ 40 yr of age were recruited from four community primary care health centers of northern Taiwan in July 1986 for a cohort study with a 4-yr follow-up. No patient required insulin therapy within 1 yr of diagnosis nor had a history of diabetic ketoacidosis. All were able to participate independently in the activities of daily living. BP and ECG were measured, and a structured questionnaire was asked of each patient. Venous blood after overnight fasting was collected every year to measure cholesterol, HDL cholesterol, plasma glucose, and HbA1c. Results— The duration of diabetes was associated with the development of stroke with a relative risk of 1.063 for every 1-yr increment (P = 0.07). As for HVDs, the significant risk factors were serum cholesterol and HbA1c. For every 1-mg/dl increase in mean total cholesterol level, the relative risk of developing HVD increased 1.016-fold (P = 0.04). For every 1% increase in HbA1c, the relative risk of developing HVD increased 1.170-fold (P = 0.01). With regard to leg VDs, sex and cigarette smoking were significant risk factors. Women diabetic subjects had a higher relative risk than men. Cigarette smoking was significantly associated with leg VD with a relative risk of 6.9 for smokers compared with nonsmokers. The most significant risk factor for LVD was the total cholesterol level. For every 1-mg/dl increase in mean serum cholesterol level, the relative risk of LVD increased 1.013-fold. Conclusions— In the prevention of macrovascular diseases, effective intervention of the nondiabetic cardiovascular risk factors may be as important as or even more important than the good control of diabetes.
Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers–Danlos syndrome
Authors: Lee B. Smith, Patrick W.F. Hadoke, Emma Dyer, Martin A. Denvir, David Brownstein, Eileen Miller, Nancy Nelson, Sara Wells, Michael Cheeseman, Andy Greenfield
Journal: Cardiovascular Research (2010)

The vascular type of Ehlers–Danlos syndrome (EDS IV) is an autosomal-dominant disorder characterized by thin translucent skin and extensive bruising. Patients with EDS IV have reduced life expectancy (median 45–50 years) due to spontaneous rupture of arteries (particularly large arteries) or bowel. EDS IV results from mutation of the COL3A1 gene, which encodes the pro-α1 chains of type III collagen that is secreted into the extracellular matrix, e.g. by smooth muscle cells. A mouse model of EDS IV produced by targeted ablation of Col3a1 has been of limited use as only 10% of homozygous animals survive to adulthood, whereas heterozygous animals do not die from arterial rupture. We report a novel, exploitable model of EDS IV in a spontaneously generated mouse line. Mice were identified by predisposition to sudden, unexpected death from dissection of the thoracic aorta. Aortic dissection inheritance was autosomal-dominant, presented at an early age (median, 6 weeks) with incomplete penetrance, and had a similar sex ratio bias as EDS IV (2:1, male:female). Molecular genetic analysis demonstrated that the causal mutation is a spontaneous 185 kb deletion, including the promoter region and exons 1–39, of the Col3a1 gene. As in EDS IV, aortic dissection was not associated with elevated blood pressure, aneurysm formation, or infection, but may result from aberrant collagen fibrillogenesis within the aortic wall. This novel, exploitable mouse line that faithfully models the vascular aspects of human EDS IV provides an important new tool for advancing understanding of EDS IV and of aortic dissection in general.