tbuckley/cabot-search huggingface dataset:
Rheumatic Fever with Pericarditis: Hyperpyrexia: Treatment by Cold: Recovery
Authors: J. M. Finny
Journal: BMJ (1881)

when the suture is applied ; they had better be too long than too short.5.The apices of the tongues-are very small, so that a very small needle should be used to carry the suture.6.In shaping the tongues the line of the natural web should be carefully observed.If the tongues heal by first intention,; no web can redevelop.There is no reasoXi whatever why union by -the first intention should not invariably take place if the above points are remembered whilst performing the operation, and t-hus one of the most troublesome and unsuccessful of operations is converted into one of the most simple and most certain of success.
Interleukin-6 Overexpression Induces Pulmonary Hypertension
Authors: M. Kathryn Steiner, Olga L. Syrkina, Narasaish Kolliputi, Eugene J. Mark, Charles A. Hales, Aaron B. Waxman
Journal: Circulation Research (2008)

Inflammatory cytokine interleukin (IL)-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated role of IL-6 in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung-specific IL-6–overexpressing transgenic mice (Tg + ) and compared to wild-type (Tg − ) controls in both normoxic and chronic hypoxic conditions. The Tg + mice exhibited elevated right ventricular systolic pressures and right ventricular hypertrophy with corresponding pulmonary vasculopathic changes, all of which were exacerbated by chronic hypoxia. IL-6 overexpression increased muscularization of the proximal arterial tree, and hypoxia enhanced this effect. It also reproduced the muscularization and proliferative arteriopathy seen in the distal arteriolar vessels of PAH patients. The latter was characterized by the formation of occlusive neointimal angioproliferative lesions that worsened with hypoxia and were composed of endothelial cells and T-lymphocytes. IL-6–induced arteriopathic changes were accompanied by activation of proangiogenic factor, vascular endothelial growth factor, the proproliferative kinase extracellular signal-regulated kinase, proproliferative transcription factors c-MYC and MAX, and the antiapoptotic proteins survivin and Bcl-2 and downregulation of the growth inhibitor transforming growth factor-β and proapoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through proproliferative antiapoptotic mechanisms.
Innate secretory antibodies protect against natural <i>Salmonella typhimurium</i> infection
Authors: Odilia L.C. Wijburg, Tania K. Uren, Kim Simpfendorfer, Finn-Eirik Johansen, Per Brandtzaeg, Richard A. Strugnell
Journal: The Journal of Experimental Medicine (2006)

The production of IgA is induced in an antigen-unspecific manner by commensal flora. These secretory antibodies (SAbs) may bind multiple antigens and are thought to eliminate commensal bacteria and self-antigens to avoid systemic recognition. In this study, we addressed the role of “innate” SAbs, i.e., those that are continuously produced in normal individuals, in protection against infection of the gastrointestinal tract. We used polymeric immunoglobulin receptor (pIgR−/−) knock-out mice, which are unable to bind and actively transport dimeric IgA and pentameric IgM to the mucosae, and examined the role of innate SAbs in protection against the invasive pathogen Salmonella typhimurium. In vitro experiments suggested that innate IgA in pIgR−/− serum bound S. typhimurium in a cross-reactive manner which inhibited epithelial cell invasion. Using a “natural” infection model, we demonstrated that pIgR−/− mice are profoundly sensitive to infection with S. typhimurium via the fecal-oral route and, moreover, shed more bacteria that readily infected other animals. These results imply an important evolutionary role for innate SAbs in protecting both the individual and the herd against infections, and suggest that the major role of SAbs may be to prevent the spread of microbial pathogens throughout the population, rather than protection of local mucosal surfaces.
Noninvasive Visualization of Adenovirus Replication with a Fluorescent Reporter in the E3 Region
Authors: Hidetaka A. Ono, Long P. Le, Julia G. Davydova, Tatyana Gavrikova, Masato Yamamoto
Journal: Cancer Research (2005)

Abstract To overcome the inefficacy and undesirable side effects of current cancer treatment strategies, conditionally replicative adenoviruses have been developed to exploit the unique mechanism of oncolysis afforded by tumor-specific viral replication. Despite rapid translation into clinical trials and the established safety of oncolytic adenoviruses, the in vivo function of these agents is not well understood due to lack of a noninvasive detection system for adenovirus replication. To address this issue, we propose the expression of a reporter from the adenovirus E3 region as a means to monitor replication. Adenovirus replication reporter vectors were constructed with the enhanced green fluorescent protein (EGFP) gene placed in the deleted E3 region under the control of the adenoviral major late promoter while retaining expression of the adenovirus death protein to conserve the native oncolytic capability of the virus. Strong EGFP fluorescence was detected from these vectors in a replication-dependent manner, which correlated with viral DNA replication. Fluorescence imaging in vivo confirmed the ability to noninvasively detect fluorescent signal during replication, which generally corresponded with the underlying level of viral DNA replication. EGFP representation of viral replication was further confirmed by Western blot comparison with the viral DNA content in the tumors. Imaging reporter expression controlled by the adenoviral major late promoter provides a viable approach to noninvasively monitor adenovirus replication in preclinical studies and has the potential for human application with clinically relevant imaging reporters.
Japanese-US Common-Arm Analysis of Paclitaxel Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer: A Model for Assessing Population-Related Pharmacogenomics
Authors: David R. Gandara, Tomoya Kawaguchi, John Crowley, James Moon, Kiyoyuki Furuse, Masaaki Kawahara, Satoshi Teramukai, Yuichiro Ohe, Kaoru Kubota, Stephen K. Williamson, Oliver Gautschi, Heinz Josef Lenz, Howard L. McLeod, Primo N. Lara, Charles Arthur Coltman, Masahiro Fukuoka, Nagahiro Saijo, Masanori Fukushima, Philip C. Mack
Journal: Journal of Clinical Oncology (2009)

Purpose To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. Methods We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non–small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m 2 ) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P &lt; .0001), ERCC2 K751Q (P &lt; .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C→T was 1.84 (95% CI, 0.77 to 4.48; P = .19). Conclusion Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.
Gene Expression Profiling of Breast Cancer: A New Tumor Marker
Authors: Laura J. van't Veer, Soonmyung Paik, Daniel F. Hayes
Journal: Journal of Clinical Oncology (2005)

In ideal clinical oncology practice, one would like to have a single platform assay that can provide both prognostic (estimates of risk for failure after surgery alone) and predictive (estimate of benefit from specific therapy) information. Despite years of research, only estrogen receptors (ER), progesterone receptors, and HER-2 have been widely accepted for routine use in breast cancer, serving as predictive factors for endocrine and trastuzumab therapy, respectively. Until recently, new markers have been tested one, or at most two, at a time, a process that results in inefficient tissue usage, long delays in analysis, and, if positive, implementation.
A molecular model of type I allergy: Identification and characterization of a nonanaphylactic anti-human IgE antibody fragment that blocks the IgE-FcϵRI interaction and reacts with receptor-bound IgE
Authors: Sylvia Laffer, Erik Hogbom, Kenneth H. Roux, Wolfgang R. Sperr, Peter Valent, Hans C. Bankl, Luca Vangelista, Franz Kricek, Dietrich Kraft, Hans Grönlund, Rudolf Valenta
Journal: Journal of Allergy and Clinical Immunology (2001)
Ocular Anti-VEGF Therapy for Diabetic Retinopathy: Overview of Clinical Efficacy and Evolving Applications
Authors: Ning Cheung, Ian Y. Wong, Tien Y. Wong
Journal: Diabetes Care (2014)

Ocular anti-vascular endothelial growth factor (VEGF) therapy represents one of the most significant advances in modern medicine. The introduction and widespread use of ocular anti-VEGF therapy for age-related macular degeneration heralded a new era in the treatment of vascular and exudative diseases of the retina. Its expanding indications now include diabetic macular edema and proliferative diabetic retinopathy, two vision-threatening forms of diabetic retinopathy. It is widely anticipated that ocular anti-VEGF therapy could spark a dramatic shift in the treatment paradigm for diabetic retinopathy. However, despite its clear efficacy shown in clinical trials, the dynamic landscape of evolving medical, ethical, and economic issues related to this new treatment suggests significant challenges ahead. In this article, we provide a discussion of this topic as part of this two-part Bench to Clinic narrative. Here, our Clinic contribution provides an overview of the current evidence from clinical trials on anti-VEGF therapy for diabetic retinopathy, and highlights the hopes and fears of this new treatment from clinical and public health standpoints. In the Bench narrative that precedes this contribution, Simó et al. provide an overview of the role of VEGF in the pathogenesis of diabetic retinopathy.
New Function of Calreticulin
Authors: Mitsuhiro Yokoyama, Ken-ichi Hirata
Journal: Circulation Research (2005)

alreticulin was first identified as a Ca 2ϩ -binding protein of the muscle sarcoplasmic reticulum in 1974, and the DNA encoding this protein was isolated in 1989. 1 Calreticulin is a ubiquitous protein, found in a wide range of species and in all nucleated cell types, and has a variety of important biological functions.The human gene for calreticulin contains 9 exons and 8 introns.The deduced amino acid sequence indicates that calreticulin has a 17 amino acid hydrophobic signal sequence at its N terminus and that mature calreticulin contains 400 amino acids.The structure of calreticulin has been well characterized. 2 It has at least 3 structural and functional domains (Figure).Proposed functions for calreticulin range from chaperoning in the endoplasmic reticulum (ER) to antithrombotic effects at the cell surface, and from the regulation of Ca 2ϩ signaling to the modulation of gene expression and cellular adhesion (Table ). 2 Two major functions of calreticulin in the ER lumen, ie, chaperoning and regulation of Ca 2ϩ homeostasis, were intensively investigated and well characterized.Altered expression of calreticulin also has profound effects on many cellular functions.How can this one protein play a role in so many important cellular functions, and where within the cell does it carry out these functions?It is accepted that the majority of cellular calreticulin is located in the ER, where it plays important roles in molecular chaperoning and Ca 2ϩ signaling.There is considerable evidence to indicate that calreticulin is found outside the ER, although how the protein relocates from the ER to the outside of the ER remains unclear.Functions of calreticulin outside the ER include modulation of cell adhesion, integrin-dependent Ca 2ϩ signaling, and steroid-sensitive gene expression as well as mRNA destabilization both in vitro and in vivo.One major controversy in the calreticulin research field concerns the mechanisms involved in calreticulin-dependent modulation of functions outside the ER.
Involvement of Illegitimate V(D)J Recombination or Microhomology-Mediated Nonhomologous End-Joining in the Formation of Intragenic Deletions of the<b><i>Notch1</i></b>Gene in Mouse Thymic Lymphomas
Authors: Hideo Tsuji, Hiroko Ishii-Ohba, Takanori Katsube, Hideki Ukai, Shiro Aizawa, Masahiro Doi, Kyoji Hioki, Toshiaki Ogiu
Journal: Cancer Research (2004)

Abstract Deregulated V(D)J recombination-mediated chromosomal rearrangements are implicated in the etiology of B- and T-cell lymphomagenesis. We describe three pathways for the formation of 5′-deletions of the Notch1 gene in thymic lymphomas of wild-type or V(D)J recombination-defective severe combined immune deficiency (scid) mice. A pair of recombination signal sequence-like sequences composed of heptamer- and nonamer-like motifs separated by 12- or 23-bp spacers (12- and 23-recombination signal sequence) were present in the vicinity of the deletion breakpoints in wild-type thymic lymphomas, accompanied by palindromic or nontemplated nucleotides at the junctions. In scid thymic lymphomas, the deletions at the recombination signal sequence-like sequences occurred at a significantly lower frequency than in wild-type mice, whereas the deletions did not occur in Rag2−/− thymocytes. These results show that the 5′-deletions are formed by Rag-mediated V(D)J recombination machinery at cryptic recombination signal sequences in the Notch1 locus. In contrast, one third of the deletions in radiation-induced scid thymic lymphomas had microhomology at both ends, indicating that in the absence of DNA-dependent protein kinase-dependent nonhomologous end-joining, the microhomology-mediated nonhomologous end-joining pathway functions as the main mechanism to produce deletions. Furthermore, the deletions were induced via a coupled pathway between Rag-mediated cleavage at a cryptic recombination signal sequence and microhomology-mediated end-joining in radiation-induced scid thymic lymphomas. As the deletions at cryptic recombination signal sequences occur spontaneously, microhomology-mediated pathways might participate mainly in radiation-induced lymphomagenesis. Recombination signal sequence-mediated deletions were present clonally in the thymocyte population, suggesting that thymocytes with a 5′-deletion of the Notch1 gene have a growth advantage and are involved in lymphomagenesis.
Stress-induced modulation of skin immune function: two types of antigen-presenting cells in the epidermis are differentially regulated by chronic stress
Authors: Y. Nakano
Journal: British Journal of Dermatology (2004)

Background Inflammatory skin diseases are exacerbated by psychiatric stress. Previous studies have shown that the activity of epidermal antigen-presenting cells (APCs), Langerhans cells (LCs) and keratinocytes (KCs), is affected by stress. Hapten application causes migration of LCs to draining lymph nodes (DLNs). Recently, we found that hapten application also activates epidermal cells (ECs) to mature potent APCs, and that the main APCs in these populations are KCs. Thus, DLN cells and ECs following hapten application are available for estimating the APC function of LCs and KCs in stress studies. Objectives To investigate the mechanism of exacerbation of skin inflammation by chronic stress by observing the effect of isolation stress transversally on the skin immune and neurohormonal systems. Methods Contact sensitivity (CS) was elicited in BALB/c mice. The APC function of LCs and ECs following hapten application was assessed by the CS-inducing activity in the recipient mice. Levels of neurohormonal transmitters and proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. Cell surface molecules were detected using flow cytometry. Expression of mRNA for cytokines, neurohormonal receptors and a differentiation marker by ECs was determined by reverse transcription–polymerase chain reaction. Results Acute stress (2-day isolation) suppressed induction of CS, while chronic stress (30-day isolation) markedly enhanced induction of CS. DLN cells from chronically stressed mice contained increased numbers of LCs and exhibited enhanced APC function for inducing CS. In contrast, the APC function of KCs from these mice was markedly suppressed. Serum corticosterone levels were enhanced in acute stress, while substance P (SP) levels were enhanced in chronic stress. Corticotrophin-releasing hormone receptor-1 mRNA expression in ECs was enhanced in acute stress, while SP receptor (i.e. neurokinin-1 receptor) mRNA expression in ECs was enhanced in chronic stress. Production and mRNA expression of the proinflammatory cytokines interleukin-1α and tumour necrosis factor-α by ECs following hapten application was markedly suppressed in chronic stress. Expression by ECs of E-cadherin, which adheres LCs and KCs homophilically, was suppressed in chronic stress. In addition, these cells exhibited impaired differentiation, i.e. suppressed spontaneous proliferation and enhanced mRNA expression for transglutaminase-3. Conclusions Chronic isolation stress may enhance CS responses by upregulation of the APC activity of LCs and the SP system. However, dysregulation of KC function and differentiation by chronic stress suggests that KCs may not contribute to the enhancement of the CS response positively. These complex changes suggest that chronic isolation stress in mice may provide a possible model system for studying the mechanism of exacerbation of skin inflammation by stress.
Hemochromatosis in Italy in the last 30 years: Role of genetic and acquired factors
Authors: Anna Ludovica Fracanzani, Alberto Piperno, Luca Valenti, Mirella Fraquelli, Sabina Coletti, Alessandra Maraschi, Dario Consonni, Enzo Coviello, Dario Conte, Silvia Fargion
Journal: Hepatology (2009)

The clinical presentation of hereditary hemochromatosis has changed markedly in recent years. The aim of this study was to analyze a large series of consecutive Italian patients with hemochromatosis diagnosed between 1976 and 2007 to determine whether the genetic background and the presence of acquired risk factors influenced the severity of iron overload and the natural history of the disease. A cohort of 452 Italian patients with iron overload-338 HFE-related (C282Y homozygotes or compound C82Y/H63D heterozygotes) and 114 non-HFE-related-were followed prospectively for a median of 112 months. Alcohol intake, smoking habits, and iron removed to depletion were similar in patients with and without HFE-related iron overload. Hepatitis B virus (4% and 9%; P = 0.04) and hepatitis C virus (6% and 19%; P = 0.002) infections were more frequent in patients with non-HFE-related iron overload. Seventy-three percent of patients with HFE and 61% of patients with non-HFE-related disease had no acquired risk factor. Cirrhosis was significantly more frequent in non-HFE patients independent of the presence of acquired risk factors (P = 0.02). Sex, alcohol intake, prevalence of smoking, hepatitis C virus infection, glucose, lipids, iron-related parameters, and prevalence of C282Y/H63D differed significantly over the years. At enrollment, cirrhosis was present in 145 cases and was significantly more frequent in the first decade (80%, 47%, and 13%; P = 0.001). Survival did not differ across the decades in cirrhotic patients; hepatocellular carcinoma occurred similarly in HFE and non-HFE patients.Patients with HFE and non-HFE-related iron overload have comparable iron overload and similar clinical history. Patients who were diagnosed during the last 10 years and were not identified as cirrhotic at enrollment have less severe disease and lower prevalence of acquired risk factors, independent of genetic background.
CLINICAL OUTCOMES ASSOCIATED WITH OFF-LABEL USE OF SIROLIMUS- VERSUS PACLITAXEL-ELUTING STENTS
Authors: Myong Hwa Yamamoto, Masahiko Ochiai, Kazuhiro Ashida, Tadayuki Yakushiji, Kennosuke Yamashita, Shigeo Saito, Koichi Hoshimoto, Yuki Mikoshiba, Naoei Isomura, Hiroshi Araki, Chiaki Obara
Journal: Journal of the American College of Cardiology (2010)
Predicted Plasma 25-Hydroxyvitamin D and Risk of Renal Cell Cancer
Authors: Hee‑Kyung Joh, Edward L. Giovannucci, Kimberly A. Bertrand, Soo Lim, Eunyoung Cho
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundAlthough the kidney is a primary organ for vitamin D metabolism, the association between vitamin D and renal cell cancer (RCC) remains unclear.
Improved Adenoviral Vector for Vascular Gene Therapy
Authors: Hu Sheng Qian, Keith Channon, Valentina Neplioueva, Qing Wang, Mitchell Finer, Lisa Tsui, Samuel E. George, James McArthur
Journal: Circulation Research (2001)

Abstract —First-generation, E1-deleted adenoviral vectors (ΔE1-AV) can transduce the vascular endothelium with high efficiency, but their use is limited by the resulting acute endothelial injury and the long-term development of intimal hyperplasia. To reduce the impact of viral proteins on the gene-modified cells, a second-generation adenoviral vector with an additional pair of deletions in the E4 region was developed. To determine whether this ΔE1/ΔE4-AV vector would be useful for vascular gene transfer, we directly compared the efficiency of gene transfer to uninjured rabbit carotid arteries using either an ΔE1/ΔE4-AV or an ΔE1-AV vector encoding β-galactosidase. Both vectors efficiently transduced vascular endothelium; however, the ΔE1/ΔE4-AV vector gene–modified vessels showed higher β-galactosidase expression 10 days after gene transfer. Importantly, the ΔE1/ΔE4-AV vector produced substantially less endothelial cell activation, less inflammation, and reduced neointimal hyperplasia compared with the ΔE1-AV vector–treated vessels. The ΔE1-AV vector–transduced vessels also demonstrated significantly impaired endothelium-dependent relaxation whereas the ΔE1/ΔE4-AV vector did not impact vasomotor function, even at doses of virus in 5-fold excess of the amount required for &gt;90% transduction of the endothelium. We conclude that the ΔE1/ΔE4-AV vector is superior to the ΔE1-AV vector for vascular gene therapy because of the prolonged transgene expression, reduced vascular inflammation, reduced intimal hyperplasia, and maintenance of normal vasomotor function.