tbuckley/cabot-search huggingface dataset:
Transient Receptor Potential Channels Regulate Myogenic Tone of Resistance Arteries
Authors: Donald G. Welsh, Anthony D. Morielli, Mark T. Nelson, Joseph E. Brayden
Journal: Circulation Research (2002)

Elevation of intravascular pressure causes depolarization and constriction (myogenic tone) of small arteries and arterioles, and this response is a key element in blood flow regulation. However, the nature of pressure-induced depolarization has remained elusive. In the present study, we provide evidence that a transient receptor potential channel (TRPC6) homologue has a major role in this depolarizing response to pressure. Antisense oligodeoxynucleotides to TRPC6 decreased TRPC6 protein expression and greatly attenuated arterial smooth muscle depolarization and constriction caused by elevated pressure in intact cerebral arteries. Suppressing the expression of this channel protein also reduced the current density of a major cation current in resistance artery smooth muscle cells. We propose that TRPC6 channels play an essential role in regulation of myogenic tone.
Restoration of Hearing.
Authors: Maury M. Stapler
Journal: JAMA (1899)

Macon, Ga., Jan. 4, 1899. <h3>To the Editor:</h3> —I send you the following sketch of a case which I believe to be unique: In July of last year there was brought to me for treatment a young white man, and the following history given: Born in Georgia, 18 years of age, he had never had any serious sickness, and gave no history of any of the eruptive fevers, but was born deaf. On careful examination I found him in a generally good physical condition, all organs except the ears performing their proper functions. Bone conduction of sound was acute and a rudiment of hearing by aerial conduction sufficient to catch only the highest pitch of the human voice thrown directly into the left ear. The tympanic membranes were tightly distended and the turbinated bones enlarged. Since he could not hear he could not speak. He exhibited a great desire for
Myoblasts in pattern formation and gene therapy
Authors: Helen M. Blau, Jyotsna Dhawan, Grace K. Pavlath
Journal: Trends in Genetics (1993)

The tissues of a multicellular animal are composed of diverse cell types arranged in a precisely organized pattern. Features unique to muscle allow an analysis of pattern formation and maintenance in mammals. The progeny of single cells can be taken full cycle from the animal to the culture dish and back to the animal where they fuse into mature myofibers of the host. These features not only facilitate the use of genetically engineered myoblasts in studies of pattern formation, but also in cell-mediated gene therapy: a novel mode of drug delivery for the treatment of muscle and nonmuscle diseases such as hemophilia, cardiac disease and cancer.
Aleutian-Mink Disease in Man
Authors: Irving Chapman, Fidelio A. Jimenez
Journal: New England Journal of Medicine (1963)

IN 1955 a patient in the Brooklyn Veterans Administration Hospital died after a two-year illness that was undiagnosed despite intensive examination by many physicians. Autopsy revealed widespread, unusual anatomic alterations that were not recognized by any of the pathologists who examined the tissues as ever having been previously described.Helmboldt and Jungherr,1 in 1958, reported the anatomic pathology of a newly recognized disease in mink, which because of the particular susceptibility of Aleutian mink was named Aleutian-mink disease. The tissue changes in this disease were similar to those found in our patient. This is especially noteworthy because our patient raised . . .
Therapeutic Substitution: Usurpation of the Physician's Prerogative
Authors: Steven L. Smith
Journal: JAMA (1987)

<h3>To the Editor.—</h3> I would like to reply to the editorial by Dr Ballin entitled "Therapeutic Substitution—Usurpation of the Physician's Prerogative."<sup>1</sup>The author states rather broadly that therapeutic substitution is a practice in which the pharmacist can substitute any drug believed by the pharmacist to have a similar therapeutic effect as the drug prescribed by the physician. He gives the impression that the pharmacist acts totally independently of the physician in deciding which drug to substitute. I feel that this is misleading for several reasons. First, pharmacists are not authorized, in any state, to make therapeutic substitutions without physician approval. Second, in all the examples cited by Dr Ballin, the pharmacist is making substitutions only with the authorization of the physician or the institution. The example of how pharmacy and therapeutics committees determine therapeutic substitutions best represents the cooperative effort between physicians and pharmacists. Rational decisions are made by
Hypotension in Tetanus
Authors: J. L. Corbett, J. M. K. Spalding, P. J. Harris
Journal: BMJ (1973)

Three patients with severe tetanus had episodes of profound arterial hypotension lasting from minutes to hours. The blood pressure was recorded continuously for 13, 19, and six days respectively by an intra-arterial catheter, and other measurements included heart rate, central venous pressure, cardiac output, and blood gases.The hypotension was distinguished from that of "shock", for there was no clinical evidence of peripheral vasoconstriction and no tachycardia. It could not be attributed to disturbances of salt and water balance. During episodes of hypotension the blood pressure fell as low as 32/16 mm Hg, the heart rate fell from a mild tachycardia to normal values or a mild bradycardia, and the central venous pressure did not rise. The onset and the end of such episodes was often abrupt and the hypotension was often produced in response to a stimulus. In one patient extreme hypotension followed the aspiration of secretions from the trachea. These changes may represent another effect of tetanus on autonomic nervous activity, including impairment of baroreceptor reflexes.
Antitumor Effects of Systemically Delivered Adenovirus Harboring <i>Trans</i>-Splicing Ribozyme in Intrahepatic Colon Cancer Mouse Model
Authors: Jin-Sook Jeong, Seong-Wook Lee, Seung-Hee Hong, Yoon-Jong Lee, Haeng-Im Jung, Kyung-Sook Cho, Hye-Hyun Seo, Sang-Jin Lee, Sohee Park, Min-Sun Song, Chang-Min Kim, In-Hoo Kim
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Our previous studies suggested that human telomerase reverse transcriptase (hTERT) RNA-targeting trans-splicing ribozyme could be a useful tool for cancer gene therapy. Here, we investigated whether adenoviruses harboring this ribozyme can be systemically delivered to mice, and whether they selectively mark tumors expressing hTERT and sensitize them to ganciclovir treatments. Experimental Design: We constructed adenoviral vectors containing modified hTERT-targeting trans-splicing ribozyme with downstream reporter gene (Ad-Ribo-LacZ) or suicide gene (Ad-Ribo-HSVtk) driven by a cytomegalovirus promoter. The tumor-specific trans-splicing reaction and the tumor-killing effect of adenoviruses harboring ribozyme were investigated both in vitro and in vivo using mice with intrahepatic colon cancer metastasis via systemic administration. The safety of systemic administration of the viruses was also evaluated. Results: We showed that Ad-Ribo-LacZ, when injected i.v., performs a highly specific trans-splicing reaction on hTERT mRNA and that it selectively marks tumors expressing hTERT in mice. More importantly, i.v. injection of Ad-Ribo-HSVtk plus ganciclovir significantly reduced tumor burden, with minimal liver toxicity, in mice with metastatic liver cancer, compared with the untreated group (P = 0.0009). Moreover, animals receiving Ad-Ribo-HSVtk showed improved survival compared with controls (P &amp;lt; 0.0001). Conclusions: This study shows that systemically delivered adenovirus harboring trans-splicing ribozyme can recognize cancer-specific transcripts and reprogram them to combat the cancer cells. Use of trans-splicing ribozymes seems to be a potentially useful gene therapy for cancer.
Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis
Authors: Tingting Weng, Jens M. Poth, Harry Karmouty-Quintana, Luis J. Garcia-Morales, Ernestina Melicoff, Fayong Luo, Ning-yuan Chen, Christopher M. Evans, Raquel R. Bunge, Brian A. Bruckner, Matthias Loebe, Kelly A. Volcik, Holger K. Eltzschig, Michael R. Blackburn
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with few therapeutic options. Apoptosis of alveolar epithelial cells, followed by abnormal tissue repair characterized by hyperplastic epithelial cell formation, is a pathogenic process that contributes to the progression of pulmonary fibrosis. However, the signaling pathways responsible for increased proliferation of epithelial cells remain poorly understood.To investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis.DCK expression was examined in the lungs of patients with IPF and mice exposed to bleomycin. The regulation of DCK expression by hypoxia was studied in vitro and the importance of DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice.DCK was elevated in hyperplastic alveolar epithelial cells of patients with IPF and in mice exposed to bleomycin. Increased DCK was localized to cells associated with hypoxia, and hypoxia directly induced DCK in alveolar epithelial cells in vitro. Hypoxia-induced DCK expression was abolished by silencing hypoxia-inducible factor 1α and treatment of bleomycin-exposed mice with a DCK inhibitor attenuated pulmonary fibrosis in association with decreased epithelial cell proliferation. Furthermore, DCK expression, and proliferation of epithelial cells and pulmonary fibrosis was attenuated in mice with conditional deletion of hypoxia-inducible factor 1α in the alveolar epithelium.Our findings suggest that the induction of DCK after hypoxia plays a role in the progression of pulmonary fibrosis by contributing to alveolar epithelial cell proliferation.
Regulation of the Immune Response
Authors: K. Bendtzen
Journal: Allergy (1983)

Regulation of the Immune ResponseRegulation of the immune response involves a cotuplex series of cell-cell interactions and a plethora of extracellular tnediators which modulate the type and magnitude of the response.Abnortnalities of immunity frequently reflect defects not simply in the relative or absolute numbers of T and B lymphocytes but rather in the function of antigen-presenting cells, T lymphocyte subpopulations, B lymphocytes or their mediators.As discussed in the teview article in this issue of "Allergy", the recognition of two hormone-like substances, interleukin I and interleukin 2, as the driving forces behind T cell activation (and, subsequently, B cell activation) has allowed the dissection of the system into its elementary components on a luiictional basis.As a consequetice, it has now become possible to carry out pharmacological studies to create a more rational therapeutical approach to immunologically based human diseases.For instance, it is now possible to identify the site and mechanism of action of substances known to modulate the immune response.These include not only drugs, such as glucocorticoids, cyclooxygenase inhibitors, levamisole, cyclosporin A, and histamine H ;,-receptor-blocking agents, but also recently recognized physiological tegulators of the immune systetii, such as cyclic nucleotides, nucleosides, piostaglandins, leukotrienes, histamine and zinc ions.Furthermore, the advent of genetic engineering in immunological research as well as the ability to propagate and maintain lymphokine-producing lymphocytes in culture will no doubt provide therapeutic amounts of several highly potent regulatory hormones produced by the immune system itself.Some of these substances have already been introduced into the clinical field (e.g., thymic hormones, interferons, transfer factors) but almost always on an empirical basis.Renewed functional evaluations ol their detailed modes of action in the series of events leading to the various effector phases of the immune response are therefore warranted and will undoubtedly provide a more sound basis for their future therapeutic application.From the above, it is clear that the way is now open for a fascinating area of research that will help us understand more fully both physiologic and pathophysiologic states of the immune lesponse and thus enable intelligent clinical manipulation of the fine tuning of the systetn.
Transurethral Implantation of Macroplastique&lt;sup&gt;&amp;reg;&lt;/sup&gt; for the Treatment of Female Stress Urinary Incontinence Secondary to Urethral Sphincter Deficiency
Authors: S.C. Radley, C.R. Chapple, I.C. Mitsogiannis, K.S. Glass
Journal: European Urology (2001)
Mechanism of enhanced fibroblast arachidonic acid metabolism by mononuclear cell factor.
Authors: P J Whiteley, P Needleman
Journal: Journal of Clinical Investigation (1984)

Chronic inflammation is associated with an infiltration of mononuclear cells, fibroblast proliferation, and elevated levels of prostaglandin (PG) E2. Mononuclear cell conditioned factor (MNCF) medium (5%) stimulated a 100-fold increase in basal human dermal fibroblast PGE2 release over 48 h as compared with fibroblasts that were incubated with control medium (conditioned medium prepared without cells). The MNCF-induced PGE2 production was suppressed by protein synthesis inhibitors. Fibroblasts pretreated with control medium released PGE2 only modestly in response to 1 nM bradykinin for 1 h (basal, 50 +/- 7 pg PGE2/micrograms protein; stimulated, 104 +/- 12 pg PGE2/micrograms protein), whereas cells that had been pretreated with MNCF showed a greatly facilitated bradykinin-induced release of PGE2. (basal, 297 +/- 59 pg PGE2/micrograms protein; stimulated, 866 +/- 85 pg PGE2/micrograms protein). The exaggerated agonist response is not specific for bradykinin because platelet-derived growth factor elicits a similar response. Exogenous arachidonic acid conversion to PGE2 was also facilitated (two- to threefold) by MNCF pretreatment as compared with control. Both the enhanced agonist-stimulated and exogenous arachidonic acid-induced PGE2 release from the MNCF pretreated cells were inhibited by actinomyin D or cycloheximide. A kinetic study of microsomal cyclooxygenase prepared from fibroblasts pretreated with MNCF showed a threefold increase in the maximum velocity (Vmax) but the same Michaelis constant (Km) as control-treated cells. This augmented arachidonic acid metabolism and subsequent enhanced PGE2 production may play an important role in macrophage-fibroblast interactions at sites of inflammation.
The Cost of Continuing Medical Education for Family Physicians
Authors: Margaret E. Faithe
Journal: JAMA (1979)

THE QUESTION often raised is how much does it cost practicing physicians to attend various continuing medical education endeavors? Family practitioners participating in a twoweek review course at the University of Nebraska College of Medicine provided information regarding their years in practice, size of community, and type of practice in order to determine the direct and indirect costs of one kind of continuing medical education. Results indicate that this type of review course incurs considerable cost to the family physician, but may present a small investment in terms of improved patient care. Twenty-four states have passed legislation requiring participation in continuing medical education as a condition for reregistration of the license to practice medicine, and more states are drafting such legislation.<sup>1</sup>Among the questions raised herein are those relating to cost of continuing medical education, weighted against the potential value of the educational programs to practitioners and their patients.
An Alternative Approach in Endocrine Pathology Research: MALDI-IMS in Papillary Thyroid Carcinoma
Authors: Veronica Mainini, Fabio Pagni, Mattia Garancini, Vittorio Giardini, Gabriele De Sio, Carlo Cusi, Cristina Arosio, Gaia Roversi, Clizia Chinello, Paola Caria, Roberta Vanni, Fulvio Magni
Journal: Endocrine Pathology (2013)
Cdc7 Inhibition Reveals a p53-Dependent Replication Checkpoint That Is Defective in Cancer Cells
Authors: Alessia Montagnoli, Pierluigi Tenca, Francesco Sola, Daniela Carpani, Deborah Brotherton, Clara Albanese, Corrado Santocanale
Journal: Cancer Research (2004)

Abstract Cdc7 is an evolutionarily conserved kinase that regulates S phase by promoting replication origin activation. Down-regulation of Cdc7 by small interfering RNA in a variety of tumor cell lines causes an abortive S phase, leading to cell death by either p53-independent apoptosis or aberrant mitosis. Unlike replication fork blockade, Cdc7-depleted tumor cells do not elicit a robust checkpoint response; thus, inhibitory signals preventing additional cell cycle progression are not generated. In normal fibroblasts, however, a p53-dependent pathway actively prevents progression through a lethal S phase in the absence of sufficient Cdc7 kinase. We show that in this experimental system, p53 is required for the lasting maintenance of this checkpoint and for cell viability. With this work we reveal and begin to characterize a novel mechanism that regulates DNA synthesis in human cells, and we suggest that inhibition of Cdc7 kinase represents a promising approach for the development of a new generation of anticancer agents.
THE BLOOD IN CASES AFFECTED WITH FILARIASIS AND BILHARZIA HAEMATOBIA
Authors: A. C. Coles
Journal: BMJ (1902)

THE BLOOD IN FILARIASIS.[ 'oA II37 tuberculosis to which they refer, the effect of the tubercle on the leukaemia was seen in a reduction of the leucocytes.In Lichtheim's patient the numbers became normal, and he adds that no one would have dreamed from the state of the blood that there ever had been leukaemia.A. Sturmdorf3 mentions that as febrile temperature from phthisis came on the myelo- cytes decreased and polynuclear cells multiplied.Baldwin, however, gives an instance where the advance of tuberculosis failed to check the increase of leucocytes in general.The addition of septic or other infection usually causes a marked reduction, though the improvement may only be temporary.Elsner and Groat refer to instances of typhoid, sepsis, and influenza where this has been seen.In Kraus's case of pneu- monia as a complication there was a fall from 393,000 leuco- cytes to 4,000 in a few days' time,4 and M'Crae' gives a list of similar instances.Thus a lymphatic case with staphylococcus infection showed a fall from 89,ooo to 6,ooo, and a second from 220,000 to 6,ooo in a few days, also an acute leukaemia under Muller in a child with staphylococcus infection, where 109,600 cells were reduced to 6,800.M'Crae notices also:a similar fall, often seen before
Aging-related induction of inducible nitric oxide synthase is vasculo-protective to the arterial media
Authors: M Ferrini
Journal: Cardiovascular Research (2004)

Aging associated erectile dysfunction (ED) is primarily caused by the reduction in smooth muscle cells (SMC) and an increase in collagen within the corpora cavernosa, assumed to result from an increase in reactive oxygen species (ROS). This is accompanied by the expression of inducible nitric oxide synthase (iNOS) to produce nitric oxide that scavenges ROS and inhibits collagen deposition. We investigated whether with aging similar processes occur within the arterial media SMC that share some common physiological functions with the cavernosal SMC.Aged (22-24 months) male Brown Norway rats received water with or without an inhibitor of iNOS activity (L-N-(iminoethyl)-lysine acetate [L-NIL], 0.1 g/l), for 3 weeks. Young (3 months) untreated rats were used as control (n=5 per group). Tissue sections from the penis, abdominal aorta, femoral and brachial arteries were stained for collagen, SMC, iNOS, ROS plasminogen activator inhibitor (PAI) and apoptosis, and evaluated by quantitative image analysis. ROS were also determined in fresh tissue and whole blood by the GSH/GSSG ratio.It was observed that most aging-induced changes in the media of the arterial tree from the aorta to the resistance arteries in the penis are similar to what occurs in the corpora cavernosa, i.e. a decrease in the SMC/collagen ratio and an increase in ROS and iNOS, and specifically in the case of the resistance arteries, an increase in SMC apoptosis and PAI. iNOS inhibition by L-NIL further increased ROS and decreased the SMC/collagen ratio in the media.These observations suggest that ED and arteriosclerosis in the aging male may share a common etiology, and that the expression of iNOS by the SMC is an attempt to counteract this fibrosis.
Myelosuppressive Effect of Colaspase (L-Asparaginase) in Initial Treatment of Acute Lymphoblastic Leukaemia
Authors: P. G. B. Johnston, R. M. Hardisty, H. E. M. Kay, P. G. Smith
Journal: BMJ (1974)

Analysis of the remission induction phase in three Medical Research Council trials of treatment of acute lymphoblastic leukaemia has provided evidence of the adverse effect of the combination of colaspase (L-asparaginase) with vincristine and prednisolone. Significant myelosuppression, particularly of the granulocytic series, resulted in an increase in Gram-negative sepsis and death during the neutropenic phase induced by colaspase. The rate of blast-cell regression was increased by colaspase. It is suggested that the introduction of colaspase should be delayed until there is evidence of bone marrow regeneration in order to procure this benefit without the attendant toxicity.