tbuckley/cabot-search huggingface dataset:
Molecular basis of permeation in voltage-gated ion channels.
Authors: G F Tomaselli, P H Backx, E Marban
Journal: Circulation Research (1993)

J on channels are pore-forming macromolecules that provide a passive conduit for ion transfer across membranes.Although simple ionophores such as gramicidin and nystatin' fall within this legalistic defi- nition, the ion channels of eukaryotic cells are integral membrane proteins, many of which have now been isolated biochemically, reconstituted, cloned, and ex- pressed.These fascinating proteins play a particularly prominent role in the function of the cardiovascular system by conferring excitability in an exquisitely tissue- specific manner and by mediating a number of key steps in signal transduction.The ion channels in a nodal cell enable it to pace, whereas those in a myocyte enable it to contract.In addition to mediating ionic fluxes across cell membranes, ion channels are the primary receptors for a variety of clinically important drugs including antiarrhythmic agents and calcium channel antagonists.'Therefore, it is of considerable interest to cardiovascular biologists to consider how ion channels work.Two distinct sets of properties characterize each type of ion channel: those that determine whether the channel is open or closed, collectively known as the "gating" properties, and those that define just how the channel moves ions when it is open, known as the "permeation" properties.The structure-function correlation of volt- age-gated ion channels is the subject of several general reviews.The present Mini Review focuses specifically on the mechanism of permeation in ion channels, with particular emphasis on the structural domains that form the pore, determine selectivity, and interact with pore- blocking molecules. Development of Molecular Approaches to the Studyof Ion Channels Cloning of the voltage-dependent Na+ channel from the electric organ of Electrophorus electricus in 19842 heralded a new era in electrophysiology.The availabil- ity of cDNA for ion channels enabled systematic analysis of structure by mutagenesis and heterologous expression.Since then, ion channels of many classes have been cloned, sequenced, and functionally ex- pressed.(Ironically, the original eel Na+ channel has
Epimorphin Overexpression in the Mouse Mammary Gland Promotes Alveolar Hyperplasia and Mammary Adenocarcinoma
Authors: Jamie L. Bascom, Jimmie E. Fata, Yohei Hirai, Mark D. Sternlicht, Mina J. Bissell
Journal: Cancer Research (2005)

Abstract Epimorphin/syntaxin-2 (EPM) is a plasma membrane–anchored protein that has at least two distinct functions depending on its membrane topology: vesicle fusion when localized to the cytoplasmic surface and morphogenic signaling when localized to the extracellular surface. Transgenic mice that express full-length extracellular EPM fused to the NH2-terminal signal sequence of interleukin-2, under the control of the whey acidic protein (WAP) gene promoter, exhibit aberrant mammary gland morphogenesis associated with increased expression of CCAAT enhancer binding protein β (C/EBPβ). Here we report that aged nulliparous and uniparous female WAP-EPM transgenic mice develop alveolar hyperplasias and well-differentiated adenocarcinomas that express high levels of C/EBPβ, keratin-14, matrix metalloproteinase-3, and β-catenin. This study reveals another pathway in which overexpression and alteration of a normal morphogenic process promote the development of cancer in the mammary gland.
Phase I/II Study of AT-101 with Topotecan in Relapsed and Refractory Small Cell Lung Cancer
Authors: Rebecca Suk Heist, Jerry Fain, Bernard Chinnasami, Waseem Khan, Julian R. Molina, Lecia V. Sequist, Jennifer S. Temel, Panos Fidias, Valari Brainerd, Lance Leopold, Thomas J. Lynch
Journal: Journal of Thoracic Oncology (2010)
Periostin: A novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals
Authors: Go Takayama, Kazuhiko Arima, Taisuke Kanaji, Shuji Toda, Hiroyuki Tanaka, Shunsuke Shoji, Andrew N.J. McKenzie, Hiroichi Nagai, Takao Hotokebuchi, Kenji Izuhara
Journal: Journal of Allergy and Clinical Immunology (2006)
Postnatal Changes in Rat Ventricular Function
Authors: SIDNEY F. HOPKINS, ERNEST P. MCCUTCHEON, DAVID R. WEKSTEIN
Journal: Circulation Research (1973)

Experiments were designed to assess the intrinsic changes in myocardial function with age and to determine the role of increasing left ventricular mass in this process. Isometric ventricular pressure-volume curves and length-tension curves were measured in isolated perfused rat hearts of different ages and masses. Incremental tension, peak active tension, and peak passive tension were less for 10-day-old hearts than they were for older hearts subjected to proportionately equal increases in length. At resting length, peak active tension developed by hearts at least 16 days old was 78% higher than that developed by 10-day-old hearts, and peak passive tension was 133% higher. There was no significant difference between 16-day-old rats and older rats. Thus, by the sixteenth postnatal day, the heart had developed functional maturity. These functional changes appeared to be related to age rather than to left ventricular mass. Histological studies of the left ventricle showed that, at birth, the myofibrils were disoriented with a high ratio of nonmyofibrillar elements to myofibrillar elements. Within 16-20 days after birth, the structural organization and the ratio of nonmyofibrillar elements to myofibrillar elements were similar to the organization and the ratio found in an adult. Thus a direct relationship existed between the functional properties and the anatomical development of the myocardium. Mass per se was not the sole factor that contributed to improved myocardial function with age.
Evaluation of investigations to diagnose the cause of dizziness in elderly people: a community based controlled study
Authors: N. R Colledge, R. M Barr-Hamilton, S. J Lewis, R. J Sellar, J. A Wilson
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objective</b>: To compare the findings in dizzy elderly people with those in controls of a similar age to identify which investigations differentiate dizzy from non-dizzy patients and to design an investigational algorithm. <b>Design</b>: Community based study of clinical and laboratory findings in dizzy and control elderly people. <b>Setting</b>: Research outpatient clinic at a teaching hospital. <b>Subjects</b>: 149 dizzy and 97 control subjects aged over 65 years recruited from a community survey and articles in the local press. <b>Main outcome measures</b>: Findings on physical examination, blood testing, electrocardiography (at rest and over 24 hours), electronystagmography, posturography, and magnetic resonance imaging of head and neck (125 (84%) dizzy subjects and 86 (89%) controls); hospital anxiety and depression score; responses to hyperventilation, carotid sinus massage, and the Hallpike manoeuvre. <b>Results</b>: Blood profile, electrocardiography, electronystagmography, and magnetic resonance imaging failed to distinguish dizzy from control subjects because of the frequency of asymptomatic abnormalities in controls. Posturography and clinical assessment (physical examination, dizziness provocation, and psychological assessment) showed significant differences between the groups. A cause of the dizziness was identified from clinical diagnostic criteria based on accepted definitions in 143 subjects, with 126 having more than one cause. The most common diagnoses were central vascular disease (105) and cervical spondylosis (98), often accompanied by poor vision and anxiety. <b>Conclusion</b>: Expensive investigations are rarely helpful in dizzy elderly people. The cause of the dizziness can be diagnosed in most cases on the basis of a thorough clinical examination without recourse to hospital referral. <h3>Key messages</h3> Expensive investigations are rarely helpful in the diagnosis of dizziness in elderly people The most common causes of dizziness in older people are central vascular disease and cervical spondylosis Poor vision and anxiety often accompany but are rarely the sole cause of dizziness These findings point to a definitive role for the general practitioner in the assessment of dizzy elderly patients
Endoscopic Management of Colocutaneous Fistula After Percutaneous Endoscopic Gastrostomy
Authors: H. S. Kim, D. K. Lee, S. K. Baik, S. O. Kwon
Journal: Endoscopy (2002)

A 53-year-old man with a history of hypoxic brain damage and diabetes mellitus underwent insertion of a percutaneous endoscopic gastrostomy (PEG) tube because of difficulty in swallowing and accompanying malnutrition. At 2 weeks after the PEG procedure, he suddenly developed diarrhea and vomiting of feculent material, which was also found from PEG tube aspiration. An immediate fistulogram showed the tipp of the PEG tube in the transverse colon and a gastrocolic fistulous tract formation without peritoneal leakage. After 10 days of total parenteral nutrition and systemic antibiotics, a follow-up gastroscopy demonstrated complete healing of the gastrocolic fistula. After an enema had been administered, colonoscopy was undertaken in an attempt to remove the PEG tube. After the external PEG tube had been cut, and the internal tube had been pulled using a polypectomy snare, the 7-mm opening of the colocutaneous fistula was revealed (Figure [1]). Considering the high risk of delayed wound healing and infection related to the patient's diabetes, we tried to close the fistulous opening endoscopically using a metallic clip. The open clip prong was easily applied to close the fistulous opening after some deflation of the air. Closure was ascertained by rapid expansion of the colon with air insufflation (Figure [2]). At 6 hours after the procedure, the patient was restarted on a liquid diet orally and 3 days later he was discharged without significant sequalae.
Go Big and Go Fast — Vaccine Refusal and Disease Eradication
Authors: Saad B. Omer, Walter A. Orenstein, Jeffrey P. Koplan
Journal: New England Journal of Medicine (2013)

Eradication efforts for vaccine-preventable diseases face many challenges, including vaccine refusal. Clusters of vaccine refusers develop in part because of changing attitudes toward vaccines, paradoxically fostered by successful control efforts.
Lymphocyte Response Depressive Factor in Multiple Sclerosis
Authors: E. J. Field, E. A. Caspary
Journal: BMJ (1971)

Normal serum contains a lymphocyte response depressive factor and this is more active against the lymphocytes of the blood from which the serum was obtained than against lymphocytes from a different normal blood. The suppressive factor is thus "tailor-made" to its own lymphocytes though cross-reactivity with other lymphocytes does occur. The significance of this is discussed. The suppressive factor has a higher titre in serum from patients with multiple sclerosis or other destructive neurological disease than in normal serum. This may be an instance of a general phenomenon in which lymphocyte sensitization is ordinarily accompanied by production of a suppressor factor able to damp down response so that this is controlled by an "acceleratorbrake" mechanism. The possibilities of imbalance in the pathogenesis of disease and therapeutic manipulation of the level of suppressor substance are briefly discussed.
Maternal smoking in pregnancy alters neonatal cytokine responses
Authors: P. S. Noakes, P. G. Holt, S. L. Prescott
Journal: Allergy (2003)

Background: Maternal cigarette smoking in pregnancy is an important, common and avoidable exposure that has been linked with elevated cord blood (CB) immunoglobulin E levels and subsequent asthma and allergic disease in childhood. Despite this, there is still very little information about the immunological effects of maternal smoking on the fetus. Methods: This aim of this study was to compare cord blood mononuclear cell (CBMC) cytokine responses to allergens [ovalbumin (OVA) or house dust mite (HDM)] and mitogens [concanavalin A (ConA) or phytohemaglutinen (PHA)] in neonates whose mothers smoked throughout pregnancy ( n = 17) with responses of neonates whose mothers never smoked ( n = 40). Cell cultures were stimulated for 24 h and supernatants collected for cytokine detection by enzyme‐linked immunosorbent assay [interleukin (IL)‐13, IL‐6, interferon (IFN) γ and IL‐10]. Cell pellets were also collected for cytokine mRNA detection (IL‐5, IL‐9, IFN γ ). Results: Maternal smoking in pregnancy was associated with significantly higher neonatal T helper type 2 (IL‐13 protein) responses to both HDM ( P = 0.01) and OVA ( P = 0.035). These effects remained statistically significant after allowing for confounding factors, including the effects of maternal atopy. Similar trends were also seen for IL‐9mRNA, IL‐5mRNA and IL‐6 responses, although these were not statistically significant. Although IFN γ mRNA responses to PHA ( P = 0.015) and ConA ( P = 0.025) were lower if mothers smoked in pregnancy, there were no differences in neonatal (Th1) IFN γ protein responses to allergens or mitogens. Conclusions: These findings indicate that maternal cigarette smoking can modify aspects of fetal immune function and highlight the need for further studies in this area.
Amiodarone Hepatotoxicity
Authors: BASIL RIGAS
Journal: Annals of Internal Medicine (1986)

Five patients had amiodarone hepatotoxicity detected on routine biochemical monitoring. Symptoms attributable to hepatotoxicity were minimal or absent; reversible hepatomegaly was seen in two patients, whereas three patients had signs of nonhepatic amiodarone toxicity before or with hepatotoxicity. Serum aminotransferase levels were elevated in all patients and alkaline phosphatase levels in four; no patient had hyperbilirubinemia or prolongation of the prothrombin time. Light microscopy showed steatosis, cellular degeneration, and cellular necrosis in the biopsy samples of four patients, whereas the fifth patient's sample had a granulomatous injury pattern. Electron microscopic study of liver tissue done in two patients showed phospholipidladen lysosomal lamellar bodies. These findings suggest that both toxic and hypersensitivity liver injury can occur in response to amiodarone. The presence of phospholipidladen lysosomal lamellar bodies may help differentiate amiodarone hepatotoxicity from alcoholic liver disease or other causes of hepatic steatosis.
Novel 68 kDa autoantigen detected by rheumatoid arthritis specific antibodies.
Authors: S Blass, C Specker, H J Lakomek, E M Schneider, M Schwochau
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To improve the understanding of the pathogenesis of rheumatoid arthritis (RA) by identifying novel, disease specific autoantibodies. METHODS--Total protein preparations from synovial membranes were separated electrophoretically and immunoblotted. Sera from RA patients were screened for predominant immunoreactions by blotting. A 68 kDa antigen target of the most predominant reaction was detected and further characterised. RESULTS--The dominant immunoreaction in most of the RA sera tested was with a 68 kDa antigen. The antigen is probably ubiquitously expressed. It has an isoelectric point of 5.1, is O-glycosylated, and is located in the endoplasmic reticulum, the cytoplasm, or both. Antibodies to the 68 kDa autoantigen were present in 64% of 167 RA patients tested, and could also be detected in seronegative RA patients, but were present in only 1% of 98 patients with other rheumatic diseases. They could not be detected in 55 healthy controls. CONCLUSIONS--Because of its high sensitivity (64%) and specificity (99%), the anti-68 kDa autoantibody not only provides another valuable parameter for diagnosis, but also represents an antibody that may be involved in the pathological mechanisms leading to RA. This hypothesis can be tested by investigating if 68 kDa specific T cells are present in RA patients.
Deafness Associated With Lassa Fever
Authors: Leonard P. Rybak
Journal: JAMA (1990)

Viral infections are now being recognized with increasing frequency to be causes of inner ear disorders, including deafness, vertigo, and facial palsy.<sup>1</sup>Sudden deafness has been associated with a significant rise in antibody titers directed against adenovirus, parainfluenza, and herpesviruses.<sup>2</sup>More recent serological surveys of patients who have idiopathic sudden hearing loss demonstrated seroconversions for antibodies against single or multiple viral agents. The most common viruses implicated were mumps, rubeola (measles), varicella-zoster, cytomegalovirus, and influenza B. It was interesting to note that the incidence of viral seroconversion and sudden hearing loss tracked each other closely, suggesting a relationship between viral infections and idiopathic sudden deafness. Sudden deafness was most prevalent in the spring in Boston during a 3-year study.<sup>3</sup>In England, serological studies of patients with sudden deafness revealed that mumps, measles, and herpes zoster were most commonly associated.<sup>4</sup>Histopathologic study of temporal bones removed during
Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency
Authors: Marlene Carmo, Kimberly A Risma, Paritha Arumugam, Swati Tiwari, Adrianne E Hontz, Claudia A Montiel-Equihua, Maria E Alonso-Ferrero, Michael P Blundell, Axel Schambach, Christopher Baum, Punam Malik, Adrian J Thrasher, Michael B Jordan, H Bobby Gaspar
Journal: Molecular Therapy (2014)

Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8(+) T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8(+) lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL.
ABO Blood Groups and Cancer of Oesophagus, Cancer of Pancreas, and Pituitary Adenoma
Authors: I. Aird, D. R. Lee, J. A. F. Roberts
Journal: BMJ (1960)

It is a striking fact that up to the present time the diseases for which really strong evidence of associations with the ABO blood groups have emerged are, with one exception, conditions of, or associated with, the upper part of the gastro-intestinal tract. The one exception is Helmbold's (1958) finding of a highly significant excess of group A among women suffering from uterine cancers. Hence diseases of the gastro-intestinal tract not hitherto studied are of particular interest. Cancer of the pancreas and cancer of the oesophagus are diseases for which serious operation is often required, hence blood-grouping is frequently carried out and retrospective studies become possible. Neither condition is, however, common enough to make it easy to secure adequate numbers. The series reported in this paper are distinctly small, but it is hoped that other workers may be able to add further samples in due course.
Dihydroxypropoxymethyl guanine in the treatment of AIDS related retinitis due to cytomegalovirus.
Authors: M L Harris, M B Mathalone
Journal: BMJ (1987)

La retinite a cytomegalovirus liee au SIDA evolue generalement vers la cecite (5 cas sur 7). Le traitement nouveau par dihydroxypropoxymethyl guanine se montre efficace dans 2 cas mais la recidive est probable
Awkward Moments in Patient-Physician Communication about HIV Risk
Authors: Ronald M. Epstein
Journal: Annals of Internal Medicine (1998)

Background: Physicians frequently encounter patients who are at risk for HIV infection, but they often evaluate risk behaviors ineffectively. Objective: To describe the barriers to and facilitators of comprehensive HIV risk evaluation in primary care office visits. Design: Qualitative thematic and sequential analysis of videotaped patient–physician discussions about HIV risk. Tapes were reviewed independently by physician and patient and were coded by the research team. Setting: Physicians' offices. Participants: Convenience sample of 17 family physicians and general internists. Twenty-six consenting patients 18 to 45 years of age who indicated concern about or risks for HIV infection on a 10-item questionnaire administered before the physician visit were included. Measurements: A thematic coding scheme and a five-level description of the depth of HIV-related discussion. Results: In 73% of the encounters, physicians did not elicit enough information to characterize patients' HIV risk status. The outcome of HIV-related discussions was substantially influenced by the manner in which the physician introduced the topic, handled awkward moments, and dealt with problematic language and the extent to which the physician sought the patient's perspective. Feelings of ineffectiveness and strong emotions interfered with some physicians' ability to assess HIV risk. Physicians easily recognized problematic communication during reviews of their own videotapes. Conclusions: Comprehensive HIV risk discussions included providing a rationale for discussion, effectively negotiating awkward moments, repairing problematic language, persevering with the topic, eliciting the patient's perspective, responding to fears and expectations, and being empathic. Educational programs should use videotape review and should concentrate on physicians' personal reactions to discussing emotionally charged topics.
Leading campaigner for legalising assisted suicide dies from starvation
Authors: C. Dyer
Journal: BMJ (2014)

Debbie Purdy, the leading campaigner and activist for the legalisation of assisted suicide in the United Kingdom, has died at the age of 51 after starving herself to death.

Purdy, who had primary progressive multiple sclerosis, ended her life on 23 December in the Marie Curie hospice in Bradford, West Yorkshire, by refusing food. In her final interview with the BBC last July she said that she had taken the decision in December 2013 to die by refusing to eat but had found it “so much more difficult than I thought it would be.”

She first hit the headlines in …
UNILATERAL PROVOKED BRONCHIAL ASTHMA IN MAN*
Authors: Mυns Arborelius, Bertil Ekwall, Ragnar Jernérus, Gunnar Lundin, Lawe Svanberg
Journal: Journal of Clinical Investigation (1962)

Ventilatory and volumetric changes during provoked asthma have been studied by several au- thors, using a variety of methods such as spirom- etry, compliance measurements, and nitrogen washout with oxygen.During an asthmatic at- tack the effort necessary to maintain sufficient ven- tilation is greater than normal, owing to the in- creased bronchial resistance.This increase in re- sistance is apparently not uniform throughout the -TO DOUGLAS BAG