tbuckley/cabot-search huggingface dataset:
Report on ISN Forefronts, Melbourne, Australia, 4–7 October 2012: tubulointerstitial disease in diabetic nephropathy
Authors: Josephine M. Forbes, David C.H. Harris, Mark E. Cooper
Journal: Kidney International (2013)

The mechanisms involved in expansion of the tubulointerstitial compartment of the kidney in individuals with diabetes are not well understood. Given that tubulointerstitial damage is an important predictor of progression to end-stage kidney disease in most forms of chronic kidney disease it is imperative to gain a greater understanding of the processes involved. With this in mind, a very clear objective for the scientific content of this meeting was to spend more than half the program outside the comfort zone of nephrology, gaining insights from sources such as neurodegenerative and mitochondrial diseases, stem cells, cancer and high-level computing to reconstruct organ systems. The meeting also aimed to place the new concepts presented in the context of current knowledge in diabetic kidney disease and the milestones achieved to date in this area. The presenters were all extremely generous, giving not only their time, but also showing a large proportion of unpublished data to stimulate discussions, questions and innovation.
Case 51-1978
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Milton Elkin, John C. Long
Journal: New England Journal of Medicine (1978)

Presentation of CaseA 65-year-old man was admitted to the hospital because of pain in the flank.He was well until six months earlier, when anorexia, fatigue and malaise developed, associated with urinary urgency and frequency and a diminution of the urinary stream. Three months before admission he began to have intermittent dull pain in the left flank that did not radiate and was relieved by aspirin. A physician found a mass in the left upper quadrant of the abdomen; a stool specimen gave a negative test for occult blood. Eight days before entry a nephrotomographic examination revealed uniform enlargement . . .
Evidence for Possible Involvement of 5-HT <sub>2B</sub> Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications
Authors: Richard B. Rothman, Michael H. Baumann, Jason E. Savage, Laura Rauser, Ace McBride, Sandra J. Hufeisen, Bryan L. Roth
Journal: Circulation (2000)

Background —Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Methods and Results —Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (−)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (−)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m -chlorophenylpiperazine. (±)-, (+)-, and (−)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT 2B receptor and were partial to full agonists at the 5-HT 2B receptor. Conclusions —Our data imply that activation of 5-HT 2B receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT 2B receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT 2B receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT 2B receptors.
Low blood pressure, low mood?
Authors: C. Pritchard
Journal: BMJ (1992)

ground.2Damage to the mitral valve may occur when the heart is violently compressed at the end ofdiastole, when the left ventricle is full.'This may cause rupture of the chordae tendineae or papillary muscles or damage to the valve leaflets themselves.4In severe cases symptoms may occur directly after the injury, but in some cases they may be delayed for several years.'Our patient's posterior mitral valve prolapse was probably due to damage to the chordae tendineae sustained during the crush at the football ground.Such cases have medicolegal implications as mitral valve surgery may become necessary.
STANDARDIZATION IN TREATMENT OF BACILLURIA
Authors: Justina H. Hill
Journal: JAMA (1935)

<h3>To the Editor:—</h3> Dr. Crance in his article entitled "The Necessity for Standardization of the Treatment of Bacilluria" (The Journal, January 26, p. 285) makes a definite advance by his recognition of the necessity of differentiating colon group bacilli into their two genera. This step is of such importance, especially in the evaluation of therapeusis, that it is greatly to be regretted that Dr. Crance has not given information in regard to the bacteriologic details necessary for this differentiation. This cannot be done on the basis used by Dr. Crance; i. e., the fermentation of sucrose. This test is employed for the differentiation of species of the genus Escherichia, of which our old friend B. coli-communior most familiarly represents the sucrose fermenting group and B. coli-communis the sucrose negative group (Zinsser, Hans, and Bayne-Jones, Stanhope: A Textbook of Bacteriology, 1934, p. 561). Only by use of the Voges-Proskauer and methyl
Ocular and systemic causes of retinopathy in patients without diabetes mellitus
Authors: Jayant Venkatramani, Paul Mitchell
Journal: BMJ (2004)

Most general practitioners and physicians are familiar with the risk factors, clinical presentation, and management of retinopathy in patients with diabetes mellitus, commonly termed diabetic retinopathy.Fewer doctors are fully informed about other ocular and systemic causes of retinopathy or the clinical significance of retinopathy in patients without diabetes (referred to as non-diabetic retinopathy in this review).However, retinopathy is fairly common in adults without diabetes, 1-4 and doctors routinely encounter such patients in whom clinical or laboratory evidence of hyperglycaemia is consistently absent.Although some patients with retinopathy will have an obvious aetiology (for example, severe anaemia, systemic lupus erythematosis, or underlying carotid disease), many do not have an easily identifiable cause for their retinal signs.What course of action should the doctor take when faced with retinopathy in a patient without diabetes?What are the common ocular and systemic causes of retinopathy?What is the clinical significance of these retinopathy lesions?These and other matters are discussed in this review. Sources and selection criteriaWe reviewed studies on ocular and systemic causes of "retinopathy" from Medline and textbooks.We specifically excluded "diabetic retinopathy." Non-diabetic retinopathy2][3] The ocular and systemic causes of retinopathy in people without diabetes are varied (see table on bmj.com). Ocular causes of non-diabetic retinopathy Retinal vein occlusionCentral retinal vein occlusion and branch retinal vein occlusion can present with non-diabetic retinopathy.The appearance on funduscopy is usually characteristic, with flame shaped haemorrhages present within the distribution of the affected vein (fig 1).The patient may complain of a sudden painless unilateral loss of
LIP-RMDVA composed of liposomal cDNA encoding recombinant multimodular proteins RMDVA comprising disintegrin/cysteine rich disulfide bond 2RGD, C-terminal domain, metalloprotease-domain, and dimeric disintegrin/MLD-VGD domain eradicated CRC
Authors: J. Giannios
Journal: Gut (2011)

<h3>Introduction</h3> We investigate if venom proteome of vipera ammodytes can induce apoptosis in CRC. <h3>Methods</h3> We developed a large scale expression system with CRC cell line which we modified genetically by cloning. We expressed cDNA encoding multimodular disintegrin (rMDVA) comprising 3 domains from the venom of vipera ammodytes. The cDNA of rMDVA was cloned into the plasmid vector pcDNAIII, which was transferred into CRC. The multimodular peptide rMDVA was encapsulated in the hydrophilic phase of liposomes termed as LIP-rMDVA. The <i>in vivo</i> studies with human metastatic CRC were performed in an orthotopic xenograft-model. <h3>Results</h3> The venom proteome contained 140 proteins. We isolated the multimodular disintegrin displaying cysteine rich disulfide bond 2RGD and C-terminal motif (ammodystatin), the dimeric MLD/VGD motif (VADD), and metalloprotease-domain (ammodylysin). Ammodystatin with the 2 (ARG-GLY-ASP) RGD motifs interacts with integrins avb5, a5b1 inhibiting invasion and angiogenesis/vasculogenesis. It also blocked the bFGF-induced avb3 integrin and avb5 downregulating VEGF, and Ras. It also disrupts the actin cytoskeleton inducing G1 DNA replicative phase arrest, and blocks endothelial cell (EC) secretion of MMP-2, MMP-9 and urokinase-type plasminogen activator with its receptor inhibiting proteolysis and dissolution of ECM blocking invasion. Ammodystatin and ammodylysin lead to type I PCD/apoptosis of tumour cells in masses up to 2 mm and EC. Beyond that size, ammodystatin inhibits the development of the required vascular network according to HUVEC, MVD and IHC. VADD causes burring and blocked adhesion of a4b1 integrin to VCAM1. LDH, BrdU and MTT exhibited inhibition of tumour and EC proliferation. TEM exhibited apoptotic signs of irreversible D2 stage in tumour and ECs. <h3>Conclusion</h3> Novel liposomal formulation LIP-rMDVA is an effective angiostatic and cytostatic agent against metastatic CRC inducing apoptosis with minimum systemic toxicity.
Can the NHS cut costs without substantially damaging the quality of health care? Yes
Authors: R. Rosen
Journal: BMJ (2010)

Rebecca Rosen and Paul Corrigan (doi: 10.1136/bmj.c1999) think that the NHS cost cutting that will occur over the next few years does not inevitably mean that the quality of care it provides will suffer. John Appleby (doi: 10.1136/bmj.c1959) and James Owen Drife (doi: 10.1136/bmj.c1966) are not so sure
Role of Autoantibodies in the Pathogenesis and Association of Endocrine Autoimmune Disorders*
Authors: M. SALVI, H. FUKAZAWA, N. BERNARD, Y. HIROMATSU, J. HOW, J. R. WALL
Journal: Endocrine Reviews (1988)

This review has focused on the nature and significance of aAB detected in the serum of patients with EAD. Although many antibodies are characteristically detected in the serum of patients with such disorders, only a few are of known pathogenic significance. Antibodies that react with soluble cytoplasmic antigens are not expected to be harmful. On the other hand, membrane or cell surface-directed antibodies are likely to be damaging, either by lysis of the cell membrane, or by reaction with hormone or other surface receptors. Clinically, measurement of aAB has important diagnostic and management value. Moreover, detection of certain antibodies before the onset of disease raises hope that the corresponding disorders may be preventable, e.g. by specific immunosuppression of those subjects, or patients, with positive tests. The possible role of aAB in the association of organ-specific AID by cross-reacting with shared epitopes in various tissues has been highlighted by the recent finding, from the authors' laboratory, of antibodies reactive with a 64-kDa membrane protein found in several tissues, including thyroid, eye muscle, and pancreas, which are frequent sites for autoimmune inflammation. Study of such antibodies and the molecular characterization of the corresponding antigens in the various involved tissues should provide information concerning the role of cross-reactivity in autoimmunity as well as leading to the development of specific immunotherapeutic agents.
High-frequency Ultrasound Imaging and Spectral Analysis in Traumatic Hyphema
Authors: Norma Allemann, Ronald H. Silverman, Dan Z. Reinstein, D. Jackson Coleman
Journal: Ophthalmology (1993)

Purpose: High-frequency (50-MHz) ultrasound allows high-resolution imaging of anterior ocular structures. Spectrum analysis of acoustic backscatter is sensitive to the concentration, size, and density of tissue in homogeneities. The authors sought to determine whether acoustic imaging and spectrum analysis of hyphema would allow them to distinguish organized from fluid hyphema and recent from old hemorrhage in the eye. Methods: Trauma-induced hyphemas were followed by slit-lamp photography and high-frequency ultrasonography in six New Zealand white rabbits. The blood collections were analyzed using the normalized power spectra of the digitized radio frequency ultrasound data and compared with in vitro references. Results: The 50-MHz acoustic images permitted differentiation between fluid (diffuse) and clotted (organized) blood. Spectrum analysis allowed quantitative characterization of the degree of blood organization. Significant changes were observed in spectral properties during the time course of absorption both for initial and after-rebleeding hemorrhages. The characteristics of a human postsurgical hyphema also were examined and found to be similar to those seen in the experimental model. Conclusion: Spectrum analysis of high-frequency ultrasound data was able to distinguish organized from recent hemorrhage, which is clinically helpful for planning hyphema therapy. Purpose: High-frequency (50-MHz) ultrasound allows high-resolution imaging of anterior ocular structures. Spectrum analysis of acoustic backscatter is sensitive to the concentration, size, and density of tissue in homogeneities. The authors sought to determine whether acoustic imaging and spectrum analysis of hyphema would allow them to distinguish organized from fluid hyphema and recent from old hemorrhage in the eye. Methods: Trauma-induced hyphemas were followed by slit-lamp photography and high-frequency ultrasonography in six New Zealand white rabbits. The blood collections were analyzed using the normalized power spectra of the digitized radio frequency ultrasound data and compared with in vitro references. Results: The 50-MHz acoustic images permitted differentiation between fluid (diffuse) and clotted (organized) blood. Spectrum analysis allowed quantitative characterization of the degree of blood organization. Significant changes were observed in spectral properties during the time course of absorption both for initial and after-rebleeding hemorrhages. The characteristics of a human postsurgical hyphema also were examined and found to be similar to those seen in the experimental model. Conclusion: Spectrum analysis of high-frequency ultrasound data was able to distinguish organized from recent hemorrhage, which is clinically helpful for planning hyphema therapy.
Immunochemical and molecular characterization of anti-RNA polymerase I autoantibodies produced by tight skin mouse.
Authors: S Shibata, T Muryoi, Y Saitoh, T D Brumeanu, C A Bona, K N Kasturi
Journal: Journal of Clinical Investigation (1993)

Autoantibodies against nuclear proteins like RNA polymerase I (RNA pol I) are produced in a number of rheumatic autoimmune diseases. Production of antibodies specific for the 190-kD subunit of RNA pol I appears to be characteristic in the patients with systemic sclerosis. Previous investigations have shown that the tight skin (TSK) mouse is an experimental model for systemic sclerosis. In the present study we show that the TSK mice produce high titers of anti-RNA pol I antibodies, both of IgM and IgG classes. To characterize the immunochemical properties of these antibodies we obtained a large panel of hybridomas from these mice. Analysis of these hybridomas revealed that clonal frequency of autoreactive B cells specific for RNA pol I are higher in the TSK mice that in the controls. mAbs obtained from the TSK mice were specific for the 190-kD subunit and cross-reacted with Escherichia coli and phage T7 RNA polymerases (155-, 150-, and 107-kD polypeptides). We have also demonstrated that these antibodies bind better to the phosphorylated enzymes. The anti-RNA pol I mAbs were divided into three groups in terms of their functional property. The first group of antibodies increased the catalytic activity of the enzyme whereas the antibodies of the second group inhibited the enzymatic activity. Competitive inhibition RIAs showed that these two groups of antibodies bound to distinct epitopes. The third group of antibodies was neutral and had no activity on the enzyme function. These results suggest that TSK mouse anti-RNA pol I antibodies recognize three or more conserved epitopes. To understand the molecular basis of the generation of such autoreactive antibodies we analyzed their V gene repertoire. Northern analysis of RNAs of 14 TSK hybridomas showed that the VH genes encoding these antibodies were mainly from VH J558 family. It is possible that these genes were derived from a single germline gene or from a set of related genes of a single subgroup.
The Early Diagnosis of Extrauterine Pregnancy
Authors: J. W. Taylor
Journal: BMJ (1890)

The domestic dog’s olfactory sense is widely recognized as being highly sensitive with a diverse function, however, little is known about the structure of their olfactory system. This study examined a cohort of mixed sex mesaticephalic canines and used Diffusion MRI (DTI), to map connections from the olfactory bulb to other cortical regions of the brain. The results were validated using the Klingler dissection method. An extensive pathway composed of five white matter tracts connecting to the occipital lobe, cortical spinal tract, limbic system, piriform lobe and entorhinal pathway was identified. This is the first documentation of a direct connection between the olfactory bulb and occipital lobe in any species and is a step towards further understanding how the dog integrates olfactory stimuli in their cognitive function. <b>Significance Statement</b> The highly sensitive olfactory system of the domestic dog is largely unexplored. We applied diffusion tractography and dissection techniques to evaluate the white matter connections associated with the olfactory system in a large cohort of dogs. We discovered an extensive white matter network extending from the olfactory bulb to form novel connections directly to other cortices of the brain. This is the first documentation of these novel olfactory connections and provides new insight into how the dog integrates olfactory stimuli in their cognitive functioning.
Book Review Thomas Phaer and The Boke of Chyldren (1544) (Medieval &amp; Renaissance Text &amp; Studies. Vol. 201). By Rick Bowers. 100 pp. Tempe, Ariz. Arizona Center for Medieval and Renaissance Studies, 1999. $22. 0-86698-243-4
Authors: Ralph J. Wedgwood
Journal: New England Journal of Medicine (2000)
Identification of a DNA Segment Exhibiting Rearrangement Modifying Effects upon Transgenic δ-deleting Elements
Authors: Karen M. Janowski, Stephanie Ledbetter, Matthew S. Mayo, Richard D. Hockett
Journal: The Journal of Experimental Medicine (1997)

Control of the rearrangement and expression of the T cell receptor α and δ chains is critical for determining T cell type. The process of δ deletion is a candidate mechanism for maintaining separation of the α and δ loci. Mice harboring a transgenic reporter δ deletion construct show α/β T cell lineage–specific use of the transgenic elements. A 48-basepair segment of DNA, termed HPS1A, when deleted from this reporter construct, loses tight lineage-specific rearrangement control of transgenic elements, with abundant rearrangements of transgenic δ-deleting elements now in γ/δ T cells. Furthermore, HPS1A augments recombination frequency of extrachromosomal substrates in an in vitro recombination assay. DNA binding proteins recognizing HPS1A have been identified and are restricted to early B and T cells, during the time of active rearrangement of endogenous TCR and immunoglobulin loci. These data are consistent with δ deletion playing an important role in maintaining separate TCR α and δ loci.
Change in Tumor Size by RECIST Correlates Linearly With Overall Survival in Phase I Oncology Studies
Authors: Rajul K. Jain, J. Jack Lee, Chaan Ng, David Hong, Jing Gong, Aung Naing, Jennifer Wheler, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

Purpose RECIST is used to quantify tumor changes during exposure to anticancer agents. Responses are categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Clinical trials dictate a patient's management options based on the category into which his or her response falls. However, the association between response and survival is not well studied in the early trial setting. Patients and Methods To study the correlation between response as quantified by RECIST and overall survival (OS, the gold-standard survival outcome), we analyzed 570 participants of 24 phase I trials conducted between October 2004 and May 2009, of whom 468 had quantifiable changes in tumor size. Analyses of Kaplan-Meier estimates of OS by response and null Martingale residuals of Cox models were the primary outcome measures. All analyses are landmark analyses. Results Kaplan-Meier analyses revealed strong associations between change in tumor size by RECIST and survival (P = 4.5 × 10 −6 to &lt; 1 × 10 −8 ). The relationship was found to be near-linear (R 2 = 0.75 to 0.92) and confirmed by the residual analyses. No clear inflection points were found to exist in the relationship between tumor size changes and survival. Conclusion RECIST quantification of response correlates with survival, validating RECIST's use in phase I trials. However, the lack of apparent boundary values in the relationship between change in tumor size and OS demonstrates the arbitrary nature of the CR/PR/SD/PD categories and questions emphasis placed on this categorization scheme. Describing tumor responses as a continuous variable may be more informative than reporting categoric responses when evaluating novel anticancer therapies.
Pioneer Inoculators on Cape Cod
Authors: Fred B. Rogers
Journal: New England Journal of Medicine (1964)

NEAR the end of the eighteenth century, in the Cape Cod town of Falmouth, two physicians, Francis Wicks and Hugh George Donaldson, made noteworthy contributions toward erasing smallpox from Massachusetts. These men instituted the practice of variolation at inoculation hospitals that they established at Falmouth Heights and Wood's Hole; they later promoted vaccination after its introduction by Benjamin Waterhouse of Cambridge in 1800. The obscurity of information concerning the lives of these remarkable doctor citizens and their roles in the struggle against a dreaded scourge warrants this brief account.Smallpox was so common in the eighteenth century that only the . . .