tbuckley/cabot-search huggingface dataset:
An Address on the Necessity for Education in Radiology and Electro-therapeutics: Delivered to the Electro-therapeutical Section of the Royal Society of Medicine
Authors: G. H. Orton
Journal: BMJ (1917)

IAIWOLOGY. [DEC.29, i9i7 performance of a suprapubic cystotoiny.I lhave advised operation, and I lhope shlortly to help my colleague, under wlhose care the inan is, to perform laiiminectoiny to be followred by excision of the damaged area of the cord and transplantation of one or lore sections of a rabbit's cord into tlle gap, in or'der to try to secure condduction of impressions between the upper and lower sedments of the man's spinal cord.Tlhere are, I feel suire, many similar cases of invalided soldiers in various institutions throughout the country wlho wvould doubtless be willing to undergo operation even if it gives the barest possibility of success.
Spectrum of Phosphatidylinositol 3-Kinase Pathway Gene Alterations in Bladder Cancer
Authors: Fiona M. Platt, Carolyn D. Hurst, Claire F. Taylor, Walter M. Gregory, Patricia Harnden, Margaret A. Knowles
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The phosphatidylinositol 3-kinase (PI3K) pathway can be activated by alterations affecting several pathway components. For rational application of targeted therapies, detailed understanding of tumor biology and approaches to predict efficacy in individual tumors are required. Our aim was to assess the frequency and distribution of pathway alterations in bladder cancer. Experimental Design: We examined the pathway components (PIK3CA, PTEN, TSC1, RHEB, and LKB1) and putative upstream regulators (FGFR3 and RAS genes) for mutation, allelic loss, copy number alteration, and expression in bladder tumors and cell lines. Results: No mutations were found in RHEB and only a single mutation in LKB1. PIK3CA mutations were detected in 25% of tumors and 26% of cell lines with a significant excess of helical domain mutations (E542K and E545K). There was over-representation but not amplification of the gene. Loss of heterozygosity of the PTEN region and homozygous deletion were found in 12% and 1.4% of tumors, and reduced expression in 49%. Forty-six percent of cell lines showed alterations that implicated PTEN. Sixteen percent of tumors and 11% of cell lines showed TSC1 mutation, and 9q loss of heterozygosity was common (57%). Pathway alterations were independently distributed, suggesting that the mutation of two pathway members may have additive or synergistic effects through noncanonical functions. Conclusions: PI3K pathway alterations are common in bladder cancer. The lack of redundancy of alterations suggests that single-agent PI3K-targeted therapy may not be successful in these cancers. This study provides a well-characterized series of cell lines for use in preclinical studies of targeted agents. (Clin Cancer Res 2009;15(19):6008–17)
US residents hours must be shorter to protect patients
Authors: J. Hopkins Tanne
Journal: BMJ (2002)

Tired resident hospital doctors who work up to 120 hours a week are as impaired as if they were drunk drivers and are a danger to patients and themselves, says an article in the New England Journal of Medicine .

The research, by Drs David Gaba and Steven Howard of the Patient Safety Center of Inquiry at the Veterans Affairs Palo Alto Health Care System in California, is supported by a commentary that explores ways to make up for the shortened hours in residency programmes that will start in July 2003 ( New England Journal of …
Metformin in therapy naive patients with polycystic ovary syndrome
Authors: S. Palomba, A. Falbo
Journal: Human Reproduction Update (2008)

Metformin in therapy naı ¨ve patients with polycystic ovary syndrome Sir, We have read with great interest the paper by Moll et al. (2007) recently published on Human Reproduction Update.The aim of this systematic review was to assess the efficacy of metformin administration in the total spectrum of treatment possibilities for polycystic ovary syndrome (PCOS) patients in terms of fertility improvement, and having as primary end-point the live-birth rate.The authors (Moll et al., 2007) concluded that clomiphene citrate (CC) is still the first choice therapy for infertile women with PCOS.To draw this conclusion, the authors evaluated eight randomized controlled trials (El-Biely and Habba, 2001;
Enzyme‐linked immunosorbent assay for detection of antibodies to the unmodified beta‐lactam ring
Authors: G. F. Klein, U. Stanzl, P. O. Fritsch, J. M. Varga
Journal: Allergy (1993)

Dose‐ and pH‐ dependent carbodiimide‐mediated coupling of Penicillin‐G to polystyrene microtiter‐plates that leaves the beta‐lactam ring unchanged is described. A new ELISA method was developed using Penicillin‐G coated plates. The binding of 3 different monoclonal antibodies as well as human IgG antibodies of the IgG 1 and IgG 3 subclasses is demonstrated, whereas IgG 2 , IgG 4 and IgE antibodies did not bind. Thus, covalently coupled Penicillin‐G can be used to study the immune‐response to the unchanged β‐lactam ring in patients receiving penicillin therapy. The new method is complementary to hitherto described techniques, which generally only allow detection of antibodies binding to penicilloyl‐groups.
Glycemic Control and Neuropsychologic Function during Hypoglycemia in Patients with Insulin-Dependent Diabetes Mellitus
Authors: Barbara Widom
Journal: Annals of Internal Medicine (1990)

Study Objective: To evaluate counterregulatory hormone secretion and neuropsychologic function during hypoglycemia in two groups of patients with insulin-dependent diabetes mellitus: those with good and those with poor glycemic control. Design: Cross-sectional physiologic and neuropsychologic evaluation. Setting: Clinical research unit of a referral-based diabetes clinic. Patients: Eight patients with well controlled diabetes (glycosylated hemoglobin [HgbA1], 8.0% ± 0.2%), nine patients with poorly controlled diabetes (HgbA1, 11.8% ± 0.4%), and ten healthy persons. Interventions: The insulin clamp technique was used to produce a stepwise decline in plasma glucose from 5.0 to 2.2 mmol/L over 3 hours. Tests of attention, memory, visual-spatial skills, visual-motor skills, and global cognition; a symptom survey; and counterregulatory hormone measurements were done at glucose decrements of 0.6 mmol/L. Measurements and Main Results: Patients with well controlled diabetes did not differ statistically from those with poorly controlled diabetes regarding the median glucose threshold for dysfunction in visual-spatial skills, visual-motor skills, or global cognition. In contrast, glycemic thresholds for an increase in adrenergic symptoms and release of epinephrine, norepinephrine, cortisol, and growth hormone were lower in patients with well controlled diabetes than in those with poorly controlled diabetes (P < 0.05 to 0.005). Conclusions: Despite alterations in the glucose levels at which adrenergic symptoms of hypoglycemia occur and counterregulation begins, there is no statistically detectable change in the glucose threshold at which cognitive deterioration occurs in diabetic persons with strict glycemic control. This dissociation of neuropsychologic function and counterregulatory hormone secretion suggests that diabetic patients with good glycemic control are at increased risk for developing cognitive impairment before the onset of adrenergic symptoms during hypoglycemia.
Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia
Authors: Robin R Vann, Carol L Karp
Journal: Ophthalmology (1999)

ObjectiveTo evaluate the role of combined subconjunctival and topical interferon alfa-2b (IFNα2b) in the treatment of conjunctival and corneal intraepithelial neoplasia (CIN).DesignNoncomparative case series.ParticipantsSix patients with histologically proven CIN or recurrences of histologically proven CIN were studied prospectively.InterventionPatients were given a single subconjunctival/perilesional injection of recombinant IFNα2b (Schering Plough, Kenilworth, NJ) 3 million international units (IU) in 0.5 ml and then started receiving topical interferon drops (1 million U/ml) four times a day. Patients were followed weekly until complete resolution of the tumor. After 1 week, patients with minimal response while receiving topical therapy were retreated with perilesional injections three times a week until resolution. Patients received topical interferon drops for a month after clinical resolution of the lesion.Main outcome measuresPatients were followed clinically and photographically for evidence of tumor resolution.ResultsThe authors present a series of six patients who were treated successfully with a combination of subconjunctival/perilesional and topical IFNα2b. All six patients had complete clinical resolution of the CIN lesion within 6 weeks of initiation of treatment. In the time of follow-up (average, 7.2 months; range, 2–11 months), there have been no treatment failures or recurrences.ConclusionIFNα2b may be a viable medical alternative to surgical excision for primary or recurrent CIN.
FACTORS IN THE SUCCESS OF A PUBLIC MENTAL HEALTH PROGRAM
Authors: MAURICE E. LINDEN, KENNETH E. APPEL, JOHN E. DAVIS, ROBERT A. MATTHEWS
Journal: American Journal of Psychiatry (1959)

The following factors have likely been paramount in the operational success of the Philadelphia regional mental health program: 1. Excellent timing of the program coinciding with the peak development of interest and goodwill on the part of an informed public and dedicated governments; 2. Intensified and continuous communication among popular representatives, professional staffs and political bodies; 3. Creation of two important cooperating governmental mental health units–the Philadelphia division of mental health within the Department of Public Health and the State of Pennsylvania's office of the Commissioner of Mental Health within the Department of Welfare (now Public Welfare); 4. Establishment and continuation of the Conjoint Mental Health Board; 5. Creation and intensification of the programs of the reception center; 6. Maintenance of continuous and perpetual statistical control over all aspects of the program; 7. Constant application and initiation of various researches and surveys including program self-reevaluation; 8. Attention to all of the community's mental health needs in a comprehensive program; 9. Utilization of operational elements proved effective in other localities (profiting vicariously from others' mistakes); 10. Involvement of the lay and professional communities wherever possible; 11. Encouragement of leadership at the lowest possible echelon of responsibility in the overall administrative pattern. 12. Giving credit where due in public and press relations.
Gastro-oesophageal refluxate: does it always have to be acid to be noxious?
Authors: J S DE CAESTECKER
Journal: Gut (1997)

See article on page297 

No-one doubts that acid and pepsin are the major factors responsible for symptoms and oesophageal mucosal damage which comprise the clinical spectrum of gastro-oesophageal reflux disease. Clinical and in vitro studies overwhelmingly support this view. However, the relations between both symptoms and increasing oesophageal injury on the one hand and increasing duration of acid reflux (assessed by oesophageal pH monitoring) on the other have not always been shown to be as close as one might expect.1 Symptom occurrence reflects changes in oesophageal mucosal sensitivity which do not always vary as expected with increases in oesophageal acid exposure.2 The production of mucosal damage is influenced by the ability to clear or neutralise the refluxate (primary and secondary peristalsis, saliva and possibly oesophageal bicarbonate production). Another factor which has been studied in this latter regard has been the role of refluxed duodenal contents, in particular bile acids and trypsin. The impetus for study came from clinical observations of both symptoms and oesophagitis in patients with achlorhydria (for example, pernicious anaemia) and following total gastrectomy.3 Animal models using surgical diversion of bile or duodenal contents into the oesophagus have clearly shown their ability to cause oesophagitis. During oesophageal perfusion experiments, …
Time course of changes in adenosine 5′-monophosphate airway responsiveness with inhaled heparin in allergic asthma☆, ☆☆, ★
Authors: R POLOSA, S MAGRI, C VANCHERI, F ARMATO, G SANTONOCITO, A MISTRETTA, N CRIMI
Journal: Journal of Allergy and Clinical Immunology (1997)
Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts
Authors: Sonya C. Tate, Shufen Cai, Rose T. Ajamie, Teresa Burke, Richard P. Beckmann, Edward M. Chan, Alfonso De Dios, Graham N. Wishart, Lawrence M. Gelbert, Damien M. Cronier
Journal: Clinical Cancer Research (2014)

Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors.LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts.The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations.Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
ANTIBODIES TO HUMAN T CELL LEUKAEMIA VIRUS-ASSOCIATED MEMBRANE ANTIGENS IN HAEMOPHILIACS: EVIDENCE FOR INFECTION BEFORE 1980
Authors: BruceL Evatt, DonaldP Francis, MaryF Mclane, TunH Lee, Cirilo Cabradilla, SidneyF Stein, DaleN Lawrence, J.Steven Mcdougal, ThomasJ Spira, JamesI Mullens, Myron Essex
Journal: The Lancet (1983)
Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice
Authors: Tatiana Takiishi, Hannelie Korf, Tom L. Van Belle, Sofie Robert, Fabio A. Grieco, Silvia Caluwaerts, Letizia Galleri, Isabella Spagnuolo, Lothar Steidler, Karolien Van Huynegem, Pieter Demetter, Clive Wasserfall, Mark A. Atkinson, Francesco Dotta, Pieter Rottiers, Conny Gysemans, Chantal Mathieu
Journal: Journal of Clinical Investigation (2012)

Current interventions for arresting autoimmune diabetes have yet to strike the balance between sufficient efficacy, minimal side effects, and lack of generalized immunosuppression. Introduction of antigen via the gut represents an appealing method for induction of antigen-specific tolerance. Here, we developed a strategy for tolerance restoration using mucosal delivery in mice of biologically contained Lactococcus lactis genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10. We show that combination therapy with low-dose systemic anti-CD3 stably reverted diabetes in NOD mice and increased frequencies of local Tregs, which not only accumulated in the pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, which argues against excessive immunosuppression. Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigen-specific long-term tolerance, allowing reversal of established autoimmune diabetes. Therefore, we believe this method could be an effective treatment strategy for type 1 diabetes in humans.
Cellular Mechanisms for the Repression of Apoptosis
Authors: Carl D. Bortner, John A. Cidlowski
Journal: The Annual Review of Pharmacology and Toxicology (2002)

Apoptosis, also known as programmed cell death, is a ubiquitous mode of cell death known to play an important role during embryogenesis, development, and adult cellular homeostasis. Disruption of this normal physiological cell death process can result in either excessive or insufficient apoptosis, which can lead to various disease states and pathology. Since most cells contain the machinery that brings about apoptosis, it is clear that living cells must contain inherent repressive mechanisms to keep the death process in check. In this review, we examine several modes of repression of apoptosis that exist in cells.
Genomic Signature of Selective Sweeps Illuminates Adaptation of<i>Medicago truncatula</i>to Root-Associated Microorganisms
Authors: Maxime Bonhomme, Simon Boitard, Hélène San Clemente, Bernard Dumas, Nevin Young, Christophe Jacquet
Journal: Molecular Biology and Evolution (2015)

Medicago truncatula is a model legume species used to investigate plant–microorganism interactions, notably root symbioses. Massive population genomic and transcriptomic data now available for this species open the way for a comprehensive investigation of genomic variations associated with adaptation of M. truncatula to its environment. Here we performed a fine-scale genome scan of selective sweep signatures in M. truncatula using more than 15 million single nucleotide polymorphisms identified on 283 accessions from two populations (Circum and Far West), and exploited annotation and published transcriptomic data to identify biological processes associated with molecular adaptation. We identified 58 swept genomic regions with a 15 kb average length and comprising 3.3 gene models on average. The unimodal sweep state probability distribution in these regions enabled us to focus on the best single candidate gene per region. We detected two unambiguous species-wide selective sweeps, one of which appears to underlie morphological adaptation. Population genomic analyses of the remaining 56 sweep signatures indicate that sweeps identified in the Far West population are less population-specific and probably more ancient than those identified in the Circum population. Functional annotation revealed a predominance of immunity-related adaptations in the Circum population. Transcriptomic data from accessions of the Far West population allowed inference of four clusters of coregulated genes putatively involved in the adaptive control of symbiotic carbon flow and nodule senescence, as well as in other root adaptations upon infection with soil microorganisms. We demonstrate that molecular adaptations in M. truncatula were primarily triggered by selective pressures from root-associated microorganisms.
Interim Guidelines for Management of Abnormal Cervical Cytology
Authors: Robert J. Kurman, Donald E. Henson, Arthur L. Herbst, Kenneth L. Noller, Mark H. Schiffman, Thomas Bonfiglio, Henry Buck, Christopher Crum, John P. Curtin, Mitchell Greenberg, Kenneth Hatch, Donald Earl Henson, A. Bennett Jenson, Peter Johnson, Howard Jones, Harold Kaminetsky, Luella Klein, Leopold Koss, Burton Krumholz, Nancy Lee, Ronald Luff, Jeanne Mandelblatt, Richard Reid, Ralph Richart, Thomas Sedlacek, Charles Sneiderman, Diane Solomon, Mark Stoler, Floyd Taub, Edward Trimble, Ernest Tucker, Leo B. Twiggs, Edward Wilkinson, Barbara Atkinson, Harvey E. Averette, William Creasman, Sandra Fryhofer, Julie Noy, Mary Nielsen, Kenneth Noller, Robert Park, Douglas Westhoff
Journal: JAMA (1994)

THE INCIDENCE of and mortality from cervical cancer in the United States have decreased dramatically over the past 40 years, in part because of early diagnosis and treatment of cervical cancer precursor lesions. The success of cervical cytological screening has served as a model for early diagnosis of other types of cancer. Although numerous studies have shown that lack of cytological screening is a major risk factor for the development of invasive cervical cancer,<sup>1-3</sup>it is important to emphasize that none of the screening, diagnostic, or therapeutic techniques used in medicine are perfect.<i>Accordingly, a few women will develop cervical cancer despite adherence to accepted screening protocols</i>. In addition, problems inherent with sampling, interpretation, and effective clinical follow-up preclude total prevention of cervical cancer. In recent years it has become evident that the cost and morbidity associated with the detection and treatment of low-grade cervical lesions have escalated, probably
CINEMICROPHOTOGRAPHIC OBSERVATIONS ON GRANULE LYSIS IN POLYMORPHONUCLEAR LEUCOCYTES DURING PHAGOCYTOSIS
Authors: James G. Hirsch
Journal: The Journal of Experimental Medicine (1962)

Phagocytosis of yeast cell walls and of Bacillus megaterium by human, rabbit, and chicken polymorphonuclear leucocytes has been observed by phase contrast microscopy and recorded on motion picture film. In suitably thin preparations intracellular events could be visualized well. Lysis of cytoplasmic granules began early in the course of the ingestion process, rupture occurring only in granules adjacent to the microorganism being engulfed. Formation of a visible vacuole about the ingested particle frequently followed degranulation. Chicken polymorphonuclear leucocytes, with their large phase-dense granules, were particularly suitable subjects for observations on detailed morphologic aspects of granule lysis. Rupture took place rapidly (0.1 second or less); in place of the granule there appeared a clear zone, often with a small phase-dense round structure in its center. Also accompanying granule lysis was an increase in phase density of the adjacent surface of the microorganism. Over the course of the following few seconds the darkening on the organism faded, the dense small body disappeared from view, and the clear zone contracted towards the engulfed particle. The observations are discussed in relation to the hypothesis that fusion takes place between the granule membrane and the invaginated cell membrane overlying the ingested particle, with discharge of granule contents directly into the phagocytic vacuole.
The Interleukin-1 receptor antagonist is a direct target gene of PPARα in liver
Authors: Rinke Stienstra, Stéphane Mandard, Nguan Soon Tan, Walter Wahli, Christian Trautwein, Terrilyn A. Richardson, Elgin Lichtenauer-Kaligis, Sander Kersten, Michael Müller
Journal: Journal of Hepatology (2007)