tbuckley/cabot-search huggingface dataset:
Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome.
Authors: A Dunaif, M Graf
Journal: Journal of Clinical Investigation (1989)

We have investigated the hypothesis that hyperinsulinemia may cause the polycystic ovary syndrome (PCO) by directly stimulating gonadal steroidogenesis and/or gonadotropin secretion. 10 insulin-resistant women with PCO and 5 age- and weight-matched ovulatory normal women had pulsatile gonadotropin release, gonadotrope sensitivity to gonadotropin-releasing hormone, and sex hormone levels studied on two consecutive study days, basally and during the infusion of insulin (mean +/- SEM steady state insulin levels, 1,254 +/- 63 microU/ml PCO vs. 907 +/- 92 microU/ml normal, P less than or equal to 0.01). Insulin acutely increased mean delta (6 h minus prestudy) levels of androstenedione (A) (P less than or equal to 0.001) and estradiol (E2) (P less than or equal to 0.05) and decreased mean plasma pool (0-6 h) levels of testosterone (T) (P less than 0.05), nonsex hormone binding globulin-bound T (P less than 0.05), and dihydrotestosterone (P less than or equal to 0.01) in the PCO women. Insulin also decreased mean plasma 6 h A to estrone (E1) ratios and increased 6 h E1 levels (both P less than or equal to 0.05) in the PCO women. There were significant sequence effects (insulin + day) in the PCO women on T/E2 ratios, indicating a carryover action of insulin. Insulin had no effects on gonadotropin release in the PCO women. In the normal women, the only significant change was an insulin or study day effect that increased mean 6 h E2 levels (P less than or equal to 0.01). There were significant spontaneous decreases in mean luteinizing hormone (p less than 0.05) and follicle-stimulating hormone levels (p less than or equal to 0.01) in the PCO but not the normal women on the second day of study. This study indicates that insulin can directly alter peripheral sex hormone levels independent of changes in gonadotropin release in insulin-resistent PCO women. Insulin decreased the levels of potent androgens in PCO women and did not increase androgen levels in normal women, arguing against a simple, direct causal relationship between hyperinsulinemia and hyperandrogenism in PCO.
Therapeutic potential of interleukin 1 inhibitors in the treatment of alcoholic liver disease
Authors: Stephanie Mathews, Bin Gao
Journal: Hepatology (2013)

Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1β. IL-1β, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1β maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1β activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1β signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1β was due to upregulation of Casp-1 activity and inflammasome activation. The pathogenic role of IL-1 signaling in ALD was attributable to the activation of the inflammasome in BM-derived Kupffer cells. Importantly, in vivo intervention with a recombinant IL-1Ra blocked IL-1 signaling and markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Furthermore, physiological doses of IL-1β induced steatosis, increased the inflammatory and prosteatotic chemokine MCP-1 in hepatocytes, and augmented TLR4-dependent upregulation of inflammatory signaling in macrophages. In conclusion, we demonstrated that Casp-1-dependent upregulation of IL-1β and signaling mediated by IL-1R1 are crucial in ALD pathogenesis. Our findings suggest a potential role of IL-1R1 inhibition in the treatment of ALD.
Walter and Israel General Pathology
Authors: Ashton B. Morrison
Journal: JAMA (1996)

This seventh edition of<i>Walter and Israel General Pathology</i>will serve as a first reference for the doctor who needs to update understanding of a particular disease mechanism as seen from the laboratory. As the authors point out in their preface, pathology is coming more and more to be regarded as laboratory medicine. Accordingly, general pathology, which deals with the basic mechanisms of disease, needs wide coverage and explanation of its laboratory background. This text amply provides this for the inquiring doctor and student. All aspects of general pathology are covered thoroughly in this text. Thus, the material on the acute inflammatory reaction incorporates all that the beginning student should be aware of. Moreover, those who need more detailed study of laboratory aspects of the topic are directed in a selected bibliography of general reading to the more comprehensive monographs. Thus, the reader is referred to the thorough review of
Elevation of Asymmetrical Dimethylarginine (ADMA) and Coronary Artery Disease in Men with Erectile Dysfunction
Authors: Renke Maas, Sven Wenske, Marcus Zabel, Rodolfo Ventura, Edzard Schwedhelm, Anna Steenpaß, Hanno Klemm, Joachim Noldus, Rainer H. Böger
Journal: European Urology (2005)
A CLASSIFICATION OF CHOREA IN RELATION TO ITS CAUSES
Authors: C. J. Macalister
Journal: BMJ (1924)

OVER a period of many years a large number of cases of chorea lhave passed through my hands at the Royal Liveipool Hospital for Cllildren at Heswall, and aln oppor- tuniity lhas thus been afforded for investigating the causes of tlhe disorder.Although chorea is classed as a disease and is described as such in the textbooks, it really is a con- ditioni of a nieuro-muscular inco-ordination which may result fromii very different causes.It is a symptom rather than a disease, and I have come to classify it with r eference to its origin, and not to mass all the cases under a single genieric title.Thus we have:
Clearance of HIV Infection in a Perinatally Infected Infant
Authors: Yvonne J. Bryson, Shen Pang, Lian S. Wei, Ruth Dickover, Amadou Diagne, Irvin S.Y. Chen
Journal: New England Journal of Medicine (1995)

We describe a child who was identified shortly after birth as infected with the human immunodeficiency virus type 1 (HIV-1), but whose infection appears to have completely cleared. Asymptomatic HIV-1 infection was diagnosed in the mother during the fourth month of pregnancy. The infant was delivered vaginally at 36 weeks, received no blood products, and was not breast-fed.HIV-1 was detected by culture of the infant's peripheral-blood mononuclear cells at 19 and 51 days of age. Plasma from the infant was also culture-positive for HIV-1 at 51 days of age by DNA polymerase chain reaction (PCR). Nucleotide-sequence analysis of HIV-1 DNA showed extremely close homology of the cultures obtained 32 days apart, and forensic markers of genetic identity for the two cultures were identical. Hence, inadvertent viral contamination or error in the collection of specimens was highly unlikely. At 12 months of age the infant was seronegative for HIV-1, and numerous subsequent cultures and tests by PCR have also been negative for HIV-1. The child is five years of age at this writing, is HIV-seronegative, and remains well, with normal growth and development and no laboratory or clinical evidence of HIV-1 infection.The infant we describe was infected perinatally with HIV-1, but the infection subsequently cleared and the infant remained without detectable HIV-1 infection five years later.
The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor
Authors: Ivana Malovic, Karen K. Sφrensen, Kjetil H. Elvevold, Geir Ivar Nedredal, Steinar Paulsen, Alexander V. Erofeev, Bård H. Smedsrφd, Peter A. G. McCourt
Journal: Hepatology (2007)

The purpose of this study was to identify the receptor responsible for endocytosis of denatured collagen from blood. The major site of clearance of this material (at least 0.5 g/day in humans) is a receptor on liver sinusoidal endothelial cells (LSECs). We have now identified an 180-kDa endocytic receptor on LSECs, peptide mass fingerprinting of which revealed it to be the mannose receptor. Challenge of mannose-receptor knockout mice and their cultured LSECs revealed significantly reduced blood clearance and a complete absence of LSEC endocytosis of denatured collagen. Organ analysis of wild-type versus knockout mice after injection of denatured collagen revealed significantly reduced liver uptake in the knockout mice. Clearance/endocytosis of ligands for other receptors in these animals was as that for wild-type mice, and denatured collagen uptake in wild-type mice was not affected by other ligands of the mannose receptor, namely mannose and mannan. Furthermore, unlike that of mannose and mannan, endocytosis of denatured collagen by the mannose receptor is calcium independent. This suggests that the binding site for denatured collagen is distinct from that for mannose/mannan. Mannose receptors on LSECs appear to have less affinity for circulating triple helical type I collagen. Conclusion: The mannose receptor is the main candidate for being the endocytic denatured collagen receptor on LSECs. (Hepatology 2007.)
Genome-wide study of methotrexate clearance replicates SLCO1B1
Authors: Laura B. Ramsey, John C. Panetta, Colton Smith, Wenjian Yang, Yiping Fan, Naomi J. Winick, Paul L. Martin, Cheng Cheng, Meenakshi Devidas, Ching-Hon Pui, William E. Evans, Stephen P. Hunger, Mignon Loh, Mary V. Relling
Journal: Blood (2012)
POEMS syndrome: Failure of newly suggested diagnostic criteria to anticipate the development of the syndrome
Authors: Ofran Yishay, Elinav Eran
Journal: American Journal of Hematology (2005)

POEMS syndrome is a unique clinical entity. Although it's a diagnosis of exclusion, it was previously described by the presence of several typical characteristics as paraproteinemia, polyneuropathy, organomegaly, endocrinopathy, and skin changes. Recently, new criteria were proposed, and the presence of two major and one minor criterion was claimed to suffice for a diagnosis. Both methods considered other important characteristics germane to the syndrome unessential for diagnosis. Retrospective evaluation of patients with lymphoproliferative disease was carried out to reveal the presence of the syndrome according to these different methods. Patients' clinical progression during follow-up will be used to validate the criteria's sensitivity and specificity. Six hundred twenty-nine consecutive files of patients with paraproteinemia who were followed-up at a tertiary medical center were reviewed. Of 12 patients who fulfilled the new criteria for diagnosis of POEMS, 3 remain stable during long-term follow-up and only 5 finally developed the full-blown syndrome. Four patients developed other diseases that accounted for their clinical findings. Patients presenting with neuronal vasculitic changes on biopsy, kappa light-chain monoclonal gammopathy, and cryoglobulinemia were unlikely to develop POEMS syndrome, even though they fulfilled the newly suggested criteria. Although they are not in the criteria, sclerotic bone lesions were found only in patients who eventually developed the full syndrome. The diagnosis of POEMS syndrome according to the newly suggested criteria should not be definitive in the presence of atypical clinical features of the syndrome.
Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Blockade Accelerates the Acute Rejection of Cardiac Allografts in CD28-deficient Mice: CTLA4 Can Function Independently of CD28
Authors: Hua Lin, Jeffrey C. Rathmell, Gary S. Gray, Craig B. Thompson, Jeffrey M. Leiden, Maria-Luisa Alegre
Journal: The Journal of Experimental Medicine (1998)

Cytotoxic T lymphocyte antigen 4 (CTLA4) appears to negatively regulate T cell activation. One mechanism by which CTLA4 might antagonize T cell function is through inhibition of CD28 signaling by competing for their shared ligands B7-1 and B7-2. In addition, CTLA4 ligation could initiate a signaling cascade that inhibits T cell activation. To address whether CTLA4 could inhibit immune responses in the absence of CD28, rejection of heart allografts was studied in CD28-deficient mice. H-2q hearts were transplanted into allogeneic wild-type or CD28-deficient mice (H-2b). Graft rejection was delayed in CD28-deficient compared with wild-type mice. Treatment of wild-type recipients with CTLA4-immunoglobulin (Ig), or with anti–B7-1 plus anti–B7-2 mAbs significantly prolonged allograft survival. In contrast, treatment of CD28-deficient mice with CTLA4-Ig, anti–B7-1 plus anti–B7-2 mAbs, or a blocking anti-CTLA4 mAb induced acceleration of allograft rejection. This increased rate of graft rejection was associated with more severe mononuclear cell infiltration and enhanced levels of IFN-γ and IL-6 transcripts in donor hearts of untreated wild-type and CTLA4-Ig– or anti-CTLA4 mAb–treated CD28-deficient mice. Thus, the negative regulatory role of CTLA4 extends beyond its potential ability to prevent CD28 activation through ligand competition. Even in the absence of CD28, CTLA4 plays an inhibitory role in the regulation of allograft rejection.
Maintaining the accuracy of a computer practice register: household index
Authors: F Difford, P M Hook, M Sledge
Journal: BMJ (1985)

In this practice, with a family practitioner committee list of 9726 patients, we use a computer register for recall, screening, morbidity data, audit, and repeat prescribing. The computing techniques used to achieve accuracy in maintaining the register are described. After one year of full use the register was validated by using the computer to select a random sample of 200 patients from patients' computer records that had not been updated recently. Two patients were untraceable, and in only 11 records were errors of information found, none of which was important. We think that it is feasible and valuable to have a household index.
Paternal concentrations of dioxin and sex ratio of offspring
Authors: Paolo Mocarelli, Pier Mario Gerthoux, Enrica Ferrari, Donald G Patterson, Stephanie M Kieszak, Paolo Brambilla, Nicoletta Vincoli, Stefano Signorini, Pierluigi Tramacere, Vittorio Carreri, Eric J Sampson, Wayman E Turner, Larry L Needham
Journal: The Lancet (2000)
Visualization of cardiac muscle thin filaments and measurement of their lengths by electron tomography
Authors: Thomas Burgoyne, Farina Muhamad, Pradeep K. Luther
Journal: Cardiovascular Research (2008)

AimsAn intriguing difference between vertebrate skeletal and cardiac muscles is that the lengths of the thin filaments are constant in the former but variable in the latter. The thick filaments have constant lengths in both types of muscles. The contractile behaviour of a muscle is affected by the lengths of both types of filaments as the tension generated during contraction depends on the amount of filament overlap. To understand the behaviour of cardiac muscle, it is important to know the distribution of the thin filament lengths. The previous detailed analysis by Robinson and Winegrad used serial transverse sections to determine the lengths of the thin filaments. However, the precision, set by the 100 nm section thickness, was low. Here, we have used electron tomography to produce 3D images of rat and mouse cardiac muscles in which we can actually see individual thin filaments up to the free ends and see that these free ends have variable locations. For comparison, we also measure the thin filament lengths in skeletal muscle (frog sartorius).
Importance of diastolic fractional flow reserve and dobutamine challenge in physiologic assessment of myocardial bridging
Authors: Javier Escaned, Jorge Cortés, Alex Flores, Javier Goicolea, Fernando Alfonso, Rosana Hernández, Antonio Fernández-Ortiz, Manel Sabaté, Camino Bañuelos, Carlos Macaya
Journal: Journal of the American College of Cardiology (2003)
Thyroid Surgery, with a Contribution on Intrathoracic Goitre
Authors: G. Keynes
Journal: BMJ (1950)

Your Dean has done me honour by inviting me to deliver the second lecture in memory of Thomas Percy Legg, formerly surgeon to this hospital.Legg belonged to a much earlier generation of students than I at St. Bartholomew's, and I do not remember that I ever was privileged to meet him-not even at Queen Square, though he examined there for many years.He was not a prolific writer, and I would say that he was not very well known in the outside world; but the foundation of this lecture is a testimony to the esteem in which he was held in his own hospital.He was in the truest sense one of that disappearing genus the general surgeon, and his range was wide, so that two of his main interests were subjects so diverse as cleft palate and the surgery of the thyroid gland.The former of these subjects was commemorated in the first Legg Memorial Lecture by Denis Browne in 1948.It now falls to my lot to consider the state of the thyroid surgery of his time, adding as a pendant a small contribution of my own.
Pneumonia and Bronchial Vesiculation Associated with Herpes Zoster
Authors: R. H. Andrews
Journal: BMJ (1957)

<h3>Abstract</h3> Numerous species of Lepidoptera have transparent wings, which often possess scales of altered morphology and reduced size, and the presence of membrane surface nanostructures that dramatically reduce reflection. Optical properties and anti-reflective nanostructures have been characterized for several ‘clearwing’ Lepidoptera, but the developmental basis of wing transparency is unknown. We apply confocal and electron microscopy to create a developmental time-series in the glasswing butterfly, <i>Greta oto</i>, comparing transparent and non-transparent wing regions. We find that scale precursor cell density is reduced in transparent regions, and cytoskeletal organization differs between flat scales in opaque regions, and thin, bristle-like scales in transparent regions. We also reveal that sub-wavelength nanopillars on the wing membrane are wax-based, derive from wing epithelial cells and their associated microvillar projections, and demonstrate their role in enhancing-anti-reflective properties. These findings provide insight into morphogenesis of naturally organized micro- and nanostructures and may provide bioinspiration for new anti-reflective materials.
Reversal of Central Anticholinergic Syndrome in Man by Physostigmine
Authors: Roger C. Duvoisin
Journal: JAMA (1968)

Physostigmine salicylate in doses of 1 to 2 mg administered parenterally was found to be an effective antidote to intoxication with centrally active anticholinergic agents. Confusion, agitation, hallucinations, stupor, ataxia, dysarthria, and other symptoms were promptly reversed in 26 consecutive patients in whom toxic reactions developed after receiving scopolamine, atropine, or drugs for Parkinson's disease. Physostigmine deserves a place in therapeutics as an antidote to anticholinergic intoxication.
Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for <i>In vivo</i> Efficacy under Intermittent Dosing Conditions
Authors: Murray J. Towle, Kathleen A. Salvato, Bruce F. Wels, Kimberley K. Aalfs, Wanjun Zheng, Boris M. Seletsky, Xiaojie Zhu, Bryan M. Lewis, Yoshito Kishi, Melvin J. Yu, Bruce A. Littlefield
Journal: Cancer Research (2010)

Abstract Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival. Similar results occurred in U937, Jurkat, HL-60, and HeLa cells, ruling out cell type–specific effects. Studies with other tubulin agents suggest that mitotic block reversibility is a quantifiable, compound-specific characteristic of antimitotic agents in general. Bcl-2 phosphorylation patterns parallel eribulin and ER-076349 mitotic block reversibility patterns, suggesting persistent Bcl-2 phosphorylation contributes to long-term cell-viability loss after eribulin's irreversible blockade. Drug uptake and washout/retention studies show that [3H]eribulin accumulates to lower intracellular levels than [3H]ER-076349, yet is retained longer and at higher levels. Similar findings occurred with irreversible vincristine and reversible vinblastine, pointing to persistent cellular retention as a component of irreversibility. Our results suggest that eribulin's in vivo superiority derives from its ability to induce irreversible mitotic blockade, which appears related to persistent drug retention and sustained Bcl-2 phosphorylation. More broadly, our results suggest that compound-specific reversibility characteristics of antimitotic agents contribute to interactions between cell-based pharmacodynamics and in vivo pharmacokinetics that define antitumor efficacy under intermittent dosing conditions. Cancer Res; 71(2); 496–505. ©2011 AACR.
Verapamil Prophylaxis of Migraine
Authors: Glen D. Solomon
Journal: JAMA (1983)

We undertook a double-blind, placebo-controlled study to determine the effectiveness of verapamil hydrochloride for the prophylaxis of migraine. Twelve patients were given either verapamil hydrochloride, 80 mg four times daily, or placebo in random order during two consecutive three-month periods. Migraine frequency, severity, and duration were quantified by daily logs and monthly questionnaires. Ten of the 12 patients had fewer migraines during verapamil therapy. Migraine frequency decreased from 6.7 to 3.8 migraines per patient per month, for a mean decrease of 49%. Headache unit index fell from an average of 0.61 to 0.44. We conclude that verapamil is effective in the prophylaxis of migraine and that verapamil might be considered one alternative in the development of a regimen for the prophylaxis of migraine.
Queries and Minor Notes
Authors: W. B. Welch
Journal: JAMA (1906)

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