tbuckley/cabot-search huggingface dataset:
Hepatic α1-antitrypsin mRNA content in cirrhosis with normal and abnormal protease inhibitor phenotypes
Authors: Sarah Jane Schwarzenberg, Harvey L. Sharp, Robin D. Manthei, Steven Seelig
Journal: Hepatology (1986)

We quantitated α 1 -antitrypsin mRNA in normal, α 1 -antitrypsin-deficient cirrhotic and biliary cirrhotic livers using two-dimensional electrophoretograms of [ 35 S ] methionine-labeled translational products of total hepatic RNA and RNA/DNA hybridization. α 1 -antitrypsin precursor product was identified by immunoprecipitation. The relative abundance of α 1 -antitrypsin product from normal (0.989 ± 0.197), cirrhotic (0.956 ± 0.062) and α 1 -antitrypsin deficient (0.818 ± 0.12) livers was not significantly different. Although (RNA/DNA) was decreased in the PiZZ cirrhotic livers compared to normal (0.56 ± 0.045 vs. 0.95 ± 0.225), it equaled that found in the PiM cirrhotic livers (0.56 ± 0.055). The concentration of α 1 -antitrypsin mRNA [relative abundance × (RNA/DNA)], while decreased in PiZZ compared to normal liver, is thus no different in PiZZ cirrhotics than in PiM cirrhotics. We confirmed this observation by quantitation of the α 1 -antitrypsin mRNA using an α 1 -antitrypsin genomic probe. By RNA/DNA hybridization, α 1 -antitrypsin mRNA was equal in PiM cirrhotic and PiZZ cirrhotic (38.48 ± 4.5 vs. 31.93 ± 2.1), but significantly decreased from noncirrhotic PiM liver (58.36 ± 12.7). We conclude that α 1 -antitrypsin mRNA is decreased in cirrhosis of any etiology, and this decrease appears to represent a general response of the liver to injury. Since the decreased α 1 -antitrypsin mRNA in PiM cirrhotics is associated with normal serum α 1 -antitrypsin levels, it is unlikely that the decreased α 1 -antitrypsin mRNA in PiZZ cirrhotics accounts for their decreased serum levels.
Effect of diltiazem on silent ischemic episodes,plasma bradykinin and prostaglandin metabolism
Authors: Bonpei Takase, Akira Kurita, Akimi Uehata, Toshihiko Nishioka, Toshiharu Maruyama, Hirokazu Nagayoshi, Hiroyuki Hikita, Haruo Nakamura
Journal: Journal of the American College of Cardiology (1991)
Dutch doctor convicted of murdering disabled infant
Authors: J. Goodall
Journal: BMJ (1995)

EDITOR,—Tony Sheldon reports the death at the hands of a Dutch gynaecologist of a baby with serious congenital malformations who was in great pain and had a limited life expectancy; the doctor was convicted of murder but not sentenced.1 Bringing about the death of a severely disabled infant is an attempt to wipe out a distressing problem for the attendant adults by attributing their anguish to the child and then bringing that to a quick end. This overlooks three important facts.

Firstly, the …
The new antiarrhythmic drug vernakalant: ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation
Authors: Erich Wettwer, Torsten Christ, Sebastian Endig, Nadiia Rozmaritsa, Klaus Matschke, Joseph J. Lynch, Marc Pourrier, John K. Gibson, David Fedida, Michael Knaut, Ursula Ravens
Journal: Cardiovascular Research (2013)

AimsVernakalant is a newly developed antiarrhythmic drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown.
Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury
Authors: C.-X. Sun
Journal: Journal of Clinical Investigation (2006)

Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A2BAR in vivo, ADA-deficient mice were treated with the selective A2BAR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADA-deficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely, CVT-6883-treated ADA-deficient mice showed less pulmonary inflammation, fibrosis, and alveolar airspace enlargement. A2BAR antagonism significantly reduced elevations in proinflammatory cytokines and chemokines as well as mediators of fibrosis and airway destruction. In addition, treatment with CVT-6883 attenuated pulmonary inflammation and fibrosis in wild-type mice subjected to bleomycin-induced lung injury. These findings suggest that A2BAR signaling influences pathways critical for pulmonary inflammation and injury in vivo. Thus in chronic lung diseases associated with increased adenosine, antagonism of A2BAR-mediated responses may prove to be a beneficial therapy.
The Inflammatory Cytokine Tumor Necrosis Factor-α Regulates Chemokine Receptor Expression on Ovarian Cancer Cells
Authors: Hagen Kulbe, Thorsten Hagemann, Piotr W. Szlosarek, Frances R. Balkwill, Julia L. Wilson
Journal: Cancer Research (2005)

Abstract Epithelial ovarian cancer cells express the chemokine receptor, CXCR4, which may be associated with increased survival and metastatic potential, but the regulation of this receptor is not understood. The inflammatory cytokine tumor necrosis factor-α (TNF-α) is found in ovarian cancer biopsies and is associated with increased tumor grade. In this report, we show that CXCR4 expression on human epithelial ovarian cancer cells is associated with, and can be modulated by, TNF-α. Ovarian cancer cells with high endogenous expression of TNF-α expressed higher levels of CXCR4 mRNA and protein than cells with low TNF-α expression. Stimulation of ovarian cancer cell lines and primary epithelial cancer cells with TNF-α resulted in increased CXCR4 mRNA and protein. The TNF-α–stimulated increase in CXCR4 mRNA was due partly to de novo synthesis, and up-regulation of CXCR4 cell surface protein increased migration to the CXCR4 ligand CXCL12. CXCR4 mRNA and protein was down-regulated by anti-TNF-α antibody or by targeting TNF-α mRNA using RNAi. TNF-α stimulation activated components of the nuclear factor κB pathway, and overexpression of the inhibitor of κB also reduced CXCR4 expression. Coculture of macrophages with ovarian cancer cells also resulted in cancer cell up-regulation of CXCR4 mRNA in a TNF-α–dependent manner. Finally, there was a correlation between the levels of TNF-α and CXCR4 mRNA in clinical biopsies of ovarian cancer, and TNF-α protein was expressed in CXCR4-positive tumor cells. TNF-α is a critical mediator of tumor promotion in a number of experimental cancers. Our data suggest that one mechanism may be through nuclear factor κB–dependent induction of CXCR4.
Bactericidal and Sterilizing Activities of Antituberculosis Drugs during the First 14 Days
Authors: Amina Jindani, Caroline J. Doré, Denis A. Mitchison
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Colony-forming units of Mycobacterium tuberculosis in sputum were counted at 2-day intervals in 100 patients treated with 22 regimens of isoniazid, rifampin, pyrazinamide, ethambutol, or streptomycin, given alone or in combinations. The exponential fall in colony-forming units was measured by linear regression coefficients of the log counts during the initial 2-day phase of rapid, drug-determined killing and during the subsequent 12 days of much slower sterilizing activity. The regression coefficients during the first 2 days varied significantly according to the drug; the greatest effects in multiple regression analyses were due to isoniazid (p < 0.001) and rifampin (p = 0.027). The rapid kill obtained with isoniazid was unaffected by addition of other drugs, so that a change in activity after adding an unknown drug to isoniazid would not be measurable. In multiple regression analysis of the coefficients during Days 2-14, rifampin and streptomycin had significant effects (p = 0.007 and 0.006, respectively), indicating that both drugs had important sterilizing activity, streptomycin particularly early. Isoniazid and pyrazinamide had no significant effects. In analyses of combined drug regimens only, ethambutol had an effect (p = 0.01) in reverse direction to that of rifampin, suggesting it antagonized the sterilizing activity of other drugs.
Hepatic organic anion uptake in the rat.
Authors: B F Scharschmidt, J G Waggoner, P D Berk
Journal: Journal of Clinical Investigation (1975)

The hepatic uptake of bilirubin (BR), indocyanine green (ICG), and sulfobromophthalein (BSP) was studied in 350 anesthetized Sprague-Dawley rats by determining the initial plasma disappearance rate (V) of various doses of unlabeled ICG, or of tracer quantities of [3H]BR or [35S]BSP injected into the jugular vein simultaneously with varying amounts of unlabeled BR or BSP. Similar studies were also performed involving the simultaneous injection of potential inhibitors of hepatic uptake. The results indicate that: (a) hepatic uptake determined by direct tissue measurement could be accurately estimated from the plasma disappearance data; (b) saturation of hepatic uptake with increasing dose was readily demonstrated for each of these three organic anions, and in each instance a plot of V versus dose took the form of a rectangular hyperbola analyzable in terms of Michaelis-Menten kinetics; (c) for BR, the saturable uptake process showed a Vmax more than 100 times the normal net transfer rate from plasma to bile; (d) hepatic uptake of BR, BSP, and ICG showed relatively selective, mutually competitive inhibition; glycoholic acid did not inhibit hepatic uptake of any of these substances; and (e) "counter-transport" could be demonstrated for each of the three test substances. These data are compatible with the existence of a carrier-mediated transport process for hepatic uptake of each of these three organic anions and clarify the relationship of hepatic BR uptake to its overall transport from plasma to bile.
TREATMENT OF PROLAPSUS ANI.
Authors: J. F. Jenkins
Journal: JAMA (1883)

per centage on the wages of all the employes to pay it.Yellow Fever.\p=m-\Onthe sixteenth of August Sur- geon Owen, in charge of the medical department of the naval station, Pensacola, reported to the Sur- geon General of the Navy that two well marked cases of this disease had occurred among the Marine Guard and had been sent to the Naval Hospital.The au- thorities of the city of Pensacola immediately estab- lished quarintine and a cordon for preventing all in- tercourse with the naval station and hospital.Com- mander Welch received instructions to transfer the Marine Guard to Cape Ason, six miles from the navy yard, for isolation.Active measures have been taken
Hemodynamic Sequelae of Cardiac Arrhythmias
Authors: PHILIP SAMET
Journal: Circulation (1973)

The hemodynamic consequences of cardiac arrhythmias depend on various factors, including the ventricular rate and the duration of the abnormal rate, the temporal relationship between atrial and ventricular activity, the sequence of ventricular activation, the functional state of the heart, the irregularity of the cycle length, associated drug therapy, the peripheral vascular vasomotor system, disease in organ systems other than the heart, and the degree of anxiety caused by the disease processes. Sinus bradycardia, even with rates as low as 40 beats/min, may not be associated with significant hemodynamic consequences unless the stroke volume is limited by myocardial or valvular disease, as in acute myocardial infarction. Cardiac output usually, but not invariably, falls when atrial fibrillation replaces normal sinus rhythm, even at comparable ventricular rates, both at rest and during exercise. Similar observations have been made during the development of atrial flutter despite the persistence of effective mechanical atrial activity in at least some cases. Marked hemodynamic changes are frequent in the course of ventricular tachycardia with systemic arterial hypotension, a decrease in cardiac output, and evidence of cerebral, coronary, and renal vascular insufficiency. Cyclic variations in systemic and pulmonary arterial pressures are common during atrioventricular dissociation. Cardiac output is generally depressed during the severe bradycardia of acquired complete heart block with evidence of atrioventricular valvular insufficiency. Increase of the heart rate by ventricular pacing reverses all or some of these abnormalities. The changes in congenital complete heart block are considerably less severe because myocardial insufficiency is less frequently seen in congenital complete heart block.
Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications.
Authors: L S Brady, H J Whitfield, R J Fox, P W Gold, M Herkenham
Journal: Journal of Clinical Investigation (1991)

Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression.
Timed-Disintegration Capsules
Authors: Theodore M. Feinblatt, Edgar A. Ferguson
Journal: New England Journal of Medicine (1956)

THE purpose of timed-disintegration capsules is to provide sustained therapeutic effect throughout the daytime period by administration of a single capsule in the morning. In this way the inconvenience and uncertainty attending administration of the drug three times daily are eliminated.Timed disintegration may be accomplished by incorporation inside the capsule of a number of tiny pellets variously coated for different disintegration intervals to cover the desired span of action.LiteratureVery little has been published on the subject of timed-disintegration capsules. In describing the dosage of dextroamphetamine sulfate, New and Nonofficial Remedies 1 1955 states: "A capsule containing 10 or . . .
THE PROBLEM OF ENDEMIC GOITRE
Authors: R. McCarrison
Journal: BMJ (1937)

There are two types of endemic goitre, with many transi- tional forms between them, differing in their histological features, in their distribution, and in the constitutional states produced by or associated with them.It can hardly be doubted, so marked are these differences, that the two types differ also in their aetiology.Two Types of Endemic Goitre The first is the classical type prevalent in mountainous regions, such as the Alps and Himalayas, occurring as a colloid-poor diffuse parenchymatous goitre in childhood, and as an adeno-parentchymatouts, nodular goitre, with its degenerative forms in adults.The second is the difJuse colloid goitre prevalent in lowland regions, such as the plains of Central Europe, and in England.The geo- graphical limits of these two types are not clearly defined.Both may occur together in the same locality, but in general the former predominates in mountainous and the latter in lowland regions.The former is rarely associated with hyperthyroidism or Graves's disease; the latter is commonly associated with both.The former is usually associated with congenital goitre, cretinism, deaf-mutism, and various grades of physical and mental deterioration; the latter is rarely associated with these congenital mani- festations of the disease.The former, in its adeno- parenchymatous form, increases in incidence as age advances, attaining to its acme between the ages of 50 and 60 years; the latter is more prevalent about the age of puberty, lessening rapidly or gradually dis- appearing after the age of 25 to 30 years.Both vary greatly in incidence in different localities.In regions of high endemicity the two sexes are affected in approxi- mately equal proportions.In regions of low endemicity the incidence is higher in females.
A woman with forgetfulness and falls
Authors: L. Pealing, S. Iliffe
Journal: BMJ (2011)

A 69 year old woman presented to her general practitioner with a six month history of occasional falls and fluctuating forgetfulness and attention.Although she reported no difficulties with names and dates she needed help with taking drugs and preparing meals.She had also had two episodes of apparent visual hallucinations of a woman standing at the foot of her bed.Her sleep behaviour had been poor for many years, with frequent strong physical jerks and motion while sleeping.She had no symptoms of altered or low mood.Her medical history included hypothyroidism, osteoporosis, and cholesteatoma, and she was being investigated for a mixed fibre peripheral sensory neuropathy of unknown cause.Current drugs included levothyroxine, calcitriol, calcium carbonate-colecalciferol, and lansoprazole.She did not drink alcohol and was a non-smoker.On examination she was fully orientated in time and place and her AMTS (abbreviated mental test score) was 10/10 with an MMSE (mini-mental state examination) score of 26/30.Her blood pressure, temperature, and cardiovascular and respiratory examinations were normal.Cranial nerve examination was normal with no primitive reflexes or supranuclear gaze palsy.Tone and power were normal throughout all limbs, as were sensation and reflexes in the upper limbs.The lower limbs showed reduced vibration and pin prick sensation to the mid-shin bilaterally, and joint position sense was limited to large movements.She showed no evidence of bradykinesia or apraxia, but her gait was ataxic in keeping with her peripheral sensory impairment.
Human endocardial innervation and its relationship to the endothelium: an immunohistochemical, histochemical, and quantitative study
Authors: K Marron, J Wharton, M N Sheppard, S Gulbenkian, D Royston, M H Yacoub, R H Anderson, J M Polak
Journal: Cardiovascular Research (1994)

The endocardium contains an extensive neural plexus, the composition and function of which are unclear. The aim of this study was to characterise the innervation of the endocardium in terms of the relative density and distribution of its autonomic and sensory nerve subpopulations and to assess the relationship between these nerves and endocardial endothelial cells.Immunohistochemical, histochemical, confocal, and quantitative image processing techniques were applied to whole mount preparations of human postmortem endocardium obtained within 24 h of death.The overall distribution of nerve fibres and fascicles was demonstrated using antisera to the general neural marker protein gene product 9.5 (PGP 9.5). Nerves displaying acetylcholinesterase activity represented the main nerve subpopulation, occupying 9-18% of the quantified field area. Neuropeptide Y immunoreactive nerves formed the most numerous peptide containing nerve subpopulation identified, occupying 5-19% and 2-7% of the field area in the ventricle and atrial endocardium respectively and having similar distribution patterns to tyrosine hydroxylase immunoreactive nerves. Nerves showing immunoreactivity for somatostatin, vasoactive intestinal polypeptide, and substance P were detected at a lower density, occurred more frequently in the ventricular than atrial endocardium, and showed a similar distribution in the right and left sides of the heart. Combined peptide immunofluorescence and acetylcholinesterase staining, of the same preparation, indicated that putative sympathetic and sensory nerve subpopulations could be distinguished from presumed parasympathetic, acetylcholinesterase positive, nerves. The relationship between immunostained nerves and endothelial cells was assessed using confocal microscopy. Varicose nerve fibres were detected within 0.2 micron of overlying endothelial cells in the right ventricle and between 0.4-0.6 micron in the left ventricle.The heterogeneous population of nerve fibres demonstrated in the human endocardium may influence the known interaction between endocardial endothelial cells and the myocardium.
The Determinants of Glycemic Responses to Diet Restriction and Weight Loss in Obesity and NIDDM
Authors: Tania P Markovic, Arthur B Jenkins, Lesley V Campbell, Stuart M Furler, Edward W Kraegen, Donald J Chisholm
Journal: Diabetes Care (1998)

OBJECTIVE To examine the mechanisms by which weight loss improves glycemic control in overweight subjects with NIDDM, particularly the relationships between energy restriction, improvement in insulin sensitivity, andregional and overall adipose tissue loss. RESEARCH DESIGN AND METHODS Hyperinsulinemic glucose clamps wereperformed in 20 subjects (BMI = 32.0 ± 0.5 [SEM] kg/m2, age = 48.4 ± 2.7 years) with normal glucose tolerance (NGT) (n = 10) or mild NIDDM (n = 10) before and on the 4th (d4) and 28th (d28) days of a reduced-energy (1,100 ± 250 [SD] kcal/day) formula diet. Body composition changes were assessed by dual energy x-ray absorptiometry and insulin secretory changes were measured by insulin response to intravenous glucose before and after weight loss. RESULTS In both groups, energy restriction (d4) reduced fasting plasma glucose (FPG) (ΔFPG: NGT = −0.4 ± 0.2 mmol/1 and NIDDM = −1.1 ± 0.03 mmol/1, P = 0.002), which was independently related to reduced carbohydrate intake (partial r = 0.64, P = 0.003). There was a marked d4 increase in percent of insulin suppression of hepatic glucose output(HGO) in both groups (ΔHGO suppression: NGT = 28 ± 15% and NIDDM = 32 ± 8%, P = 0.002). By d28, with 6.3 ± 0.4 kg weight loss, FPG was further reduced (d4 vs. d28) in NIDDM only (P = 0.05), and insulin sensitivity increased in both groups (P = 0.02). Only loss of abdominal fat related to improvements in FPG (r = 0.51, P = 0.03) and insulin sensitivity afterweight loss (r = 0.48, P = 0.05). In contrast to insulin action, there were only small changes in insulin secretion. CONCLUSIONS Both energy restriction and weight loss have beneficial effects on insulin action and glycemic control in obesity and mild NIDDM. The effect of energy restriction is related to changes in individual macronutrients, whereas weight loss effects relate to changes in abdominal fat.