tbuckley/cabot-search huggingface dataset:
Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors.
Authors: V K Chatterjee, T Nagaya, L D Madison, S Datta, A Rentoumis, J L Jameson
Journal: Journal of Clinical Investigation (1991)

Thyroid hormone (T3) resistance is inherited in most cases in an autosomal dominant manner. The disorder is characterized by elevated free thyroid hormone levels and partial resistance to thyroid hormone at the cellular level. Distinct single amino acid substitutions in the ligand binding domain of the beta form of the thyroid hormone receptor have been described in two kindreds with this disorder. We used transient expression assays to characterize the functional properties of these receptor mutants, one containing a Gly to Arg change at amino acid 340 (G340R) and the other a Pro to His change at amino acid 448 (P448H). A nine amino acid carboxy terminal deletion (delta 448-456), analogous to an alteration that occurs in v-erbA, was also studied for comparison with the mutations that occur in the T3 resistance syndrome. None of the receptor mutants were able to mediate thyroid hormone dependent activation (TreTKCAT) or repression (TSH alpha CAT) of reporter genes when compared with the wild type receptor. In addition, the mutants inhibited the activity of normal alpha and beta receptor isoforms when examined in coexpression assays. This activity, referred to as dominant negative inhibition, was manifest with respect to both the positively and negatively regulated reporter genes. Although mutant receptor binding to DNA was unaffected, ligand binding studies showed that the G340R and delta 448-456 mutants failed to bind T3, whereas the P448H mutant bound hormone with reduced affinity (approximately 10% of normal) compared to the wild type receptor. Consistent with this finding, the P448H mutant receptor was partially active at higher T3 concentrations. Furthermore, the dominant negative inhibition elicited by the P448H receptor mutant at higher T3 concentrations was reversed in the presence of high doses of T3. These findings indicate that mutant beta receptors in patients with thyroid hormone resistance have reduced affinity for T3 and are functionally deficient, but impair the activity of normal receptors, thereby providing a mechanism for the dominant mode of inheritance in this disorder.
EFFECTS OF ANTIBODIES ON MITOCHONDRIA*
Authors: John S. Davis, Alfred Jay Bollet
Journal: Journal of Clinical Investigation (1962)

Since the demonstration of the lupus erythema- tosus phenomenon by Hargraves, Richmond, and Nforton (1), a great deal of attention has been paid to the numerous antibody-like serum factors in patients with active systemic lupus erythematosus (SLE).Until recently, this attention has been concentrated on those factors that react with whole nuclei or nuclear subunits, such as DNA and his- tone.Asherson (2) and Deicher, Holman, and Kunkel (3) now have demonstrated other common serum factors in SLE that fix complement with cytoplasmic components, including mitochondria and microsomes from a variety of animal and human sources.The observation of low serum com- plement levels in active SLE (4-10) suggests the possibility that complement-fixing antigen-anti- body interactions might occur in vivo and play a role in the pathogenesis of the disease.Antibodies which react with these mitochondria in.vivo might interfere with important metabolic functions, since mnitochondria contain enzymes in- volved in the regulation of oxidation and high- energy bond formation.A study of the effect of induced antimitochondrial antibodies in rabbits on mitochondrial enzyme activity was therefore un- dertaken to define the possible metabolic effects of such antibodies preliminary to study of the effects of the antimitochondrial antibodies found in SLE.This report describes several effects of antimitochondrial serum in various immunologic systems; such serum caused inhibition of mitochondrial enzymes, particularly those in the elec- tron transport chain.A heat-labile serum com- ponent, presumably complement, potentiated in- hibition of DPNH oxidase by mitochondrial anti- body. METHODSPreparation of mintochondria.Albino Wistar rats weighing 200 to 300 g (Charles River Breeding Labora- * Supported by U.
ABC of mental health: Anxiety
Authors: A. S Hale
Journal: BMJ (1997)

Anxiety is an unpleasant emotional state characterised by fearfulness and unwanted and distressing physical symptoms.It is a normal and appropriate response to stress but becomes pathological when it is disproportionate to the severity of the stress, continues after the stressor has gone, or occurs in the absence of any external stressor.Neurotic disorders with anxiety as a prominent symptom are common: a recent British survey found that 16% of the population suffered from some form of pathological anxiety.Anxiety disorders should be differentiated from stress reactions, in which anxiety may be a prominent feature.These include acute stress reactions-a rapid response (in minutes or hours) to sudden stressful life events, leading to anxiety with autonomic arousal and some disorientation-and adjustment reactions-slower responses to life events (such as loss of job, moving house, or divorce) that occur days or weeks later as symptoms of anxiety, irritability, and depression (without biological symptoms).These are generally self limiting and are helped by reassurance, ventilation, and problem solving.A more profound stress reaction, post-traumatic stress disorder, is described below.Until recently, the commonest response to a presentation of anxiety has been to prescribe a benzodiazepine.This has been much criticised and alternatives have been evaluated, including almost all the available antidepressants and psychological treatments, especially cognitive behaviour therapy.For most general practitioners, constraints on resources are likely to mean that drugs remain the mainstay of treatment.
Progression of radiographic joint damage in different eras: trends towards milder disease in rheumatoid arthritis are attributable to improved treatment
Authors: A Finckh, H K Choi, F Wolfe
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> Severity of rheumatoid arthritis and progression of radiographic joint damage have decreased over the last decades. <b>Aim:</b> To examine whether this trend is attributable to an underlying trend towards milder disease or to improved treatment. <b>Methods:</b> The study used an inception cohort of patients with early rheumatoid arthritis seen at the Wichita Arthritis Center, Wichita, Kansas, USA, since 1973 and monitored prospectively since their first clinic visit through clinical, radiographic, laboratory, demographic and self-reported data. The radiographic disease progression in patients with disease onset in the 1970s, 1980s and 1990s was compared using a multivariate regression model for longitudinal data. The analysis was adjusted for differences in baseline predictors, type of disease-modifying antirheumatic drugs (DMARDs) and steroid use. <b>Results:</b> 418 patients with rheumatoid arthritis with radiographic follow-up were included. Patients in earlier decades used fewer DMARDs, had longer disease durations and higher tender joint counts at their first visit. Other important predictors of disease progression did not differ significantly between decades of disease onset. The unadjusted rates of radiographic progression differed between decades (analysis of variance, p = 0.01), with a significant trend towards less radiographic progression in more recent times (trend, p&lt;0.001). However, after adjusting for DMARD use, steroid use and baseline predictors, differences between decades vanished (analysis of variance, p = 0.40) and the trend towards less radiographic progression disappeared (trend, p = 0.45). <b>Conclusion:</b> These results suggest that the observed trend towards milder disease in rheumatoid arthritis is attributable to more effective antirheumatic treatment and not to a secular trend.
Effect of Coronary Artery Reperfusion on Transmural Myocardial Remodeling in Dogs
Authors: Shiro Ono, Lewis K. Waldman, Hirohisa Yamashita, James W. Covell, John Ross
Journal: Circulation (1995)

Background The effects of reperfusion after coronary occlusion on transmural remodeling of the ischemic region early and late after nontransmural infarction must importantly affect the recovery of regional function. Accordingly, analysis of local volume and three-dimensional strain was performed using a finite element method to determine regional remodeling. Systolic and remodeling strains were measured using radiographic imaging of three columns (≈1 cm apart) of four to six gold beads implanted across the left ventricular posterior wall in 6 dogs. Methods and Results After a control study, infarction was produced by 2 to 4 hours of proximal left circumflex coronary artery occlusion followed by reperfusion. Follow-up studies were performed at 2 days, 3 weeks, and 12 weeks with the dogs under anesthesia and in closed-chest conditions. Biplane cineradiography was performed to obtain the three-dimensional coordinates of the beads. At 2 days, end-systolic strains were akinetic with loss of normal transmural gradients of shortening and thickening. Remodeling strains (RS) were determined by use of a nonhomogeneous finite element method by referring the end-diastolic configuration during follow-up studies to its control state at matched end-diastolic pressures and heart rates. Tissue volume at 2 days increased substantially, more at the endocardium (30±7%) than at the epicardium (5±12%, P &lt;.01); the increase was associated with an average RS in the wall-thickening direction of 0.18±0.15 ( P &lt;.01) with all other RS near zero. At 12 weeks systolic function partially recovered, with normal wall thickening in the epicardium (radial strain, 0.081±0.056 [control] versus 0.113±0.088 [12 weeks]) but with dysfunction in the endocardium (0.245±0.108 [control] versus 0.111±0.074 [ P &lt;.01] [12 weeks]). This inability of the inner wall to recover function may be related to increased transmural torsional shear and negative longitudinal-radial transverse shear in the inner wall. Volume loss occurred at 12 weeks in the endocardium (−36±16%) corresponding to transmural gradients in longitudinal RS and both transverse shear RS. Negative longitudinal RS was greater at the endocardium (−0.20±0.10) than at the epicardium (−0.06±0.05, P &lt;.01). Conclusions These results indicate the presence of marked subendocardial edema 2 days after reperfusion following 2 to 4 hours of coronary occlusion. At 3 months after reperfusion, however, there was volume loss in the inner wall due to shrinkage along the myofiber direction with reduced transmural function and loss of longitudinal shortening, while both tissue volume and function recovered completely in the outer wall.
The Permanent Artificial Heart
Authors: William C. DeVries
Journal: JAMA (1988)

This article describes the clinical course of four patients in whom the Jarvik-7-100 total artificial heart was implanted as a permanent device. Details of their preoperative assessment and comprehensive summaries of their postoperative course are presented. The neurological, hematological, renal, and infectious complications they experienced and the interventions initiated to achieve resolution of these problems are described. Finally, revisions in the treatment protocols as a consequence of the experience and knowledge gained are examined.
Transplanting the enteric nervous system: a step closer to treatment for aganglionosis
Authors: M. D Gershon
Journal: Gut (2007)

Autologous transplantation can be used to treat Hirschsprung’s disease by implantation and proliferation of the crest-derived stem cells in vitro

One might think that Hirschsprung’s disease (congenital megacolon) should be passe as a medical problem. After all, many genes, including RET , GDNF , NRTN , EDNRB , EDN3 , ECE1 , PHOX2b , SOX10 , PAX3 and SMADIP1 (SIP1, ZBFX1B),1–7 have successfully been linked to its pathogenesis. Knowledge of the actions and interactions of these genes and their products has enabled the processes by which the bowel is colonised to be, if not completely understood, at least comprehended in general terms.3,8,9,10 Effective treatment for Hirschsprung’s disease, moreover, exists in the surgical removal of the aganglionic segment of bowel.11–13 Unfortunately, the medical problems posed by Hirschsprung’s disease continue despite the lengthy list of genes implicated in its generation and the progress that has recently been made in understanding enteric nervous system (ENS) development. Unresolved medical problems continue because advances made in comprehending genes and pathogenesis have not been translated into new and improved methods of treatment; moreover, although surgical techniques are evolving and associated morbidity is decreasing,12,13 the surgical treatment of Hirschsprung’s disease essentially converts an otherwise lethal defect into a chronic condition with which many, if not most, patients must learn to cope.14,15

Hirschsprung’s disease occurs when a variable length of terminal bowel is congenitally aganglionic. Because the reflexes and behaviours mediated by the ganglionated plexuses of the ENS are essential for propulsive motility and normal secretion,16 aganglionosis results in a pseudoobstruction that, if left untreated, is incompatible with life. Reliable modern statistics on untreated Hirschsprung’s disease are not available because failure to treat it is immoral; however, aganglionosis is lethal to animals …
Goodbye and hello
Authors: Colin Douglas
Journal: BMJ (2005)

Quite a few years ago I went to hear a valedictory lecture by a retiring director of public health. No, really, I did. But please read on. It was fascinating, a crisp analysis of her 30 years in the business: optimism proved false, delusive complacency, and eventual nemesis—the stuff of tragedy.

When she joined, all the great infectious scourges of mankind—at least in their Scottish manifestation—had been conquered. Immunisation, better housing, and, of course, antibiotics, had vanquished the …
Abstract 4736: Inhibition of STAT3 sensitizes neuroblastoma xenografts cells to Etoposide
Authors: Shuang Yan, Carol Thiele
Journal: Cancer Research (2014)

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for more than 7% of malignancies in patients younger than 15 years and causing 10% of all pediatric oncology deaths. Chemoresistance remains a major obstacle to the successful treatment of high-risk NB patients. Since STAT3 is a determinant of chemoresistance and associated with tumor recurrence in several adult tumor model systems, we investigated the biologic consequences of targeting STAT3 in neuroblastoma. Using a Tet-inducible STAT3 shRNA in 3 representative NB cell line models (AS, NGP and IMR32), inhibition of constitutively activated STAT3 (P-STAT3) in NB cells statistically decreased cell proliferation, colony formation and motility as defined by a wound healing assay. NB cell lines with decreased P-STAT3 exhibited increased sensitivity to cisplatin and etoposide-induced cell death (EC50 in each cell line decreased 52% to 80% compared with parental cell lines) which could be partially rescued by caspase inhibitor Z-VAD. In vivo, STAT3 inhibition by Tet-inducible STAT3 shRNA in AS had little effect on tumor growth and survival in tumor-bearing mice, however the combination of STAT3 inhibition with etoposide significantly decreased tumor growth and increased the survival of tumor-bearing mice (P=0.009). Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional cytotoxic therapy for patients with high-risk NB. Citation Format: Shuang Yan, Carol Thiele. Inhibition of STAT3 sensitizes neuroblastoma xenografts cells to Etoposide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4736. doi:10.1158/1538-7445.AM2014-4736
Extrathymic development of murine T cells after bone marrow transplantation
Authors: Amanda M. Holland, Johannes L. Zakrzewski, Jennifer J. Tsai, Alan M. Hanash, Jarrod A. Dudakov, Odette M. Smith, Mallory L. West, Natalie V. Singer, Jessie Brill, Joseph C. Sun, Marcel R.M. van den Brink
Journal: Journal of Clinical Investigation (2012)

Restoring T cell competence is a significant clinical challenge in patients whose thymic function is severely compromised due to age or cytoreductive conditioning. Here, we demonstrate in mice that mesenteric LNs (MLNs) support extrathymic T cell development in euthymic and athymic recipients of bone marrow transplantation (BMT). Furthermore, in aged murine BMT recipients, the contribution of the MLNs to the generation of T cells was maintained, while the contribution of the thymus was significantly impaired. Thymic impairment resulted in a proportional increase in extrathymic-derived T cell progenitors. Extrathymic development in athymic recipients generated conventional naive TCRαβ T cells with a broad Vβ repertoire and intact functional and proliferative potential. Moreover, in the absence of a functional thymus, immunity against known pathogens could be augmented using engineered precursor T cells with viral specificity. These findings demonstrate the potential of extrathymic T cell development for T cell reconstitution in patients with limited thymic function.
Electrophysiological actions of mexiletine on isolated rabbit atria and canine ventricular muscle and Purkinje fibres
Authors: I. YAMAGUCHI, B. N. SINGH, W. J. MANDEL
Journal: Cardiovascular Research (1979)

The electrophysiological effects of varying concentrations of mexiletine on isolated rabbit sinus node and atrial preparations. Purkinje fibres, Purkinje-fibre-ventricular muscle junction and distal conduction system ('gate') were studied in oxygenated Tyrode solution at 35 degrees C using standard microelectrode techniques. 'Therapeutic' concentrations of mexiletine (0.5 to 2.0 micrograms.cm-3) had little effect on the atrial action potentials or on sinus node automaticity but sino-atrial conduction was delayed. In Purkinje fibres, these concentrations of the drug depressed the dV/dtmax of phase 0, conduction velocity and membrane responsiveness accompanied by significant shortening of the action potential duration and the effective refractory period, the change in the former always being greater than that in the latter. Mexiletine decreased antegrade as well as retrograde conduction at the Purkinje-fibre-ventricular muscle junction, while producing a uniform shortening of the action potential duration in the distal conduction system without a preferential effect at the 'gate'. The mechanisms of antiarrhythmic actions of mexiletine are thus complex but resemble those of lignocaine in superfused isolated cardiac muscle.
Fish Oil and SI Units
Authors: Daniel M. Lane
Journal: JAMA (1989)

<h3>To the Editor.—</h3> Having been in and around the world of medicine for more than 30 years, the decision to implement the use of SI units for publications hardly is surprising to me.<sup>1</sup>Unfortunately, the use of the SI units in certain instances breaks a rule of major scientific importance, ie, data should be reported in the units in which they were measured. Converting milligrams per deciliter to millimoles per liter for reporting is little more than a mathematical exercise when the compound measured has a known and constant molecular weight. It can produce major inaccuracies when the molecular weights either are not known or a calculated figure is used to estimate an average molecular weight. For example, when high-density lipoprotein cholesterol is reported in millimoles per liter, the result given is for cholesterol from a mixture containing at least five major peptide groups, free cholesterol, and many different
"Well Sir Thomas?": oration to commemorate the tercentenary of the death of Sir Thomas Browne.
Authors: F L Huntley
Journal: BMJ (1982)

Now that we celebrate the three hundredth anniversary of the death of Sir Thomas Browne rather than his birth I intend to concentrate not on Browne's melancholia but on his joy, not on Hydriotaphia but on his happiest, most difficult, and most challenging piece, The Garden of Cyrus.Of his five major works, the Religio Medici an acknowledged masterpiece-was written by a physician not quite 30 years of age.Browne's best known book, it has inspired by its quiet faith, detachment, and charming mixture of pride and humility millions of thoughtful people around the world.The young doctor seems to delight in his often very bad poetry while being oblivious to the fact that he could write perhaps the finest prose in the English language.Take, for example, this passage on Judgment Day: "This is the day that must make good that great attribute of God, his Justice, that must reconcile those unanswerable doubts that torment the wisest understandings, and reduce those seeming inequalities, and respective distributions in this world, to an equality and recompensive Justice in the next.This is that one day, that shall include and compre- hend all that went before it, wherein as in the last scene, all the Actors must enter to compleate and make up the Catastrophe of this great peece.This is the day whose memory hath onely power to make us honest in the darke, and to bee vertuous without a witnesse" (p 119).1He had forgotten that he could write like this until Andrew Crooke in 1642 pirated the first edition.Browne's corrected version became immediately popular in England, and its Latin translation soon gave him a continental reputation.Now married and settled in Norwich with his expanding practice and collections of books, coins, zoological specimens, and medicinal herbs, Browne was busy working on his Pseudo- doxia Epidemica, the epidemic disease of fallacious opinions, solving the problem as any doctor would, first by determining the cause and then by applying the cure.