https://www.mdc-berlin.de/de/veroeffentlichungstypen/clinical- journal-club

Als gemeinsame Einrichtung von MDC und Charité fördert das Experimental and Clinical Research Center die Zusammenarbeit zwischen Grundlagenwissenschaftlern und klinischen Forschern. Hier werden neue Ansätze für Diagnose, Prävention und Therapie von Herz-Kreislauf- und Stoffwechselerkrankungen, Krebs sowie neurologischen Erkrankungen entwickelt und zeitnah am Patienten eingesetzt. Sie sind eingelanden, um uns beizutreten. Bewerben Sie sich! A fully immunized 48-year-old man presented to an urgent care clinic with a 3-day history of odynophagia, fever, and progressive dyspnea. Physical examination demonstrated stridor and use of accessory muscles for respiration. A lateral radiograph of the neck was performed. What is the most likely diagnosis?

Inhaled foreign body

La Delfa malformation

Epiglottitis

Relapsing polychondritis

Tracheal perforation

The correct answer is epiglottitis. The lateral radiograph of the neck shows “thumb sign” which is suggestive of an enlarged epiglottis. Laryngoscopy showed erythema, edema, and exudative inflammation of the epiglottis, and the patient required urgent tracheostomy. Intraoperative cultures were positive for Streptococcus pyogenes. Die Epiglottitis ist eine Entzündung der Epiglottis, die von seltenen Ausnahmen abgesehen, durch bakterielle Infektion verursacht wird. Sie verläuft als hochakute, lebensbedrohliche Erkrankung. Die Epiglottitis war bis zur breitflächigen Anwendung der HiB-Impfung eine häufige Erkrankung des Kindes zwischen 2-6 Jahren. Mittlerweile ist die Epiglottitis durch die hohe Immunisierungsrate bei Kleinkindern eine seltene Erkrankung. Bei Erwachsenen ist eine Epiglottitis ebenfalls selten, kann jedoch insbesondere bei unzureichendem Impfstatus durch Infektion mit Haemophilus influenzae Typ B und andere Bakterien auftreten. Historische Analysen legen den Schluss nahe, dass George Washington, der erste Präsident der USA, an einer fulminanten Epiglottitis verstarb. Die Symptomatik ist charakteristisch. Betroffene Patienten klagen über starke Halsschmerzen (DD: keine Halsschmerzen beim Krupp-Syndrom) und weisen inspiratorisch einen Stridor auf. Es besteht in der Regel hohes Fieber. Die Sprache ist kloßig, es besteht keine Heiserkeit. Das Schlucken ist schmerzhaft (Dysphagie). Oft besteht eine Hypersalivation. Betroffene Patienten wollen als Ausdruck der behinderten Atmung lieber sitzen als stehen, halten den Mund offen und strecken die Zunge leicht heraus. Ein Hustenreiz tritt in der Regel nicht auf, da die Epiglottis keine entsprechenden Rezeptoren besitzt. Die Polychondritis ist eine chronische, langfristig das Knorpelgewebe zerstörende Erkrankung, deren genaue Ursache bisher noch ungeklärt ist. Es wird vermutet, dass Autoimmunprozesse die Entzündungsschübe auslösen. Daher wird die Polychondritis den Autoimmunerkrankungen zugeordnet. Im Abstand von einigen Wochen bis Monaten treten starke Entzündungsherde am Knorpel auf, wodurch dieser zunehmend an Festigkeit verliert und seine Funktion immer weniger wahrnehmen kann. Obwohl die Polychondritis alle Knorpel enthaltenden Körperregionen treffen kann, sind die Gelenke besonders häufig betroffen. Als Folge der ständigen Entzündungen treten starke Schmerzen und eine zunehmende Bewegungsunfähigkeit auf. Ebenfalls häufig betroffen ist die knorpelreiche Ohr- und Nasenregion. Der Knorpel in der Nase wird weicher und senkt sich ab. Die Folge ist eine Formveränderung. Am Ohr kommt es begleitend zu einer Perichondritis. Feinstaub ist ein Teil des Schwebstaubs. Die aktuelle Definition des Feinstaubs geht zurück auf den im Jahr 1987 eingeführten National Air Quality-Standard for Particulate Matter (kurz als PM-Standard bezeichnet) der US-amerikanischen Umweltschutzbehörde EPA (Environmental Protection Agency). Die ursprüngliche Definition des Feinstaubs basierte auf der Johannesburger Konvention aus dem Jahr 1959 und sah als Trennkorndurchmesser einen aerodynamischen Durchmesser von 5 µm vor. PM10 In der ersten Fassung der amerikanischen Richtlinie wurde der Standard PM10 definiert, für den seit Anfang 2005 auch in der EU ein Grenzwert einzuhalten ist. Im Gegensatz zu der üblicherweise genannten Definition stellt PM10 keine scharfe Aufteilung der Immissionen bei einem aerodynamischen Durchmesser von 10 Mikrometern (10 µm) dar; vielmehr wurde versucht, das Abscheideverhalten der oberen Atemwege nachzubilden: Partikel mit einem aerodynamischen Durchmesser von weniger als 1 µm werden vollständig einbezogen, bei größeren Partikeln wird ein gewisser Prozentsatz gewertet, der mit zunehmender Partikelgröße abnimmt und bei ca. 15 µm schließlich 0 % erreicht. Technisch gesehen entspricht dies der Anwendung einer Gewichtungsfunktion (in der Fachsprache Trennkurve bzw. Trennfunktion) auf die Immissionen (in der Praxis wird dies durch einen größenselektiven Einlass an den Messgeräten erreicht). Aus dem Verlauf dieser Gewichtungsfunktion leitet sich letztendlich auch die Bezeichnung PM10 ab, da bei ca. 10 µm genau die Hälfte der Partikel in die Gewichtung eingehen. PM2,5 Im Jahr 1997 wurde die amerikanische Richtlinie um PM2,5 ergänzt, die dem lungengängigen (alveolengängigen) Feinstaub (auch Feinststaub genannt) entspricht. Die Definition ist analog zu PM10, allerdings ist die Gewichtungsfunktion wesentlich steiler (100 % Gewichtung < 0,5 µm; 0 % Gewichtung > 3,5 µm; 50 % Gewichtung bei ca. 2,5 µm). Diese wesentlich schärfere Trennung lässt sich bei der Messung nicht mehr durch einen speziellen Einlass erreichen, hierfür kommen in der Praxis Impaktoren oder Zyklone zum Einsatz.

Glasfaserstreifen zur Erfassung von Feinstaub mittels Einzelproben Ambient Particulate Air Pollution and Daily Mortality in 652 Cities

The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias. We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration– response curves from each city were pooled to allow global estimates to be derived. Distribution of the Cities with Data on PM10.

Shown is the geographic distribution of the 598 cities in the 24 countries and regions that had available data on particulate matter with an aerodynamic diameter of 10 μm or less (PM10) and were included in the analysis. Also shown are the annual mean PM10 concentrations. Distribution of Cities with Data on PM2.5.

Shown is the geographic distribution of the 499 cities in the 16 countries and regions that had data on particulate matter with an aerodynamic diameter of 2.5 μm or less (PM2.5) and were included in the analysis. Also shown are the annual mean PM2.5 concentrations.

Pooled Concentration–Response Curves.

Shown are the pooled concentration–response curves for the associations of 2-day moving average concentrations of PM10 (Panel A) and PM2.5 (Panel B) with daily all-cause mortality. The y axis represents the percentage difference from the pooled mean effect (as derived from the entire range of PM concentrations at each location) on mortality. Zero on the y axis represents the pooled mean effect, and the portion of the curve below zero denotes a smaller estimate than the mean effect. The dashed lines represent the air-quality guidelines or standards for 24-hour average concentrations of PM10 or PM2.5 according to the World Health Organization Air Quality Guidelines (WHO AQG), WHO Interim Target 1 (IT-1), WHO Interim Target 2 (IT-2), WHO Interim Target 3 (IT-3), European Union Air Quality Directive (EU AQD), U.S. National Ambient Air Quality Standard (NAAQS), and China Air Quality Standard (AQS). Discussion

Our study analyzed multisite data on air pollution and mortality in 652 cities across different countries and regions, although most countries and cities were in the northern hemisphere. Because the data from each city were analyzed according to the same protocol, the estimate of the percentage change in mortality per 10-μg-per-cubic-meter increase in PM concentration was based on a large data set. This study also provides the statistical power to examine the global concentration–response functions of particulate air pollution at both low and high baseline levels. Our multicountry time-series analysis provides evidence on positive associations between short- term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality. This study indicated independent associations of PM10 and PM2.5 concentrations with daily mortality after adjustment for gaseous pollutants. Further, concentration–response curves for the effects of PM on mortality showed a consistent increase, with flattening of the slopes at higher concentrations, and the associations were still detectable at concentrations below the current air- quality guidelines and regulatory limits. Eine Herzinsuffizienz liegt vor, wenn das Herz unfähig ist, das vom Organismus benötigte Herzzeitvolumen bei normalem enddiastolischen Ventrikeldruck bereit zu stellen. Die Aktivierung des Renin-Angiotensin-Aldosteron-Systems führt über eine erhöhte Produktion von Angiotensin II zur Vasokonstriktion und damit zur Erhöhung der Vorlast. Dieser Effekt wird durch Aldosteron verstärkt, das eine Natrium- und Wasserretention bewirkt.

Relaxin ist ein Peptidhormon, das bei Frauen und Männern in verschiedenen Orten gebildet wird und unterschiedliche Funktionen übernimmt. Relaxin ist ein Heterodimer aus zwei Peptidketten mit 24 und 29 Aminosäuren, die durch Disulfidbrücken verbunden sind. Es besteht eine strukturelle Ähnlichkeit zum Insulin. Beim Menschen sind drei Relaxine bekannt: Relaxin-1 (RLN1) Relaxin-2 (RLN2) Relaxin-3 (RLN3) Ihnen lassen sich vier verschiedene Relaxinrezeptoren zuordnen - dabei handelt es sich um G-- gekoppelte Rezeptoren. Bei schwangeren Frauen wird Relaxin im Uterus, in der Plazenta und in den Brustdrüsen, vor allem aber im Corpus luteum gebildet. Zum Ende der Schwangerschaft bewirkt es eine Umgestaltung der Extrazellulärmatrix des Zervixkanals und eine starke Auflockerung und Dehnung des Muttermundes ("Reife Zervix"). Darüber hinaus wird die Symphyse des weiblichen Beckens entspannt, was den Geburtsvorgang erleichtert. Neben diesen Mechanismen wird vermutet, dass Relaxin zusammen mit Progesteron bis zum letzten Monat der Schwangerschaft den Uterus "stillhält", also vorzeitige Uteruskontraktionen verhindert. Bei Männern wird Relaxin in der Prostata synthetisiert und scheint sich positiv auf die Motilität der Spermien und die Befruchtung auszuwirken. Effects of Serelaxin in Patients with Acute Heart Failure

Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. Serelaxin, a recombinant form of human relaxin-2, was developed as a potentially useful therapeutic agent because of both its vasodilatory effects (to relieve congestion) and its direct protective effects on organs. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, administration of serelaxin resulted in a lower incidence of worsening heart failure during hospitalization and, in an exploratory analysis, lower cardiovascular mortality at 180 days than placebo. Systolic Blood Pressure through 120 Hours According to Group.

Asterisks indicate time points at which the between-group difference was significant (P<0.05)

Efficacy End Points.

Panel A shows Kaplan–Meier estimates of the probability of death from cardiovascular causes. At day 180, death from cardiovascular causes had occurred in 285 patients in the serelaxin group and in 290 patients in the placebo group. Panel B shows Kaplan–Meier estimates of the probability of worsening heart failure during the first 5 days. At 5 days, worsening heart failure had occurred in 227 patients in the serelaxin group and in 252 patients in the placebo group. Panel C shows Kaplan–Meier estimates of the probability of death from any cause. At day 180, death from any cause had occurred in 367 patients in the serelaxin group and in 388 patients in the placebo group. In each panel, the inset shows the same data on an enlarged y axis. Adverse events and serious adverse events that occurred up to and including day 14 were also similar in the two groups; 55.3% in the serelaxin group and 54.5% in the placebo group had an adverse event, and 12.6% and 13.1%, respectively, had a serious adverse event. Additional information about adverse events and laboratory data that were collected for safety analyses are provided in the supplement.

Discussion

In the RELAX-AHF-2 trial, a 48-hour infusion of serelaxin in patients with acute heart failure did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. In addition, serelaxin was not associated with a shorter length of index hospital stay or a lower incidence of rehospitalization for heart failure or renal failure than placebo. Administration of serelaxin resulted in a greater reduction in blood pressure than did placebo, which is consistent with a pharmacologic effect. In conclusion, the RELAX-AHF-2 trial evaluated the effect of serelaxin in patients with acute heart failure. Serelaxin treatment resulted in a significantly greater reduction in blood pressure than placebo, a finding consistent with a pharmacologic effect of serelaxin. However, serelaxin did not result in lower cardiovascular mortality at 180 days or a smaller percentage of patients with worsening heart failure at 5 days than placebo. The incidence of adverse events was similar in the two groups. ist ein monomeres G-Protein, welches das Nukleotid GTP bindet und den Import und Export von Proteinen am Nukleus reguliert. Die Transkription findet im Zellkern statt, die Translation dagegen im Zytosol. Proteine, die für den Zellkern bestimmt sind, müssen posttranslational importiert werden. Der Transport findet durch die Kernporen in den Kernmembranen statt. Gleichzeitg müssen bestimmte Proteine, wie z.B. Transkriptionsfaktoren unter bestimmten Bedingungen aus dem Kern exportiert werden. Ran hat ein molekulares Gewicht von 25 kDa und kann GTP oder GDP binden. Die GTPase-Aktivität (Hydrolyse von GTP unter Abspaltungen von Phosphat) des wird durch ein Ran-GAP (GTPase activating protein) aktiviert. Der Austausch von GDP gegen GTP wird durch ein Ran-GEF (Guanine nucleotide exchange factor) induziert. Ran-GEF ist an das Chromatin gebunden und dadurch im Zellkern lokalisiert. Ran-GAP ist dagegen an die äußere Seite der Kernmembran gebunden. Durch die spezifische Lokalisation von GEF und GAP liegt Ran im Zellkern vorwiegend in der GTP- Form vor, im Zytosol dagegen in der GDP-Form. Nukleäre Proteine tragen eine bestimmte Kernlokalisationssequenz mit vorwiegend positiv geladenen Aminosäuren, die sie für den Import markiert. Über diese Sequenz binden sie im Zytosol die Transportrezeptoren α und Importin β, die das Protein durch die Kernporen in den Zellkern transportieren. Ran-GTP stimuliert hier die Dissoziation des Rezeptor-Protein- Komplexes und bindet selbst den Rezeptor. Selinexor (INN, trade name Xpovio; codenamed KPT-330) is a selective inhibitor of nuclear export used as an anti- cancer drug. It works by quasi-irreversibly binding to exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action. Selinexor was granted accelerated approval by the U.S. Food and Drug Administration in July 2019, for use as a drug of last resort in people with multiple myeloma. In clinical trials, it was associated with a high incidence of severe side effects, including low platelet counts and low blood sodium levels. Selinexor is restricted for use in combination with the steroid dexamethasone in people with relapsed or refractory multiple myeloma which has failed to respond to at least four or five other therapies (so-called "quad-refractory" or "penta-refractory" myeloma), for whom no other treatment options are available. It is the first drug to be approved for this Schematic illustration of the Ran indication. In the clinical study used to support FDA cycle of . Selinexor approval, selinexor was associated with high rates of inhibits this process at the nuclear pancytopenia, including leukopenia (28%), neutropenia export receptor (upper right). (34%, severe in 21%), thrombocytopenia (74%, severe in 61% of patients), and anemia (59%). Like other so-called selective inhibitors of nuclear export (SINEs), selinexor works by binding to exportin 1 (also known as CRM1). CRM1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressors, oncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; it is often overexpressed and its function misregulated in several types of cancer. Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma

Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.

Duration of Response to Treatment.

An asterisk indicates that the patient was still receiving treatment at the date of data cutoff. Kaplan–Meier Analysis of Progression- free Survival, Overall Survival, and Overall Survival According to Response.

CI denotes confidence interval, MR minimal response, NE not able to be evaluated, PD progressive disease, PR partial response, and SD stable disease. Tick marks indicate censored data.

Discussion

In this trial, 26% of the patients with penta-exposed, triple-class refractory myeloma who received oral selinexor, a first-in-class XPO1 inhibitor, with dexamethasone twice weekly had a partial response or better. Two patients had stringent complete responses, and 6 had very good partial responses. Although all patients entered the study with progressive disease, 26 (21%) had persistent disease progression or their disease could not be evaluated for response. Among the patients who had a response, efficacy was consistent across subgroups, including patients with high-risk cytogenetic abnormalities (53% of the patients). The results of this study are notable for several reasons. The trial was permissive, allowing patients with reduced renal function, thrombocytopenia, and neutropenia to enroll. These patients were heavily pretreated, with a median of 7 previous therapeutic regimens, including a median of 10 unique antimyeloma agents. Patients had rapidly progressing myeloma, with a 22% increase in disease burden in the 12 days from screening to initial therapy. These characteristics are consistent with the growing population of patients who have exhausted available therapies but still desire to continue therapy. Preclinical studies of selinexor show enhancement of IκB, which supports its synergy in combination with proteasome inhibitors, additivity with immunomodulatory drugs, and sensitization of myeloma cells to anti-CD38 monoclonal antibodies. In conclusion, the results of the STORM Part 2 study showed that oral selinexor with low-dose dexamethasone induced responses in 26% of patients with refractory myeloma. The most common toxic effects of grade 3 or higher included thrombocytopenia without bleeding, anemia, neutropenia without fever, and hyponatremia. Ischemic cardiomyopathy is a type of cardiomyopathy caused by a narrowing of the coronary arteries which supply blood to the heart. Typically, patients with ischemic cardiomyopathy have a history of acute myocardial infarction, however, it may occur in patients with coronary artery disease, but without a past history of acute myocardial infarction. This cardiomyopathy is one of the leading causes of sudden cardiac death.[6] The adjective ischemic means characteristic of, or accompanied by, ischemia — local anemia due to mechanical obstruction of the blood supply. Ischemic cardiomyopathy can be diagnosed via magnetic resonance imaging (MRI) protocol, imaging both global and regional function. Also the Look-Locker technique is used to identify diffuse fibrosis; it is therefore important to be able to determine the extent of the ischemic scar.[2] Some argue that only left main- or proximal-left anterior descending artery disease is relevant to the diagnostic criteria for ischemic cardiomyopathy. Myocardial imaging usually demonstrates left ventricular dilation, severe ventricular dysfunction, and multiple infarctions. Signs include congestive heart failure, angina edema, weight gain and fainting, among others.Restoring adequate blood flow to the heart muscle in people with heart failure and significant coronary artery disease is strongly associated with improved survival, some research showing up to 75% survival rates over 5 years. A stem cell study indicated that using autologous cardiac stem cells as a regenerative approach for the human heart (after a heart attack) has great potential. Myocardial Viability and Long-Term Outcomes in Ischemic Cardiomyopathy

The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear. Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years. The findings of this study do not support the concept that myocardial viability is associated with a long- term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. Kaplan–Meier Analysis of the Incidence of Death from Any Cause.

Panel A shows Kaplan–Meier curves for the incidence of death from any cause among patients who underwent a myocardial viability test, according to treatment group; results were compared with the use of a Cox proportional- hazards model with adjustment for baseline covariates. Panel B shows Kaplan–Meier curves for the incidence of death from any cause among patients without viable myocardium (left panel) and among those with viable myocardium (right panel), according to treatment group. Panel C shows the results of a Cox proportional-hazards model that tested for the interaction between myocardial viability and treatment, with adjustment for baseline covariates. CABG denotes coronary- artery bypass grafting. Incidence of Death from Any Cause, According to Changes in Left Ventricular Ejection Fraction.

Shown are the results of a landmark analysis that included data from the 318 patients who underwent myocardial viability testing and had paired imaging (i.e., assessed with the same imaging method at each time point) at baseline and at 4 months for measurement of left ventricular ejection fraction (LVEF). Kaplan–Meier estimates of death from any cause among patients with improvement in LVEF and among patients without such improvement were compared with the use of a Cox proportional- hazards model with adjustment for baseline covariates. Change in Left Ventricular Ejection Fraction, According to Myocardial Status and Treatment Group.

Shown is the least-squares mean change in LVEF from baseline to month 4 in the four subgroups of patients defined according to the presence or absence of viable myocardium and treatment assignment. � bars denote 95% confidence intervals. Discussion

The findings of the current study do not support the concept that assessment of myocardial viability determines the likelihood of long-term benefit from surgical revascularization in patients with ischemic cardiomyopathy. Our study showed a lower incidence of death from any cause with CABG plus medical therapy than with medical therapy alone. However, the tests of interaction between myocardial viability and treatment effect of CABG were not significant for any of the three end points. Therefore, we must conclude that there is no statistical evidence of association between myocardial viability and benefit from CABG. A number of various possibilities, alone or in combination, may account for the negative results of our study. It is certainly possible that a true biologic interaction exists between myocardial viability and the benefit of revascularization and that we were unable to unveil it because of the relatively small number of patients, especially patients without myocardial viability, included in our study. A complementary explanation is that the physiological complexity underpinning the potential therapeutic benefit of surgical revascularization cannot be surmised from the results of a single test of myocardial viability, particularly when those results are expressed in a dichotomous fashion (i.e., patients having or not having viability). In fact, previous results from the STICH trial showed that the degree of left ventricular systolic dysfunction and remodeling and the number of stenotic coronary arteries appear to be stronger determinants of the benefit of revascularization than myocardial viability. A putative mechanism that mediates the benefit of CABG among patients with myocardial viability is the improvement in left ventricular systolic function that results from revascularization. In our study, a modest but significant increase in left ventricular ejection fraction at 4 months was indeed observed among patients with viable myocardium. This increase was similar in patients in the CABG group and those in the medical-therapy group, a finding that is consistent with the known relationship between myocardial viability and improvement in systolic function, both with revascularization and with beta-blocker therapy, that has been reported in previous studies. In conclusion, this 10-year follow-up study of the STICH trial does not confirm the hypothesis that the presence of substantial amounts of viable myocardium is associated with the long-term beneficial effect of CABG. At the same time, our findings indicate that improvement in left ventricular ejection fraction is more likely to occur among patients with myocardial viability, is not restricted to patients who undergo revascularization, and is not an important mechanism for the long-term survival of patients with ischemic cardiomyopathy treated medically or surgically. Drug Effects on the Thyroid

There is a growing list of medications known to adversely affect thyroid function or interpretation of the results of standard thyroid laboratory testing. Many of these drugs are commonly used preparations, ranging from over-the-counter supplements to advanced medical therapy, and include antiarrhythmic agents, antineoplastic agents, and glucocorticoids. The unintended consequences of pharmacologic therapy on the thyroid vary in importance from artifactual laboratory effects to severe thyroid dysfunction. This review provides a systematic approach to drug-induced thyroid dysfunction, with an emphasis on clinically relevant interactions and on artifacts on laboratory assays. Hypothalamic–pituitary control of thyroid function is subject to negative feedback by triiodothyronine (T3). Thyrotropin-releasing hormone (TRH), which is derived from paraventricular neurons in the hypothalamus, stimulates the release of thyrotropin from the pituitary thyrotroph. Pituitary T3 is derived from both the systemic circulation and intrapituitary 5′- deiodination of thyroxine (T4) by type 2 deiodinase. Thyroid hormone synthesis occurs within thyroid follicles, each consisting of hundreds of thyrocytes surrounding a follicular lumen filled with colloid matrix. Thyroglobulin produced in the thyrocyte is secreted into the follicular lumen, where it serves as a backbone for thyroid hormone synthesis. Iodide is actively transported into the thyrocyte through the sodium–iodide symporter (NIS) and then transferred to the follicular lumen through the anion exchange protein . In the lumen, iodide is oxidized and bound to specific tyrosine residues within thyroglobulin. This reaction, and the subsequent coupling of two iodinated tyrosine molecules to form T4 or T3, is catalyzed by thyroid peroxidase (TPO) in a reaction dependent on hydrogen peroxide, which is produced by dual oxidase 2 (DUOX2). Drugs Affecting Hypothalamic–Pituitary Control of the Thyroid The synthetic retinoid bexarotene induces rapid and profound thyrotropin suppression, leading to overt central hypothyroidism in 40 to 70% of treated patients, with recovery of normal function within weeks after drug discontinuation. Immune checkpoint inhibitors, including those that inhibit cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptor, have a variety of adverse endocrine effects. Drugs Affecting Thyroid Hormone Synthesis or Release Excess intrathyroidal iodine inhibits thyroid hormone synthesis, resulting in the Wolff–Chaikoff effect. Although the exact mechanism is unknown, acute inhibition of thyroid peroxidase may occur through the generation of intrathyroidal iodinated compounds such as iodolactones and iodoaldehydes. Amiodarone, a class III antiarrhythmic agent, is 37.3% iodine by weight and undergoes partial deiodination, releasing approximately 7 mg of iodide per 200-mg tablet. Lithium use causes goiter and hypothyroidism by decreasing thyroid hormone release through the inhibition of colloid pinocytosis. In a study involving patients with manic depression, 50% of those treated with lithium had a goiter on thyroid ultrasonography, as compared with 16% of patients who did not receive lithium. Anatomical Sites of Interactions between Drugs and Thyroid Function. Multiple sites of interaction between various drugs and the thyroid have been identified, including central control at the pituitary–hypothalamic level, direct effects on thyroid hormone synthesis, initiation of destructive thyroiditis, interference with protein binding or delivery to target tissues, and interference with activation and disposition of thyroid hormone. Unique drug interactions occur in patients taking exogenous thyroid hormone, including inhibition of pill dissolution and levothyroxine malabsorption. LT4 denotes levothyroxine. Drugs That Enhance Thyroid Autoimmunity Newer drugs designed to promote immune system targeting of cancer cells also increase the risk of autoimmune disorders. Primary thyroid dysfunction is noted variably in the literature as affecting approximately 5 to 10% of patients treated with CTLA-4 inhibitors, 10 to 20% of those treated with PD-1 inhibitors. Drugs Causing Direct Thyroid Damage Amiodarone causes a destructive thyroiditis, referred to as type 2 amiodarone-induced thyrotoxicosis, in 5 to 10% of treated patients. This disorder is believed to result from direct cytotoxic effects of amiodarone on thyrocytes. Drugs Affecting Protein Binding of Thyroid Hormone Several drugs lead to increases in thyroxine-binding globulin, including oral estrogen and selective estrogen- receptor modulators, methadone, heroin, mitotane, and fluorouracil. Conversely, reductions in this protein occur with the use of androgens, glucocorticoids, and niacin. The most common and clinically relevant changes in thyroxine-binding globulin occur with the use of estrogen-containing drugs in patients receiving thyroid hormone replacement therapy. Drugs Affecting Thyroid Hormone Activation, Metabolism, and Excretion

Conversion of T4 to T3 is inhibited by several drugs, including amiodarone, dexamethasone (and other glucocorticoids), propranolol at high doses, the cholecystographic agents ipodate and iopanoic acid (the latter no longer available in the United States), and the antithyroid drug propylthiouracil. Drugs Affecting Absorption of Thyroid Hormone Preparations Thyroid hormone tablets taken orally require an acid milieu for dissolution before being transported to the small bowel for absorption. Biotin-Related Interference in Two-Site Thyrotropin Assay Measurements.

Excess biotin results in variable interference in assays using biotinylated reagents. In two-site (sandwich) assays, including those for thyrotropin, the thyrotropin level is falsely low or undetectable. Assay components include a biotinylated antithyrotropin antibody as the capture antibody and a second antithyrotropin antibody to which a signal component has been attached (Panel A). Under normal conditions, the complex consisting of thyrotropin bound to the two antithyrotropin antibodies, one of which is biotinylated, binds to streptavidin, which has been fixed to a solid phase such as an enzyme-linked immunosorbent assay well. After washing, the signal will be directly proportional to the level of thyrotropin in the specimen (Panel B). In the presence of excess biotin (Panel C), the complex of thyrotropin with the antithyrotropin antibodies cannot compete effectively for streptavidin binding on the solid phase. After washing, a low signal results in a falsely low thyrotropin value (Panel D). Biotin-Related Interference in Competitive Free T4 Immunoassays.

In some competitive immunoassays, including those for free T4, free T3, and thyrotropin receptor antibodies, the results may be falsely elevated. Free T4 assay components include labeled T4 and a biotinylated anti-T4 antibody, as well as streptavidin bound to a solid phase, such as beads coated with streptavidin (Panel A). Free T4 in serum from the patient competes with labeled T4 for binding to the biotinylated anti-T4 antibody (Panel B). The amount of signal after washing will be inversely proportional to the level of free T4 in the patient’s serum. Excess biotin in the serum monopolizes the streptavidin binding sites, preventing binding of either free T4–anti-T4 antibody or labeled T4–anti-T4 antibody complexes (Panel C). Since the patient’s free T4 value in the assay is inversely proportional to the amount of label still present after washing, the low or absent signal leads to calculation of a falsely elevated free T4 value (Panel D). Amiodarone In addition to causing true hypothyroidism and thyrotoxicosis, amiodarone leads to predictable changes in thyroid laboratory test results in euthyroid persons. Inhibition of peripheral and central T4-to-T3 conversion by amiodarone and its major active metabolite, desethylamiodarone, leads to reductions in circulating and intrapituitary T3 levels, thereby stimulating thyrotropin-releasing hormone and thyrotropin release through an absence of negative feedback. Increases in thyrotropin prompt thyroidal release of T4, which accumulates further because of inhibited conversion to T3. The net effect of these changes is a serum thyrotropin level that is elevated or at the high end of the normal range, high levels of total and free T4, and a T3 level at the low end of the normal range in a euthyroid patient. Elevated T4 levels in this context can be confused with primary thyrotoxicosis, but an unsuppressed thyrotropin level rules out this possibility. Heparins Heparin liberates lipoprotein lipase from the vascular endothelium. Blood samples from a patient receiving heparin have increased lipoprotein lipase activity, which persists in vitro. Free thyroid hormone assays with prolonged incubation periods, such as measurement by means of equilibrium dialysis, are most affected, since free fatty acids released by the lipase displace T4 and T3 from binding proteins, causing spuriously high values. Phenytoin, Carbamazepine, and Salsalate

In addition to enhancing the metabolism of thyroid hormone, phenytoin and carbamazepine displace T4 from binding proteins. Although the immediate effect is a transiently elevated free T4 level with reciprocal thyrotropin suppression, both levels are expected to normalize after an equilibrium is reached. Effect of Thyroid Dysfunction on Drug Metabolism Both hyperthyroidism and hypothyroidism can affect the pharmacokinetics and efficacy of common drugs, as well as the frequency of adverse effects. Salient examples include warfarin, with a counterintuitive lower dose requirement during hyperthyroidism as a result of accelerated turnover of vitamin K–dependent clotting factors, and statins, which are associated with an increased risk of myopathy in the presence of hypothyroidism. Conclusions Drugs interact with the thyroid through diverse mechanisms, disrupting control of the thyroid at the hypothalamic– pituitary level, triggering immune and nonimmune thyroid destruction, inducing or aggravating thyroid autoimmunity, and causing both hypothyroidism and thyrotoxicosis. Drugs affect the binding of thyroid hormone to protein carriers and the conversion of T4 to T3, as well as the ultimate metabolism and recycling of thyroid hormone. A 73-year-old man presented to the emergency department with the acute onset of severe lower abdominal pain. He recalled eating yellowtail fish the day before the onset of the pain. His temperature was 38°C, blood pressure 122/69 mm Hg, and heart rate 77 beats per minute. On physical examination, he had tenderness across the lower abdomen with rebound tenderness. Laboratory tests showed a white-cell count of 10,300 per cubic millimeter (reference range, 3300 to 8600) with 83% neutrophils. Computed tomography of the abdomen revealed a thickened gut wall and penetration of the small intestine by a linear, high-density body (Panel A). Laparotomy revealed a small-bowel perforation from a fish bone 2 cm in length (Panel B). Small-bowel resection was performed, and the patient received treatment with antibiotic agents. The postoperative course was uncomplicated, and the patient was discharged home on day 8 after surgery. An 80-year-old man with a history of hypertension presented to the emergency department with a 2-day history of abdominal pain in the right upper quadrant. The patient was febrile. On physical examination, he had abdominal tenderness in the right upper quadrant, and Murphy’s sign was positive. Laboratory studies revealed a white-cell count of 20,000 per cubic millimeter (reference range, 4000 to 10,000). The alanine aminotransferase, aspartate aminotransferase, bilirubin, and lipase levels were normal. Findings on computed tomography of the abdomen included the presence of air encircling an inflamed gallbladder, with air tracking along the wall of the superior mesenteric vein, and a diagnosis of emphysematous cholecystitis was made. Intravenous broad-spectrum antibiotic agents were initiated, and a laparoscopic cholecystectomy was performed. A gangrenous and perforated gallbladder, including two gallstones, was resected. Bile cultures grew Escherichia coli and Klebsiella pneumoniae. The patient recovered after the surgery and was treated with a 10- day course of antibiotics. At a follow-up visit 4 weeks after discharge from the hospital, he was doing well and reported no abdominal pain. A 27-Year-Old Woman with Opioid Use Disorder and Suicidal Ideation

Approximately 3 months before admission, the patient became homeless and was staying intermittently with friends. Two months before admission, she began to ingest clonazepam daily, and 3 weeks before admission, she began to use intranasal heroin daily. She had depression and anxiety, and 2 days before admission, she expressed that she felt “tired of living this life” and wanted “to end it all.” On the evening of presentation, the patient reportedly smashed her cell phone on the ground and ate the glass shards as a suicide attempt. Nausea and diffuse abdominal discomfort developed, and she reportedly had an episode vomiting, with the vomit containing 2 teaspoons (10 ml) of blood. Three hours after the ingestion, she presented to the emergency department of this hospital with throat, chest, and abdominal pain. She reported that she had “regret” about the ingestion and wanted “help” with her substance use and suicidality. On examination, the temperature was 36.8°C, the pulse 70 beats per minute, and the oxygen saturation Coronal and axial images (Panels A and B, 96% while the patient was breathing ambient air. She respectively) of the abdomen and pelvis, obtained appeared disheveled, tearful, and anxious. Abdominal after the administration of intravenous contrast examination revealed mild tenderness on the right side material, show gallbladder wall thickening (arrows) on palpation. On examination by a psychiatrist, she had and trace perihepatic fluid (Panel A, arrowhead). These findings can be seen in patients with acute limited eye contact and mumbling speech, along with hepatitis. There is no evidence of poor concentration, depressed mood with a congruent pneumoperitoneum or of a foreign body. affect, and poor insight and judgment. Intravenous normal saline, morphine sulfate, and piperacillin–tazobactam were administered. The patient was evaluated by the surgery and psychiatry services. Because of concern about the patient’s risk of self- harm, an order that authorized temporary involuntary hospitalization was implemented. The next evening, the patient reported that while she was trying to get out of a stretcher, she “heard a pop” in her right elbow, which was accompanied by immediate pain without any numbness or tingling. On examination by an orthopedic surgeon, the olecranon process appeared to protrude posteriorly and medially without ecchymosis. The patient was not able to move the arm at the elbow, although range of motion was intact at the shoulder and wrist. After the administration of acetaminophen, ibuprofen, oxycodone, and intravenous morphine, the elbow was manually reduced and a splint was applied. Additional radiographic images were obtained. During the next 18 hours, the patient remained under observation, with a plan for transfer to an inpatient psychiatric hospital for ongoing care. One hour before A lateral image of the right elbow obtained after the patient reported that she “heard a pop” (Panel A) shows posterior transfer, the patient went to the bathroom without her dislocation of the elbow with impaction of the olecranon observer and then reported that she could not move her process of the ulna into the distal humerus outside the right arm. olecranon fossa. An anteroposterior image of the right Intravenous morphine was administered. The elbow elbow (Panel B) confirms dislocation of the elbow with was again reduced, and a circumferential fiberglass malalignment of the ulnotrochlear joint (arrowhead) and cast was placed. A lateral image of the right elbow radiocapitellar joint (arrow). A lateral image of the right elbow obtained after closed reduction and splinting (Panel obtained after the second closed reduction and casting C) shows normal alignment. An anteroposterior image of showed normal alignment and the presence of a cast. the right elbow (Panel D) confirms normal alignment of the ulnotrochlear and radiocapitellar joints. The next afternoon, after the plan for transfer to a psychiatric hospital was shared with the patient, she was found in the bathroom without her observer, where she was banging her left arm against the wall. She reported pain, and oral oxycodone and intramuscular hydromorphone were administered. A lateral image of the left elbow obtained hours after the second reduction and casting of the right elbow (Figure 2E) showed posterior dislocation of the left elbow and a fragment from a displaced fracture of the trochlea. There were two screws in the lateral humeral epicondyle from previous open reduction and internal fixation. Intraarticular nerve block was performed. The left elbow was reduced, and a long-arm A lateral image of the left elbow (Panel E) shows circumferential fiberglass cast was placed. posterior dislocation of the elbow and a fragment My concern regarding this patient’s overall engagement and from a displaced fracture of the trochlea. There are two screws in the lateral humeral epicondyle from truthfulness with the team is further confirmed on review of previous open reduction and internal fixation. her subsequent stay in the surgery unit. Over the course of 3 days, the patient had two episodes of seemingly spontaneous dislocation of the right elbow before she was observed actively attempting to dislocate her left elbow. Despite the presence of an observer, details regarding the way in which the first two injuries occurred are scarce; in both cases, the patient reported afterward that the dislocation was spontaneous and claimed to have no insight into the event. Despite prompt orthopedic treatment, she reported clinically significant pain with each dislocation and intravenous opioids were administered. Furthermore, the second and third dislocations had a notable temporal correlation with the planned transfer to an inpatient psychiatric facility, with the injuries occurring mere hours before the transfer was meant to occur. In summary, a young woman with polysubstance use disorder self-presented after a self-reported suicidal gesture, and ultimately, no objective evidence of foreign-body ingestion was discovered. During routine surgical observation for clearance before planned transfer to an inpatient psychiatric facility, the patient appears to have engaged in repeated acts of self-harm, and until she was discovered engaging in such an act, she described each new injury as unintentional. With each incident, she reported clinically significant pain and intravenous opioids were administered. In the presence of intentional and repetitive self-harm, a diagnosis in the category of somatic symptom and related disorders could also be explored. A deception syndrome (factitious disorder or malingering) is a strong consideration, given the multiple inconsistencies in the available information and ultimate evidence of deliberate self-infliction of injuries. To rule out an occult medical cause, I performed a literature search for spontaneous and recurrent elbow dislocations. The review offered limited data but provided reassurance that spontaneous elbow dislocation is an uncommon finding outside specific populations (e.g., children and male athletes), and when it occurs, it is often linked with preexisting joint vulnerability. Psychiatric diagnosis: Severe opioid use disorder and malingering (deception syndrome). Management of Deception Syndromes Only case reports and experience guide the clinical management of malingering. In practice, management occurs in three domains: treatment, shifting of the patient’s strategies, and punishment. Treatment addresses the consequences of self-harm; in this case, it involved casting of the affected limbs. Treating an objective pathologic condition (e.g., an infection or ingestion) must proceed independently of and in parallel with addressing its cause. Psychiatric treatment for malingering focuses on possible coexisting conditions (e.g., substance use or personality disorder). Management of Opioid Use Disorder When treating a patient with opioid use disorder and coexisting acute pain in the inpatient setting, I keep three major components in mind: opioid withdrawal, undertreated pain, and longitudinal treatment through medication- assisted strategies (suboxone or methadone maintenance therapy). In this case, I was concerned about the patient’s risk of opioid withdrawal, given her consistent use of heroin. When I met the patient, it had been 3 days since her last opioid use, so she was still within the window for withdrawal symptoms but had been receiving short-acting opioids for pain along with agents for the management of opioid withdrawal symptoms (dicyclomine for abdominal cramps and acetaminophen for muscle aches). The patient declined treatment for substance use disorder and social-work assistance with shelter. After discharge from the hospital, she presented to the emergency department five times in the following week.

Das Lhermitte-Zeichen ist ein bei der neurologischen Untersuchung prüfbares klinisches Zeichen. Es ist nicht zu verwechseln mit dem Meningismus. Zur Prüfung des Lhermitte-Zeichens wird der Kopf des Patienten passiv nach vorne gebeugt. Bei einem positiven Lhermitte-Zeichen gibt der Patient Missempfindungen (Parästhesien, "elektrisierendes Gefühl") in den Extremitäten oder am Rumpf an. Meistens geht die Missempfindung vom Nacken aus. Ein positives Lhermitte-Zeichen entsteht durch die Dehnung der Hirnhäute durch Beugung der Wirbelsäule im Halsbereich. Es kommt unter anderem bei entzündlichen Veränderungen und Tumoren des Rückenmarks, ausgeprägten Spondylarthrosen und bei der Encephalomyelitis disseminata (Multiple Sklerose) vor.

Jean Jacques Lhermitte (* 20. Januar 1877 in Mont-Saint-Père, Département Aisne; † 24. Januar 1959 in Paris) war ein französischer Neurologe und Neuropsychiater.