What Can We Do About Moles

Reprint from Gardening Without Poisons, Beatrice Trum Hunter, pp. 157-

Mittelfristige Ergebnisse der Chemosynoviorthese mit Natriummorrhuat

Die chemische Synoviorthese mit Natriummorrhuat nimmt eine Zwischenstellung zwischen einer rein medikamentösen Therapie und dem definitiven alloplastischen Gelenkersatz ein. Sie ist unter anderem dann indiziert, wenn der entzündliche Zustand medikamentös nicht mehr beherrscht werden kann, bei �noch- fehlender Indikation für ein operatives Vorgehen sowie speziell beim Befall einzelner Gelenke. Die Rückzugsmöglichkeit auf eine � evtl. komplikationsträchtigere � endoprothetische Versorgung bleibt erhalten. Die gefäßverödenden Eigenschaften des Natriummorrhuat finden klinische Anwendung bei der Behandlung der rheumatoiden Arthritis (RA) und rezidivierender Reizergüsse des Kniegelenkes, oder auch als Ergänzung einer operativen Synovialektomie. In der vorliegenden Studie wurden Patienten nach Chemosynoviorthese (CSO) nachuntersucht. 92 Patienten (w=59, m=33) mit einem Durchschnittsalter von 49 Jahren wurden nach einem mittleren Zeitraum von 3 Jahren untersucht. Jünger als 40 Jahre waren 22 Patienten (25 Kniegelenke). 39 Patienten litten an einer rheumatoiden Arthritis. Es wurde die subjektive Zufriedenheit, Schmerz und Funktion auf der VAS, Aktivitätsgrad, Scores nach Lysholm und Gillquist, sowie KOOS erhoben. Neben objektiv messbaren Parametern wie der Beweglichkeit sind Schmerzfreiheit und die Durchführbarkeit von Alltagsaktivitäten für die Patienten das Leitkriterium zur Beurteilung einer Behandlungsmaßnahme. Die chemische Synoviorthese mit Natriummorrhuat ist ein Eingriff, der den Patientenerwartungen in puncto Schmerzreduktion und Bewegungszugewinn vollends gerecht wird. 57% aller Patienten und 67% der Patienten mit RA waren mit der Behandlung zufrieden. Schmerzen wurden mit 3,7 auf der VAS angegeben, die Funktion mit 69,2% beurteilt. Einen eingeschränkten Aktivitätsgrad gaben vor der Behandlung 91 Patienten an, nach CSO noch 34 Patienten. Der Lysholm Score verbesserte sich von 99% schlechter Ergebnisse auf 43%. Der KOOS verbesserte sich bei 87% der RA und 81% der anderen Patienten. In der Gruppe bis 40 Jahre waren 80% der Patienten mit der CSO zufrieden. Bei allen Patienten war die Aktivität vor CSO eingeschränkt, wohingegen 22 Patienten eine normale Aktivität nach CSO angaben. Der Lysholm Score besserte sich bei 76%, der KOOS bei 92%. Die chemische Synoviorthese ist eine komplikationsarme Behandlungsmethode, die einen Funktionszugewinn ohne neu auftretende relevante kollaterale Instabilitäten sowie eine deutliche Schmerzreduktion und eine hohe Patientenzufriedenheit auch im längerfristigen Verlauf garantiert. Die vorgestellte chemische Synoviorthese mit Natriummorrhuate ist somit neben einer adäquaten medikamentösen Einstellung mit ihren guten Ergebnissen ein wesentlicher Bestandteil eines stadienadaptierten multimodalen Therapiekonzeptes in der Behandlung der rheumatoiden Arthritis. Schlussfolgerung: Bei jungen Patienten empfehlen wir die CSO, da diese überdurchschnittlich gut von der CSO profitieren. Bei älteren Patienten sollte die Indikation vom Einzelfall abhängig gemacht werden

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer

Inhibidores de la aromatasa; Terapia de progestinaAromatase inhibitors; Progestin therapyInhibidors de l'aromatasa; Teràpia amb progestinaBackground Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy. Objective This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy. Study Design Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction–based messenger RNA model to measure the activity of estrogen receptor–related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival. Results Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9–43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2–64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9–68.9) and 75.0% (95% confidence interval, 62.2–87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1–73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20–48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20–52) with an estrogen receptor pathway activity score of >15 had not progressed. Conclusion The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study

Loss of skeletal muscle density during neoadjuvant chemotherapy in older women with advanced stage ovarian cancer is associated with postoperative complications

Objective: To assess the association between loss of lumbar skeletal muscle mass and density during neoadjuvant chemotherapy (NACT) and postoperative complications after interval cytoreductive surgery (CRS) in older patients with ovarian cancer. Materials and methods: This multicenter, retrospective cohort study included patients aged 70 years and older with primary advanced stage ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV), treated with NACT and interval CRS. Skeletal muscle mass and density were retrospectively assessed using Skeletal Muscle Index (SMI) and Muscle Attenuation (MA) on routinely made Computed Tomography scans before and after NACT. Loss of skeletal muscle mass or density was defined as >2% decrease per 100 days in SMI or MA during NACT. Results: In total, 111 patients were included. Loss of skeletal muscle density during NACT was associated with developing any postoperative complication ≤30 days after interval CRS both in univariable (Odds Ratio (OR) 3.69; 95% Confidence Interval (CI) 1.57–8.68) and in multivariable analysis adjusted for functional impairment and WHO performance status (OR 3.62; 95%CI 1.27–10.25). Loss of skeletal muscle density was also associated with infectious complications (OR 3.67; 95%CI 1.42–9.52) and unintended discontinuation of adjuvant chemotherapy (OR 5.07; 95%CI 1.41–18.19). Unlike loss of skeletal muscle density, loss of skeletal muscle mass showed no association with postoperative outcomes. Conclusion: In older patients with ovarian cancer, loss of skeletal muscle density during NACT is associated with worse postoperative outcomes. These results could add to perioperative risk assessment, guiding the decision to undergo surgery or the need for perioperative interventions

Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in isolated mouse ventricular myocytes

BackgroundThe Bruton tyrosine kinase (BTK) inhibitor Ibrutinib is associated with a higher incidence of cardiotoxic side effects including heart failure (HF).ObjectivesIbrutinib is capable of inhibiting PI3K/Akt signaling in neonatal rat ventricular cardiomyocytes when stimulated with insulin-like growth factor 1 (IGF-1). We therefore hypothesized that Ibrutinib might disrupt IGF-1-mediated activation of intracellular Ca handling in adult mouse cardiomyocytes by inhibiting PI3K/Akt signaling.MethodsIsolated ventricular myocytes (C57BL6/J) were exposed to IGF-1 at 10 nmol/L in the presence or absence of Ibrutinib (1 µmol/L) or Acalabrutinib (10 µmol/L; cell culture for 24 ± 2 h). Intracellular Ca handling was measured by epifluorescence (Fura-2 AM) and confocal microscopy (Fluo-4 AM). Ruptured-patch whole-cell voltage-clamp was used to measure ICa. Levels of key cardiac Ca handling proteins were investigated by immunoblots.ResultsIGF-1 significantly increased Ca transient amplitudes by ∼83% as compared to vehicle treated control cells. This was associated with unaffected diastolic Ca, enhanced SR Ca loading and increased ICa. Co-treatment with Ibrutinib attenuated both the IGF-1-mediated increase in SR Ca content and in ICa. IGF-1 treated cardiomyocytes had significantly increased levels of pS473Akt/Akt and SERCA2a expression as compared to cells concomitantly treated with IGF-1 and Ibrutinib. SR Ca release (as assessed by Ca spark frequency) was unaffected by either treatment. In order to test for potential off-target effects, second generation BTK inhibitor Acalabrutinib with greater BTK selectivity and lower cardiovascular toxicity was tested for IGF1-mediated activation of intracellular Ca handling. Acalabrutinib induced similar effects on Ca handling in IGF-1 treated cultured myocytes as Ibrutinib in regard to decreased Ca transient amplitude and slowed Ca transient decay, hence implying a functional class effect of BTK inhibitors in cardiac myocytes.ConclusionsInhibition of BTK by Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in adult ventricular mouse myocytes in the face of disrupted Akt signaling and absent SERCA2a upregulation

: Forschungsbericht im Rahmen der Projektstudienphase 2021/22

Die vorliegende Studie untersuchte Intermedia-Agenda-Setting-Effekte (IAS-Effekte) zwischen Artikeln deutscher Online-Nachrichtenmedien und Beiträgen deutschsprachiger nicht-etablierter Akteure auf Twitter mit Bezug auf den Israel-Gaza-Konflikt im Mai 2021. Zur Untersuchung wurde ein Mixed-Method-Design angewendet. Zunächst wurden mittels qualitativer Inhaltsanalyse Themenfelder, mögliche Desinformationen, sowie identifizierte Miniframes in den Tweets und Online-Artikeln erhoben. Das Twitter-Sample besteht dabei aus Tweets (N = 2585) nicht-etablierter Akteure, die im Untersuchungszeitraum vom 10. Mai bis zum 15. Mai 2021 veröffentlicht wurden. Das Sample der untersuchten Online-Nachrichtenanbieter beinhaltet sämtliche im selben Zeitraum veröffentlichten Artikel (N = 475). In einem zweiten Schritt wurden leitfadengestützte qualitative Expert*inneninterviews durchgeführt, um sich einer Erklärung der Ergebnisse aus der qualitativen Inhaltsanalyse zu nähern. Die Interviews wurden mit Journalist*innen aus fünf unterschiedlichen Redaktionen geführt, wobei das Sample sowohl überregionale als auch regionale sowie private und öffentlich-rechtliche Nachrichtenanbieter abdeckte. Die Ergebnisse der Inhaltsanalyse können eine einseitige Beeinflussung von Twitter auf die ausgewählten deutschen Online-Nachrichtenanbieter nicht bestätigen. Weder direkte Übernahmen von Miniframes noch ein konstanter einseitiger, signifikanter, indirekter Einfluss von Twitter auf die Berichterstattung über den Israel-Gaza-Konflikt lassen sich statistisch nachweisen. Vielmehr sprechen die gewonnen Daten für eine reziproke Orientierung zwischen nicht-etablierten Akteuren auf Twitter und Journalist*innen der Online-Nachrichtenmedien. Gleichzeitig ist festzuhalten, dass etwaige beobachtbare Beeinflussungen in Abhängigkeit von unterschiedlichen Themengebieten sowie von unterschiedlichen Nachrichtenmedien variieren. Die Aussagen aus den Interviews bestätigen die Erkenntnis, dass nicht-etablierte Akteure auf Twitter im Vergleich zu etablierten Akteuren, insbesondere der politischen Elite, nur eine geringe Rolle innerhalb des Produktionsprozesses von Online-Nachrichten spielen. Die Ergebnisse dieser Studie zeigen Potential für weiterführende Forschungen zur Relevanz Sozialer Medien im Journalismus. Insbesondere eine Ausweitung der Untersuchung von IAS in Bezug auf verschiedene, möglicherweise auch nationale Themen sowie zwischen der Berichterstattung verschiedener Nachrichtenanbieter und anderen Sozialer Medien scheint sinnvoll

Empagliflozin inhibits Na + /H + exchanger activity in human atrial cardiomyocytes

Aims Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na+/H(+)exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes. Methods and results Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH(4)(+)pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 mu mol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 mu mol/L, 10 min). Conclusions This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials

CaMKIIδ-dependent dysregulation of atrial Na+ homeostasis promotes pro-arrhythmic activity in an obstructive sleep apnea mouse model

Background: Obstructive sleep apnea (OSA) has been linked to various pathologies, including arrhythmias such as atrial fibrillation. Specific treatment options for OSA are mainly limited to symptomatic approaches. We previously showed that increased production of reactive oxygen species (ROS) stimulates late sodium current through the voltage-dependent Na+ channels via Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), thereby increasing the propensity for arrhythmias. However, the impact on atrial intracellular Na+ homeostasis has never been demonstrated. Moreover, the patients often exhibit a broad range of comorbidities, making it difficult to ascertain the effects of OSA alone. Objective: We analyzed the effects of OSA on ROS production, cytosolic Na+ level, and rate of spontaneous arrhythmia in atrial cardiomyocytes isolated from an OSA mouse model free from comorbidities. Methods: OSA was induced in C57BL/6 wild-type and CaMKIIδ-knockout mice by polytetrafluorethylene (PTFE) injection into the tongue. After 8 weeks, their atrial cardiomyocytes were analyzed for cytosolic and mitochondrial ROS production via laser-scanning confocal microscopy. Quantifications of the cytosolic Na+ concentration and arrhythmia were performed by epifluorescence microscopy. Results: PTFE treatment resulted in increased cytosolic and mitochondrial ROS production. Importantly, the cytosolic Na+ concentration was dramatically increased at various stimulation frequencies in the PTFE-treated mice, while the CaMKIIδ-knockout mice were protected. Accordingly, the rate of spontaneous Ca2+ release events increased in the wild-type PTFE mice while being impeded in the CaMKIIδ-knockout mice. Conclusion: Atrial Na+ concentration and propensity for spontaneous Ca2+ release events were higher in an OSA mouse model in a CaMKIIδ-dependent manner, which could have therapeutic implications

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

Large-scale clinical outcome studies demonstrated the efficacy of SGLT2 inhibitors in patients with type II diabetes. Besides their therapeutic efficacy in diabetes, significant renoprotection was observed in non-diabetic patients with chronic kidney disease (CKD), suggesting the existence of glucose-independent beneficial effects of SGLT2 inhibitors. However, the relevant mechanisms by which SGLT2 inhibition delays the progression of renal injury are still largely unknown and speculative. Previous studies showed that SGLT2 inhibitors reduce diabetic hyperfiltration, which is likely a key element in renoprotection. In line with this hypothesis, this study aimed to investigate the nephroprotective effects of the SGLT2 inhibitor empagliflozin (EMPA) in different mouse models with non-diabetic hyperfiltration and progressing CKD to identify the underlying diabetes-independent cellular mechanisms. Non-diabetic hyperfiltration was induced by unilateral nephrectomy (UNx). Since UNx alone does not result in renal damage, renal disease models with varying degrees of glomerular damage and albuminuria were generated by combining UNx with high NaCl diets ± deoxycorticosterone acetate (DOCA) in different mouse strains with and without genetic predisposition for glomerular injury. Renal parameters (GFR, albuminuria, urine volume) were monitored for 4–6 weeks. Application of EMPA via the drinking water resulted in sufficient EMPA plasma concentration and caused glucosuria, diuresis and in some models renal hypertrophy. EMPA had no effect on GFR in untreated wildtype animals, but significantly reduced hyperfiltration after UNx by 36%. In contrast, EMPA did not reduce UNx induced hyperfiltration in any of our kidney disease models, regardless of their degree of glomerular damage caused by DOCA/salt treatment. Consistent with the lack of reduction in glomerular hyperfiltration, EMPA-treated animals developed albuminuria and renal fibrosis to a similar extent as H2O control animals. Taken together, the data clearly indicate that blockade of SGLT2 has the potential to reduce non-diabetic hyperfiltration in otherwise untreated mice. However, no effects on hyperfiltration or progression of renal injury were observed in hypervolemic kidney disease models, suggesting that high salt intake and extracellular volume might attenuate the protective effects of SGLT2 blockers