From the Total Synthesis of Semi-Viriditoxin, Semi-Viriditoxic Acid and Dimeric Naphthopyranones to their Biological Activities in Burkitt B Cell Lymphoma.

Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,ß-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,ß-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all.

Laparoscopic cholecystectomy during the COVID-19 pandemic in a tertiary care hospital in Germany: higher rates of acute and gangrenous cholecystitis in elderly patients.

BACKGROUND: The COVID-19 pandemic caused a global health crisis in 2020. This pandemic also had a negative impact on standard procedures in general surgery. Surgeons were challenged to find the best treatment plans for patients with acute cholecystitis. The aim of this study is to investigate the impact of the COVID-19 pandemic on the outcomes of laparoscopic cholecystectomies performed in a tertiary care hospital in Germany. PATIENTS AND METHODS: We examined perioperative outcomes of patients who underwent laparoscopic cholecystectomy during the pandemic from March 22, 2020 (first national lockdown in Germany) to December 31, 2020. We then compared these to perioperative outcomes from the same time frame of the previous year. RESULTS: A total of 182 patients who underwent laparoscopic cholecystectomy during the above-mentioned periods were enrolled. The pandemic group consisted of 100 and the control group of 82 patients. Subgroup analysis of elderly patients (> 65 years old) revealed significantly higher rates of acute [5 (17.9%) vs. 20 (58.8%); p = 0.001] and gangrenous cholecystitis [0 (0.0%) vs. 7 (20.6%); p = 0.013] in the "pandemic subgroup". Furthermore, significantly more early cholecystectomies were performed in this subgroup [5 (17.9%) vs. 20 (58.8%); p = 0.001]. There were no significant differences between the groups both in the overall and subgroup analysis regarding the operation time, intraoperative blood loss, length of hospitalization, morbidity and mortality. CONCLUSION: Elderly patients showed particularly higher rates of acute and gangrenous cholecystitis during the pandemic. Laparoscopic cholecystectomy can be performed safely in the COVID-19 era without negative impact on perioperative results. Therefore, we would assume that laparoscopic cholecystectomy can be recommended for any patient with acute cholecystitis, including the elderly.

CRISPLD1: a novel conserved target in the transition to human heart failure.

Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are lacking. We sampled myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure and used transcriptomics to study the transition to failure. Sequencing and comparative analysis of analogous samples of mice with transverse aortic constriction identified 25 candidate genes with similar regulation in response to pressure overload, reflecting highly conserved molecular processes. The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is upregulated in the transition to failure in human and mouse and its function is unknown. Homology to ion channel regulatory toxins suggests a role in Ca2+ cycling. CRISPR/Cas9-mediated loss-of-function leads to dysregulated Ca2+ handling in human-induced pluripotent stem cell-derived cardiomyocytes. The downregulation of prohypertrophic, proapoptotic and Ca2+-signaling pathways upon CRISPLD1-KO and its upregulation in the transition to failure implicates a contribution to adverse remodeling. These findings provide new pathophysiological data on Ca2+ regulation in the transition to failure and novel candidate genes with promising potential for therapeutic interventions.

Risk Factors for Postoperative Pulmonary Complications Leading to Increased In-Hospital Mortality in Patients Undergoing Thoracotomy for Primary Lung Cancer Resection: A Multicentre Retrospective Cohort Study of the German Thorax Registry.

Postoperative pulmonary complications (PPCs) represent the most frequent complications after lung surgery, and they increase postoperative mortality. This study investigated the incidence of PPCs, in-hospital mortality rate, and risk factors leading to PPCs in patients undergoing open thoracotomy lung resections (OTLRs) for primary lung cancer. The data from 1426 patients in this multicentre retrospective study were extracted from the German Thorax Registry and presented after univariate and multivariate statistical processing. A total of 472 patients showed at least one PPC. The presence of two PPCs was associated with a significantly increased mortality rate of 7% (p < 0.001) compared to that of patients without or with a single PPC. Three or more PPCs increased the mortality rate to 33% (p < 0.001). Multivariate stepwise logistic regression analysis revealed male gender (OR 1.4), age > 60 years (OR 1.8), and current or previous smoking (OR 1.6), while the pre-operative risk factors were still CRP levels > 3 mg/dl (OR 1.7) and FEV1 < 60% (OR 1.4). Procedural independent risk factors for PPCs were: duration of surgery exceeding 195 min (OR 1.6), the amount of intraoperative blood loss (OR 1.6), partial ligation of the pulmonary artery (OR 1.5), continuing invasive ventilation after surgery (OR 2.9), and infusion of intraoperative crystalloids exceeding 6 mL/kg/h (OR 1.9). The incidence of PPCs was significantly lower in patients with continuous epidural or paravertebral analgesia (OR 0.7). Optimising perioperative management by implementing continuous neuroaxial techniques and optimised fluid therapy may reduce the incidence of PPCs and associated mortality.