Sicherheit und Wirksamkeit von subkutan angewendetem GA-EPO zur Behandlung der Anämie bei Patienten mit chronischer Niereninsuffizienz

Bei 16 niereninsuffizienten Patienten wurden Hämoglobin, Hämatokrit, hypochrome Erythrozyten, Serumferritin sowie Transferrinsättigung als Wirksamkeitsparameter bestimmt. Als Sicherheitsparameter dienten Thrombozyten- und Leukozytenzahl, Aluminiumspiegel, Parathormon sowie Blutdruck, Sollgewicht und unerwünschte Ereignisse. Zum Vergleich mit rHuEPO wurden Daten von 6 Monaten vor Studienbeginn herangezogen. Ziel war ein Hämoglobinwert zwischen 10-12 g/dl. Der Hämoglobinspiegel stieg unter GA-EPO-Therapie und Eisensubstitution initial auf 12,5 g/dl an und lag bei Studienende bei 11,2 g/dl. Serumferritin und Transferrinsättigung verzeichneten einen adäquaten Anstieg, die hypochromen Erythrozyten fielen im Sinne einer eisensuffizienten Erythropoese ab. Insgesamt konnte eine Reduktion der EPO-Dosis um 31% verzeichnet werden. Vom Sicherheitsprofil unterschied sich GA-EPO nicht von rHuEPO. GA-EPO ist ein dem rHuEPO vergleichbares Medikament zur Anämiekorrektur bei chronischer Niereninsuffizienz. Der deutliche Hämoglobinanstieg kann jedoch sowohl der GA-EPO-Therapie als auch der Eisensubstitution zu Grunde liegen

On the popularity of agentic and communal narcissists: The tit-for-tat hypothesis

Among well-acquainted people, those high on agentic narcissism are less popular than those low on agentic narcissism. That popularity-difference figures prominently in the narcissism literature. But why are agentic narcissists less popular? We propose a novel answer―the tit-for-tat hypothesis. It states that agentic narcissists like other people less than non-narcissists do and that others reciprocate by liking agentic narcissists less in return. We also examine whether the tit-for-tat hypothesis generalizes to communal narcissism. A large round-robin study (N = 474) assessed agentic and communal narcissism (Wave 1) and included two round-robin waves (Waves 2-3). The round-robin waves assessed participants’ liking for all round-robin group members (2,488 informant-reports). The tit-for-tat hypothesis applied to agentic narcissists. It also applied to communal narcissists, albeit in a different way. Compared with non-narcissists, communal narcissists liked other people more and―in return―those others liked communal narcissists more. Our results elaborate on and qualify the thriving literature on narcissists’ popularity

The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid β Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer’s Disease

Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer’s disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients’ brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile

The CARF protein MM_0565 affects transcription of the casposon-encoded cas1-solo gene in Methanosarcina mazei Gö1

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) loci are found in bacterial and archaeal genomes where they provide the molecular machinery for acquisition of immunity against foreign DNA. In addition to the cas genes fundamentally required for CRISPR activity, a second class of genes is associated with the CRISPR loci, of which many have no reported function in CRISPR-mediated immunity. Here, we characterize MM_0565 associated to the type I-B CRISPR-locus of Methanosarcina mazei Gö1. We show that purified MM_0565 composed of a CRISPR-Cas Associated Rossmann Fold (CARF) and a winged helix-turn-helix domain forms a dimer in solution; in vivo, the dimeric MM_0565 is strongly stabilized under high salt stress. While direct effects on CRISPR-Cas transcription were not detected by genetic approaches, specific binding of MM_0565 to the leader region of both CRISPR-Cas systems was observed by microscale thermophoresis and electromobility shift assays. Moreover, overexpression of MM_0565 strongly induced transcription of the cas1-solo gene located in the recently reported casposon, the gene product of which shows high similarity to classical Cas1 proteins. Based on our findings, and taking the absence of the expressed CRISPR locus-encoded Cas1 protein into account, we hypothesize that MM_0565 might modulate the activity of the CRISPR systems on different levels

The Risk of Acute Kidney Injury and Its Impact on 30-Day and Long-Term Mortality after Transcatheter Aortic Valve Implantation

Background. Transcatheter aortic valve implantation (TAVI) is widely used in high risk patients (pts) with aortic stenosis. Underlying chronic kidney disease implicates a high risk of postprocedural acute kidney injury (AKI). We analyzed its occurrence, impact on hospital stay, and mortality. Methods. 150 consecutive pts underwent TAVI in our institution (mean age 81 ± 7 years; logistic EuroSCORE 24 ± 15%). AKI definition was a creatinine rise of 26.5 μmol/L or more within 48 hours postprocedural. Ten patients on chronic hemodialysis were excluded. Results. AKI occurred in 28 pts (20%). Baseline creatinine was higher in AKI pts (126.4 ± 59.2 μmol/L versus 108.7 ± 45.1 μmol/L, P=0.09). Contrast media use was distributed evenly. Both, 30-day mortality (29% versus 7%, P<0.0001) and long-term mortality (43% versus 18%, P<0.0001) were higher; hospital stay was longer in AKI pts (20 ± 12 versus 15 ± 10 days, P=0.03). Predicted renal failure calculated STS Score was similar (8.0 ± 5.0% [AKI] versus 7.1 ± 4.0% [non-AKI], P=0.32) and estimated lower renal failure rates than observed. Conclusion. AKI remains a frequent complication with increased mortality in TAVI pts. Careful identification of risk factors and development of more suitable risk scores are essential

Secondary Prevention in Lower Extremity Artery Disease Patients: Lipid-Lowering Therapy and Long-Term Guideline Adherence

Lower extremity artery disease (LEAD) affects millions of elderly patients and is associated with elevated cardiovascular morbidity and mortality. Risk factor modification, including the therapy of dyslipidaemia, is mandatory to reduce cardiovascular event rates and to improve survival rates. However, only a minority achieve the recommended low-density lipoprotein cholesterol (LDL-C) target level &lt; 55 mg/dL, according to the current ESC/EAS guidelines on the treatment of dyslipidaemia. This study elucidated the implementation of the lipid-lowering guideline recommendations of 400 LEAD patients with LDL-C &gt; 100 mg/dL and their adherence to treatment adjustment during follow-up. Despite a sustained statin prescription in 93% of the patients, including 77% with high-intensity statins at follow-up, only 18% achieved the target level. Ezetimibe appeared in 21% and LDL-C goals were reached significantly more often with combination therapy. Recurrent revascularization appeared more often (28%) than coronary artery or cerebrovascular disease progression (14%) and 7% died. Despite the frequent use of high-intensity statins and expandable rates of ezetimibe, the progression of cardiovascular events remained inevitable. Only 18% of the patients had received recommendations on lifestyle modification, including dietary adaptations, which is key for a holistic approach to risk factor control. Thus, efforts for both pharmacological and behavioral strategies are needed to improve clinical outcomes and survival rates

Medikamentöse Sekundärprävention bei Patienten mit peripherer arterieller Verschlusskrankheit

Background!#!Peripheral arterial occlusive disease (PAOD) is an atherosclerotic vascular disease with high morbidity and mortality. A consistent medication-based secondary prevention is part of the essential and evidence-based treatment of PAOD. The aim of this study was to ascertain the status quo of medicinal secondary prevention based on submitted prescriptions.!##!Methods!#!In the time period from 2014 to 2017 patients with a confirmed PAOD coding (I70.2-/I73.9-) were identified based on secondary data of the Association of Statutory Health Insurance Physicians Westphalia-Lippe (KVWL). The prescriptions submitted with respect to platelet inhibitors, oral anticoagulants, lipid lowering therapy (LLT) and angiotensin-converting enzyme (ACE) inhibitors in the fourth quarter year after diagnosis coding were collated.!##!Results!#!In the diagnosis period 2014/2015 a total of 238,397 patients had PAOD in the catchment area of the KVWL. The proportion of submitted prescriptions in the fourth quarter year after diagnosis was 25.9% for LLT, 13.6% for acetylsalicylic acid, 4.5% for clopidogrel, 5.5% for vitamin K antagonists (VKA), 3.5% for non-vitamin K‑dependent oral anticoagulants (NOAC) and 26.8% for ACE inhibitors. Over the course of the 3 years (n = 241,375 patients with PAOD 2016/2017) the proportion of submitted prescriptions for all substances except VKA increased (p &amp;lt; 0.001), whereby the largest relative increase was noted for NOAC (relative increase of 81.7%).!##!Conclusion!#!The guideline-conform medicinal secondary prevention in patients with PAOD in Germany is still in need of improvement. A consistent implementation of evidence-based medicinal secondary prevention harbors a great potential for improvement of the overall prognosis in patients with PAOD

Study protocol of an open-label, single arm phase II trial investigating the efficacy, safety and quality of life of neoadjuvant chemotherapy with liposomal irinotecan combined with Oxaliplatin and 5-fluorouracil/Folinic acid followed by curative surgical resection in patients with hepatic Oligometastatic adenocarcinoma of the pancreas (HOLIPANC)

Background: According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available. Methods: In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection. Discussion: This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer