Zur Frage der Existenz Eines Besonderen Thyreotropen Hormons für Kaltblüter

Ohne Zusammenfassung     

Richard Paltauf

Ohne Zusammenfassung     

Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression

Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell–cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell–cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19.     

17β-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes

17β-Estradiol (E2) rapidly, by binding to membrane estrogen receptors, activates cell signaling cascades which induce formation of new dendritic spines in the hippocampus of males as in females, but the interaction with other metabolic processes, such as extracellular adenine nucleotides metabolism, are currently unknown. Extracellular adenine nucleotides play significant roles, controlling excitatory glutamatergic synapses and development of neural circuits and synaptic plasticity. Their precise regulation in the synaptic cleft is tightly controlled by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)/ecto-5′-nucleotidase (eN) enzyme chain. Therefore, we sought to clarify whether a single systemic injection of E2 in male rats is accompanied by changes in the expression of the pre- and postsynaptic proteins and downstream kinases linked to E2-induced synaptic rearrangement as well as alterations in NTPDase/eN pathway in the hippocampal synaptosomes. Obtained data showed activation of mammalian target of rapamycin and upregulation of key synaptic proteins necessary for spine formation, 24 h after systemic E2 administration. In E2-mediated conditions, we found downregulation of NTPDase1 and NTPDase2 and attenuation of adenine nucleotide hydrolysis by NTPDase/eN enzyme chain, without changes in NTPDase3 properties and augmentation of synaptic tissue-nonspecific alkaline phosphatase (TNAP) activity. Despite reduced NTPDase activities, increased TNAP activity probably prevents toxic accumulation of ATP in the extracellular milieu and also hydrolyzes accumulated ADP due to unchanged NTPDase3 activity. Thus, our initial evaluation supports idea of specific roles of different ectonucleotidases and their coordinated actions in E2-mediated spine remodeling and maintenance.     

Secondary biogenic amine deficiencies: genetic etiology,therapeutic interventions,and clinical effects

neurogenetics - Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that...     

The prognostic role of diabetes mellitus type 2 in the setting of hepatocellular carcinoma: a systematic review and meta-analysis

AimTo evaluate the effect of diabetes mellitus type 2 (T2DM) on the outcomes after treatment of hepatocellular carcinoma (HCC).MethodsPubMed and Cochrane Central Register of Controlled Trials Databases were systematically searched. Three HCC clinical outcomes were explored: death, progressive disease after locoregional therapies, and recurrence. Sub-analysis was performed according to the use of potentially curative (resection, transplantation, termo-ablation) or non-curative therapies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the pooled data between T2DM and non-T2DM groups.ResultsA total of 27 studies were analyzed. Overall, 85.2% of articles were from Asia. T2MD was associated with an increased risk of death (OR 3.60; 95%CI 2.18-5.95; P < 0.001), irrespective of the treatment approach: curative (OR 1.30 95%CI 1.09-1.54; P = 0.003) or non-curative (OR 1.05; 95%CI 1.00-1.10; P = 0.045), increased HCC recurrence (OR 1.30; 95%CI 1.03-1.63; P = 0.03), and increased disease progressiveness (OR 1.24; 95%CI 1.09-1.41; P = 0.001).ConclusionsCurrent data provide strong evidence that T2DM unfavorably affects HCC progression and recurrence, and patients'' survival after treatment, irrespective of the approach used.

The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) is increasing (1,2) as the result of the globally increased prevalence of NALFD, which is estimated to be about 25% (3). NAFLD patients have a two- to three-fold increase in the risk of developing diabetes mellitus type 2 (T2DM), and the risk is even higher in those with more severe hepatic disease and fibrosis (4-6). On the other hand, patients with T2DM have a higher prevalence of non-alcoholic steatohepatitis (NASH), liver fibrosis, and end-stage liver disease (7).Several studies have documented the relation between T2DM and the incidence of different cancer types, while the data on the relationship between T2DM and increased risk of incident HCC seem especially robust and clinically reliable (8-10). Observational studies suggest higher mortality of patients developing HCC in the presence of T2DM (11,12). On the other hand, data from meta-analyses suggest that both the risk and prognosis of patients with HCC and diabetes might be influenced by the type of anti-diabetic treatment, where metformin, unlike sulphonylurea, potentially protects against cancer and leads to better prognosis in case of cancer development (13,14).The underlying mechanisms linking T2DM and HCC are still under scientific scrutiny. However, the interconnections between metabolic derangements characteristic for T2DM, obesity, and NAFLD suggest that insulin resistance on the hepatic and systemic level and the release of pro-inflammatory cytokines, vasoactive factors, and pro-oxidant molecules are potentially implicated in the development and progression of HCC.With the intent to gain a better insight into this issue, we performed a meta-analysis to evaluate the effect of T2DM on poor outcomes after HCC treatment. To explore several different clinical settings, three outcomes of interest were investigated: death, progressive disease after locoregional therapies, and recurrence. Moreover, sub-analyses were performed according to the use of potentially curative (resection, transplantation, termo-ablation) or non-curative therapies.     

Hemangiomas of the external auditory canal:a literature review and two new case reports

Aim  

The aim of this paper is to present two case reports of patients with hemangiomas of the external auditory canal, and to overview all cases published in English language literature so far.     

The Effect of Maternal Dose on Lead Retention in Suckling Rats

Lead (Pb) transfer from mother to litter was investigated at the late stage of lactation after a single intraperitoneal injection of 2.0 μg Pb/ml marked with ²⁰³Pb . After 48 hr almost 20% of the maternal dose of ²⁰³Pb was found in the litter, and about 0.6 and 0.2% of the injected dose was found in the liver and kidneys of suckling rats, respectively. Similar whole-body retention was observed earlier in suckling rats after a 20 times lower dose of stable lead was injected intravenously into their mothers.     

Assessment of Resting-State Blood Flow Through Anterior Cerebral Arteries Using Trans-cranial Doppler Recordings

Trans-cranial Doppler (TCD) recordings are used to monitor cerebral blood flow in the main cerebral arteries. The resting state is usually characterized by the mean velocity or the maximum Doppler shift frequency (an envelope signal) by insonating the middle cerebral arteries. In this study, we characterized cerebral blood flow in the anterior cerebral arteries. We analyzed both envelope signals and raw signals obtained from bilateral insonation. We recruited 20 healthy patients and conducted the data acquisition for 15 min. Features were extracted from the time domain, the frequency domain and the time-frequency domain. The results indicate that a gender-based statistical difference exists in the frequency and time-frequency domains. However, no handedness effect was found. In the time domain, information-theoretic features indicated that mutual dependence is higher in raw signals than in envelope signals. Finally, we concluded that insonation of the anterior cerebral arteries serves as a complement to middle cerebral artery studies. Additionally, investigation of the raw signals provided us with additional information that is not otherwise available from envelope signals. Use of direct trans-cranial Doppler raw data is therefore validated as a valuable method for characterizing the resting state.     

“Marina-Trinkkur” and a few more modern-time hydrotherapeutic myths from the Kvarner region of NW Croatia

Purpose. The present paper tries to address the rise and decay of the sea-water “cult” in regional health tourism in NW Croatia, concentrating upon and analysing more thoroughly the example of Marina, chemicaly processed sea water, an invention of Dr Géza Fodor, the Hungarian physician practicing in that part of Croatia.

Method. The original documents and archived items related to the topic were examined. Furthermore, we investigated numerous comunal bulletins and medical authorities' records of respective time.

Results. Our research showed that the sea-water baths, introduced thanks to the influence of balneologists (like J. Glax), and “drinking cures” (advocated by M.-J. Örtel, for instance) were surprisingly popular not only among tourists of the time, but also among the physicians that used them extensively for therapeutical purposes. These baths and “drinking cures” enriched and completed the medical offer of the resorts regardless of their sometimes dubious effectiveness.

Conclusions. This simple distilled sea-water preparation, advertised as a real panacea, demonstrates a paradigm that elucidates the mentality of physicians, merchants, and patients/consumers of the time.