C1 esterase inhibitor and the contact system in COVID-19

Coronavirus disease 2019 (COVID-19) is frequently associated with severe systemic consequences, including vasculitis, a hyperinflammatory state and hypercoagulation. The mechanisms leading to these life-threatening abnormalities are multifactorial. Based on the analysis of publicly available interactomes, we propose that severe acute respiratory syndrome coronavirus-2 infection directly causes a deficiency in C1 esterase inhibitor, a pathogen-specific mechanism that may help explain significant systemic abnormalities in patients with COVID-19.     

Ethanol-Induced Extracellular Signal Regulated Kinase: Role of Dopamine D1 Receptors

Background:  Addictive drugs activate extracellular signal regulated kinase (ERK) in brain regions critically involved in their affective and motivational properties. The aim of this study was to demonstrate the ethanol-induced activation of ERK in the nucleus accumbens (Acb) and in the extended amygdala [bed nucleus of the stria terminalis lateralis (BSTL) and central nucleus of the amygdala (CeA)] and to highlight the role of dopamine (DA) D₁ receptors in these effects.
Methods:  Ethanol (0.5, 1, and 2 g/kg) was administered by gavage and ERK phosphorylation was determined in the nucleus Acb (shell and core), BSTL, and CeA by immunohistochemistry. The DA D₁ receptor antagonist, SCH 39166 (SCH) (50 μg/kg), was administered 10 minutes before ethanol (1 g/kg).
Results:  Quantitative microscopic examination showed that ethanol, dose-dependently increased phospho-ERK immunoreactivity (optical and neuronal densities) in the shell and core of nucleus Acb, BSTL, and CeA. Pretreatment with SCH fully prevented the increases elicited by ethanol (1 g/kg) in all brain regions studied.
Conclusions:  The results of this study indicate that ethanol, similar to other addictive drugs, activates ERK in nucleus Acb and extended amygdala via a DA D₁ receptor-mediated mechanism. Overall, these results suggest that the D₁ receptors/ERK pathway may play a critical role in the motivational properties of ethanol.     

Growth hormone response to growth hormone-releasing hormone in normal and uraemic children. Comparison with hypoglycaemia following insulin administration

The uraemic syndrome is characterized by several endocrinological disturbances. This study was undertaken in order to evaluate the GH response to growth hormone-releasing hormone (GRH) in children with chronic renal failure (CRF) and to compare the results with those observed after insulin hypoglycaemia. Twenty-two children with CRF, 10 undergoing continuous ambulatory peritoneal dialysis (CAPD) and 12 on conservative treatment (CT), age ranges 2-15 years, were studied and the data were compared with those from 14 children with normal renal function and normal hormonal behaviour, affected by short stature (NC), and those form 13 healthy adult volunteers (NA). The GRH test (l micrograms/kg body weight, iv) was carried out in 8 CAPD, 8 CT, 9 NC and 10 NA subjects. The blood samples were taken every 30 min for 3 h in CAPD and CT and for 2 h in NC and NA starting at 09.00 h. The following hormones were measured: GH, LH, FSH, Prl, TSH and cortisol (F). The insulin test (0.1 U/kg body weight, iv) was carried out in 5 CAPD, 5 CT, 10 NC and 9 NA on blood samples taken every 30 min for 2 h, measuring GH and glycaemia. No adverse effects were observed after the infusion of GRH. GRH administration induced a prompt response in all subjects, but GH plasma levels were significantly higher in uraemic children than in adults (peak value of 43.5 +/- 8.2, 45.0 +/- 8.4, 27.8 +/- 6.0; 13.5 +/- 2.6 micrograms/ml in CAPD, CT, NC and NA, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Congenital hypofibrinogenemia: characterization of two missense mutations affecting fibrinogen assembly and secretion

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by abnormally low levels of fibrinogen in plasma, generally due to heterozygous mutations in one of the three fibrinogen genes (FGA, FGB, and FGG, coding for Aα, Bβ, and γ chain, respectively). Hypofibrinogenemic patients are usually asymptomatic, whereas individuals bearing similar mutations in the homozygous or compound heterozygous state develop a severe bleeding disorder: afibrinogenemia. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations affecting fibrinogen assembly or secretion, distributed throughout the 50-kb fibrinogen gene cluster. In this study, we report the mutational screening of two unrelated hypofibrinogenemic patients leading to the identification of two missense mutations, one hitherto unknown (αCys45Phe), and one previously described (γAsn345Ser). The involvement of αCys45Phe and γAsn345Ser in the pathogenesis of hypofibrinogenemia was investigated by in-vitro expression experiments. Both mutations were demonstrated to cause a severe impairment of intracellular fibrinogen processing, either by affecting half-molecule dimerization (αCys45Phe) or by hampering hexamer secretion (γAsn345Ser).