Notes

Connection of DUX4 and target gene phrase within FSHD myocytes.
There has been a global outbreak of coronavirus disease 2019 (COVID-19) since December 2019. In clinical practice, not only fever and respiratory tract symptoms but also multiple organ symptoms are observed in patients diagnosed with COVID-19. Herein, we report a rare case of a patient diagnosed with COVID-19 who manifested with concomitant neurological symptoms. The patient developed fever and respiratory symptoms at disease onset, followed by muscle soreness, and subsequently altered consciousness and psychiatric symptoms, with positive signs based on neurological examination. The patient tested positive for the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) nucleic acid (throat swab). Further, chest computed tomography (CT) revealed typical COVID-19 findings, and head CT did not reveal significant abnormalities. The patient recovered after treatment and was discharged. This rare case indicates that SARS-CoV-2 can invade the central nervous system, thus causing neurological symptoms and signs. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.The discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the outbreak of coronavirus disease 2019 (COVID-19) are causing public health emergency. A handful of literatures have summarized its clinical and radiologic features, whereas therapies for COVID-19 are rather limited. In order to evaluate the efficacy of convalescent plasma therapy in COVID-19 patients, we did this timely descriptive study. 6 laboratory confirmed COVID-19 patients were enrolled and received the transfusion of ABO-compatible convalescent plasma. The efficacy of this intervention was determined by the alleviation of symptoms, changes in radiologic abnormalities and laboratory tests. No obvious adverse effect observed during the treatment. Transfusion of convalescent plasma led to a resolution of ground glass opacities (GGOs) and consolidation in patient #1, #2, #3, #4 and #6. In patient #1 and #5 who presented with SARS-CoV-2 in throat swab, convalescent plasma therapy elicited an elimination of virus. Serologic analysis indicated an immediate increase in anti-SARS-CoV-2 antibody titers in patient #2 and #3, but not in patient #1. This study indicates that convalescent plasma therapy is effective and specific for COVID-19. This intervention has a special significance for eliminating SARS-CoV-2 and is believed to be a promising state-of-art therapy during COVID-19 pandemic crisis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Thunderstorm asthma risk in geographic regions with temperate grasses is strongly correlated with the trifecta of ryegrass pollen (RGP) sensitization (serum RGP-specific IgE), seasonal allergic rhinitis (SAR) and exposure to a thunderstorm during the pollen season.[1,2] Perennial ryegrass (Lolium perenne) is a wind-pollinated pasture grass prevalent in southeastern Australia, North America and Southern Europe. This article is protected by copyright. All rights reserved.Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now overwhelming spreading in the world. As of April 11, 2020, totally 1.61 million COVID-19 patients were confirmed in more than 200 countries and regions with 99690 deaths. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.COVID-19 infection and its severity can be explained by the concentration of glycosylated SARS- CoV-2 viral particles in the lung epithelium, the concentration of glycosylated angiotensin converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8-10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV- 2 spike protein form at day 7-10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It is also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Recently, the first case of HIV and SARS-CoV-2 infection was reported in the literature. With this letter, we proposed a hypothesis that could explain the interaction between HIV infection and the clinical course of SARS-CoV-2 infection. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE Biased agonism describes the ability of ligands to differentially regulate multiple signalling pathways when coupled to a single receptor. Signalling is affected by rapid agonist-induced receptor internalisation. Hence, the conventional use of equilibrium models may not be optimal, because (i) receptor numbers vary with time and, in addition, (ii) some pathways may show non-monotonic profiles over time. EXPERIMENTAL APPROACH Data were available from internalisation, cAMP inhibition and phosphorylation of ERK (pERK) of the cannabinoid-1 (CB1 ) receptor using a concentration series of six CB1 ligands (CP55,940, WIN55,212-2, anandamide, 2-arachidonylglycerol, Δ9 -tetrahydrocannabinol, BAY59,3074). The joint kinetic model of CB1 signalling was developed to simultaneously describe the time-dependent activities in three signalling pathways. Based on the insights from the kinetic model, fingerprint profiles of CB1 ligand bias were constructed and visualised. KEY RESULTS A joint kinetic model was able to capture the signalling profiles across all pathways for the CB1 receptor simultaneously for a system that was not at equilibrium. WIN55,212-2 had a similar pattern as 2-arachidonylglycerol (reference). The other agonists displayed bias towards internalisation compared to cAMP inhibition. However, only Δ9 -tetrahydrocannabinol and BAY59,3074 demonstrated bias in the pERK-cAMP pathway comparison. Furthermore, all the agonists exhibited little preference between internalisation and pERK. CONCLUSION AND IMPLICATIONS This is the first joint kinetic assessment of biased agonism at a GPCR (e.g., CB1 receptor) under non-equilibrium conditions. Kinetic modelling is a natural method to handle time-varying data when traditional equilibria are not present and enables quantification of ligand bias. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE Type 2 diabetes is one of the most severe chronic diseases and is becoming an increasingly serious public health trouble worldwide. There are several glucagon-like peptide-1 receptor agonists (GLP-1RAs) were developed to treat the type 2 diabetes. However, most of them are injectable form, which immensely reduce the tolerance of patients and increase the risk of infection. Here, we designed a novel orally available GLP-1RA with only replacing the amino acids in exendin-4, named oral hypoglycemic peptide 2 (OHP2), and investigated the pharmacokinetic profiles, therapeutic effects and absorption mechanism of it. EXPERIMENTAL APPROACH Healthy Wistar rats were applied for pharmacokinetic research. Diabetic db/db mice were administrated with OHP2 for 8 weeks to evaluate the effects on hyperglycemia, dyslipidemia, basal metabolism, tissue injury. Moreover, the endocytosis and transcytosis mechanism of OHP2 were explored by using the Caco-2 cell monolayer model. KEY RESULTS The absolute bioavailability of OHP2 at 1.31% revealed the orally available of it. In db/db mice, OHP2 exhibits great potential in glucose-lowing and weight loss by oral administration in a dosage dependent manner. OHP2 also alleviates hyperlipidemia, ameliorates the energy metabolism, and promotes tissue repair in diabetic mice. Furthermore, we found that the uptake of OHP2 is dependent on caveolae-mediated transcytosis rather than GLP-1R-mediated endocytosis. CONCLUSIONS AND IMPLICATIONS Our findings indicated that OHP2 could be used as a potential oral candidate for the treatment of type 2 diabetes and the uncovered transcytosis mechanism could help us to develop absorption enhancers of OHP2 in the future. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE BF2.649 (pitolisant, Wakix®) is a novel histamine H3 receptor (H3R) inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo H3R occupancy of BF2.649 using positron emission tomography (PET) brain imaging with the H3R antagonist radioligand [11 C]GSK189254. EXPERIMENTAL APPROACH Six healthy adult participants were scanned with [11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 hours after oral administration of placebo or after pitolisant hydrochloride (40 mg). [11 C]GSK189254 regional total distribution volumes were estimated in 9 brain regions of interest with the 2 tissue-compartment model with arterial input function using a common VND across the regions. Brain receptor occupancies were calculated with the Lassen plot. KEY RESULTS Pitolisant 40 mg promoted 84±7% (x̅±SD) occupancy of H3R. The drug was well -tolerated and participants experienced few adverse events. CONCLUSION AND IMPLICATIONS The administration of pitolisant 40 mg produces a high occupancy of H3R and may bea new tool for the treatment of various central nervous system disorders that are associated with H3R mechanisms. This article is protected by copyright. All rights reserved.We are presenting the difficulties we encountered with the female patient with previously diagnosed primary pigmented nodular adrenal disease (PPNAD) and conflicting hormonal and radiological findings a few years later. The patient underwent unilateral adrenalectomy in 2010. Despite repeated search, no other components of Carney's complex have ever been discovered. 8 years later, she was diagnosed with ACTH-dependant Cushing's syndrome. Pituitary MRI showed a lesion of less than 3 mm on the left side of adenohypophysis (suggesting microadenoma) and bilateral inferior petrosal sinus sampling (BIPSS) confirmed this suspicion. The patient underwent effective transsphenoidal adenomectomy and is now eucortisolaemic. The genetic testing for PRKAR1A mutations was negative and the second histopathological evaluation raised some considerable doubts whether the diagnosis of PPNAD was stated correctly.INTRODUCTION Peptide Receptor Radionuclide Therapy (PRRT) using radiolabeled somatostatin analogues is a treatment option for patients with disseminated neuroendocrine tumours (NET). The aim of the study was evaluation the role of [18F]FDG PET/CT in predicting response, progression-free survival (PFS) and overall survival (OS) after tandem therapy [90Y]Y/[177Lu]Lu-DOTATATE. MATERIAL AND METHODS 75 patients with histopathologically proven NET G1 and G2 were included in the study. Before treatment [68Ga]Ga-DOTATATE PET/CT and [18F]FDG PET/CT was performed. Patients were treated with [90Y]Y/[177Lu]Lu-DOTATATE (11) with mixed amino-acid infusion for kidney protection. RESULTS PFS was 22.2 months for patients [18F]FDG positive and 59.3 months for [18F]FDG negative (p=0.003). The OS from diagnosis (OS-D) and from the start of PRRT (OS-T) was not reached in [18F]FDG negative patients, in [18F]FDG positive patients was 71.8 months and 55.8 months respectively. The observed overall 1-year survival in [18F]FDG positive vs [18F]FDG negative was 96.
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