Phosphorylation of telokin by cyclic nucleotide kinases and the identification of in vivo phosphorylation sites in smooth muscle

AbstractThe Ca2+-independent acceleration of dephosphorylation of the regulatory light chain of smooth muscle myosin and relaxation of smooth muscle by telokin are enhanced by cyclic nucleotide-activated protein kinase(s) [Wu et al. (1998) J. Biol. Chem. 273, 11362–11369]. The purpose of this study was to determine the in vivo site(s) and in vitro rates of telokin phosphorylation and to evaluate the possible effects of sequential phosphorylation by different kinases. The in vivo site(s) of phosphorylation of telokin were determined in rabbit smooth muscles of longitudinal ileum and portal vein. Following stimulation of ileum with forskolin (20 μM) the serine at position 13 was the only amino acid to exhibit increased phosphorylation. Rabbit portal vein telokin was phosphorylated on both Ser-13 and -19 as a result of forskolin and GTPγS stimulation in vivo. Point mutation of Ser-13 (to Ala or Asp) abolished in vitro phosphorylation by cyclic nucleotide-dependent protein kinases

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Mid-term health-related quality of life in community-acquired bacterial meningitis survivors; the COMBAT study

Background Community Acute Bacterial Meningitis (CABM) is a rare infectious disease leading to important impairments. Our aim was to describe CABM survivors’ quality of life (QOL) 12 months post-CABM and to assess its associations with CABM sequelae. Methods Patients included in the CABM COMBAT cohort were evaluated one year after the CABM episode. Data were collected by questionnaire, via phone calls with the patients. The WHOQOL-BREF was used to measure CABM survivors’ QOL. Hierarchical multivariate linear regressions were performed. Results Study population was composed of 284 patients. At 12 months, 53.9% (153/284) reported at least incident headache/worsening headache intensity at 12 months post-CABM, and/or incident hearing impairment, and/or unfavourable disability outcome (GOS). Unfavourable disability outcome was associated with lower physical health QOL (B = -30.35, pConclusions 12 month-CABM burden is heavy. Early detection and management of CABM impairments should be performed in clinical practice as early as possible to optimize patients’ psychological and psychosocial functioning. ClinicalTrial. Gov identification number NCT01730690

Mid-term health-related quality of life in community-acquired bacterial meningitis survivors; the COMBAT study.

BackgroundCommunity Acute Bacterial Meningitis (CABM) is a rare infectious disease leading to important impairments. Our aim was to describe CABM survivors' quality of life (QOL) 12 months post-CABM and to assess its associations with CABM sequelae.MethodsPatients included in the CABM COMBAT cohort were evaluated one year after the CABM episode. Data were collected by questionnaire, via phone calls with the patients. The WHOQOL-BREF was used to measure CABM survivors' QOL. Hierarchical multivariate linear regressions were performed.ResultsStudy population was composed of 284 patients. At 12 months, 53.9% (153/284) reported at least incident headache/worsening headache intensity at 12 months post-CABM, and/or incident hearing impairment, and/or unfavourable disability outcome (GOS). Unfavourable disability outcome was associated with lower physical health QOL (B = -30.35, pConclusions12 month-CABM burden is heavy. Early detection and management of CABM impairments should be performed in clinical practice as early as possible to optimize patients' psychological and psychosocial functioning.Clinicaltrial. gov identification numberNCT01730690

Reverse Regulatory Pathway (H2S / PGE2 / MMP) in Human Aortic Aneurysm and Saphenous Vein Varicosity.

Hydrogen sulfide (H2S) is a mediator with demonstrated protective effects for the cardiovascular system. On the other hand, prostaglandin (PG)E-2 is involved in vascular wall remodeling by regulating matrix metalloproteinase (MMP) activities. We tested the hypothesis that endogenous H2S may modulate PGE(2), MMP-1 activity and endogenous tissue inhibitors of MMPs (TIMP-1/-2). This regulatory pathway could be involved in thinning of abdominal aortic aneurysm (AAA) and thickening of saphenous vein (SV) varicosities. The expression of the enzyme responsible for H2S synthesis, cystathionine-gamma-lyase (CSE) and its activity, were significantly higher in varicose vein as compared to SV. On the contrary, the endogenous H2S level and CSE expression were lower in AAA as compared to healthy aorta (HA). Endogenous H2S was responsible for inhibition of PGE(2) synthesis mostly in varicose veins and HA. A similar effect was observed with exogenous H2S and consequently decreasing active MMP-1/TIMP ratios in SV and varicose veins. In contrast, in AAA, higher levels of PGE(2) and active MMP-1/TIMP ratios were found versus HA. These findings suggest that differences in H2S content in AAA and varicose veins modulate endogenous PGE(2) production and consequently the MMP/TIMP ratio. This mechanism may be crucial in vascular wall remodeling observed in different vascular pathologies (aneurysm, varicosities, atherosclerosis and pulmonary hypertension)

mPGES-1 expression and PGE₂ production are regulated by H₂S.

<p>Western blot quantifications of microsomal prostaglandin E synthase-1 expression (mPGES-1; normalized to β actin) and representative images are presented. In <b>(A)</b> healthy SV untreated (Ct, black bar) or treated (white bars) with NaHS (10⁻⁵ and 10⁻⁴ mol/L, 24h, n = 4), in (<b>B</b>) healthy aortas (HA, n = 5) and abdominal aneurysmal aortas (AAA, n = 5). PGE₂ content <b>(C)</b> in healthy saphenous veins (SV, n = 14), in small and large diameter varicosities (paired SDv and LDv, n = 14), in <b>(D)</b> healthy aorta (HA, n = 3) and abdominal aortic aneurysm (AAA, n = 3) preparations. PGE₂ concentrations were measured by EIA after 24h incubation with or without the treatments indicated: NaHS (10⁻⁵–10⁻² mol/L, n = 4–5) or CSE inhibitor β-cyano-L-alanine (BCA, 10⁻⁵–10⁻³ mol/L, n = 4–5). *<i>P</i><0.05, ****<i>P</i><0.0001 versus respective untreated healthy vessels without treatment; §<i>P</i><0.05 between SDv and LDv; #<i>P</i><0.05 versus respective control.</p