Abstract
Peptide hormones and neuropeptides encompass a large class of bioactive peptides that regulate physiological processes like anxiety, blood glucose, appetite, inflammation and blood pressure. ...Here, we execute a focused discovery strategy to provide an extensive map of O-glycans on peptide hormones. We find that almost one third of the 279 classified peptide hormones carry O-glycans. Many of the identified O-glycosites are conserved and are predicted to serve roles in proprotein processing, receptor interaction, biodistribution and biostability. We demonstrate that O-glycans positioned within the receptor binding motifs of members of the neuropeptide Y and glucagon families modulate receptor activation properties and substantially extend peptide half-lives. Our study highlights the importance of O-glycosylation in the biology of peptide hormones, and our map of O-glycosites in this large class of biomolecules serves as a discovery platform for an important class of molecules with potential opportunities for drug designs.
In this study, patients with severe sepsis were assigned to fluid resuscitation with starch (HES 130/0.4) or Ringer's acetate. The starch group had an increased risk of death at day 90 and increased ...use of renal-replacement therapy, as compared with the Ringer's acetate group.
Intravenous fluids are the mainstay of treatment for patients with hypovolemia due to severe sepsis. Colloid solutions are used to obtain rapid and lasting circulatory stabilization, but there are limited data to support this practice.
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The Surviving Sepsis Campaign guidelines recommend the use of either colloids or crystalloids,
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but high-molecular-weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis, as observed in two randomized trials.
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Those trials had substantial limitations, and participants received HES solutions with a molecular weight of 200 kD and a substitution ratio (the number of hydroxyethyl groups per glucose molecule) of . . .
Hydroxyethyl starch (HES) corrected is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.
In ...this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.
Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval CI, 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.
Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.).
Abstract
Background
C-type natriuretic peptide (CNP) is a cardioprotective peptide with high affinity for the ectoenzyme neutral endopeptidase (neprilysin). We aimed to determine whether angiotensin ...receptor-neprilysin inhibitor treatment acutely affects circulating concentrations of bioactive CNP and its molecular amino-terminal precursor (NT-proCNP).
Methods
We included 9 and 10 healthy young men in 2 randomized crossover trials with sacubitril/valsartan vs control (Trial 1) and sacubitril/valsartan and sitagliptin vs sitagliptin (Trial 2). The participants were randomized to a single dose of sacubitril/valsartan (194/206 mg) or control at the first visit 30 min prior to a standardized meal intake. We obtained blood samples at 12 time points over 5 h and measured plasma concentrations of NT-proCNP in both trials and CNP in Trial 2.
Results
NT-proCNP concentrations increased 3.5 h after sacubitril/valsartan treatment, and at 4.5 h concentrations were 42% and 65% higher compared with control in Trial 1 and Trial 2, respectively. The total area under the curve (tAUC)15–270 min was 22% higher (P = 0.007) in Trial 1 and 17% higher with treatment (P = 0.017) in Trial 2. Concentrations of bioactive CNP followed a similar temporal pattern with an increase of 93% at 4.5 h and a 31% higher tAUC15–270 min compared with control (P = 0.001) in Trial 2.
Conclusions
Sacubitril/valsartan augments circulating concentrations of both bioactive CNP and NT-proCNP in healthy young men. The increase in bioactive CNP is most likely caused by de novo synthesis and secretion rather than diminished breakdown through neprilysin inhibition.
ClinicalTrials.gov registration number NCT03717688
Combined inhibition of neprilysin and dipeptidyl peptidase 4 (DPP-4) has been shown to augment plasma concentrations of glucagon-like peptide-1(GLP-1) in animal models, but whether this occurs in ...humans is unknown.
To investigate the effects of inhibition of neprilysin by sacubitril/valsartan alone or in combination with a DPP-4 inhibitor (sitagliptin) on plasma concentrations of GLP-1 in healthy men.
Two open-labeled crossover studies were performed in human subjects.
General community.
Nine and 10 healthy young men were included in study 1 and study 2, respectively.
Study participants received a standardized meal (34% carbohydrates, 45% fat, 21% protein; total caloric content, 2106 kJ) combined with a prior dose of either sacubitril/valsartan (194/206 mg) or control in study 1 and in study 2, with a prior dose of sitagliptin (2 ×100 mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206 mg).
Plasma concentrations of total and intact GLP-1.
Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% total area under the curve (tAUC)0-240min: 3929 ± 344 vs 2348 ± 181 minutes × pmol/L, P = 0.0023 and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021 ± 114 vs 660 ± 80 minutes × pmol/L, P = 0.01). Plasma concentrations of glucose, insulin, and GIP were not significantly (P > 0.10) changed upon sacubitril/valsartan treatment.
Sacubitril/valsartan combined with a DPP-4 inhibitor led to markedly higher concentrations of intact GLP-1 than DPP-4 inhibition alone, supporting a role for both neprilysin and DPP-4 in the metabolism of GLP-1 in humans, a finding that may have therapeutic implications.
Most mammalian protein-coding gene promoters are divergent, yielding promoter upstream transcripts (PROMPTs) in the reverse direction from their conventionally produced mRNAs. PROMPTs are rapidly ...degraded by the RNA exosome rendering a general function of these molecules elusive. Yet, levels of certain PROMPTs are altered in stress conditions, like the DNA damage response (DDR), suggesting a possible regulatory role for at least a subset of these molecules. Here we manipulate PROMPT levels by either exosome depletion or UV treatment and analyze possible effects on their neighboring genes. For the CTSZ and DAP genes we find that TFIIB and TBP promoter binding decrease when PROMPTs accumulate. Moreover, DNA methylation increases concomitant with the recruitment of the DNA methyltransferase DNMT3B. Thus, although a correlation between increased PROMPT levels and decreased gene activity is generally absent, some promoters may have co-opted their divergent transcript production for regulatory purposes.
A large Scandinavian randomized trial showed no important outcome differences between hemoglobin levels of 7 g per deciliter and 9 g per deciliter as transfusion thresholds in patients with septic ...shock.
Blood transfusions are frequently given to patients with septic shock.
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Some of these transfusions are given to patients who are bleeding, but many nonbleeding patients also undergo transfusion.
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The recommendations of the Surviving Sepsis Campaign regarding blood transfusion in patients with septic shock are complex and include a recommendation for transfusion to maintain a hematocrit of more than 30% in the presence of hypoperfusion in the first 6 hours.
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After that, the transfusion threshold should be a hemoglobin level of less than 7 g per deciliter, aiming at levels between 7 g and 9 g per deciliter in patients . . .
Diabetes is an independent risk factor for heart failure. Treatment with a neprilysin inhibitor-angiotensin receptor blocker (sacubitril/valsartan) was demonstrated to improve glycemia and reduce ...time to initiation of insulin therapy but the underlying mechanism(s) are unknown. We hypothesized that sacubitril/valsartan attenuates neprilysin-dependent degradation of GLP-1, and that combined inhibition of the other enzyme cleaving intact GLP-1, dipeptidyl peptidase 4 (DPP-4), would have synergistic effects on levels of intact GLP-1. In two open-labeled clinical trials, a total of 16 healthy men received a standardized meal (34% carbohydrates, 45% fat, 21% protein) combined with a prior single dose of sacubitril (194mg)/valsartan(206mg), sitagliptin (2x100mg), sacubitril(194mg)/valsartan(206mg) and sitagliptin (2x100mg), or control. Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% and had synergistic effects on intact GLP-1 when combined with sitagliptin. Concentrations of glucose, insulin, and GIP were not significantly changed upon sacubitril/valsartan treatment. Sacubitril/valsartan synergistically protects intact GLP-1 when combined with a DPP-4 inhibitor pointing to a therapeutic potential for the combination in patients with cardiovascular disease and diabetes.
Disclosure
N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. P.D. Mark: None. L.H. Hansen: None. U.Ø. Andersen: None. B. Hartmann: None. R.D. Carr: Employee; Self; Merck & Co., Inc. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Merck & Co., Inc. F. Gustafsson: Advisory Panel; Self; Abbott, Corvia Medical, Inc. Consultant; Self; Bayer AG. Employee; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Speaker's Bureau; Self; Novartis AG, Novo Nordisk A/S. C.F. Deacon: Employee; Spouse/Partner; Merck Sharp & Dohme Corp. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. J.P. Gøtze: None. P. Plomgaard: None.
Funding
Rigshopitalet
Sepsis and complications to sepsis are major causes of mortality in critically ill patients. Rapid treatment of sepsis is of crucial importance for survival of patients. The infectious status of the ...critically ill patient is often difficult to assess because symptoms cannot be expressed and signs may present atypically. The established biological markers of inflammation (leucocytes, C-reactive protein) may often be influenced by other parameters than infection, and may be unacceptably slowly released after progression of an infection. At the same time, lack of a relevant antimicrobial therapy in an early course of infection may be fatal for the patient. Specific and rapid markers of bacterial infection have been sought for use in these patients.
Multi-centre randomized controlled interventional trial. Powered for superiority and non-inferiority on all measured end points. Complies with, "Good Clinical Practice" (ICH-GCP Guideline (CPMP/ICH/135/95, Directive 2001/20/EC)). Inclusion: 1) Age > or = 18 years of age, 2) Admitted to the participating intensive care units, 3) Signed written informed consent.Exclusion: 1) Known hyper-bilirubinaemia. or hypertriglyceridaemia, 2) Likely that safety is compromised by blood sampling, 3) Pregnant or breast feeding. Computerized Randomisation: Two arms (1:1), n = 500 per arm: Arm 1: standard of care. Arm 2: standard of care and Procalcitonin guided diagnostics and treatment of infection. Primary Trial Objective: To address whether daily Procalcitonin measurements and immediate diagnostic and therapeutic response on day-to-day changes in procalcitonin can reduce the mortality of critically ill patients.
For the first time ever, a mortality-endpoint, large scale randomized controlled trial with a biomarker-guided strategy compared to the best standard of care, is conducted in an Intensive care setting. Results will, with a high statistical power answer the question: Can the survival of critically ill patients be improved by actively using biomarker procalcitonin in the treatment of infections? 700 critically ill patients are currently included of 1000 planned (June 2008). Two interim analyses have been passed without any safety or futility issues, and the third interim analysis is soon to take place. Trial registration number at clinicaltrials.gov: Id. nr.: NCT00271752).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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