Watson–Crick and Sugar-Edge Base Pairing of Cytosine in the Gas Phase: UV and Infrared Spectra of Cytosine·2-Pyridone

While keto-amino cytosine is the dominant species in aqueous solution, spectroscopic studies in molecular beams and in noble gas matrices show that other cytosine tautomers prevail in apolar environments. Each of these offers two or three H-bonding sites (Watson–Crick, wobble, sugar-edge). The mass- and isomer-specific S1 ← S0 vibronic spectra of cytosine·2-pyridone (Cyt·2PY) and 1-methylcytosine·2PY are measured using UV laser resonant two-photon ionization (R2PI), UV/UV depletion, and IR depletion spectroscopy. The UV spectra of the Watson–Crick and sugar-edge isomers of Cyt·2PY are separated using UV/UV spectral hole-burning. Five different isomers of Cyt·2PY are observed in a supersonic beam. We show that the Watson–Crick and sugar-edge dimers of keto-amino cytosine with 2PY are the most abundant in the beam, although keto-amino-cytosine is only the third most abundant tautomer in the gas phase. We identify the different isomers by combining three different diagnostic tools: (1) methylation of the cytosine N1–H group prevents formation of both the sugar-edge and wobble isomers and gives the Watson–Crick isomer exclusively. (2) The calculated ground state binding and dissociation energies, relative gas-phase abundances, excitation and the ionization energies are in agreement with the assignment of the dominant Cyt·2PY isomers to the Watson–Crick and sugar-edge complexes of keto-amino cytosine. (3) The comparison of calculated ground state vibrational frequencies to the experimental IR spectra in the carbonyl stretch and NH/OH/CH stretch ranges strengthen this identification

Copeptin predicts 10-year all-cause mortality in community patients: a 10-year prospective cohort study

Copeptin, the C-terminal part of the arginine vasopressin (AVP) precursor peptide, is secreted in response to stress and correlates with adverse clinical outcomes in the acute-care hospital setting. There are no comprehensive data regarding its prognostic value in the community. We evaluated associations of copeptin levels with 10-year mortality in patients visiting their general practitioner (GP) for a respiratory infection included in a previous trial.; This is a post hoc analysis including data from 359 patients included in the PARTI trial. Copeptin was measured in batch-analysis on admission and after 7 days. We calculated Cox regression models and area under the receiver operating characteristic curve (AUC) to assess an association of copeptin with mortality and adverse outcome. Follow-up data were collected by GP, patient and relative tracing through phone interviews 10 years after trial inclusion.; After a median follow-up of 10.0 years, mortality was 9.8%. Median admission copeptin levels (pmol/L) were significantly elevated in non-survivors compared to survivors (13.8, IQR 5.9-27.8; vs. 6.3 IQR 4.1-11.5; p>0.001). Admission copeptin levels were associated with 10-year all-cause mortality [age-adjusted hazard ratio 1.7 (95% CI, 1.2-2.5); p>0.001, AUC 0.68]. Results were similar for discharge copeptin levels. Copeptin also predicted adverse outcomes defined as death, pulmonary embolism and major adverse cardiac and cerebrovascular events.; In a sample of community-dwelling patients visiting their GP for a respiratory infection, copeptin levels were associated with 10-year all-cause mortality. In conjunction with traditional risk factors, this marker may help to better direct preventive measures in this population

Prospective evaluation of biomarkers for prediction of quality of life in community-acquired pneumonia

Most clinical research investigated prognostic biomarkers for their ability to predict cardiovascular events or mortality. It is unknown whether biomarkers allow prediction of quality of life (QoL) after survival of the acute event. Herein, we investigated the prognostic potential of well-established inflammatory/cardiovascular blood biomarkers including white blood cells (WBC), C-reactive protein (CRP), procalcitonin (PCT), pro-adrenomedullin (proADM) and pro-atrial natriuretic peptide (proANP) in regard to a decline in QoL in a well-defined cohort of patients with community-acquired pneumonia (CAP).; Within this secondary analysis including 753 patients with a final inpatient diagnosis of CAP from a multicenter trial, we investigated associations between admission biomarker levels and decline in QoL assessed by the EQ-5D health questionnaire from admission to day 30 and after 6 years.; Admission proADM and proANP levels significantly predicted decline of the weighted EQ-5D index after 30 days (n=753) with adjusted odds ratios (ORs) of 2.0 ([95% CI 1.1-3.8]; p=0.027) and 3.7 ([95% CI 2.2-6.0]; p>0.001). Results for 6-year outcomes (n=349) were similar with ORs of 3.3 ([95% CI 1.3-8.3]; p=0.012) and 6.2 ([95% CI 2.7-14.2]; p>0.001). The markers were associated with most of the different QoL dimensions including mobility, self-care, and usual activities, but not pain/discomfort and to a lesser degree anxiety/depression and the visual analogue scale (VAS). Initial WBC, PCT and CRP values did not well predict QoL at any time point.; ProADM and proANP accurately predict short- and long-term decline in QoL across most dimensions in CAP patients. It will be interesting to reveal underlying physiopathology in future studies

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

As part of the immune defense during infection, an increase in enzyme activity of indoleamine 2,3-dioxygenase (IDO) leads to a breakdown of tryptophan to kynurenine. In previous animal studies, therapeutic antagonism of IDO resulted in reduced sepsis mortality. We investigated the prognostic ability of tryptophan, serotonin, kynurenine and IDO (represented by the ratio of kynurenine/tryptophan) to predict adverse clinical outcomes in patients with community-acquired pneumonia (CAP).; We measured tryptophan, serotonin and kynurenine on admission plasma samples from CAP patients included in a previous multicenter trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We studied their association with inflammation (C-reactive protein), infection (procalcitonin) and clinical outcome.; Mortality in the 268 included patients was 45% within 6 years of follow-up. IDO and kynurenine showed a strong positive correlation with markers of infection (procalcitonin) and inflammation (C-reactive protein) as well as sepsis and CAP severity scores. Tryptophan showed similar, but negative correlations. In a multivariate regression analysis adjusted for age and comorbidities, higher IDO activity and lower tryptophan levels were strongly associated with short-term adverse outcome defined as death and/or ICU admission within 30 days with adjusted odds ratios of 9.1 [95% confidence interval (CI) 1.4-59.5, p=0.021] and 0.11 (95% CI 0.02-0.70, p=0.021). Multivariate analysis did not reveal significant associations for kynurenine and serotonin.; In hospitalized CAP patients, higher IDO activity and lower tryptophan levels independently predicted disease severity and short-term adverse outcome. Whether therapeutic modulation of IDO has positive effects on outcome needs further investigation

Prospective evaluation of biomarkers for prediction of quality of life in community-acquired pneumonia

AbstractBackground: Most clinical research investigated prognostic biomarkers for their ability to predict cardiovascular events or mortality. It is unknown whether biomarkers allow prediction of quality of life (QoL) after survival of the acute event. Herein, we investigated the prognostic potential of well-established inflammatory/cardiovascular blood biomarkers including white blood cells (WBC), C-reactive protein (CRP), procalcitonin (PCT), pro-adrenomedullin (proADM) and pro-atrial natriuretic peptide (proANP) in regard to a decline in QoL in a well-defined cohort of patients with community-acquired pneumonia (CAP). Methods: Within this secondary analysis including 753 patients with a final inpatient diagnosis of CAP from a multicenter trial, we investigated associations between admission biomarker levels and decline in QoL assessed by the EQ-5D health questionnaire from admission to day 30 and after 6 years. Results: Admission proADM and proANP levels significantly predicted decline of the weighted EQ-5D index after 30 days (n=753) with adjusted odds ratios (ORs) of 2.0 ([95% CI 1.1-3.8]; p=0.027) and 3.7 ([95% CI 2.2-6.0]; p<0.001). Results for 6-year outcomes (n=349) were similar with ORs of 3.3 ([95% CI 1.3-8.3]; p=0.012) and 6.2 ([95% CI 2.7-14.2]; p<0.001). The markers were associated with most of the different QoL dimensions including mobility, self-care, and usual activities, but not pain/discomfort and to a lesser degree anxiety/depression and the visual analogue scale (VAS). Initial WBC, PCT and CRP values did not well predict QoL at any time point. Conclusions: ProADM and proANP accurately predict short- and long-term decline in QoL across most dimensions in CAP patients. It will be interesting to reveal underlying physiopathology in future studies

Copeptin predicts 10-year all-cause mortality in community patients: a 10-year prospective cohort study

AbstractBackground: Copeptin, the C-terminal part of the arginine vasopressin (AVP) precursor peptide, is secreted in response to stress and correlates with adverse clinical outcomes in the acute-care hospital setting. There are no comprehensive data regarding its prognostic value in the community. We evaluated associations of copeptin levels with 10-year mortality in patients visiting their general practitioner (GP) for a respiratory infection included in a previous trial. Methods: This is a post hoc analysis including data from 359 patients included in the PARTI trial. Copeptin was measured in batch-analysis on admission and after 7 days. We calculated Cox regression models and area under the receiver operating characteristic curve (AUC) to assess an association of copeptin with mortality and adverse outcome. Follow-up data were collected by GP, patient and relative tracing through phone interviews 10 years after trial inclusion. Results: After a median follow-up of 10.0 years, mortality was 9.8%. Median admission copeptin levels (pmol/L) were significantly elevated in non-survivors compared to survivors (13.8, IQR 5.9-27.8; vs. 6.3 IQR 4.1-11.5; p<0.001). Admission copeptin levels were associated with 10-year all-cause mortality [age-adjusted hazard ratio 1.7 (95% CI, 1.2-2.5); p<0.001, AUC 0.68]. Results were similar for discharge copeptin levels. Copeptin also predicted adverse outcomes defined as death, pulmonary embolism and major adverse cardiac and cerebrovascular events. Conclusions: In a sample of community-dwelling patients visiting their GP for a respiratory infection, copeptin levels were associated with 10-year all-cause mortality. In conjunction with traditional risk factors, this marker may help to better direct preventive measures in this population

Watson–Crick and Sugar-Edge Base Pairing of Cytosine in the Gas Phase: UV and Infrared Spectra of Cytosine·2-Pyridone

While keto-amino cytosine is the dominant species in aqueous solution, spectroscopic studies in molecular beams and in noble gas matrices show that other cytosine tautomers prevail in apolar environments. Each of these offers two or three H-bonding sites (Watson–Crick, wobble, sugar-edge). The mass- and isomer-specific S1 ← S0 vibronic spectra of cytosine·2-pyridone (Cyt·2PY) and 1-methylcytosine·2PY are measured using UV laser resonant two-photon ionization (R2PI), UV/UV depletion, and IR depletion spectroscopy. The UV spectra of the Watson–Crick and sugar-edge isomers of Cyt·2PY are separated using UV/UV spectral hole-burning. Five different isomers of Cyt·2PY are observed in a supersonic beam. We show that the Watson–Crick and sugar-edge dimers of keto-amino cytosine with 2PY are the most abundant in the beam, although keto-amino-cytosine is only the third most abundant tautomer in the gas phase. We identify the different isomers by combining three different diagnostic tools: (1) methylation of the cytosine N1–H group prevents formation of both the sugar-edge and wobble isomers and gives the Watson–Crick isomer exclusively. (2) The calculated ground state binding and dissociation energies, relative gas-phase abundances, excitation and the ionization energies are in agreement with the assignment of the dominant Cyt·2PY isomers to the Watson–Crick and sugar-edge complexes of keto-amino cytosine. (3) The comparison of calculated ground state vibrational frequencies to the experimental IR spectra in the carbonyl stretch and NH/OH/CH stretch ranges strengthen this identification