Accumulation of advanced glycation end (AGEs) products in intensive care patients: an observational, prospective study

<p>Abstract</p> <p>Background</p> <p>Oxidative stress plays an important role in the course and eventual outcome in a majority of patients admitted to the intensive care unit (ICU). Markers to estimate oxidative stress are not readily available in a clinical setting. AGEs accumulation has been merely described in chronic conditions, but can also occur acutely due to oxidative stress. Since AGEs have emerged to be stable end products, these can be a marker of oxidative stress. Skin autofluorescence (AF) is a validated marker of tissue content of AGEs. We hypothesized that AGEs accumulate acutely in ICU patients.</p> <p>Methods</p> <p>We performed an observational prospective study in a medical surgical ICU in a university affiliated teaching hospital. All consecutively admitted ICU patients in a 2 month period were included. Skin AF was measured using an AGE reader in 35 consecutive ICU patients > 18 yrs. As a comparison, historical data of a control group (n = 231) were used. These were also used to calculate age-adjusted AF-levels (AF_adj). Values are expressed as median and interquartile range [P₂₅-P₇₅]. Differences between groups were tested by non parametric tests. P < 0.05 was considered statistically significant.</p> <p>Results</p> <p>AF_adjvalues were higher in ICU patients (0.33 [0.00 - 0.68]) than in controls (-0.07 [-0.29 - 0.24]; P < 0.001). No differences in skin AF_adjwere observed between acute or planned admissions, or presence of sepsis, nor was skin AF_adjrelated to severity of disease as estimated by APACHE-II score, length of ICU, hospital stay or mortality.</p> <p>Conclusion</p> <p>Acute AGE accumulation in ICU patients was shown in this study, although group size was small. This can possibly reflect oxidative stress in ICU patients. Further studies should reveal whether AGE-accumulation will be a useful parameter in ICU patients and whether skin AF has a predictive value for outcome, which was not shown in this small study.</p

Infusion fluids contain harmful glucose degradation products

PURPOSE: Glucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients' blood. METHODS: The content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated. RESULTS: All investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing. CONCLUSIONS: These findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients

Consensus Paper: Cerebellum and Social Cognition.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions

Early Release Science of the exoplanet WASP-39b with JWST NIRSpec G395H

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordData Availability: The data used in this paper are associated with JWST program ERS 1366 (observation #4) and are available from the Mikulski Archive for Space Telescopes (https://mast.stsci.edu). Science data processing version (SDP_VER) 2022_2a generated the uncalibrated data that we downloaded from MAST. We used JWST Calibration Pipeline software version (CAL_VER) 1.5.3 with modifications described in the text. We used calibration reference data from context (CRDS_CTX) 0916, except as noted in the text. All the data and models presented in this publication can be found at 10.5281/zenodo.7185300.Code Availability: The codes used in this publication to extract, reduce and analyze the data are as follows; STScI JWST Calibration pipeline45 (https://github.com/spacetelescope/jwst), Eureka!53 (https://eurekadocs.readthedocs.io/en/latest/), ExoTiC-JEDI47 (https://github.com/ExoTiC/ExoTiC-JEDI), juliet71 (https://juliet.readthedocs.io/en/latest/), Tiberius15,49,50, transitspectroscopy51 (https://github.com/nespinoza/transitspectroscopy). In addition, these made use of batman65 (http://lkreidberg.github.io/batman/docs/html/index.html), celerite86 (https://celerite.readthedocs.io/en/stable/), chromatic (https://zkbt.github.io/chromatic/), Dynesty72 (https://dynesty.readthedocs.io/en/stable/index.html), emcee69 (https://emcee.readthedocs.io/en/stable/), exoplanet83 (https://docs.exoplanet.codes/en/latest/), ExoTEP75–77, ExoTHETyS79 (https://github.com/ucl-exoplanets/ExoTETHyS), ExoTiCISM57 (https://github.com/Exo-TiC/ExoTiC-ISM), ExoTiC-LD58 (https://exoticld.readthedocs.io/en/latest/), george68 (https://george.readthedocs.io/en/latest/) JAX82 (https://jax.readthedocs.io/en/latest/), LMFIT70 (https://lmfit.github.io/lmfit-py/), Pylightcurve78 (https://github.com/ucl-exoplanets/pylightcurve), Pymc3138 (https://docs.pymc.io/en/v3/index.html) and Starry84 (https://starry.readthedocs.io/en/latest/), each of which use the standard python libraries astropy139,140, matplotlib141, numpy142, pandas143, scipy64 and xarray144. The atmospheric models used to fit the data can be found at ATMO[Tremblin2015,Drummond2016,Goyal2018,Goyal2020]88–91, PHOENIX92–94, PICASO98,99 (https://natashabatalha.github.io/picaso/), Virga98,107 (https://natashabatalha.github.io/virga/), and gCMCRT115 (https://github.com/ELeeAstro/gCMCRT).Measuring the abundances of carbon and oxygen in exoplanet atmospheres is considered a crucial avenue for unlocking the formation and evolution of exoplanetary systems. Access to an exoplanet’s chemical inventory requires high precision observations, often inferred from individual molecular detections with low-resolution space-based and high-resolution ground-based facilities. Here we report the medium-resolution (R≈600) transmission spectrum of an exoplanet atmosphere between 3–5 μm covering multiple absorption features for the Saturn-mass exoplanet WASP-39b, obtained with JWST NIRSpec G395H. Our observations achieve 1.46× photon precision, providing an average transit depth uncertainty of 221 ppm per spectroscopic bin, and present minimal impacts from systematic effects. We detect significant absorption from CO2 (28.5σ ) and H2O (21.5σ ), and identify SO2 as the source of absorption at 4.1 μ m (4.8σ ). Best-fit atmospheric models range between 3× and 10× solar metallicity, with sub-solar to solar C/O ratios. These results, including the detection of SO2, underscore the importance of characterising the chemistry in exoplanet atmospheres, and showcase NIRSpec G395H as an excellent mode for time series observations over this critical wavelength range.Science and Technology Facilities Council (STFC)UKR

Simple non-invasive assessment of advanced glycation endproduct accumulation

Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects. Methods. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age- and sex-matched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL). Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, pless than or equal to0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA(1)c of the previous year and creatinine levels. Conclusions/interpretation. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation