Therapeutic Drug Monitoring (TDM) is a valid tool to optimise pharmacotherapy. It enables the clinician to adjust the dosage of drugs according to the characteristics of the individual patient. In ...psychiatry, TDM is an established procedure for lithium, some antidepressants and antipsychotics. In spite of its obvious advantages, however, the use of TDM in everyday clinical practice is far from optimal. The interdisciplinary TDM group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has therefore worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs. Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs: (1) strongly recommended, (2) recommended, (3) useful, (4) probably useful and (5) not recommended. A second approach defined indications to use TDM, e. g. control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning the drug metabolism, children, adolescents and elderly patients. Indications for TDM are relevant for all drugs either with or without validated therapeutic ranges. When studies on therapeutic ranges are lacking, target ranges should be plasma concentrations that are normally observed at therapeutic doses of the drug. Therapeutic ranges of plasma concentrations that are considered to be optimal for treatment are proposed for those drugs, for which the evaluation of the literature demonstrated strong evidence. Moreover, situations are defined when pharmacogenetic (phenotyping or genotyping) tests are informative in addition to TDM. Finally, practical instructions are given how to use TDM. They consider preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM in psychiatry.
Hybrid solid electrolytes, composed of 3D ordered bicontinuous conducting ceramic and insulating polymer microchannels are reported. The ceramic channels provide continuous, uninterrupted pathways, ...maintaining high ionic conductivity between the electrodes, while the polymer channels permit improvement of the mechanical properties from that of the ceramic alone, in particular mitigation of the ceramic brittleness. The conductivity of a ceramic electrolyte is usually limited by resistance at the grain boundaries, necessitating dense ceramics. The conductivity of the 3D ordered hybrid is reduced by only the volume fraction occupied by the ceramic, demonstrating that the ceramic channels can be sintered to high density similar to a dense ceramic disk. The hybrid electrolytes are demonstrated using the ceramic lithium ion conductor Li 1.4 Al 0.4 Ge 1.6 (PO 4 ) 3 (LAGP). Structured LAGP 3D scaffolds with empty channels were prepared by negative replication of a 3D printed polymer template. Filling the empty channels with non-conducting polypropylene (PP) or epoxy polymer (epoxy) creates the structured hybrid electrolytes with 3D bicontinuous ceramic and polymer microchannels. Printed templating permits precise control of the ceramic to polymer ratio and the microarchitecture; as demonstrated by the formation of cubic, gyroidal, diamond and spinodal (bijel) structures. The electrical and mechanical properties depend on the microarchitecture, the gyroid filled with epoxy giving the best combination of conductivity and mechanical properties. An ionic conductivity of 1.6 × 10 −4 S cm −1 at room temperature was obtained, reduced from the conductivity of a sintered LAGP pellet only by the volume fraction occupied by the ceramic. The mechanical properties of the gyroid LAGP–epoxy electrolyte demonstrate up to 28% higher compressive failure strain and up to five times the flexural failure strain of a LAGP pellet before rupture. Notably, this demonstrates that ordered ceramic and polymer hybrid electrolytes can have superior mechanical properties without significantly compromising ionic conductivity, which addresses one of the key challenges for all-solid-state batteries.
Volatile halogenated organic compounds containing bromine and iodine, which are naturally produced in the ocean, are involved in ozone depletion in both the troposphere and stratosphere. Three ...prominent compounds transporting large amounts of marine halogens into the atmosphere are bromoform (CHBr3), dibromomethane (CH2Br2) and methyl iodide (CH3I). The input of marine halogens to the stratosphere has been estimated from observations and modelling studies using low-resolution oceanic emission scenarios derived from top-down approaches. In order to improve emission inventory estimates, we calculate data-based high resolution global sea-to-air flux estimates of these compounds from surface observations within the HalOcAt (Halocarbons in the Ocean and Atmosphere) database (https://halocat.geomar.de/). Global maps of marine and atmospheric surface concentrations are derived from the data which are divided into coastal, shelf and open ocean regions. Considering physical and biogeochemical characteristics of ocean and atmosphere, the open ocean water and atmosphere data are classified into 21 regions. The available data are interpolated onto a 1°×1° grid while missing grid values are interpolated with latitudinal and longitudinal dependent regression techniques reflecting the compounds' distributions. With the generated surface concentration climatologies for the ocean and atmosphere, global sea-to-air concentration gradients and sea-to-air fluxes are calculated. Based on these calculations we estimate a total global flux of 1.5/2.5 Gmol Br yr−1 for CHBr3, 0.78/0.98 Gmol Br yr−1 for CH2Br2 and 1.24/1.45 Gmol Br yr−1 for CH3I (robust fit/ordinary least squares regression techniques). Contrary to recent studies, negative fluxes occur in each sea-to-air flux climatology, mainly in the Arctic and Antarctic regions. "Hot spots" for global polybromomethane emissions are located in the equatorial region, whereas methyl iodide emissions are enhanced in the subtropical gyre regions. Inter-annual and seasonal variation is contained within our flux calculations for all three compounds. Compared to earlier studies, our global fluxes are at the lower end of estimates, especially for bromoform. An under-representation of coastal emissions and of extreme events in our estimate might explain the mismatch between our bottom-up emission estimate and top-down approaches.
Non-alcoholic fatty liver disease (NAFLD) is associated with abnormal mitochondrial capacity. While oxidative capacity can be increased in steatosis, hepatic ATP decreases in long-standing diabetes. ...However, longitudinal studies on diabetes-related NAFLD and its relationship to hepatic energy metabolism are lacking.
This prospective study comprised volunteers with type 1 (T1DM, n = 30) and type 2 (T2DM, n = 37) diabetes. At diagnosis and 5 years later, we used 1H/31P magnetic resonance spectroscopy to measure hepatocellular lipid (HCL), γATP and inorganic phosphate (Pi) concentrations, and to assess adipose tissue volumes. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps.
At diagnosis, individuals with T2DM had higher HCL and adipose tissue volumes, but lower whole-body insulin sensitivity than those with T1DM, despite comparable glycemic control. NAFLD was present in 38% of individuals with T2DM and 7% with T1DM. After 5 years, visceral adipose tissue only increased in individuals with T2DM, while HCL almost doubled in this group (p <0.001), resulting in a 70% prevalence of NAFLD (independent of diabetes treatment). Changes in HCL correlated with adipose tissue volume and insulin resistance (r = 0.50 and r = 0.44, both p <0.05). Pi decreased by 17% and 10% in individuals with T2DM and T1DM (p <0.05), respectively. In T1DM, HCL did not change, whereas γATP decreased by 10% and correlated negatively with glycated hemoglobin (r = -0.56, p <0.05).
The rapid increase in HCL during the early course of T2DM likely results from enlarging adipose tissue volume and insulin resistance in response to impaired hepatic mitochondrial adaptation. The decrease of phosphorus metabolites in T1DM may be due to pharmacological insulin supply.
Previous studies suggested that the impaired function of mitochondria, the power plants of cells, can promote fatty liver and type 2 diabetes mellitus. This study now shows that during the first 5 years of type 2 diabetes the increase in body fat content rapidly leads to a doubling of liver fat content, whereas the energy metabolism of the patients' livers progressively declines. These data suggest that fat tissue mass and liver mitochondria have an important role in the development of fatty liver disease in humans with diabetes.
NCT01055093
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•Hepatic lipids increase 2-fold in the early course of type 2 diabetes.•Patients with type 1 diabetes do not develop steatosis in first 5 years after diagnosis.•Adipose tissue mass and insulin resistance drive the development of steatosis.•Phosphorus metabolites decline in type 1 diabetes due to low portal insulin supply.
A serotonergic dysfunction is supposed to play a pathogenetic role in depression, but there is a considerable number of non-responders in the acute treatment of depression with serotonergic agents ...like SSRI. Thus, an indicator of central serotonergic activity could lead to a more specific pharmacological treatment of depression. In animal and human data there is a growing amount of evidence that a strong loudness dependency of late auditory evoked potentials (LDAEP) is an indicator of low serotonergic activity and vice versa.
In 29 depressive inpatients (DSM-III-R diagnosis 296.x in 28 patients, 300.4 in one patient), the hypothesis was tested that a strong LDAEP prior to treatment can predict a better clinical outcome under SSRI treatment over 4 weeks.
Patients with a strong pre-treatment LDAEP had a significantly greater decrease of depressive symptoms (Hamilton Scale for Depression) after 4 weeks than patients with a flat LDAEP. Significantly more responders fell into the group with a high LDAEP. Contrary to what might be expected, a second recording in a subsample of 19 patients after 4 weeks of treatment failed to show changes in the LDAEP.
Our finding confirms the hypothesis that a strong LDAEP, indicating a low serotonergic activity, is related to a favorable response to acute SSRI treatment in depression. The LDAEP is a promising tool for the prediction of response to serotonin agonists in depression and it seems to be of clinical importance.
Application of mixed meal tolerance tests (MMTT) to measure beta-cell function in long-term studies is limited by modification of the commercial products occurring over time. This study assessed the ...intra-individual reliability of MMTTs and compared the effects of liquid meals differing in macronutrient composition on the estimation of beta-cell function in type 2 diabetes (T2DM).
To test the reliability of MMTTs, 10 people with T2DM (age 58 ± 11 years, body mass index 30.0 ± 4.9 kg/m
) received Boost® high Protein 20 g protein three times. For comparing different meals, another 10 persons with T2DM (58 ± 5 years, 31.9 ± 5.3 kg/m
) ingested either Boost® high Protein 20 g protein or the isocaloric Boost® high Protein 15 g protein containing 35% less protein and 18% more carbohydrates. C-peptide, insulin and glucose release were assessed from the incremental area under the concentration time curve (iAUC) and the intra- and inter-individual variation of these parameters from the coefficients of variations (CV).
Repetitive ingestion of one meal revealed intra-individual CVs for the iAUCs of C-peptide, insulin and glucose, which were at least 3-times lower than the inter-individual variation of these parameters (18.2%, 19.7% and 18.9% vs. 74.2%, 70.5% and 207.7%) indicating a good reliability. Ingestion of two different meals resulted in comparable intra-individual CVs of the iAUCs of C-peptide and insulin (16.9%, 20.5%).
MMTTs provide reliable estimation of beta-cell function in people with T2DM. Furthermore, moderate differences in the protein and carbohydrate contents in a standardized liquid meal do not result in relevant changes of C-peptide and insulin responses.
Clinicaltrials.gov, Identifier number: NCT01055093. Registered 22 January 2010 - Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT01055093.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Abstract
Context/Objective
Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of ...T2D.
Design/Patients
Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with 6,6-2H2glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging.
Results
T2D patients (known diabetes duration: 2.5 0.1; 5.0 years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P < 0.01) and AT IS (P < 0.05), 73% and 31% higher HCL (P < 0.05), and DSAT-thickness (P < 0.001), but similar hepatic IS compared with CON. Mitochondrial efficiency was ~22% lower in SSAT and DSAT of T2D patients (P < 0.001) and ~8% lower in SSAT vs DSAT (P < 0.05). In both fat depots, mitochondrial coupling correlated positively with muscle IS and metabolic flexibility (r ≥ 0.40; P < 0.05), proton leak correlated positively (r ≥ 0.51; P < 0.01) and oxidative capacity negatively (r ≤ −0.47; P < 0.05) with fasting free fatty acids (FFA). Metabolic flexibility correlated positively with SAT-oxidative capacity (r ≥ 0.48; P < 0.05) and negatively with DSAT-thickness (r = −0.48; P < 0.05). DSAT-thickness correlated negatively with mitochondrial coupling in both depots (r ≤ −0.50; P < 0.01) and muscle IS (r = −0.59; P < 0.01), positively with FFA during clamp (r = 0.63; P < 0.001) and HCL (r = 0.49; P < 0.01).
Conclusions
Impaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.
ABSTRACT We present the third Fermi Large Area Telescope (LAT) source catalog (3FGL) of sources in the 100 MeV-300 GeV range. Based on the first 4 yr of science data from the Fermi Gamma-ray Space ...Telescope mission, it is the deepest yet in this energy range. Relative to the Second Fermi LAT catalog, the 3FGL catalog incorporates twice as much data, as well as a number of analysis improvements, including improved calibrations at the event reconstruction level, an updated model for Galactic diffuse γ-ray emission, a refined procedure for source detection, and improved methods for associating LAT sources with potential counterparts at other wavelengths. The 3FGL catalog includes 3033 sources above significance, with source location regions, spectral properties, and monthly light curves for each. Of these, 78 are flagged as potentially being due to imperfections in the model for Galactic diffuse emission. Twenty-five sources are modeled explicitly as spatially extended, and overall 238 sources are considered as identified based on angular extent or correlated variability (periodic or otherwise) observed at other wavelengths. For 1010 sources we have not found plausible counterparts at other wavelengths. More than 1100 of the identified or associated sources are active galaxies of the blazar class; several other classes of non-blazar active galaxies are also represented in the 3FGL. Pulsars represent the largest Galactic source class. From source counts of Galactic sources we estimate that the contribution of unresolved sources to the Galactic diffuse emission is ∼3% at 1 GeV.
The purpose of this single‐centre prospective non‐randomised study was to evaluate the effectiveness of an interdisciplinary care programme to enhance self‐management in patients with haematopoietic ...stem cell transplantation (HSCT). Patients undergoing HSCT, aged >14 years with informed consent were recruited (n = 79). Patients in the intervention group (IG) received standard care plus the SCION‐HSCT intervention to counteract three problems after HSCT: muscle weakness, oral mucositis and malnutrition. Control group patients received standard care. Primary endpoint was global health‐related quality of life (HRQoL) at discharge (EORTC QLQ C30 v. 3.0). Baseline characteristics were balanced between both groups, except physical performance (ECOG) being significantly lower for patients of the IG. At discharge, no group differences could be seen regarding HRQoL. Non‐confirmatory post hoc analyses showed for patients of the IG a shorter duration of hospitalisation (MD −10.90; 95% CI −18.05 to −3.75) and increased activity during hospitalisation (MD 2.44; 95% CI 1.27–3.61). In conclusion, clinical effectiveness of the intervention could not be proven with respect to the aspired improvement of HRQoL. However, the nurse‐led interdisciplinary caring programme could be carried out in every day ward routine. Further research should focus on working mechanisms of complex interventions aiming to improve HRQoL of patients undergoing HSCT.
We have performed an analysis of the diffuse gamma-ray emission with the Fermi Large Area Telescope (LAT) in the Milky Way halo region, searching for a signal from dark matter annihilation or decay. ...In the absence of a robust dark matter signal, constraints are presented. We consider both gamma rays produced directly in the dark matter annihilation/decay and produced by inverse Compton scattering of the e super(+)/e super(-) produced in the annihilation/decay. Conservative limits are derived requiring that the dark matter signal does not exceed the observed diffuse gamma-ray emission. A second set of more stringent limits is derived based on modeling the foreground astrophysical diffuse emission using the GALPROP code. Uncertainties in the height of the diffusive cosmic-ray halo, the distribution of the cosmic-ray sources in the Galaxy, the index of the injection cosmic-ray electron spectrum, and the column density of the interstellar gas are taken into account using a profile likelihood formalism, while the parameters governing the cosmic-ray propagation have been derived from fits to local cosmic-ray data. The resulting limits impact the range of particle masses over which dark matter thermal production in the early universe is possible, and challenge the interpretation of the PAMELA/Fermi-LAT cosmic ray anomalies as the annihilation of dark matter.
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