Quantification of the endogenous growth hormone and prolactin lowering effects of a somatostatin-dopamine chimera using population PK/PD modeling.
J Pharmacokinet Pharmacodyn. 2020 Apr 04;:
Authors: van Esdonk MJ, Burggraaf J, Dehez M, van der Graaf PH, Stevens J
A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release. During treatment with BIM23B065, growth hormone secretion was significantly reduced (maximal effect [EMAX] = - 64.8%) with significant reductions in the pulse frequency in two out of three multiple ascending dose cohorts. A circadian component in prolactin secretion was identified, modelled using a combination of two cosine functions with 24 h and 12 h periods. Dosing of BIM23B065 strongly inhibited (EMAX = - 91%) the prolactin release and demonstrated further reduction of prolactin secretion after multiple days of dosing. This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions of BIM23B065.
PMID: 32248329 [PubMed – as supplied by publisher]
Minimal important change in physical function in trauma patients: a study using the short musculoskeletal function assessment.
Qual Life Res. 2020 Apr 04;:
Authors: de Graaf MW, Reininga IHF, Heineman E, El Moumni M
PURPOSE: The Short Musculoskeletal Function Assessment (SMFA) questionnaire can be used to evaluate physical functioning in patients with traumatic injuries. It is not known what change in score reflects a meaningful change to patients. The aim was to determine minimal important change (MIC) values of the subscales (0-100) of the Dutch SMFA-NL in a sample of patients with a broad range of injuries.
METHODS: Patients between 18 and 65 years of age completed the SMFA-NL and the Global Rating of Effect (GRE) questions at 6-week and 12-month post-injury. Anchor-based MIC values were calculated using univariable logistic regression analyses.
RESULTS: A total of 225 patients were included (response rate 67%). The MIC value of the Upper Extremity Dysfunction (UED) subscale was 8 points, with a misclassification rate of 43%. The Lower Extremity Dysfunction subscale MIC value was 14 points, with a misclassification rate of 29%. The MIC value of the Problems with Daily Activities subscale was 25 points, with a misclassification rate of 33%. The MIC value of the Mental and Emotional Problems (MEP) subscale was 7 points, with a misclassification rate 37%.
CONCLUSION: MIC values of the SMFA-NL were determined. The MIC values aid interpreting whether a change in physical functioning can be considered clinically important. Due to the considerable rates of misclassification, the MIC values of the UED and MEP subscales should be used with caution.
PMID: 32248354 [PubMed – as supplied by publisher]
Danial Afscharzadeh: Decoding therapeutic roles of adipose tissue-derived stromal cells and their extracellular vesicles in liver disease Patiënten …
Time to rename COPD exacerbations: implementing the term lung attack.
Lancet Respir Med. 2020 Apr;8(4):e25
Authors: Holverda S, Rutgers MR, Kerstjens HAM
PMID: 32246930 [PubMed – as supplied by publisher]
Aortic regurgitation, a forgotten valve disease in hypertrophic cardiomyopathy?
Eur J Radiol. 2020 Mar 19;126:108971
Authors: Westenbrink BD, de Boer RA, Vliegenthart R
PMID: 32247164 [PubMed – as supplied by publisher]
Posted in Eur J Radiol
Intact protein quantification in biological samples by liquid chromatography – high-resolution mass spectrometry: somatropin in rat plasma.
J Chromatogr B Analyt Technol Biomed Life Sci. 2020 Mar 23;1144:122079
Authors: Bults P, Sonesson A, Knutsson M, Bischoff R, van de Merbel NC
The quantitative determination of intact proteins in biological samples by LC with high-resolution MS detection can be a useful alternative to ligand-binding assays or LC-MS-based quantification of a surrogate peptide after protein digestion. The 22-kDa biopharmaceutical protein somatropin (recombinant human growth hormone) was quantified down to 10 ng/mL (0.45 nM) in 75 μL of rat plasma by the combination of an immunocapture step using an anti-somatropin antibody and LC-MS on a quadrupole-time of flight instrument. Accuracy and precision of the method as well as its selectivity and sensitivity did not depend on the width of the mass extraction window nor on whether only one or a summation of multiple charge states of the protein analyte were used as the detection response. Quantification based on deconvoluted mass spectra showed equally acceptable method performance but with a less favorable lower limit of quantification of 30 ng/mL. Concentrations in plasma after dosing of somatropin to rats correlated well for the deconvolution approach and the quantification based on the summation of the response of the four most intense charge states (14+ to 17+) of somatropin.
PMID: 32247186 [PubMed – as supplied by publisher]
Sex-related differences in contemporary biomarkers for heart failure: a review.
Eur J Heart Fail. 2020 Mar 27;:
Authors: Suthahar N, Meems LMG, Ho JE, de Boer RA
The use of circulating biomarkers for heart failure (HF) is engrained in contemporary cardiovascular practice and provides objective information about various pathophysiological pathways associated with HF syndrome. However, biomarker profiles differ considerably among women and men. For instance, in the general population, markers of cardiac stretch (natriuretic peptides) and fibrosis (galectin-3) are higher in women, whereas markers of cardiac injury (cardiac troponins) and inflammation (sST2) are higher in men. Such differences may reflect sex-specific pathogenic processes associated with HF risk, but may also arise as a result of differences in sex hormone profiles and fat distribution. From a clinical perspective, sex-related differences in biomarker levels may affect the objectivity of biomarkers in HF management because what is considered to be ‘normal’ in one sex may not be so in the other. The objectives of this review are, therefore: (i) to examine the sex-specific dynamics of clinically relevant HF biomarkers in the general population, as well as in HF patients; (ii) to discuss the overlap between sex-related and obesity-related effects, and (iii) to identify knowledge gaps to stimulate research on sex-related differences in HF.
PMID: 32220046 [PubMed – as supplied by publisher]
Volume gradients in inner hair cell-auditory nerve fiber pre- and postsynaptic proteins differ across mouse strains.
Hear Res. 2020 Mar 06;390:107933
Authors: Reijntjes DOJ, Köppl C, Pyott SJ
In different animal models, auditory nerve fibers display variation in spontaneous activity and response threshold. Functional and structural differences among inner hair cell ribbon synapses are believed to contribute to this variation. The relative volumes of synaptic proteins at individual synapses might be one such difference. This idea is based on the observation of opposing volume gradients of the presynaptic ribbons and associated postsynaptic glutamate receptor patches in mice along the pillar modiolar axis of the inner hair cell, the same axis along which fibers were shown to vary in their physiological properties. However, it is unclear whether these opposing gradients are expressed consistently across animal models. In addition, such volume gradients observed for separate populations of presynaptic ribbons and postsynaptic glutamate receptor patches suggest different relative volumes of these synaptic structures at individual synapses; however, these differences have not been examined in mice. Furthermore, it is unclear whether such gradients are limited to these synaptic proteins. Therefore, we analyzed organs of Corti isolated from CBA/CaJ, C57BL/6, and FVB/NJ mice using immunofluorescence, confocal microscopy, and quantitative image analysis. We find consistent expression of presynaptic volume gradients across strains of mice and inconsistent expression of postsynaptic volume gradients. We find differences in the relative volume of synaptic proteins, but these are different between CBA/CaJ mice, and C57BL/6 and FVB/NJ mice. We find similar results in C57BL/6 and FVB/NJ mice when using other postsynaptic density proteins (Shank1, Homer, and PSD95). These results have implications for the mechanisms by which volumes of synaptic proteins contribute to variations in the physiology of individual auditory nerve fibers and their vulnerability to excitotoxicity.
PMID: 32203820 [PubMed – as supplied by publisher]
Posted in Hear Res
Maximising the potential of HPV vaccines.
Lancet Glob Health. 2020 Apr;8(4):e460-e461
Authors: Luttjeboer J, Wondimu A, Van der Schans J, Postma MJ
PMID: 32199108 [PubMed – as supplied by publisher]
PM2.5-bound PAHs exposure linked with low plasma insulin-like growth factor 1 levels and reduced child height.
Environ Int. 2020 Mar 18;138:105660
Authors: Zeng Z, Huo X, Wang Q, Wang C, Hylkema MN, Xu X
BACKGROUND: Exposure to atmospheric fine particle matter (PM2.5) pollution and the absorbed pollutants is known to contribute to numerous adverse health effects in children including to growth.
OBJECTIVE: The aim of this study was to evaluate exposure levels of atmospheric PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) in an electronic waste (e-waste) polluted town, Guiyu, and to investigate the associations between PM2.5-PAH exposure, insulin-like growth factor 1 (IGF-1) levels and child growth.
METHODS: This study recruited 238 preschool children (3-6 years of age), from November to December 2017, of which 125 were from Guiyu (an e-waste area) and 113 were from Haojiang (a reference area). Levels of daily PM2.5 and PM2.5-bound ∑16 PAHs were assessed to calculate individual chronic daily intakes (CDIs). IGF-1 and IGF-binding protein 3 (IGFBP-3) concentrations in child plasma were also measured. The associations and further mediation effects between exposure to PM2.5 and PM2.5-bound PAHs, child plasma IGF-1 concentration, and child height were explored by multiple linear regression models and mediation effect analysis.
RESULTS: Elevated atmospheric PM2.5-bound ∑16 PAHs and PM2.5 levels were observed in Guiyu, and this led to more individual CDIs of the exposed children than the reference (all P < 0.001). The median level of plasma IGF-1 in the exposed group was lower than in the reference group (91.42 ng/mL vs. 103.59 ng/mL, P < 0.01). IGF-1 levels were negatively correlated with CDIs of PM2.5, but not with CDIs of PM2.5-bound ∑16 PAHs after adjustment. An increase of 1 μg/kg of PM2.5 intake per day was associated with a 0.012 cm reduction of child height (95% CI: -0.014, -0.009), and similarly, an elevation of 1 ng/kg of PM2.5-bound ∑16 PAHs intake per day was associated with a 0.022 cm decrease of child height (95% CI: -0.029, -0.015), both after adjustment of several potential confounders (age, gender, family cooking oil, picky eater, eating sweet food, eating fruits or vegetables, parental education level and monthly household income). The decreased plasma IGF-1 concentration mediated 15.8% of the whole effect associated with PM2.5 exposure and 23.9% of the whole effect associated with PM2.5-bound ∑16 PAHs exposure on child height.
CONCLUSION: Exposure to atmospheric PM2.5-bound ∑16 PAHs and PM2.5 is negatively associated with child height, and is linked to reduced IGF-1 levels in plasma. This may suggest a causative negative role of atmospheric PM2.5-bound exposures in child growth.
PMID: 32199227 [PubMed – as supplied by publisher]
Posted in Environ Int
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