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Background: Indications for retinotomy, its procedure and efficacy are still a subject for study and discussions. Purpose: To examine the efficacy of relaxing circumferential and radial retinotomies for retinal detachment associated with marked proliferative vitreoretinopathy (PVR). Material and Methods: Twenty-seven patients (27 eyes) with retinal detachment associated with PVR were involved in the study. Eleven eyes (40%) had retinotomy of less than 90°, eight (30%), of 90° to 180°, four (15%), of 180° to 270°, and four (15%), 360° (circumferential retinotomy). Additional radial retinotomy was performed in 5 eyes (19%), and retinotomy combined with choroidectomy, in 2 eyes. Results: Of the 27 eyes, retinal reattachment was achieved after the first surgery in 20 eyes (74%), after re-surgery in 5 eyes (19%). Anatomical success was achieved after removal of silicone oil in 15 eyes (56%). By the time of analysis, silicone oil was not removed in 12 eyes (44%). Complete retinal re-attachment was achieved in 25 eyes (93%), and partial re-attachment, in 2 eyes (7%). Conclusion: Retinotomy should be performed in eyes with retinal detachment and contraction. Circumferential and radial retinotomies provide a relatively high rate of anatomical success of surgery. [ABSTRACT FROM AUTHOR]

Activation of the sympathetic nervous system is observed in pulmonary arterial hypertension patients. This study investigates whether inhibiting the conversion of dopamine into noradrenaline by dopamine β -hydroxylase (D β H) inhibition with BIA 21-5337 improved right ventricular (RV) function or remodeling in pressure overload-induced RV failure. RV failure was induced in male Wistar rats by pulmonary trunk banding (PTB). Two weeks after the procedure, PTB rats were randomized to vehicle ( n  = 8) or BIA 21-5337 ( n  = 11) treatment. An additional PTB group treated with ivabradine ( n  = 11) was included to control for the potential heart rate-reducing effects of BIA 21-5337. A sham group ( n  = 6) received vehicle treatment. After 5 weeks of treatment, RV function was assessed by echocardiography, magnetic resonance imaging, and invasive pressure-volume measurements before rats were euthanized. RV myocardium was analyzed to evaluate RV remodeling. PTB caused a fourfold increase in RV afterload which led to RV dysfunction, remodeling, and failure. Treatment with BIA 21-5337 reduced adrenal gland D β H activity and 24-h urinary noradrenaline levels confirming relevant physiological response to the treatment. At end-of-study, there were no differences in RV function or RV remodeling between BIA 21-5337 and vehicle-treated rats. In conclusion, treatment with BIA 21-5337 did not have any beneficial-nor adverse-effects on the development of RV failure after PTB despite reduced adrenal gland D β H activity., Competing Interests: B. I. and N. P were employees of BIAL‐Portela & Cª, S.A. (the sponsor of the study) at the time of the study. The remaining authors declare no conflict of interest., (© 2024 BIAL. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Different rat strains are used in various animal models of pulmonary hypertension and right ventricular (RV) failure. No systematic assessment has been made to test differences in RV response to pressure overload between rat strains. We compared RV adaptation to pulmonary trunk banding (PTB) in Wistar (W), Sprague Dawley (SD), and Fischer344 (F) rats by hemodynamic profiling focusing on diastolic function. Age-matched male rat weanlings were randomized to sham surgery (W-sham, n = 5; SD-sham, n = 4; F-sham, n = 4) or PTB (W-PTB, n = 8; SD-PTB, n = 8; F-PTB, n = 8). RV function was evaluated after 5 weeks by echocardiography, cardiac MRI, and invasive pressure-volume measurements. PTB caused RV failure and increased RV systolic pressures four-fold in all three PTB groups compared with sham. W- and SD-PTB had a 2.4-fold increase in RV end-systolic volume index compared with sham, while F-PTB rats were less affected. Diastolic and right atrial impairment were evident by increased RV end-diastolic elastance, filling pressure, and E/e' in PTB rats compared with sham, again F-PTB the least affected. In conclusions, PTB caused RV failure with signs of diastolic dysfunction. Despite a similar increase in RV systolic pressure, F-PTB rats showed less RV dilatation and a more preserved diastolic function compared with W- and SD-PTB., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Cardiac fibrosis contributes to the development of heart failure, and is the response of cardiac fibroblasts (CFs) to pressure or volume overload. Limiting factors in CFs research are the poor availability of human cells and the tendency of CFs to transdifferentiate into myofibroblasts when cultured in vitro. The possibility to generate CFs from induced pluripotent stem cells (iPSC), providing a nearly unlimited cell source, opens new possibilities. However, the behaviour of iPSC-CFs under mechanical stimulation has not been studied yet. Our study aimed to assess the behaviour of iPSC-CFs under mechanical stretch and pro-fibrotic conditions. First, we confirm that iPSC-CFs are comparable to primary CFs at gene, protein and functional level. Furthermore, iPSC-derived CFs adopt a pro-fibrotic response to transforming growth factor beta (TGF-β). In addition, mechanical stretch inhibits TGF-β-induced fibroblast activation in iPSC-CFs. Thus, the responsiveness to cytokines and mechanical stimulation of iPSC-CFs demonstrates they possess key characteristics of primary CFs and may be useful for disease modelling., (© 2024. The Author(s).)

Background: Precapillary pulmonary hypertension (precPH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness., Objectives: This study aimed to investigate RA function using pressure-volume (PV) loops, isolated cardiomyocyte, and histological analyses., Methods: RA PV loops were constructed in control subjects (n = 9) and precPH patients (n = 27) using magnetic resonance and catheterization data. RA stiffness (pressure rise during atrial filling) and right atrioventricular coupling index (RA minimal volume / RV end-diastolic volume) were compared in a larger cohort of patients with moderate (n = 39) or severe (n = 41) RV diastolic stiffness. Cardiomyocytes were isolated from RA tissue collected from control subjects (n = 6) and precPH patients (n = 9) undergoing surgery. Autopsy material was collected from control subjects (n = 6) and precPH patients (n = 4) to study RA hypertrophy, capillarization, and fibrosis., Results: RA PV loops showed 3 RA cardiac phases (reservoir, passive emptying, and contraction) with dilatation and elevated pressure in precPH. PrecPH patients with severe RV diastolic stiffness had increased RA stiffness and worse right atrioventricular coupling index. Cardiomyocyte cross-sectional area was increased 2- to 3-fold in precPH, but active tension generated by the sarcomeres was unaltered. There was no increase in passive tension of the cardiomyocytes, but end-stage precPH showed reduced number of capillaries per mm 2 accompanied by interstitial and perivascular fibrosis., Conclusions: RA PV loops show increased RA stiffness and suggest atrioventricular uncoupling in patients with severe RV diastolic stiffness. Isolated RA cardiomyocytes of precPH patients are hypertrophied, without intrinsic sarcomeric changes. In end-stage precPH, reduced capillary density is accompanied by interstitial and perivascular fibrosis., Competing Interests: Funding Support and Author Disclosures Drs Bogaard, Vonk Noordegraaf, Goumans, and de Man were supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA, CVON-2018-29 PHAEDRA-IMPACT, and CVON-2017-10 Dolphin-Genesis). Drs Vonk Noordegraaf and de Man were further supported by the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610, NWO-VIDI: 917.18.338). Dr de Man was supported by a Dutch Heart Foundation Dekker senior postdoc grant (2018T059). Drs Bogaard and Vonk Noordegraaf have received research grant support from Actelion, GSK, and Ferrer (Therabel). Dr de Man has received research grant support from Janssen and BIAL. Dr Handoko has received consultancy/speaker fees from Novartis, Boehringer Ingelheim, AstraZeneca, Vifor, Bayer, MSD, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages., Methods: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49)., Results: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAH-patients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females ≤45years had best prognosis in comparison to females ≥55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females ≤45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females ≤45years had an event at a later time point, RV function was more impaired at end-stage disease., Conclusions: Sex hormones are differently associated with RV function in male and female PAH-patients. DHEA-S appeared to be lower in male and female PAH-patients. Females ≤45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) patients eventually die of right heart failure (RHF). Currently, there is no suitable pre-clinical model to study PAH. Therefore, we aim to develop a right heart dysfunction (RHD) model using the 3-dimensional engineered heart tissue (EHT) approach and cardiomyocytes derived from patient-induced pluripotent stem cells (iPSCs) to unravel the mechanisms that determine the fate of a pressure-overloaded right ventricle. iPSCs from PAH and healthy control subjects were differentiated into cardiomyocytes (iPSC-CMs), incorporated into the EHT, and maintained for 28 days. In comparison with control iPSC-CMs, PAH-derived iPSC-CMs exhibited decreased beating frequency and increased contraction and relaxation times. iPSC-CM alignment within the EHT was observed. PAH-derived EHTs exhibited higher force, and contraction and relaxation times compared with control EHTs. Increased afterload was induced using 2× stiffer posts from day 0. Due to high variability, there were no functional differences between normal and stiffer EHTs, and no differences in the hypertrophic gene expression. In conclusion, under baseline spontaneous conditions, PAH-derived iPSC-CMs and EHTs show prolonged contraction compared with controls, as observed clinically in PAH patients. Further optimization of the hypertrophic model and profound characterization may provide a platform for disease modelling and drug screening.

In a former publication the authors showed that low amounts of amorphous content (LOQ of 0.5%) in a hydrophobic model API (Ciclesonide) can be measured with an individually adjusted one-step dynamic organic vapor sorption (DVS). In this investigation the applicability is tested on various APIs which differ in lipophilicity (poor water solubility) and hygroscopicity (absorption of water). The vapor sorption method proved to be applicable in almost all cases. Moisture sorption isotherms were determined for all five investigated crystalline and amorphous APIs. However, it was necessary to select the parameters individually for each API. The used solvents (water, methanol, isopropanol and methylene chloride) and the humidity-levels (0.05 p/p0 until 0.5 p/p0) were chosen carefully because otherwise the amorphous amounts switch to their crystalline counterparts and are not detectable. The production of fully amorphous samples (absence of crystalline material measured by DSC, mDSC and XRPD) was optimized over several trials. As successfully methods proved ball-milling, freeze-drying, spray-drying and/or quench cooling. In the next step these fully amorphous amounts were blended with crystalline starting material to calibration curves (Turbula blender, influence of electrostatic charge to homogeneity) for the calculation of amorphous content. In summary, the following presented methods were used to determine and quantify low amorphous amounts (between 1.5% and 17.0%) in jet-milled powders (grinding pressure of 8bar, 1-3 grinding cycles), respectively., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Today, a variety of devices for dry powder inhalers (DPIs) is available and many different formulations for optimized deposition in the lung are developed. However, during the production of powder inhalers, processing steps may induce changes to both, the carrier and active pharmaceutical ingredients (APIs). It is well known that standard pharmaceutical operations may lead to structural changes, crystal defects and amorphous regions. Especially operations such as milling, blending and even sieving generate these effects. These disorders may induce re-crystallization and particle size changes post-production which have a huge influence on drug delivery and product stability. In this study, pilot tests with a polar solvent (water) and hydrophilic drug (Salbutamol sulfate) were performed to receive a first impression on further possible implementation of hydrophobic samples with organic solvents. Thereafter, a reliable method for the accurate detection of low amounts of amorphous content is described up to a limit of quantification (LOQ) of 0.5% for a hydrophobic model API (Ciclesonide). The organic vapor sorption method which is a gravimetric method quantifies exactly these low amounts of amorphous content in the hydrophobic powder once the suitable solvent (isopropanol), the correct p/p0 value (0.1) and the exact temperature (25°C) have been found. Afterward it was possible to quantitate low amorphous amounts in jet-milled powders (0.5-17.0%). In summary, the data of the study led to a clearer understanding in what quantity amorphous parts were generated in single production steps and how variable these parts behave to fully crystalline material. Nevertheless it showed how difficult it was to re-crystallize hydrophobic material with water vapor over a short period. For the individual samples it was possible to determine the single humidity at which the material starts to re-crystallize, the behavior against different nonpolar solvents and the calculation of the reduction of the glass transition temperature (Tg) according to the Gordon-Taylor equation., (Copyright © 2015 Elsevier B.V. All rights reserved.)