Effects of various phosphodiesterase-inhibitors,forskolin, and sodium nitroprusside on porcine detrusor smooth muscle tonic responses to muscarinergic stimulation and cyclic nucleotide levels in vitro

The cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers involved in the regulation of contractility in various smooth muscle organs including detrusor smooth muscle. They are synthesized by activation of adenylate and guanylate cyclases, respectively, and inactivated by phosphodiesterases (PDEs). In order to delineate the intracellular regulation of porcine detrusor contractility by cyclic nucleotides and phosphodiesterases, functional organ bath studies and determinations of intracellular cyclic nucleotide contents were performed after incubation of porcine detrusor strips with forskolin (adenylate cyclase activator), sodium nitroprusside (guanylate cyclase activator), and various phosphodiesterase-inhibitors. Significant relaxant responses were achieved only by forskolin, the nonspecific phosphodiesterase-inhibitor papaverine, and the phosphodiesterase 1-inhibitor vinpocetine (62.4 ± 5.6%, 73 ± 4.3%, and 53 ± 7.9%, respectively). Sodium nitroprusside and the selective PDE-inhibitors milrinone, rolipram, zaprinast, and dipyridamole were significantly less efficacious (26.9 ± 3.9%, 15.5 ± 3.8%, 15.3 ± 3.0%, 13 ± 4.0%, and 13.2 ± 2.1%, respectively). Forskolin, papaverine, and vinpocetine elevated intracellular cAMP concentrations (7.3-, 1.9-, and 1.7-fold increase at 100 μM, respectively), whereas the other substances failed to enhance cAMP levels. cGMP levels were only increased by sodium nitroprusside (7.8-fold). The adenylate cyclase-cAMP system seems to be the more important signal transduction system involved in the relaxation of carbachol induced smooth muscle tone of the porcine detrusor. The role of the guanylate cyclase-cGMP system is less clear. In addition, the calcium/calmodulin-stimulated PDE I seems to be of major functional importance in regulating cAMP hydrolysis in the porcine detrusor smooth muscle in vitro. © 1996 Wiley-Liss, Inc.     

End-stage liver disease developing with the use of methotrexate in heterozygous α1-antitrypsin deficiency

We report a case of cirrhosis developing in a man who was heterozygous for α₁-antitrypsin deficiency and who was receiving methotrexate for severe rheumatoid arthritis. The α₁-antitrypsin phenotype PiMZ has been associated with cryptogenic cirrhosis. Our patient had no biochemical or histologic evidence of chronic liver disease during the first year of receiving methotrexate. We postulate that the PiMZ state may result in enhanced susceptibility to methotrexate-induced hepatic toxicity and should be screened for if liver function abnormalities occur during methotrexate therapy.     

Practical Approach to Eliminate Solidification Cracks by Supplementing AlMg4.5Mn0.7 with AlSi10Mg Powder in Laser Powder Bed Fusion

The range of available aluminum alloy powders for laser powder bed fusion (LPBF) is restricted to mainly Al–Si based alloys. Currently aluminum alloy powders, designed for lightweight application, based on Al–Mg (5000 series), Al–Si–Mg (6000 series), or Al–Zn–Mg (7000 series), cannot be processed by LPBF without solidification cracks. This has an impact on the potential of LPBF for lightweight applications. In fusion welding, solidification cracks are eliminated by using filler materials. This study aims to transfer the known procedure to LPBF, by supplementing EN AW-5083 (AlMg4.5Mn0.7) with AlSi10Mg. EN AW-5083 and two modifications (+7 wt.% and +15 wt.% AlSi10Mg) were produced by LPBF and analyzed. It was found that, in EN AW-5083, the solidification cracks have a length ≥200 µm parallel to the building direction. Furthermore, the solidification cracks can already be eliminated by supplementing 7 wt.% AlSi10Mg. The microstructure analysis revealed that, by supplementing AlSi10Mg, the melt pool boundaries become visible, and the grain refines by 40% relative to the base alloy. Therefore, adding a low melting point phase and grain refinement are the mechanisms that eliminate solidification cracking. This study illustrates a practical approach to eliminate solidification cracks in LPBF.     

Multi‐mode grounding and monophasic passive discharge stimulation avoid aberrant facial nerve stimulation following cochlear implantation

We report on a case with severe facial nerve stimulation via a cochlea‐facial nerve dehiscence that was most likely the result of prolonged occlusive hydrocephalus. The successful treatment of this adverse effect demonstrates for the first time its complete resolution using a multi‐mode grounding and monophasic passive discharge stimulation.     

Pneumothorax in a Thiel cadaver model of cardiopulmonary resuscitation

<正>INTRODUCTION There has been some previous research in the field of cardiopulmonary resuscitation (CPR) using cadaver models.^[1] The Thiel method was developed by Professor Walter Thiel (Graz, Austria) and described in 1992 and 2002. It consists of both an intravascular injection of the embalming solution and submersion of the bodies in a tank with the same solution for a determined period.^[2,3]     

Early commercial experience with a newly designed balloon-expandable transcatheter heart valve: 30-day outcomes and implications of preprocedural computed tomography

OBJECTIVESWe herein report a single-centre experience with the SAPIEN 3 Ultra balloon-expandable transcatheter aortic valve implantation (TAVI) system.METHODSBetween March 2019 and January 2020, a total of 79 consecutive patients received transfemoral TAVI using the SAPIEN 3 Ultra device. Data were retrospectively analysed according to updated Valve Academic Research Consortium-2 definitions. Detailed analysis of multislice computed tomography data was conducted to identify potential predictors for permanent pacemaker (PPM) implantation and residual paravalvular leakage (PVL) post TAVI.Open in a separate windowGraphical AbstractRESULTSDevice success and early safety were 97.5% (77/79) and 94.9% (75/79) with resulting transvalvular peak/mean pressure gradients of 21.1 ± 8.2/10.9 ± 4.4 and PVL >mild in 0/79 patients (0%). Mild PVL was seen in 18.9% (15/79) of cases. Thirty-day mortality was 2.5% (2/79). The Valve Academic Research Consortium-2 adjudicated clinical end points disabling stroke, acute kidney injury and myocardial infarction occurred in 1.3% (1/79), 5.1% (4/79) and 0% (0/79) of patients. Postprocedural PPM implantation was necessary in 7.6% (6/79) of patients. Multislice computed tomography analysis revealed significantly higher calcium amounts of the right coronary cusp in patients in need for postprocedural PPM implantation and a higher eccentricity index in patients with postinterventional mild PVL.CONCLUSIONSFirst experience with this newly designed balloon-expandable-transcatheter heart valve demonstrates adequate 30-day outcomes and haemodynamic results with low mortality, low rates of PPM implantation and no residual PVL >mild. The herein-presented multislice computed tomography values with an elevated risk for PPM implantation and residual mild PVL may help to further improve outcomes with this particular transcatheter heart valve in TAVI procedures.     

Depression and loneliness of older adults in Europe and Israel after the first wave of covid-19

Epidemic control measures that aim to introduce social distancing help to decelerate the spread of the COVID-19 pandemic. However, their consequences in terms of mental well-being might be negative, especially for older adults. While existing studies mainly focus on the time during the first lockdown, we look at the weeks afterward in order to measure the medium-term consequences of the first wave of the pandemic. Using data from the SHARE Corona Survey, we include retired respondents aged 60 and above from 25 European countries plus Israel. Combining SHARE data with macro-data from the Oxford COVID-19 Government Response Tracker allows us to include macro-indicators at the country level, namely the number of deaths per 100,000 and the number of days with stringent epidemic control measures, in addition to individual characteristics. The findings show that both macro-indicators are influential for increased feelings of sadness/depression, but that individual factors are crucial for explaining increased feelings of loneliness in the time after the first lockdown. Models with interaction terms reveal that the included macro-indicators have negative well-being consequences, particularly for the oldest survey participants. Additionally, the results reveal that especially those living alone had a higher risk for increased loneliness in the time after the first COVID-19 wave.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10433-021-00640-8.     

Dynamic porous organic polymers with tuneable crosslinking degree and porosity

Porous organic polymers (POPs) show enormous potential for applications in separation, organic electronics, and biomedicine due to the combination of high porosity, high stability, and ease of functionalisation. However, POPs are usually insoluble and amorphous materials making it very challenging to obtain structural information. Additionally, important parameters such as the exact molecular structure or the crosslinking degree are largely unknown, despite their importance for the final properties of the system. In this work, we introduced the reversible multi-fold nitroxide exchange reaction to the synthesis of POPs to tune and at the same time follow the crosslinking degree in porous polymer materials. We synthesised three different POPs based on the combination of linear, trigonal, and tetrahedral alkoxyamines with a tetrahedral nitroxide. We could show that modulating the equilibrium in the nitroxide exchange reaction, by adding or removing one nitroxide species, leads to changes in the crosslinking degree. Being able to modulate the crosslinking degree in POPs allowed us to investigate both the influence of the crosslinking degree and the structure of the molecular components on the porosity. The crosslinking degree of the frameworks was characterised using EPR spectroscopy and the porosity was determined using argon gas adsorption measurements. To guide the design of POPs for desired applications, our study reveals that multiple factors need to be considered such as the structure of the molecular building blocks, the synthetic conditions, and the crosslinking degree.

We synthesised three different POPs via a nitroxide exchange reaction and modulated their crosslinking degree. That allowed us to investigate the influence of the crosslinking degree and the structure of the molecular components on the porosity.

Various approaches to synthesise porous organic polymers (POPs)^1–3 and conjugated microporous polymers (CMPs)^4,5 have been developed to form extremely stable but at the same time highly porous solids based on simple organic building blocks.^6,7 The organic nature allows for functionalisation of the materials using organic chemistry, while the high porosity makes the active components accessible throughout the entire material.⁸ The combination of high porosity, high stability, and ease of functionalisation results in the enormous potential of POPs for applications in separation, organic electronics, and biomedicine.^2,9–14 However, unlike the related covalent organic frameworks (COFs),^15–20 metal–organic frameworks (MOFs)^21,22 or porous coordination polymers (PCPs),²³ the synthesis of POPs and CMPs is based on irreversible reactions, which leads to insoluble and amorphous materials and makes it very challenging to obtain structural information. Additionally, important parameters such as the exact molecular structure or the crosslinking degree are largely unknown, despite their unarguably large influence on the final properties of the system.^24,25To investigate the molecular structure of the organic linkers between the centres of two similar CMP materials, the group of Bunz and co-workers introduced molecular building blocks that were modified with digestible groups or cores, by substituting carbon with tin as the central atom.²⁴ This tin centre can be digested, resulting in molecular fragments of the frameworks, which were analysed using nuclear magnetic resonance (NMR) spectroscopy. The obtained fragments show a surprisingly varied chemical composition of these networks.²⁴ In a previous study, we could show that the introduction of digestible germanium nodes in one of the building blocks of POPs can also be used for partial disruption of the framework and therefore causing a decrease or allow tuning of the porosity.²⁵ In another approach, we introduced a poly(disulfide) hyper-crosslinked polymer, which can be surface modified using unreacted thiol functions on the surface of the material.²⁶ Digestion of the samples helped to quantify the functionalisation. Employing digestible crosslinker or nodes is an attractive approach to gain insight into the structure or functionalisation of the frameworks. However, it requires the destruction of the sample and does not allow to modulate or tune the crosslinking degree reversibly in one particular system.In order to tune and at the same time follow the crosslinking degree in porous polymer materials, we introduce the reversible multi-fold nitroxide exchange reaction to the synthesis of POPs. The nitroxide exchange reaction has been used in material science for self-assembly of polymer materials²⁷ or micron-sized crystals,²⁸ for surface functionalisation,²⁹ or introducing self-healing properties to materials.³⁰ In addition, the combination of light-sensitive alkoxyamines was employed in surface coating³¹ or the creation of systems out of their equilibrium.³² The radical nature of the involved nitroxide species allows to follow the progress of the reaction and to directly determine the crosslinking degree of the final material using fluorescence spectroscopy^33,34 and electron paramagnetic resonance (EPR) spectroscopy.^35,36 The dynamic nature of the nitroxide exchange reaction allowed us to tune the crosslinking degree of the materials by varying the ratio of the two nitroxide species involved in the reaction and thereby modulating the equilibrium conditions (see Fig. 1).Open in a separate windowFig. 1Dynamic equilibrium in the nitroxide exchange reaction using two different nitroxide species, TEMPO (red) and isoindoline (green). The free nitroxide radical species are electron paramagnetic resonance (EPR) active, while the bound species are EPR silent.Next to the crosslinking degree, also the structure, rigidity, and the intrinsic free volume of the molecular components of POPs or CMPs play an important role to obtain porosity in the final material.⁶ Cooper and co-workers showed the importance of monomer design for the pore size and surface area of CMPs by systematically varying the strut length in a series of molecular building blocks.³⁷In order to study the influence of both the molecular structure and the crosslinking degree on the porosity of the final material, we produced three different POPs based on the combination of linear, trigonal, and tetrahedral alkoxyamines with tetrahedral nitroxides. We characterised the frameworks using EPR spectroscopy and argon gas adsorption measurements to determine the crosslinking degree and porosity. Furthermore, we could show that modulating the equilibrium in the nitroxide exchange reaction, by adding or removing one nitroxide species, leads to changes in the crosslinking degree and investigated this influence on the porosity of the frameworks.