Postobstruktive Diurese bei Katzen mit FLUTD

OBJECTIVES: The objective of this retrospective study was to investigate the actual incidence of postobstructive diuresis after relief of urethral obstruction in cats, as well as to identify changes in blood and urine parameters that might be associated with postobstructive diuresis (POD), and to assess the impact of fluid therapy. METHODS: The medical records of 57 male cats with urethral obstruction that were treated with an indwelling urinary catheter were retrospectively analysed. Absolute urine output in ml/kg/h every 4 h and the incidence of cats with polyuria (urine volume >2 ml/kg/h) at any time point over a 48 h period after the re-establishment of urine flow were investigated. In addition, postobstructive diuresis in relation to fluid therapy (PODFR) was defined as urine output greater than the administered amount of intravenous fluids on at least two subsequent time points. Polyuria and PODFR were investigated for their association with blood and urine laboratory parameters. RESULTS: After 4 h, 74.1% (40/54) of the cats had polyuria, with a urine output of >2 ml/kg/h. Metabolic acidosis was present in 46.2% of the cats. Venous blood pH and bicarbonate were inversely correlated with urine output in ml/kg/h after 4 h. The overall incidence of POD within 48 h of catheterisation was 87.7%. There was a significant correlation between intravenous fluid rate at time point x and urine output at time point x + 1 at all the time points except for the fluid rate at time point 0 and the urine output after 4 h. PODFR was seen in 21/57 cats (36.8%). CONCLUSIONS AND RELEVANCE: POD is a frequent finding in cats treated for urethral obstruction, and can be very pronounced. Further studies are required to determine whether or not a change in venous blood pH actually interferes with renal concentration ability. The discrepancy between the frequency of cats with polyuria and PODFR (87.7% vs 36.8%) in the present study indicates that administered intravenous fluid therapy might be the driving force for the high incidence of polyuria in some cats with naturally occurring obstructive feline lower urinary tract disease

Postobstruktive Diurese bei Katzen mit FLUTD

OBJECTIVES: The objective of this retrospective study was to investigate the actual incidence of postobstructive diuresis after relief of urethral obstruction in cats, as well as to identify changes in blood and urine parameters that might be associated with postobstructive diuresis (POD), and to assess the impact of fluid therapy. METHODS: The medical records of 57 male cats with urethral obstruction that were treated with an indwelling urinary catheter were retrospectively analysed. Absolute urine output in ml/kg/h every 4 h and the incidence of cats with polyuria (urine volume >2 ml/kg/h) at any time point over a 48 h period after the re-establishment of urine flow were investigated. In addition, postobstructive diuresis in relation to fluid therapy (PODFR) was defined as urine output greater than the administered amount of intravenous fluids on at least two subsequent time points. Polyuria and PODFR were investigated for their association with blood and urine laboratory parameters. RESULTS: After 4 h, 74.1% (40/54) of the cats had polyuria, with a urine output of >2 ml/kg/h. Metabolic acidosis was present in 46.2% of the cats. Venous blood pH and bicarbonate were inversely correlated with urine output in ml/kg/h after 4 h. The overall incidence of POD within 48 h of catheterisation was 87.7%. There was a significant correlation between intravenous fluid rate at time point x and urine output at time point x + 1 at all the time points except for the fluid rate at time point 0 and the urine output after 4 h. PODFR was seen in 21/57 cats (36.8%). CONCLUSIONS AND RELEVANCE: POD is a frequent finding in cats treated for urethral obstruction, and can be very pronounced. Further studies are required to determine whether or not a change in venous blood pH actually interferes with renal concentration ability. The discrepancy between the frequency of cats with polyuria and PODFR (87.7% vs 36.8%) in the present study indicates that administered intravenous fluid therapy might be the driving force for the high incidence of polyuria in some cats with naturally occurring obstructive feline lower urinary tract disease

Postobstructive diuresis in cats with naturally occurring lower urinary tract obstruction: incidence, severity and association with laboratory parameters on admission

Objectives The objectives of this retrospective study were to investigate the actual incidence of postobstructive diuresis after relief of urethral obstruction in cats, as well as to identify changes in blood and urine parameters that might be associated with postobstructive diuresis (POD), and to assess the impact of fluid therapy. Methods The medical records of 57 male cats with urethral obstruction that were treated with an indwelling urinary catheter were retrospectively analysed. Absolute urine output in ml/kg/h every 4 h and the incidence of cats with polyuria (urine volume >2 ml/kg/h) at any time point over a 48 h period after the re-establishment of urine flow were investigated. In addition, postobstructive diuresis in relation to fluid therapy (PODFR) was defined as urine output greater than the administered amount of intravenous fluids on at least two subsequent time points. Polyuria and PODFR were investigated for their association with blood and urine laboratory parameters. Results After 4 h, 74.1% (40/54) of the cats had polyuria, with a urine output of >2 ml/kg/h. Metabolic acidosis was present in 46.2% of the cats. Venous blood pH and bicarbonate were inversely correlated with urine output in ml/kg/h after 4 h. The overall incidence of POD within 48 h of catheterisation was 87.7%. There was a significant correlation between intravenous fluid rate at time point x and urine output at time point x + 1 at all the time points except for the fluid rate at time point 0 and the urine output after 4 h. PODFR was seen in 21/57 cats (36.8%). Conclusions and relevance POD is a frequent finding in cats treated for urethral obstruction, and can be very pronounced. Further studies are required to determine whether or not a change in venous blood pH actually interferes with renal concentrating ability. The discrepancy between the frequency of cats with polyuria and PODFR (87.7% vs 36.8%) in the present study indicates that administered intravenous fluid therapy might be the driving force for the high incidence of polyuria in some cats with naturally occurring obstructive feline lower urinary tract disease

Efficacy of intravesical pentosan polysulfate sodium in cats with obstructive feline idiopathic cystitis

Objectives Obstructive feline idiopathic cystitis is a common emergency in small animal practice. There is evidence for a defective glycosaminoglycan layer in the urinary bladder of affected cats. The aim of this study was to investigate the effect of intravesical pentosan polysulfate sodium (PPS) in cats with obstructive feline idiopathic cystitis in a randomised, placebo-controlled, blinded clinical study. Methods Thirty-five cats with obstructive feline idiopathic cystitis were enrolled into the study. On day 0, cats were randomised to receive either 30mg PPS in saline (18 cats) or saline alone as placebo (17 cats) at the time of indwelling urinary catheter placement and then after 24 and 48h. The catheter was clamped for 30mins after administration before connecting it to a sterile urine collection system. The procedure was repeated after 24 and 48h, and then the indwelling catheter was removed. Treatment success was assessed via the incidence of recurrent urethral obstruction, results of a scoring system for physical examination and daily urinalysis from day 0 to 5. Results Recurrent urethral obstruction occurred in 3/18 cats of the verum group and 3/17 of the placebo group (P=1.000). The verum group showed a significantly lower degree of microscopic haematuria between day 5 and day 0 (P 0.05). The placebo group showed a significantly lower degree of dipstick haematuria between day 5 and day 0 (P 0.05). There was no difference in the clinical score between the groups in the investigated time period. Conclusions and relevance Intravesical instillation of PPS three times within 48h in the chosen dose had no influence on the incidence of recurrent urethral obstruction and clinical signs in cats with obstructive feline idiopathic cystitis

Nanosized Multifunctional Polyplexes for Receptor-Mediated SiRNA Delivery

Although our understanding of RNAi and our knowledge on designing and synthesizing active and safe siRNAs significantly increased during the past decade, targeted delivery remains the major limitation in the development of siRNA therapeutics. On one hand, practical considerations dictate robust chemistry reproducibly providing precise carrier molecules. On the other hand, the multistep delivery process requires dynamic multifunctional carriers of substantial complexity. We present a monodisperse and multifunctional carrier system, synthesized by solid phase supported chemistry, for siRNA delivery in vitro and in vivo. The sequence-defined assembly includes a precise cationic (oligoethanamino)amide core, terminated at the ends by two cysteines for bioreversible polyplex stabilization, at a defined central position attached to a monodisperse polyethylene glycol chain coupled to a terminal folic acid as cell targeting ligand. Complexation with an endosomolytic influenza peptide-siRNA conjugate results in nanosized functional polyplexes of 6 nm hydrodynamic diameter. The necessity of each functional substructure of the carrier system for a specific and efficient gene silencing was confirmed. The nanosized polyplexes showed stability in vivo, receptor-specific cell targeting, and silencing of the EG5 gene in receptor-positive tumors. The nanosized appearance of these particles can be precisely controlled by the oligomer design (from 5.8 to 8.8 nm diameter). A complete surface charge shielding together with the high stability result in good tolerability in vivo and the absence of accumulation in nontargeted tissues such as liver, lung, or spleen. Due to their small size, siRNA polyplexes are efficiently cleared by the kidney

Electro-mechanical whole-heart digital twins: A fully coupled multi-physics approach

Mathematical models of the human heart are evolving to become a cornerstone of precision medicine and support clinical decision making by providing a powerful tool to understand the mechanisms underlying pathophysiological conditions. In this study, we present a detailed mathematical description of a fully coupled multi-scale model of the human heart, including electrophysiology, mechanics, and a closed-loop model of circulation. State-of-the-art models based on human physiology are used to describe membrane kinetics, excitation-contraction coupling and active tension generation in the atria and the ventricles. Furthermore, we highlight ways to adapt this framework to patient specific measurements to build digital twins. The validity of the model is demonstrated through simulations on a personalized whole heart geometry based on magnetic resonance imaging data of a healthy volunteer. Additionally, the fully coupled model was employed to evaluate the effects of a typical atrial ablation scar on the cardiovascular system. With this work, we provide an adaptable multi-scale model that allows a comprehensive personalization from ion channels to the organ level enabling digital twin modeling

Study of exclusive one-pion and one-eta production using hadron and dielectron channels in pp reactions at kinetic beam energies of 1.25 GeV and 2.2 GeV with HADES

We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions

ERK Signaling Regulates Light-Induced Gene Expression via D-Box Enhancers in a Differential, Wavelength-Dependent Manner

The day-night and seasonal cycles are dominated by regular changes in the intensity as well as spectral composition of sunlight. In aquatic environments the spectrum of sunlight is also strongly affected by the depth and quality of water. During evolution, organisms have adopted various key strategies in order to adapt to these changes, including the development of clocks and photoreceptor mechanisms. These mechanisms enable the detection and anticipation of regular changes in lighting conditions and thereby direct an appropriate physiological response. In teleosts, a growing body of evidence points to most cell types possessing complex photoreceptive systems. However, our understanding of precisely how these systems are regulated and in turn dictate changes in gene expression remains incomplete. In this manuscript we attempt to unravel this complexity by comparing the effects of two specific wavelengths of light upon signal transduction and gene expression regulatory mechanisms in zebrafish cells. We reveal a significant difference in the kinetics of light-induced gene expression upon blue and red light exposure. Importantly, both red and blue light-induced gene expression relies upon D-box enhancer promoter elements. Using pharmacological and genetic approaches we demonstrate that the ERK/MAPK pathway acts as a negative regulator of blue but not red light activated transcription. Thus, we reveal that D-box-driven gene expression is regulated via ERK/MAPK signaling in a strongly wavelength-dependent manner

BRAFΔβ3−αC^{Δβ3-αC} in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAF$^{Δβ3-αC}$ oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAF$^{Δβ3-αC}$ oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAF$^{ΔLNVTAP>F}$ and two novel mutants, BRAF$^{delinsFS}$ and BRAF$^{ΔLNVT>F}$, and compare them with other BRAF$^{Δβ3-αC}$ oncoproteins. We show that BRAF$^{Δβ3-αC}$ oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAF$^{Δβ3-αC}$ oncoproteins, e.g., BRAF$^{ΔLNVTAP>F}$, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAF$^{Δβ3-αC}$ mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds

Tip- and laser-based 3D nanofabrication in extended macroscopic working areas

The field of optical lithography is subject to intense research and has gained enormous improvement. However, the effort necessary for creating structures at the size of 20 nm and below is considerable using conventional technologies. This effort and the resulting financial requirements can only be tackled by few global companies and thus a paradigm change for the semiconductor industry is conceivable: custom design and solutions for specific applications will dominate future development (Fritze in: Panning EM, Liddle JA (eds) Novel patterning technologies. International society for optics and photonics. SPIE, Bellingham, 2021. https://doi.org/10.1117/12.2593229). For this reason, new aspects arise for future lithography, which is why enormous effort has been directed to the development of alternative fabrication technologies. Yet, the technologies emerging from this process, which are promising for coping with the current resolution and accuracy challenges, are only demonstrated as a proof-of-concept on a lab scale of several square micrometers. Such scale is not adequate for the requirements of modern lithography; therefore, there is the need for new and alternative cross-scale solutions to further advance the possibilities of unconventional nanotechnologies. Similar challenges arise because of the technical progress in various other fields, realizing new and unique functionalities based on nanoscale effects, e.g., in nanophotonics, quantum computing, energy harvesting, and life sciences. Experimental platforms for basic research in the field of scale-spanning nanomeasuring and nanofabrication are necessary for these tasks, which are available at the Technische Universität Ilmenau in the form of nanopositioning and nanomeasuring (NPM) machines. With this equipment, the limits of technical structurability are explored for high-performance tip-based and laser-based processes for enabling real 3D nanofabrication with the highest precision in an adequate working range of several thousand cubic millimeters