Ultrashort Bradycardic Effect of Newly Synthesized Compounds

Changes in the heart rate induced by four different doses of two newly synthesized potential ultrashort-action antagonists of beta adrenergic receptors were tested in 90 male laboratory Wistar rats. The isoprenaline-induced tachycardia model was used. Their effects were compared with those of esmolol. In the second part of the study, approximate electro-physiological measurements were made in vitro to assess the influence of the compounds tested on ion membrane currents in isolated ventricular cardiomyocytes. Both compounds demonstrated significant bradycardic effects in all concentrations tested compared with the control group, but they differed in the time of the onset of their action. Both newly synthesized compounds induced blockade of the fast sodium current (INa) and potassium currents (Ito, IK1, IK,end)

Lipolytic and Hypolipidemic Properties of Newly Synthesized Aryloxypropanolamine Derivatives

In this study, the lipolytic effect of two newly synthesized potential β3-adrenergic agonists A482 and B496 in active acid forms was tested using isolated sliced epididymal adipose tissue of Wistar rats, and compared with Isoprenaline and BRL37344. Furthermore, effects of an eight-week oral administration of the newly synthesized substances on serum cholesterol, triglycerides, glucose, adiponectin, resistin and weight gain were studied in C57Bl/6J mice that were fed high energy diet. The newly synthesized substance A482 (4-(2-{[2-hydroxy-3-(4-methyl-carbamoylphenoxy) propyl]amino}ethyl)phenoxy-acetic acid hydrochloride) was able to produce almost full lipolysis at a 1 × 10-7 M concentration, and its effect on the rat epididymal adipose tissue was similar to the specific β3-adrenergic agonist BRL37344. Ethyl ester of this substance significantly lowered plasma total cholesterol (p p p p p 3-adrenergic agonists. Our results suggest that the newly synthesised substance A482 may represent a potent β3-adrenergic agonist

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat

Finite element model focused on stress distribution in the levator ani muscle during vaginal delivery

Cílem této práce byl vývoj sofistikovaného modelu vycházejícího ze snímků MRI a následná simulace změn levatoru ani (MLA) během vaginálního porodu. Pánev ženy a hlava dítěte byly modelovány tuhými tělesy. MLA a obturátorový sval byly reprezentovány Ogdenovým materiálovým modelem. Okrajové podmínky nahradily všechna anatomická omezení a podpory. Střední hodnota napětí ve svalu MLA během průchodu hlavy byla 4.91–7.93 MPa. Největší hodnoty napětí byly nalezeny v puboviscerální a purorektální části MLA (27.46 MPa). Sval MLA byl prodloužen 2,5 krát oproti své původní klidové pozici. Obecně řešeno, oblast největšího napětí byla odhalena v části připojení ke stydké kosti. Právě tato oblast je považována za oblast největšího rizika poranění s dlouhodobými komplikacemi.The objective of this study was to develop a sophisticated MRI-based model to simulate changes in the levator ani muscle (MLA) during vaginal delivery. The female pelvis and the fetal head were modeled by rigid bodies. The MLA and obturator were represented by Ogden material model. The boundary conditions reflected all anatomical constraints and supports. The mean stress values in the MLA during fetal head passage were 4.91–7.93 MPa. The highest stress values were induced in the pubovisceral and puborectal MLA (mean 27.46 MPa). The MLA was elongated by nearly 2.5 times from its initial resting position. The absolute stress values were highest in muscle area arising from the pubic bone. This area is at the highest risk for muscle injuries with long-term complications