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Low-frequency, high-amplitude pH-oscillations observed experimentally in the H2O2−HSO3−−S2O32−flow reaction system at 21.0 °C undergo period-doubling cascades to chemical chaos upon decreasing the temperature to 19.0 °C in small steps. Period-4 oscillations are observed at 20.0 °C and can be calculated on the basis of a simple model. A reverse transition from chaos to high-frequency limit cycle oscillations is also observable in the reaction system upon decreasing further the temperature step by step to 15.0 °C. Period-2 oscillations are measured at 18.0 °C. Such a temperature-change-induced transition between periodic and chaotic oscillatory states can be understood by taking into account the different effects of temperature on the rates of composite reactions in the oscillatory system. Small differences in the activation energies of the composite reactions are responsible for the observed transitions. Temperature-change-induced period doubling is suggested as a simple tool for determining whether an experimentally observed random behavior in chemical systems is of deterministic origin or due to experimental noise. [ABSTRACT FROM AUTHOR]

Selecting a known HTS hit with the pyrazolo[1,5- a ]pyrimidine core, our project was started from CMPPE, and its optimization was driven by a ligand-based pharmacophore model developed on the basis of published GABA B positive allosteric modulators (PAMs). Our primary goal was to improve the potency by finding new enthalpic interactions. Therefore, we included the lipophilic ligand efficiency (LLE or LipE) as an objective function in the optimization that led to a carboxylic acid derivative ( 34 ). This lead candidate offers the possibility to improve potency without drastically inflating the physicochemical properties. Although the discovery of the novel carboxyl feature was surprising, it turned out to be an important element of the GABA B PAM pharmacophore that can be perfectly explained based on the new protein structures. Rationalizing the binding mode of 34 , we analyzed the intersubunit PAM binding site of GABA B receptor using the publicly available experimental structures., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved in vitro and in vivo profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound 43 (RGH-122). The CNS activity of the compound was determined in a 3-chamber social preference test of autism in which RGH-122 successfully enhanced social preference with the lowest effective dose of 1.5 mg/kg.

Autism spectrum disorder is a neurodevelopmental disease with increasing occurrence. Recent studies focus on the development of novel V 1A receptor antagonists which can influence the core symptoms of autism through the AVP pathway. In this study, we describe the synthesis of new heterocyclic ring systems. These are a novel class of brain-penetrating V 1A antagonists with improved metabolic stability and in vivo potency. The efficacy of the compounds was strongly influenced by the position of the chlorine atom, suggesting halogen bond formation between the ligands and the V 1A receptor.

Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Starting from a moderately potent HTS hit (7), we identified a molecule (49) having nanomolar binding strength and functional activity, which is in the same range as the potency of clinically tested V1a antagonists., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Continuing our previous work, we found an in vitro and in vivo orally active V1a selective antagonist molecule (40) among [1,2,4]triazolo[4,3-a][1]benzazepines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To analyse the performance of the Fabian +NCPAP evolution ventilator during volume guarantee (VG) ventilation in neonates at maintaining the target tidal volume and what tidal and minute volumes are required to maintain normocapnia., Methods: Clinical and ventilator data were collected and analysed from 83 infants receiving VG ventilation during interhospital transfer. Sedation was used in 26 cases. Ventilator data were downloaded with a sampling rate of 0.5 Hz. Data were analysed using the Python computer language and its data analysis packages., Results: ~107 hours of ventilator data were analysed, consisting of ~194 000 data points. The median absolute difference between the actual expiratory tidal volume (VTe) of the ventilator inflations and the target tidal volume (VTset) was 0.29 mL/kg (IQR: 0.11-0.79 mL/kg). Overall, VTe was within 1 mL/kg of VTset in 80% of inflations. VTe decreased progressively below the target when the endotracheal tube leak exceeded 50%. When leak was below 50%, VTe was below VTset by >1 mL/kg in less than 12% of inflations even in babies weighing less than 1000 g. Both VTe (r=-0.34, p=0.0022) and minute volume (r=-0.22, p=0.0567) showed a weak inverse correlation with capillary partial pressure of carbon dioxide (Pco 2 ) values. Only 50% of normocapnic blood gases were associated with tidal volumes between 4 and 6 mL/kg., Conclusions: The Fabian ventilator delivers volume-targeted ventilation with high accuracy if endotracheal tube leakage is not excessive and the maximum allowed inflating pressure does not limit inflations. There is only weak inverse correlation between tidal or minute volumes and Pco 2 ., Competing Interests: Competing interests: CJM was a consultant to Acutronic Medical but not for Fabian ventilators., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Numerous potent P2X3 antagonists have been discovered and the therapeutic potential of P2X3 antagonism already comprises proof-of-concept data obtained in clinical trials with the most advanced compound. We have lately reported the discovery and optimization of thia-triaza-tricycle compounds with potent P2X3 antagonistic properties. This Letter describes the SAR of a back-up series containing a 4-oxo-quinazoline central ring. The discovery of the highly potent compounds 51 is presented., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purinergic P2X3 receptors are trimeric ligand-gated ion channels whose antagonism is an appealing yet challenging and not fully validated drug development idea. With the aim of identification of an orally active, potent human P2X3 receptor antagonist compound that can penetrate the central nervous system, the compound collection of Gedeon Richter was screened. A hit series of tricyclic compounds was subjected to a rapid, two-step optimization process focusing on increasing potency, improving metabolic stability and CNS penetrability. Attempts resulted in compound 65, a potential tool compound for testing P2X3 inhibitory effects in vivo., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Three-dimensional speckle-tracking echocardiography (3DSTE) is accepted as a reliable and feasible method in the quantification of left ventricular (LV) volumes, strains and rotational characteristics. This case aimed to demonstrate the diagnostic importance of 3DSTE in volumetric and functional assessment of an LV aneurysm.

Six active 4-aryl-5-nitro-pentan-2-ones were synthesized enantioselectively from the corresponding 5-aryl-butenones by asymmetric Michael addition of nitromethane using an imidazolidine-type enantioselective organocatalyst. The ee ratio of the products were between 67 and 100%, determined by HPLC with Chiracel OD. Molecular and crystal structure of 3,4-methylenedioxy-phenyl-5-nitro-pentan-2-one has been studied by single crystal X-ray diffraction., (2008 Wiley-Liss, Inc.)

From January 1966 through December 1985, 29 adolescents and adults underwent surgical repair of a partial atrioventricular septal defect at our institution. The patients included 20 females and 9 males, whose ages ranged from 16 to 47 years (mean, 27.6 +/- 10.1 years). Preoperatively, 24 patients were in New York Heart Association functional class I or II, and 5 were in class III. The pulmonary artery systolic pressure ranged from 22 to 62 mmHg (mean, 38.3 +/- 12.7 mmHg). The pulmonary-to-systemic flow ratio ranged from 1.4 to 2.9 (mean, 2.3 +/- 0.5). Upon left ventriculography, regurgitation through the left atrioventricular valve was trivial or nonexistent in 4 patients (13.8%), mild in 14 (48.3%), moderate in 10 (34.5%), and severe in 1 patient (3.4%). All patients underwent patch closure of the ostium primum defect, and all but 2 underwent partial or complete suturing of the septal commissure. One patient died within 30 days, for a hospital mortality of 3.4%. The follow-up period ranged from 7 to 25 years (mean, 15.2 +/- 5.3 years). Postoperatively, all patients were evaluated with 2-dimensional and Doppler echocardiography. One patient underwent early implantation of a permanent pacemaker for persistent complete heart block. Three patients succumbed to late death 10, 15, and 21 years after operation. Among the 25 long-term survivors, 1 patient required late valve replacement because of severe left atrioventricular valve regurgitation. Nine (37.5%) of the other 24 long-term survivors had little or no regurgitation. Of the 11 patients with moderate-to-severe preoperative left atrioventricular valve regurgitation, 4 had moderate postoperative regurgitation. Seventeen patients had a moderate or severe persistent apical systolic murmur. At the latest follow-up in 1991, 5 (20%) of the 25 long-term survivors had significant arrhythmias. At 25 years, the actuarial survival rate was 78.9% +/- 25.6%. All 25 surviving patients were in New York Heart Association class I or II. The rate of freedom from reoperation was 77.7% +/- 25.9%. We conclude that, in adolescents and adults, correction of a partial atrioventricular septal defect entails little risk and is likely to improve the patient's functional status. Repair of the left atrioventricular valve yields good results, even at long-term follow-up.

The blood pressure of dogs anaesthetized with 0.1 g/kg of chloralose was reduced to 40 mm Hg by arterial bleeding. Thirty percent of the drawn blood refluxed spontaneously, the rest was retransfused either suddenly arterially or slowly in 15 minutes by the venous route. In other groups a total quantity of 25 ml/kg was drawn from an artery at a rate of 50 ml/kg and after about one minute the entire quantity of blood was rapidly retransfused through the artery. The control group breathed spontaneously, the other groups were given artificial respiration, or the sinus nerves and the vagus were transected separately or simultaneously, or transection was combined with artificial ventilation.

Dogs under chloralose anasthesia were bled at a rate of 50 ml/min to a total of 25 ml/kg body weight and 2 minutes later a quick reinfusion of adequate volumes of blood, dextran, or Locke's solution was done. Within 2 minutes after reinfusion, the pH of arterial blood fell by 0.074--0.127; concurrently, PaCO2 rose by 9.2-12.9 mm Hg. A close correlation was demonstrated between these changes. After retransfusion, PaO2 and the arterial lactic acid level did not change significantly. Thus retransfusion acidosis in the dog appears after a brief hypotensive period, too, but cannot be attributed to a "washout" of lactate from the tissues.