From land to water: "Sunken" T-maze for associated learning in cichlid fish.

The study introduced and evaluated learning paradigms for Maylandia callainos cichlids using a modified version of the rodent T-maze, filled with tank water (the "sunken" modification). Both male and female fish underwent training in two distinct conditioning paradigms. Firstly, simple operant conditioning involved placing a food reward in either the right or left compartment. Cichlids demonstrated the ability to purposefully find the bait within 6 days of training, with a persistent place preference lasting up to 6 days. Additionally, the learning dynamics varied with sex: female cichlids exhibited reduction in latency to visit the target compartment and consume the bait, along with a decrease in the number of errors 3 and 4 days earlier than males, respectively. Secondly, visually-cued operant conditioning was conducted, with a food reward exclusively placed in the yellow compartment, randomly positioned on the left or right side of the maze during each training session. Visual learning persisted for 10 days until reaction time improvement plateaued. Color preference disappeared after 4 consecutive check-ups, with no sex-related interference. For further validation of visually-cued operant conditioning paradigm, drugs MK-801 (dizocilpine) and caffeine, known to affect performance in learning tasks, were administered intraperitoneally. Chronic MK-801 (0.17 mg/kg) impaired maze learning, resulting in no color preference development. Conversely, caffeine administration enhanced test performance, increasing precision in fish. This developed paradigm offers a viable approach for studying learning and memory and presents an effective alternative to rodent-based drug screening tools, exhibiting good face and predictive validity.

The novel peptide LCGM-10 attenuates metabotropic glutamate receptor 5 activity and demonstrates behavioral effects in animal models.

We employed a structural bioinformatics approach to develop novel peptides with predicted affinity to the binding site for negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5). Primary screening in zebrafish (Danio rerio) revealed a stimulatory effect of two peptides, LCGM-10 and LCGM-15. Target validation studies using calcium ion flux imaging and a luciferase reporter assay confirmed mGluR5 as the target. LCGM-10 showed greater potency than LCGM-15; it was comparable to that of the mGluR5 NAM 2-methyl-6-(phenylethynyl) pyridine (MPEP). Rodent behavioral screening in the open field and elevated plus maze revealed increased locomotor activity in both tests after acute LCGM-10 treatment, supported by further analysis of home cage spontaneous locomotor activity (SLA). The stimulating effect of a single LCGM-10 administration on SLA was evident up to 60 min after administration and was not accompanied by hypokinetic rebound observed for caffeine. According to our results, LCGM-10 has therapeutic potential to treat hypo- and dyskinesias of various etiologies. Further investigation of LCGM-10 effects in the delay discounting model of impulsive choice in rats revealed reduced trait impulsivity after single and chronic administrations, suggesting potential implication for attention deficit hyperactivity disorder, obsessive compulsive disorder, and addictions.

Surgery for Ascending Aortic Aneurysm and Aortic Valve Insufficiency in Conditions of Active Proceeding Syphilitic Aortitis and Valvulitis.

A syphilitic aortitis is a late cardiovascular lesion of tertiary syphilis that has become exceptionally rare in the antibiotic era but not eradicated completely. Syphilitic aortitis of ascending aorta complicates in ascending aortic aneurysm formation and aortic valve regurgitation, both requiring surgical treatment. After surgery, lifelong surveillance of the remainder of the aorta is recommended because of a priori supposed high incidence of delayed involvement of noninvolved aortic segments. A 3-year follow-up result of surgery of syphilitic ascending aortic aneurysm with aortic valve regurgitation in condition of active ongoing syphilitic aortitis and valvulitis is described with addressing the dimensions of remaining aortic segments. This case demonstrates that the dilatation of the remainder of the aorta does not occur during 3 years, at least when anti-syphilitic course of antibiotic is used just after operation without additional treatment during the follow-up period. A few reports on surgical treatment of syphilitic aneurysms of the ascending aorta are discussed.

The Novel Peptide Chm-273s Has Therapeutic Potential for Metabolic Disorders: Evidence from In Vitro Studies and High-Sucrose Diet and High-Fat Diet Rodent Models.

The aim of this study was to develop a novel peptide potentially applicable for the treatment of metabolic conditions, such as obesity and type 2 diabetes (T2D). We identified CHM-273S from the list of peptides from milk hydrolysate obtained by HPLC/MS-MS. In vitro analysis of primary murine fibroblasts indicated the potential of CHM-273S to upregulate IRS2 mRNA expression. CHM-273S showed a prominent anorexigenic effect in mice with the induction of a key mechanism of leptin signaling via STAT3 in the hypothalamus as a possible effector. In the animal model of metabolic disease, CHM-273S alleviated glucose intolerance and insulin resistance, and induced phosphorylation of Akt at Ser473 and Thr308 in the hepatocytes of high-sucrose diet-fed rats. In a murine model of T2D, CHM-273S mitigated high-fat diet-induced hyperglycemia and insulin resistance and improved low-grade inflammation by diminishing serum TNFα. Mice treated with chronic CHM-273S had a significant reduction in body weight, with a lower visceral fat pad weight and narrow adipocytes. The effects of the peptide administration were comparable to those of metformin. We show the potential of CHM-273S to alleviate diet-induced metabolic alterations in rodents, substantiating its further development as a therapeutic for obesity, T2D, and other metabolic conditions.

Peptide LCGA-17 Attenuates Behavioral and Neurochemical Deficits in Rodent Models of PTSD and Depression.

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant.

Pulmonary valve reconstruction by allograft replacement of underdeveloped anterior leaflet in case of late combined pulmonary restenosis after early primary repair.

INTRODUCTION: The native pulmonary valve (PV) reconstruction is an attractive alternative to a replacement but is challenging due to the systematic underdevelopment of the valve structures in congenital heart diseases. The partial replacement of underdeveloped parts of the valve and saving of well-developed may have advantages versus replacing the whole valve in terms of durability and patient outgrowth of the prosthesis. CASE PRESENTATION: This report describes a case of the PV reconstruction by allograft replacement of an underdeveloped anterior leaflet in an adolescent patient who previously corrected pulmonary stenosis during the first year of her life. The normal anatomy of the right and left leaflets was revealed. The rudimental anterior leaflet determined the annular restenosis. The monocusp with the related supporting aortic wall was sewn instead of the anterior leaflet. The Z-score of the pulmonary annulus changed from minus 3, 9 before to +0.8 after the procedure. The excellent function of the PV was observed in 1-year follow-up. DISCUSSION: Valve deterioration over time will have a less negative impact on the function when it occurs in a limited area. The annular dilatation becomes unlikely if the annulus predominantly consists of natural tissues. The procedural effectiveness allows the transcatheter valve-in-valve therapy in case of late dysfunction. The expected feature of the procedure described is that the growth of the PV remains possible. CONCLUSION: If allograft replacement of the PV is scheduled and allograft is available, the partial replacement may be superior to replacement of the whole valve in terms of durability and patient outgrowth of the prosthesis.

In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties.

The aim of the study was to develop better anxiolytics and antidepressants. We focused on GABA A receptors and the α2δ auxiliary subunit of V-gated Ca2+ channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further focused on short peptides as candidate ligands because of their high safety and tolerability profiles. We employed a structural bioinformatics approach to develop novel tetrapeptides with predicted affinity to GABA A receptors and α2δ. In silico docking studies of one of these peptides, LCGA-17, showed a high binding score for both GABA A receptors and α2δ, combined with anxiolytic-like properties in a Danio rerio behavioral screen. LCGA-17 showed anxiolytic-like effects in the novel tank test, the light-dark box, and the social preference test, with efficacy comparable to fluvoxamine and diazepam. In binding assays using rat brain membranes, [3H]-LCGA-17 was competed more effectively by gabapentinoid ligands of α2δ than ligands of GABA A receptors, suggesting that α2δ represents a likely target for LCGA-17. [3H]-LCGA-17 binding to brain lysates was unaffected by competition with ligands for GABAB, glutamate, dopamine, serotonin, and other receptors, suggesting specific interaction with α2δ. Dose-finding studies in mice using acute administration of LCGA-17 (i.p.) demonstrated anxiolytic-like effects in the open field test, elevated plus maze, and marble burying tests, as well as antidepressant-like properties in the forced swim test. The anxiolytic effects were effectively blocked by bicuculline. Therefore, LCGA-17 is a novel candidate anxiolytic and antidepressant that may act through α2δ, with possible synergism by GABA A receptors.

PeptoGrid-Rescoring Function for AutoDock Vina to Identify New Bioactive Molecules from Short Peptide Libraries.

Peptides are promising drug candidates due to high specificity and standout safety. Identification of bioactive peptides de novo using molecular docking is a widely used approach. However, current scoring functions are poorly optimized for peptide ligands. In this work, we present a novel algorithm PeptoGrid that rescores poses predicted by AutoDock Vina according to frequency information of ligand atoms with particular properties appearing at different positions in the target protein's ligand binding site. We explored the relevance of PeptoGrid ranking with a virtual screening of peptide libraries using angiotensin-converting enzyme and GABAB receptor as targets. A reasonable agreement between the computational and experimental data suggests that PeptoGrid is suitable for discovering functional leads.

Primary leiomyosarcoma of inferior vena cava adjacent to hepatic veins: complete off-pump resection and inferior vena cava graft reconstruction with application of external skin surface cooling.

OBJECTIVES: Resection of a leiomyosarcoma of the inferior vena cava (IVC) requires venovenous bypass, especially if IVC clamping above the hepatic veins is planned. This report describes the application of external skin surface cooling for off-pump resection of a primary IVC leiomyosarcoma adjacent to the hepatic veins with graft IVC reconstruction in conditions of suprahepatic caval clamping and uninterrupted Pringle's manoeuvre. METHODS: A 62-year-old woman presented with IVC leiomyosarcoma adjacent to the hepatic veins. After anaesthesia induction, the patient's head, neck, abdomen, chest, thighs and shanks were covered by polyethylene bags containing granulated ice. The ice bag was also placed between the internal surfaces of the thighs. After 108 min, the target oesophageal temperature (29°C) was achieved, all bags were removed, except the bags that were used for temperature control during the operation located on head, neck and between internal surfaces of the thighs. Off-pump resection of the tumour was performed in conditions of suprahepatic IVC and portal triad clamping via median laparotomy. RESULTS: IVC clamping was accompanied by arterial hypotension of 55-65 mmHg well-tolerating in the hypothermic background for 69 min. The simultaneous application of an uninterrupted Pringle's manoeuvre was accompanied by low levels of transaminases and bilirubin. There was no local relapse of the tumour or metastases over a 6-month follow-up. CONCLUSIONS: External skin surface cooling in cases demanding IVC clamping above the hepatic veins and Pringle's manoeuvre allows avoiding venovenous bypass. This method is safe, cost effective, easily performed and may be used in clinical cases involving systemic arterial hypotension.

Simultaneous multi-vessel coronary artery bypass grafting, ischemic mitral regurgitation repair and descending aortic aneurysm replacement: analysis of technical points.

The combination of coronary artery disease and its complications (ischemic mitral regurgitation etc.) with the aneurysm of the descending thoracic aorta is not a rare case. The single-stage correction of coronary/intracardiac/aortic lesions may be considered as a way of managing the combined patients. Simultaneous multi-vessel coronary artery bypass grafting, suture mitral annuloplasty and descending aortic aneurysm replacement with synthetic prosthesis is described. The operation was performed through the left thoracotomy with cardiopulmonary bypass established by the cannulation of the ascending aorta and of the right atrial appendage. Ventricular fibrillation and no clamping of the ascending aorta were used. The circulatory arrest was induced for the construction of the proximal anastomosis between the descending aorta and the synthetic prosthesis. No complications related to the operation were diagnosed for the 14-month follow-up. Several technical points seem optimal for the combined procedure: (1) Minimization of manipulations on the ascending aorta (using of pedicled left internal thoracic artery; construction of the proximal anastomoses with synthetic aortic prosthesis; unclamped ascending aorta). (2) Revascularization of all coronary areas and correction of intracardiac lesions through the left thoracotomy. Individual planning of the procedural technical points for every patient may provide a safe feasibility of the combined procedure.

Primary left atrial leiomyosarcoma: literature review and lessons of a case.

Primary cardiac sarcoma is an uncommon disease. In particular, leiomyosarcoma of cardiovascular origin is extremely rare. Half of all cardiac leiomyosarcomas are located in the left atrium. Due to the extreme rarity of left atrial leiomyosarcoma, there is no great experience in its management. This review includes a report of a case of left atrial leiomyosarcoma followed up over 45 months. The literature review examines the distribution of left atrial leiomyosarcoma, the physiological reasons for the tendency of cardiac leiomyosarcoma to be localized to the left atrial cavity, the clinical and physical appearance of this disease, and the key differences between left atrial leiomyosarcoma and the most common left atrial tumor, myxoma. The morphological features, using light and electron microscopy and immunochemical staining, are discussed. Treatment modalities including adjuvant therapy and surgical resection are examined and their effectiveness compared. Opinions regarding the results and optimal treatment of leiomyosarcoma are not always in agreement. This highlights the need for inter-hospital comparison to determine the optimal treatment regimen.