Administration Of Saline Research Articles

Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15-TGF-β1 under aggravated afterload.

Pathological cardiac hypertrophy exhibits complex and abnormal gene expression patterns and progresses to heart failure. Forkhead box protein O6 (FoxO6) is a key transcription factor involved in many biological processes. This study aimed to explore the role of FoxO6 in cardiac hypertrophy. Three groups of mice were established: wild-type, FoxO6 knockout, and FoxO6-overexpressing. The mice received daily administration of angiotensin-II (Ang-II) or saline for 4 weeks, after which they were examined for cardiac hypertrophy, fibrosis, and function. Elevated cardiac expression of FoxO6 was observed in Ang-II-treated mice. FoxO6 deficiency attenuated contractile dysfunction and cardiac remodeling, including cardiomyocyte hypertrophy and fibroblast proliferation and differentiation. Conversely, FoxO6 overexpression aggravated the cardiomyopathy and heart dysfunction. Further studies identified kinesin family member 15 (Kif15) as downstream molecule of FoxO6. Kif15 inhibition attenuated the aggravating effect of FoxO6 overexpression. In vitro, FoxO6 overexpression increased Kif15 expression in cardiomyocytes and elevated the concentration of transforming growth factor-β1 (TGF-β1) in the medium where fibroblasts were grown, exhibiting increased proliferation and differentiation, while FoxO6 knockdown attenuated this effect. Cardiac-derived FoxO6 promoted pathological cardiac remodeling induced by aggravated afterload largely by activating the Kif15/TGF-β1 axis. This result further complements the mechanisms of communication among different cells in the heart, providing novel therapeutic targets for heart failure.

Clenbuterol Prevents Mechanical Unloading-Induced Myocardial Atrophy via Upregulation of Transient Receptor Potential Channel-3.

Left ventricular assist device in combination with clenbuterol has been demonstrated to significantly improve heart function in patients with advanced heart failure. However, the roles of clenbuterol in mechanical unloading and its underlying mechanism are poorly understood. A rat abdominal heart transplantation model has been developed to mimic mechanical unloading of the heart. The recipient rats were randomly segregated into experimental groups for the daily administration of either saline (the "Trans" group; n = 13) or clenbuterol (2 mg/kg, the "Trans + CB" group; n = 12). Another group of 10 rats served as a treatment mimic control/sham animals (the "Sham" group). All interventions were performed via intraperitoneal injections once daily for 4 weeks. The Trans group animals exhibited myocardial atrophy and dysfunction with decreased expression levels of transient receptor potential channel 3 (TRPC3) and phospholipase C-β1 (PLC-β1) at 4 weeks post-transplantation. Administration of clenbuterol improved cardiac function, prevented myocardial atrophy, and restored expression of TRPC3 and PLC-β1 in the unloaded hearts of the "Trans + CB" animals at 4 weeks post-transplantation. Silencing of the TRPC3 gene by siRNA inhibited the pro-hypertrophic effect of clenbuterol in the rat primary cardiomyocytes in vitro. Furthermore, U73122, an inhibitor of the PLC-β1/diacylglycerol (DAG) pathway, significantly attenuated clenbuterol-induced upregulation of TRPC3 in cardiomyocytes. These findings suggest that the anti-atrophic effect of clenbuterol may be dependent on the upregulation of TRPC3 through the activation of the PLC-β1/DAG pathway during mechanical unloading. The results of our study reveal a potential target for the prevention and treatment of mechanical unloading-induced myocardial atrophy.

Development and Initial Assessment of [18F]OP-801: a Novel Hydroxyl Dendrimer PET Tracer for Preclinical Imaging of Innate Immune Activation in the Whole Body and Brain.

Innate immune activation plays a critical role in the onset and progression of many diseases. While positron emission tomography (PET) imaging provides a non-invasive means to visualize and quantify such immune responses, most available tracers are not specific for innate immune cells. To address this need, we developed [18F]OP-801 by radiolabeling a novel hydroxyl dendrimer that is selectively taken up by reactive macrophages/microglia and evaluated its ability to detect innate immune activation in mice following lipopolysaccharide (LPS) challenge. OP-801 was radiolabeled in two steps: [18F]fluorination of a tosyl precursor to yield [18F]3-fluoropropylazide, followed by a copper-catalyzed click reaction. After purification and stability testing, [18F]OP-801 (150-250 μCi) was intravenously injected into female C57BL/6 mice 24 h after intraperitoneal administration of LPS (10 mg/kg, n=14) or saline (n=6). Upon completing dynamic PET/CT imaging, mice were perfused, and radioactivity was measured in tissues of interest via gamma counting or autoradiography. [18F]OP-801 was produced with >95% radiochemical purity, 12-52 μCi/μg specific activity, and 4.3±1.5% decay-corrected yield. Ex vivo metabolite analysis of plasma samples (n=4) demonstrated high stability in mice (97±3% intact tracer >120 min post-injection). PET/CT images of mice following LPS challenge revealed higher signal in organs known to be inflamed in this context, including the liver, lung, and spleen. Gamma counting confirmed PET findings, showing significantly elevated signal in the same tissues compared to saline-injected mice: the liver (p=0.009), lung (p=0.030), and spleen (p=0.004). Brain PET/CT images (summed 50-60 min) revealed linearly increasing [18F]OP-801 uptake in the whole brain that significantly correlated with murine sepsis score (r=0.85, p<0.0001). Specifically, tracer uptake was significantly higher in the brain stem, cortex, olfactory bulb, white matter, and ventricles of LPS-treated mice compared to saline-treated mice (p<0.05). [18F]OP-801 is a promising new PET tracer for sensitive and specific detection of activated macrophages and microglia that warrants further investigation.

Zoledronate treatment exerts sex-independent effects on bone and dental physicochemical properties in mice jaw necrosis.

Bisphosphonate (BF) therapy is strongly related to the occurrence of medication-related osteonecrosis of the jaw (ONJ). However, no previous study has evaluated if there are sex-related differences on the ONJ establishment together with bone biomechanical alterations, and if they could have a synergy with the ZA treatment. This study aimed to analyze the physicochemical properties of mineralized tissues in a zoledronate (ZA)-related osteonecrosis mouse model, by a 2 × 2-factorial design, considering sex (female/male) and treatment (ZA/Saline) factors (n = 8/group). After three ZA (1.0mg/kg) or saline administrations (days 0, 7, 14), the lower left second molar was extracted (day 42). Further ZA administration (day 49) and euthanasia (day 70) were conducted. After confirmation of ZA-induced jaw necrosis (histologic and microtomographic analysis), spectroscopic and mechanical parameters were assessed. ZA-treated groups presented lower bone density due to impaired healing of tooth extraction socket. Sex-related alterations were also observed, with lower bone density in females. Regarding biomechanical parameters, sex and treatment exerted independent influences. ZA, although decreasing flexural modulus and yield stress, increases stiffness mainly due to a higher bone volume. Females show less resistance to higher loads compared to males (considering dimension-independent parameters). Additionally, ZA increases crystallinity in bone and dental structure (p < 0.05). In summary, although strongly related to osteonecrosis occurrence, ZA modifies bone and dental mineral matrix, improving bone mechanical properties. Despite sex-dependent differences in bone biomechanics and density, osteonecrosis was established with no sex influence. No synergistic association between sex and treatment factors was observed in this study.

Preservation of Testicular Tissue and Alleviation of Oxidative Stress by Carvacrol Following Torsion/ Detorsion in Adult Male Rats

Objectives: Testicular torsion is a critical medical condition necessitating prompt diagnosis and intervention. This study aimed to explore the potential safeguarding effect of carvacrol against histological damage and oxidative stress resulting from torsion/detorsion (T/D) in rat testes. Materials and Methods: A total of 32 adult male rats were randomly divided into four groups. The sham group did not undergo any intervention. The second group received an intraperitoneal injection of 75 mg/kg carvacrol half an hour before detorsion application. The third group was administered 80 mg/kg carvacrol intraperitoneally without detorsion. The fourth group (control) experienced (T/D) through the administration of saline. Following a 5-hour reperfusion period, the left testis was excised for histological slide preparation. Blood serum was used to measure antioxidant enzyme levels. Data analysis was performed using the SPSS version 19 software and analysis of variance tests. Results: Significant histological alterations were observed between the sham and other three groups. The levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), and testosterone significantly decreased in all treatment groups compared to the control group (P&lt;0.05). Conversely, malondialdehyde (MDA) levels increased in the torsion control group in contrast to the sham group (P&lt;0.05). Carvacrol administration mitigated MDA levels in the treatment groups. Also, there were significant differences in tissue parameters between the sham and the other groups (P&lt;0.05). Conclusions: According to the results of this study, carvacrol possesses the potential to mitigate testicular tissue damage, enhance testicular function, and ameliorate oxidative stress consequential to testicular rotation.

Abstract P426: Novel Peptide B7-33 Demonstrates Efficacy In Rat Models Of Preeclampsia

Background: Preeclampsia (PreE) is a hypertensive pregnancy disorder, which occurs in approximately 10% of all gestations. The literature suggests potential therapeutic role of H2 relaxin in PreE. Due to the complex insulin-like structure of relaxin (A- and B- chains, 53 amino acids, 3 disulfide bonds), a novel H2 relaxin B-chain-only peptide variant B7-33 (27 amino acids without any disulfide bonds) has recently been developed. Objective: This single-chain peptide displayed equivalent efficacy to the natural H2 relaxin in several functional assays both in vitro and in vivo . The Aim of this study is to evaluate whether B7-33 attenuates preE syndrome in rat models of PreE. Methods: Rat Model 1. The efficacy of B7-33 was evaluated in the Reduction of Uterine Perfusion Pressure (RUPP) model as described previously. RUPP rats are randomly assigned to 4 groups (N=8/group): 1) vehicle, 2) B733; 3) B733-Fc; and 4) B733-HSA. Rats are dosed twice weekly (i.v.) from GD10 to GD 20. Rat Model 2. Timed-pregnant rats are used, and the model is conducted as previously described. DOCA and saline administration begin at approximately GD2. Three groups of animals are studied (n=8 per group). 1) normal pregnant rats; 2) pregnant animals injected (i.p.) initially with 12.5 mg of DOCA, followed by a weekly injection of 6.5 mg, and whose drinking water was replaced with 0.9% saline; 3) rats administered DOCA and saline as for Group 2, and given B733 35 ug i.p. biweekly from GD10-20. BP, proteinuria and inflammatory markers were evaluated. Statistical comparisons were performed using analysis of variance with Duncan’s post hoc test. Results: RUPP rats have increased MAP, plasma TNF-α, and plasma sFlt-1 along with decreased NO index compared to normal pregnancy. Treatment with B733 and B7-33 fusion proteins lowers MAP, TNF-α, and sFlt-1 back to that of normal pregnancy. B7-33 data are consistent with earlier data with serelaxin in the RUPP model. All fusions tested ameliorate hypertension in the RUPP animals. B7-33 normalizes BP and proteinuria in the DOCA rat model of preE. Conclusion: Both B7-33 and B7-33 fusion proteins attenuate preE syndrome in RUPP and DOCA rat models of PreE. We conclude that B7-33 is an ideal candidate for development as a novel therapeutic in preE.

Human umbilical cord mesenchymal stromal cell small extracellular vesicle transfer of microRNA-223-3p to lung epithelial cells attenuates inflammation in acute lung injury in mice.

Acute lung injury (ALI), manifested as strong pulmonary inflammation and alveolar epithelial damage, is a life-threatening disease with high morbidity and mortality. Small extracellular vesicles (sEVs), secreted by multiple types of cells, are critical cellular communication mediators and can inhibit inflammation by transferring bioactive molecules, such as microRNAs (miRNAs). Thus, we hypothesized that sEVs derived from mesenchymal stromal cells (MSC sEVs) could transfer miRNAs to attenuate inflammation of lung epithelial cells during ALI. C57BL/6 male mice were intratracheally administered LPS (10mg/kg). Six hours later, the mice were randomly administered with MSC sEVs (40µg per mouse in 150µl of saline), which were collected by ultracentrifugation. Control group received saline administration. After 48h, the mice were sacrificed to evaluate pulmonary microvascular permeability and inflammatory responses. In vitro, A549 cells and primary human small airway epithelial cells (SAECs) were stimulated with LPS with or without MSC sEVs treatment. In vitro, MSC sEVs could also inhibit the inflammation induced by LPS in A549 cells and SAECs (reducing TNF-α, IL-1β, IL-6 and MCP-1). Moreover, MSC sEV treatment improved the survival rate, alleviated pulmonary microvascular permeability, and inhibited proinflammatory responses (reducing TNF-α, IL-1β, IL-6 and JE-1) in ALI mice. Notably, miR-223-3p was found to be served as a critical mediator in MSC sEV-induced regulatory effects through inhibition of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) in lung epithelial cells. Overall, these findings suggest that MSC sEVs may offer a novel promising strategy for ALI.

Association ofbisphosphonate with bone loss andpain-related behaviour inan adjuvant-induced osteoporosis model.

Osteoporosis animal models are used extensively to determine the mechanisms of disease pathology and identify potential biological targets. The study aimed to establish a bone loss model, identify pain-related behaviour in neighbouring joints using an adjuvant-induced osteoporosis model, and examine the therapeutic effect of bisphosphonates. Complete Freund's adjuvant was injected subcutaneously into the back of the right foot of 8-week-old female ddY mice. Subsequently, pain, arthritis, and bone density in the right knee were monitored over time. Pain evaluation using von Frey filaments showed a significantly exacerbated knee pain threshold compared to the control group (saline administration) at 7- and 14-day intervals after complete Freund's adjuvant administration, and bone density during the same period also significantly declined. The adjuvant-induced osteoporosis model was created similarly; alendronate 40 μg/kg was subcutaneously injected twice and vehicle once from 7 to 14 days after onset. In the alendronate administration group on the 14th day, significant improvements in bone density, arthritis, and pain threshold around the knee were observed compared to the untreated group. Alendronate may contribute to pain improvement through the simultaneous effects of bone mass improvement and suppression of osteoporotic pain.

The preventive effect of 5-hydroxytryptamine-3 receptor antagonist on blood pressure reduction and postoperative nausea and vomiting during general anesthesia induction: A double-blinded, randomized controlled trial

Study objectiveAdministering a 5-hydroxytryptamine-3 receptor (5-HT3) at anesthesia induction may aid in achieving hemodynamic stability during general anesthesia induced using opioids. Therefore, we aimed to evaluate the effect of ramosetron, a 5-HT3 antagonist, administered on hypotension at the induction of total intravenous anesthesia (TIVA) with propofol and remifentanil. Additionally, we aimed to compare the impact of ramosetron administration at anesthesia induction versus that at the end of the surgery on postoperative nausea and vomiting (PONV). DesignPatients were randomly allocated to the Induction group (administration of ramosetron [0.3 mg/5 ml] at anesthesia induction and normal saline [5 ml] at the end of the surgery) or End group (administration of normal saline [5 ml] at anesthesia induction and ramosetron [0.3 mg/5 ml] at the end of the surgery). Hemodynamic status, PONV, and postoperative pain were assessed. SettingOperating room, post-anesthetic care unit, and general ward. Patients: In total, 176 non-smoking patients without any past medical history undergoing laparoscopic gynecological surgeries under TIVA were included in the study. MeasurementsBlood pressure (BP), heart rate, PONV, visual analog scale (VAS). Main resultsThe Induction group exhibited significantly higher BP at anesthesia induction and required significantly lower doses of phenylephrine and ephedrine during anesthesia than the End group had. However, PONV and postoperative pain were similar between the two groups. ConclusionsAdministering ramosetron at anesthesia induction resulted in significantly better hemodynamic stability with significantly lesser requirement of phenylephrine and ephedrine than administering at the end of the surgery did. Therefore, we recommend ramosetron administration at anesthesia induction rather than at the end of the surgery to prevent PONV and the decrease in the mean BP during TIVA with propofol and remifentanil.

P53 and VEGF are promising biomarkers for sorafenib efficacy in an experimental model of NASH-related HCC.

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100mg/L) administration in the drinking water for 13 and 16weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5mg/kg/day) for 3weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, β-catenin and p53. A semi-quantitative score was used for VEGF, survivin and β-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in β-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and β-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16week control group may indicate a different metabolic status of HCC.

The role of alcohol extract of cranberry in improving serum indices of experimental metaproterenol-induced heart damage in rats.

Cranberry offers numerous cardiovascular benefits. According to several studies, this fruit promotes the oxidation of low-density lipoprotein, enhances high-density lipoprotein, reduces platelet coagulation, and improves vascular activity. Albino male rats were divided into five groups (n = 5 per group). The control group received intraperitoneal administration of normal saline. The second group was injected with metaproterenol (MET) 3 days a week for 4 weeks. The third, fourth, and fifth groups were given cranberry extract in doses of 75, 100, and 150, respectively, along with heart-damaging drugs. Blood samples were collected and sent to the laboratory on the fourth weekend and 1 week after completing the injections in the fourth week (the sixth weekend) for analyzing serum factors such as cardiac creatine kinase MB, cardiac troponin I (cTnI), and aspartate aminotransferase (AST). The serum activity of the cardiac evaluation parameters in the fourth week demonstrated a highly significant correlation among the groups with respect to AST and cTnI (p < .001). Additionally, a significant relationship was observed between AST and cTnI within the target groups (p < .05). Ultimately, the findings indicated that the consumption of cranberry extract, due to its impact on heart function, could effectively modify serum indicators associated with heart damage. The utilized extract also exhibited efficacy, albeit with variable effects. Therefore, it is recommended to use cranberry extract synergistically with other chemical and herbal medications to achieve more sustained effects.

Sugammadex for reversal of rocuronium-induced neuromuscular blockade during alfaxalone anesthesia in dogs

ObjectiveTo investigate the reversal effect of sugammadex on neuromuscular blockade induced by a single bolus of rocuronium in dogs under alfaxalone anesthesia. Study designRandomized, prospective, crossover experimental study. AnimalsA group of six adult Beagle dogs (three females and three males), weighing 11.3–15.8 kg and aged 6–8 years, were used. MethodsDogs were anesthetized twice with a 1.25 times minimum infusion rate of alfaxalone, with a washout period of at least 14 days between experiments. Neuromuscular function was monitored using acceleromyography with train-of-four (TOF) stimulation of the peroneal nerve. After recording the control TOF ratio (TOFRC), rocuronium (0.5 mg kg–1) was administered intravenously. Subsequently, sugammadex (4 mg kg–1) or an equal volume of saline (control treatment) was administered intravenously when the TOF count returned from 0 to 1 after neuromuscular blockade. Time from rocuronium injection to TOF count = 0 (onset time), time from TOF count = 0 to TOF count = 1 (maximum blockade period), time of first twitch amplitude recovery from 0.25 to 0.75 (recovery index), and time from sugammadex or saline administration to TOF ratio/TOFRC ≥ 0.9 (recovery time) were recorded. ResultsThe onset time and maximum blockade duration did not differ between sugammadex treatment [1.2 (0.7–1.5) minutes and 9.9 (6.3–10.5) minutes, respectively] and control treatment [median (range); 1.0 (0.7–1.1) minutes and 9.9 (8.8–11.5) minutes, respectively] (p = 0.219 and 0.844, respectively). Recovery index was 0.5 (0.3–0.7) minutes in sugammadex treatment, which was shorter than that in control treatment [4.5 (3.7–4.9) minutes] (p = 0.031). Recovery time was 0.8 (0.5–2.8) minutes in sugammadex treatment, which was shorter than that in control treatment [10.5 (6.8–14.3) minutes] (p = 0.031). Conclusions and clinical relevanceRocuronium-induced neuromuscular blockade was effectively reversed by sugammadex in dogs anesthetized with alfaxalone.

Evaluation of Strategies for Reducing Vancomycin-Piperacillin/Tazobactam Incompatibility.

Drug incompatibility is defined as a physical-chemical reaction between two or more injectable drugs and that results mainly in precipitation or insolubility. Several strategies for reducing incompatibilities have been implemented empirically in intensive care units. However, these strategies have never been compared directly (and particularly in terms of the particulate load and drug mass flow rate) under standardized conditions. The objective of the present in vitro study was to evaluate the impact of various strategies for preventing incompatibility between simultaneously infused vancomycin and piperacillin/tazobactam. An in-line filter, a dilute vancomycin solution (5 mg/mL), and an alternative saline administration line were evaluated separately. The infusion line outlet was connected to a dynamic particle counter. The antibiotic concentration was measured in an HPLC-UV assay. The use of an in-line filter and an alternative saline administration route did not significantly reduce the particulate load caused by vancomycin-piperacillin/tazobactam incompatibility. Dilution of the vancomycin solution was associated with a significantly lower particulate load and maintenance of the vancomycin mass flow rate. It is important to systematically compare the efficacy of strategies for preventing drug incompatibility. The use of diluted vancomycin solution gave the best results in the case of vancomycin-piperacillin/tazobactam incompatibility.

Effect of Quinolinic Acid on Behavior, Morphology, and Expression of Inflammatory/oxidative Status in Rats' Striatum: Is Coenzyme Q10 a Good Protector?

Quinolinic acid (QUIN) is a toxic compound with pro-oxidant, pro-inflammatory, and pro-apoptotic actions found at high levels in the central nervous system (CNS) in several pathological conditions. Due to the toxicity of QUIN, it is important to evaluate strategies to protect against the damage caused by this metabolite in the brain. In this context, coenzyme Q10 (CoQ10) is a provitamin present in the mitochondria with a protective role in cells through several mechanisms of action. Based on these, the present study was aimed at evaluating the possible neuroprotective role of CoQ10 against damage caused by QUIN in the striatum of young Wistar rats. Twenty-one-day-old rats underwent a 10-day pretreatment with CoQ10 or saline (control) intraperitoneal injections and on the 30th day of life received QUIN intrastriatal or saline (control) administration. The animals were submitted to behavior tests or euthanized, and the striatum was dissected to neurochemical studies. Results showed that CoQ10 was able to prevent behavioral changes (the open field, object recognition, and pole test tasks) and neurochemical parameters (alteration in the gene expression of IL-1β, IL-6, SOD, and GPx, as well as in the immunocontent of cytoplasmic Nrf2 and nuclear p-Nf-κβ) caused by QUIN. These findings demonstrate the promising therapeutic effects of CoQ10 against QUIN toxicity.

Inappropriate therapy of euvolemic hyponatremia, the most frequent type of hyponatremia in SARS-CoV-2 infection, is associated with increased mortality in COVID-19 patients.

Admission hyponatremia, frequent in patients hospitalized for COVID-19, has been associated with increased mortality. However, although euvolemic hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis (SIAD) is the single most common cause of hyponatremia in community-acquired pneumonia (CAP), a thorough and rigorous assessment of the volemia of hyponatremic COVID-19 subjects has yet to be described. We sought to identify factors contributing to mortality and hospital length-of-stay (LOS) in hospitalized COVID-19 patients admitted with hyponatremia, taking volemia into account. Retrospective study of 247 patients admitted with COVID-19 to a tertiary hospital in Madrid, Spain from March 1st through March 30th, 2020, with a glycemia-corrected serum sodium level (SNa) < 135 mmol/L. Variables were collected at admission, at 2nd-3rd day of hospitalization, and ensuing days when hyponatremia persisted. Admission volemia (based on both physical and analytical parameters), therapy, and its adequacy as a function of volemia, were determined. Age: 68 years [56-81]; 39.9% were female. Median admission SNa was 133 mmol/L [131- 134]. Hyponatremia was mild (SNa 131-134 mmol/L) in 188/247 (76%). Volemia was available in 208/247 patients; 57.2% were euvolemic and the rest (42.8%) hypovolemic. Hyponatremia was left untreated in 154/247 (62.3%) patients. Admission therapy was not concordant with volemia in 43/84 (51.2%). In fact, the majority of treated euvolemic patients received incorrect therapy with isotonic saline (37/41, 90.2%), whereas hypovolemics did not (p=0.001). The latter showed higher mortality rates than those receiving adequate or no therapy (36.7% vs. 19% respectively, p=0.023). The administration of isotonic saline to euvolemic hyponatremic subjects was independently associated with an elevation of in-hospital mortality (Odds Ratio: 3.877, 95%; Confidence Interval: 1.25-12.03). Hyponatremia in COVID-19 is predominantly euvolemic. Isotonic saline infusion therapy in euvolemic hyponatremic COVID-19 patients can lead to an increased mortality rate. Thus, an exhaustive and precise volemic assessment of the hyponatremic patient with CAP, particularly when due to COVID-19, is mandatory before instauration of therapy, even when hyponatremia is mild.

Microglia dysfunction drives disrupted hippocampal amplitude of low frequency after acute kidney injury.

Acute kidney injury (AKI) has been associated with a variety of neurological problems, while the neurobiological mechanism remains unclear. In the present study, we utilized resting-state functional magnetic resonance imaging (rs-fMRI) to detect brain injury at an early stage and investigated the impact of microglia on the neuropathological mechanism of AKI. Rs-fMRI data were collected from AKI rats and the control group with a 9.4-Tesla scanner at 24, 48, and 72 h post administration of contrast medium or saline. The amplitude of low-frequency fluctuations (ALFF) was then compared across the groups at each time course. Additionally, flow cytometry and SMART-seq2 were employed to evaluate microglia. Furthermore, pathological staining and Western blot were used to analyze the samples. MRI results revealed that AKI led to a decreased ALFF in the hippocampus, particularly in the 48 h and 72 h groups. Additionally, western blot suggested that AKI-induced the neuronal apoptosis at 48 h and 72 h. Flow cytometry and confocal microscopy images demonstrated that AKI activated the aggregation of microglia into neurons at 24 h, with a strong upregulation of M1 polarization at 48 h and peaking at 72 h, accompanying with the release of proinflammatory cytokines. The ALFF value was strongly correlated with the proportion of microglia (|r| > 0.80, p < 0.001). Our study demonstrated that microglia aggregation and inflammatory factor upregulation are significant mechanisms of AKI-induced neuronal apoptosis. We used fMRI to detect the alterations in hippocampal function, which may provide a noninvasive method for the early detection of brain injury after AKI.

Measuring acute effects of subanesthetic ketamine on cerebrovascular hemodynamics in humans using TD-fNIRS

Quantifying neural activity in natural conditions (i.e. conditions comparable to the standard clinical patient experience) during the administration of psychedelics may further our scientific understanding of the effects and mechanisms of action. This data may facilitate the discovery of novel biomarkers enabling more personalized treatments and improved patient outcomes. In this single-blind, placebo-controlled study with a non-randomized design, we use time-domain functional near-infrared spectroscopy (TD-fNIRS) to measure acute brain dynamics after intramuscular subanesthetic ketamine (0.75 mg/kg) and placebo (saline) administration in healthy participants (n = 15, 8 females, 7 males, age 32.4 ± 7.5 years) in a clinical setting. We found that the ketamine administration caused an altered state of consciousness and changes in systemic physiology (e.g. increase in pulse rate and electrodermal activity). Furthermore, ketamine led to a brain-wide reduction in the fractional amplitude of low frequency fluctuations, and a decrease in the global brain connectivity of the prefrontal region. Lastly, we provide preliminary evidence that a combination of neural and physiological metrics may serve as predictors of subjective mystical experiences and reductions in depressive symptomatology. Overall, our study demonstrated the successful application of fNIRS neuroimaging to study the physiological effects of the psychoactive substance ketamine in humans, and can be regarded as an important step toward larger scale clinical fNIRS studies that can quantify the impact of psychedelics on the brain in standard clinical settings.

Vagal cardiac control in rats with LPS-induced lung injury

Heart rate variability (HRV) as an index of cardiac autonomic control in acute lung injury (ALI) has been evaluated in anaesthetized rats intratracheally instilled with bacterial lipopolysaccharide (LPS) and ventilated with breathing frequency of 60/min, 40% oxygen, inspiratory time 40%, tidal volume of 6 mL/kg. ECG was recorded before and 30, 60, 120, 180 and 240 min after LPS or saline (control) administration. HRV was quantified by time and frequency-domain analysis (mean RR interval, SDRR, RMSSD and spectral power in high frequency (HF) band. Lactate in plasma, and oxidative stress, IL-1β, IL-5, IL-12p70 and IL-13 and galectin-3 in heart tissue raised in LPS-injured rats. Overall HRV magnitude (SDRR) and marker of vagal heart rate control (RMSSD), as well as frequency domain parameter, spectral power HF was increased 120 and 180 min since ALI onset. In conclusion, LPS-induced ALI is accompanied by altered vagal cardiac control mediated by autonomic nervous system, likely based on the close relationship between immune response and vagally mediated autonomic nervous activity.

Drugs possessing aryloxypropanamine pharmacophore, duloxetine, dapoxetine and propranolol, increase allopregnanolone in rat brain: Possible involvement of allopregnanolone in their central nervous system effects

Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs possessing the aryloxypropanamine (AOPA) pharmacophore, such as fluoxetine, exert their central nervous system (CNS) effects by increasing the brain AP. Although duloxetine (DLX), dapoxetine (DPX), atomoxetine (ATX) and propranolol (PRL) also possess the AOPA pharmacophore and are used to treat some psychiatric disorders, the capabilities of these drugs to increase the brain AP and the possible involvement of AP in their CNS effects remain to be fully elucidated. To clarify these points, we first developed a method for quantifying AP in the rat brain by liquid chromatography/electrospray ionization-tandem mass spectrometry. Analysis of the changes in the brain AP levels using this method revealed that the intraperitoneal administration of DLX (10 mg/kg), DPX (10 mg/kg) and PRL (20 mg/kg) significantly increased the brain AP (DLX: < 0.40–2.74 ng/g tissue, DPX: 1.48–3.83 ng/g tissue and PRL: < 0.40–2.09 ng/g tissue) compared to the saline administration (<0.40 ng/g tissue). These results suggested the possible involvement of the GABAergic neurosteroid, AP, in the central actions of DLX, DPX and PRL. In contrast, ATX (10 mg/kg) did not affect the AP levels in the brain. In addition, the brain and serum AP levels had a remarkably high positive correlation after the administration of DLX, DPX and PRL. Thus, this study proposed the AP-related novel mechanism of actions of DLX, DPX and PRL in the CNS.

Effects of the ACTH&lt;sup&gt;6-9&lt;/sup&gt;-Pro-Gly-Pro peptide on the morphofunctional state of rat colon under conditions of chronic restraint stress

Aim. To study the morphofunctional state of the colonic wall in rats when using the N–terminal analog of the adrenocorticotropic hormone (ACTH) ACTH6-9-Pro-Gly-Pro (ACTH6-9-PGP) peptide under chronic stress.Materials and methods. The study was performed on 55 male Wistar rats, which were divided into 5 groups (n = 11): group 1 – control group (administration of saline solution without stress); group 2 – chronic restraint stress (CRS) + administration of saline solution; group 3 – CRS + administration of ACTH6-9-PGP at a dose of 5 μg / kg; group 4 – administration of ACTH6-9-PGP at a dose of 50 μg / kg; group 5 – administration of ACTH6-9- PGP at a dose of 500 μg / kg. A histologic examination of the rat colon was performed. The histologic architecture of the colonic wall, the depth of crypts, and the number of goblet cells were assessed. Furthermore, the number of granulocytes, plasma cells, lymphocytes, macrophages, and mast cells was counted.Results. The study demonstrated that chronic (14 days) restraint stress resulted in the development of inflammations in the colonic wall of the animals. Intraperitoneal administration of ACTH6-9-PGP at doses of 50 and 500 μg / kg daily throughout the entire time of stress exposure prevented the development of stress-induced alterations observed in the control animals. At the same time, anti-inflammatory effects of the peptide in the colonic wall and a decrease in the level of corticosterone in the blood serum were noted.Conclusion. The results of this work and data from other studies on the effects of N-terminal analogs of ACTH indicate the need for studying the mechanisms of their effect on inflammation and searching for targets of ACTH6-9-PGP.