Consequences of NMDA receptor deficiency can be rescued in the adult brain.

N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.

Predictive Value of Calcium Test for Preoperative Diagnosis of Medullary Thyroid Carcinoma in Patients With Moderately Elevated Basal Calcitonin.

OBJECTIVE: Medullary thyroid carcinoma (MTC) can be very aggressive, and early diagnosis is based on routine measurement of serum calcitonin (CT) and RET genetic testing for hereditary forms. Basal serum CT (bCT) concentrations are useful in the early detection of MTC, although it is still unclear whether they can also be used for the differential diagnosis between MTC and C-cell hyperplasia (CCH). Since false-positive results can be obtained with the basal measurement of CT, a provocative test to evaluate stimulated CT (sCT) is often needed. The objective of this study was to investigate the utility of a calcium gluconate test for CT in distinguishing MTC from CCH, a precancerous condition in hereditary forms of MTCs but with unclear significance in sporadic MTCs. METHODS: A total of 74 patients underwent the calcium loading test before thyroidectomy, and bCT and sCT levels were compared with histologic results by receiver operating characteristic plot analyses. RESULTS: A peak CT level of 388.4 pg/mL after stimulation with calcium gluconate was able to significantly distinguish patients with MTC from those with CCH and those without C-cell pathology, with 81.8% sensitivity and 36.5% specificity. A bCT level of 16.1 pg/mL was able to distinguish between these 2 groups of patients with a sensitivity of 90%. CONCLUSION: High-dose calcium test is an effective procedure that can be applied for differential diagnosis of MTC and CCH. Reference ranges for calcium sCT levels and CT thresholds in different groups of patients have been identified.

Dopamine D1-D2 receptor heteromer expression in key brain regions of rat and higher species: Upregulation in rat striatum after cocaine administration.

BACKGROUND: Dopamine receptors interact with other receptors to form heterooligomers. One such complex, the D1-D2 heteromer, demonstrated in cultured striatal neurons and rat striatum has been linked to drug addiction, Parkinson's disease, schizophrenia, depression and anhedonia. METHODS: D1-D2 heteromer expression was evaluated using in situ proximity ligation assay, in parallel with cellular colocalization of D1 and D2 mRNA using in situ hybridization in 19 different key rat brain regions. Expression in higher species and changes in rat striatum after repeated cocaine administration were evaluated. RESULTS: Differences in D1-D2 heteromer expression in striatal subregions are documented in higher species with nonhuman primate and human demonstrating higher density of heteromer-expressing neurons compared to rodents. All species had higher density of D1-D2 neurons in nucleus accumbens compared to dorsal striatum. Multiple other brain regions are identified where D1-D2 heteromer is expressed, prominently in cerebral cortical subregions including piriform, medial prefrontal, orbitofrontal and others; subcortical regions such as claustrum, amygdala and lateral habenula. Three categories of regions are identified: D1-D2 heteromer expressed despite little to no observed D1/D2 mRNA colocalization, likely representing heteromer on neuronal projections from other brain regions; D1-D2 heteromer originating locally with the density of neurons expressing heteromer matching neurons with colocalized D1/D2 mRNA; regions with both a local origin and targeted inputs projecting from other regions. Repeated cocaine administration significantly increased density of neurons expressing D1-D2 heteromer and D1/D2 mRNA colocalization in rat striatum, with changes in both direct and indirect pathway neurons. CONCLUSION: The dopamine D1-D2 heteromer is expressed in key brain cortical and subcortical regions of all species examined. Species differences in striatum revealed greater abundance in human>nonhuman-primate>rat>mouse, suggesting an evolutionary biologic role for the D1-D2 heteromer in higher CNS function. Its upregulation in rat striatum following cocaine points to regulatory significance with possible relevance for clinical disorders such as drug addiction. The dopamine D1-D2 receptor heteromer may represent a potential target for neuropsychiatric and neurodegenerative disorders, given its distribution in highly relevant brain regions.

Maternal Separation Model of Postpartum Depression: Potential Role for Nucleus Accumbens Dopamine D1-D2 Receptor Heteromer.

Postpartum depression is a mood disorder with a distinct neurobiological and behavioural profile occurring during and after the postpartum period. Dopamine pathways in the limbic regions of the brain such as the nucleus accumbens (NAc) have been shown to be involved in the etiology of depressive disorders. Selective activation of the dopamine D1-D2 receptor heteromer has been demonsrated to cause depressive- and anxiogenic-like behaviours in rats. The maternal separation model involving three hour daily maternal separation (MS) from pups on PPD 2-15 on anxiety-, depression- and anhedonia-like behaviors in the dams was investigated, together with plasma corticosterone, oxytocin and D1-D2 heteromer expression in the NAc core and shell in non-MS and MS dams. Depression, anxiety and anhedonia-like behaviours were measured using the forced swim test, elevated plus maze and sucrose preference test, respectively. In comparison to non-MS controls, MS dams displayed slightly higher depressive and anxiety-like behaviours with no difference in anhedonia-like behaviours. The MS dams displayed significantly increased care of pups after their retrieval with higher bouts of nursing, lower latency to nurse, lower bouts of out nest behaviour and decreased self-care. There was no significant alteration in D1-D2 heteromer expression in NAc core and shell between mothers of either group (MS, non-MS) or between postpartum rats and nonpregnant female rats, remaining higher than in male rats. This data provides evidence for the maternal separation model in producing a postpartum depression-like profile, but with maternal resilience able to modify behaviours to counteract any potential deleterious consequences to the pups.

Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation.

NMDA receptor dysfunction is central to the encephalopathies caused by missense mutations in the NMDA receptor subunit genes. Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, epilepsy, and motor dysfunction. To gain insight into possible biomarkers of NMDAR hypofunction, we asked whether a loss-of-function variant in the Grin1 gene would cause structural changes in the brain that could be detected by MRI. We also studied the developmental trajectory of these changes to determine whether structural changes coincided with reported cognitive impairments in the mice. We performed magnetic resonance imaging in male Grin1-/- knockdown mice (GluN1KD) that were three, six, or twelve weeks old. Deformation-based morphometry was used to assess neuroanatomical differences. Volumetric reductions were detected in substantia nigra and striatum of GluN1KD mice at all ages. Changes in limbic structures were only evident at six weeks of age. Reductions in white matter volumes were first evident at three weeks, and additional deficits were detected at six and twelve weeks. FluoroJade immunofluorescence revealed degenerating neurons in twelve-week old GluN1KD mice. We conclude that Grin1 loss-of-function mutations cause volume reductions in dopaminergic structures early in development, while changes to limbic and white matter structures are delayed and are more pronounced in post-adolescent ages. The evidence of degenerating neurons in the mature brain indicates an ongoing process of cell loss as a consequence of NMDAR hypofunction.

Differential effects of NMDA receptor antagonism on spine density.

The authors demonstrate that different NMDAR antagonists (ketamine and MK-801) have varying effects on spine density depending on dose, drug regimen, and brain region. While acute ketamine treatment increases cortical spine density in mice, subchronic exposure to either drug reduces spine density in both the cortex and striatum.

Antioxidant and anti-inflammatory activity of Potentilla reptans L.

Potentilla species have been used in traditional medicine in the treatment of different ailment, disease or malady. Potentilla reptans (P. reptans) has been scarcely studied. The aim of this study was to test antioxidant and anti-inflammatory activity of P. reptans aerial part and rhizome. DPPH assay was used to measure antioxidant activity of aqueous plant extracts. Anti-inflammatory effect was evaluated by experimental animal model of phenol-in-acetone induced mice ear edema. DPPH radical-scavenging activity of both tested extracts was concentration dependent with IC50 values 12.11 µg/mL (aerial part) and 2.57 µg/mL (rhizome). Maximum anti-inflammatory effect (61.37%) was observed after administration of 10 mg/ear of the rhizome extract and it was 89.24% of effect induced by dexamethasone as a standard. In conclusion, P. reptans rhizome aqueous extract possesses anti-inflammatory effect and higher antioxidant activity than aerial part.

Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling.

Chronic N-methyl-d-aspartate receptor (NMDAR) hypofunction has been proposed as a contributing factor to symptoms of schizophrenia. However, it is unclear how sustained NMDAR hypofunction throughout development affects other neurotransmitter systems that have been implicated in the disease. Dopamine neuron biochemistry and activity were examined to determine whether sustained NMDAR hypofunction causes a state of hyperdopaminergia. We report that a global, genetic reduction in NMDARs led to a remodeling of dopamine neurons, substantially affecting two key regulators of dopamine homeostasis, i.e., tyrosine hydroxylase and the dopamine transporter. In NR1 knockdown mice, dopamine synthesis and release were attenuated, and dopamine clearance was increased. Although these changes would have the effect of reducing dopamine transmission, we demonstrated that a state of hyperdopaminergia existed in these mice because dopamine D2 autoreceptors were desensitized. In support of this conclusion, NR1 knockdown dopamine neurons have higher tonic firing rates. Although the tonic firing rates are higher, phasic signaling is impaired, and dopamine overflow cannot be achieved with exogenous high-frequency stimulation that models phasic firing. Through the examination of several parameters of dopamine neurotransmission, we provide evidence that chronic NMDAR hypofunction leads to a state of elevated synaptic dopamine. Compensatory mechanisms to attenuate hyperdopaminergia also impact the ability to generate dopamine surges through phasic firing.

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner.

NMDA receptors are key regulators of synaptic plasticity, and their hypofunction is thought to contribute to the pathophysiology of CNS disorders. Furthermore, NMDA receptors participate in the formation, maintenance, and elimination of synapses. The consequences of NMDA receptor hypofunction on synapse biology were explored in a genetic mouse model, in which the levels of NMDA receptors are reduced to 10% of normal levels (i.e., NR1-knockdown mice). In these mice, synapse number is reduced in an age-dependent manner; reductions are observed at the postpubertal age of 6 wk, but normal at 2 wk of age. Efforts to uncover the biochemical underpinnings of this phenomenon reveal synapse-specific reductions in 14-3-3ε protein and in Disrupted in Schizophrenia-1 (DISC1), two schizophrenia susceptibility factors that have been implicated in the regulation of spine density. Subchronic administration of MK-801, an NMDA receptor antagonist, produces similar synaptic reductions in both spine density and DISC1, indicating that synaptic levels of DISC1 are regulated by NMDA receptor function. The synaptic reduction of DISC1 and 14-3-3ε is developmentally correlated with the age-dependent decrease in striatal spine density.

Antioxidant and anxiolytic activities of Crataegus nigra Wald. et Kit. berries.

Hawthorn has been present for a long time in traditional medicine as antihypertensive, hypolipidemic, anti-inflammatory, gastroprotective, antimicrobial agent. Hawthorn can be used for the cure of stress, nervousness but there is no published paper about actions of Crataegus nigra Wald. et Kit. fruits. The present study was carried out to test free-radical-scavenging and anxiolytic activity of C. nigra fruits. DPPH (alpha,alpha-diphenyl-beta-picrylhydrazyl) assay was used to measure antioxidant activity. BHT, BHA, PG, quercetin and rutin were used as standards. The total amount of phenolic compounds, procyanidins, and flavonoids in the extracts, was determined spectrophotometrically. Results were expressed as equivalents of gallic acid, cyanidin chloride and quercetin equivalents, respectively. LC-MS/MS was used for identification and quantification of phenolic composition. The anxiety effect, expressed as the difference in time spent in the open and closed arms, was measured and compared between groups. Phenolic compound content of Crataegus nigra fruits was 72.7 mg/g. Yield of total flavonoid aglycones was 0.115 mg/g. Procyanidins were 5.6 mg/g. DPPH radical-scavenging capacity of the extracts showed linear concentration dependency, IC50 value were 27.33 microg/mL. Anxiolytic effect was observed. Species Crataegus nigra fruits hydroalcoholic extract showed antioxidant and anxiolytic activity.

Assessment of Factor VIII Activity and D-Dimer Levels in the Post-COVID Period.

Changes in the hemostatic system during COVID infection lead to hypercoagulability. Numerous studies have evaluated hemostatic abnormalities in COVID patients during acute infection, in the period of hospitalization. However, the hemostatic status following hospital discharge has not been sufficiently assessed. Considering the importance of FVIII and D-dimer levels as markers for the assessment of thrombosis, our study aimed to evaluate changes in these markers, as well as the influence of patient's age and clinical presentation of COVID infection on those hemostatic markers in the post-COVID phase. This prospective study (July 2020 to December 2022) included 115 COVID patients, 68 (59%) with asymptomatic/mild and 47 (41%) with moderate/severe clinical presentation. Patient follow-up included laboratory evaluation of FVIII and D-dimer levels at 1, 3, and 6 months following the COVID infection. Three months after the COVID infection, elevated FVIII was recorded in 44% of younger versus 65% of older individuals, p = 0.05, respectively, and 30 versus 57% (p = 0.008) 6 months post-COVID infection. With a focus on clinical presentation, a higher number of patients with moderate/severe COVID had elevated FVIII activity, but a statistically significant difference was observed only for the 6 months (32% mild vs. 53% moderate/severe, p = 0.041) post-infection time point. Following a COVID infection, an increase in FVIII activity suggests a continued hypercoagulable state in the post-COVID period and correlates with elevated D-dimer levels. This increase in FVIII is more pronounced in patients with moderate/severe clinical picture and those patients older than 50 years.

Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.

Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects.

Thrombosis risk assessment in patients with congenital thrombophilia during COVID - 19 infection.

BACKGROUND: Coagulation dysfunction represents a serious complication in patients during the COVID-19 infection, while fulminant thrombotic complications emerge as critical issues in individuals with severe COVID-19. In addition to a severe clinical presentation, comorbidities and age significantly contribute to the development of thrombotic complications in this disease. However, there is very little data on association of congenital thrombophilia and thrombotic events in the setting of COVID-19. Our study aimed to evaluate the risk of COVID-19 associated thrombosis in patients with congenital thrombophilia. METHODS: This prospective, case-control study included patients with confirmed COVID-19 infection, followed 6 months post-confirmation. The final outcome was a symptomatic thrombotic event. In total, 90 COVID-19 patients, 30 with known congenital thrombophilia and 60 patients without thrombophilia within the period July 2020-November 2021, were included in the study. Evaluation of hemostatic parameters including FVIII activity and D-dimer was performed for all patients at 1 month, 3 months and 6 months post-COVID-19 diagnosis. RESULTS: Symptomatic thrombotic events were observed in 7 out of 30 (23 %) COVID-19 patients with thrombophilia, and 12 out of 60 (20 %) without thrombophilia, P = 0.715. In addition, the two patient groups had comparable localization of thrombotic events, time to thrombotic event, effect of antithrombotic treatment and changes in FVIII activity, while D-dimer level were significantly increased in patients without thrombophilia. CONCLUSION: Our findings suggest that patients with congenital thrombophilia, irrespective of their age, a mild clinical picture and absence of comorbidities, should receive anticoagulant prophylaxis, adjusted based on the specific genetic defect.

D-dimer, CRP, PCT, and IL-6 Levels at Admission to ICU Can Predict In-Hospital Mortality in Patients with COVID-19 Pneumonia.

INTRODUCTION: Health care workers have had a challenging task since the COVID-19 outbreak. Prompt and effective predictors of clinical outcomes are crucial to recognize potentially critically ill patients and improve the management of COVID-19 patients. The aim of this study was to identify potential predictors of clinical outcomes in critically ill COVID-19 patients. METHODS: The study was designed as a retrospective cohort study, which included 318 patients treated from June 2020 to January 2021 in the Intensive Care Unit (ICU) of the Clinical Hospital Center "Bezanijska Kosa" in Belgrade, Serbia. The verified diagnosis of COVID-19 disease, patients over 18 years of age, and the hospitalization in ICU were the criteria for inclusion in the study. The optimal cutoff value of D-dimer, CRP, IL-6, and PCT for predicting hospital mortality was determined using the ROC curve, while the Kaplan-Meier method and log-rank test were used to assess survival. RESULTS: The study included 318 patients: 219 (68.9%) were male and 99 (31.1%) female. The median age of patients was 69 (60-77) years. During the treatment, 195 (61.3%) patients died, thereof 130 male (66.7%) and 65 female (33.3%). 123 (38.7%) patients were discharged from hospital treatment. The cutoff value of IL-6 for in-hospital death prediction was 74.98 pg/mL (Sn 69.7%, Sp 62.7%); cutoff value of CRP was 81 mg/L (Sn 60.7%, Sp 60%); cutoff value of procalcitonin was 0.56 ng/mL (Sn 81.1%, Sp 76%); and cutoff value of D-dimer was 760 ng/mL FEU (Sn 63.4%, Sp 57.1%). IL-6 ≥ 74.98 pg/mL, CRP ≥ 81 mg/L, PCT ≥ 0.56 ng/mL, and D-dimer ≥ 760 ng/mL were statistically significant predictors of in-hospital mortality. CONCLUSION: IL-6 ≥ 74.98 pg/mL, CRP values ≥ 81 mg/L, procalcitonin ≥ 0.56 ng/mL, and D-dimer ≥ 760 ng/mL could effectively predict in-hospital mortality in COVID-19 patients.

Trauma and Antimicrobial Resistance Are Independent Predictors of Inadequate Empirical Antimicrobial Treatment of Ventilator-Associated Pneumonia in Critically Ill Patients.

Background: We aimed to assess independent risk factors for inadequate initial antimicrobial treatment (IAT) in critically ill patients with ventilator-associated pneumonia (VAP) treated in intensive care units (ICU) and to determine whether IAT is associated with adverse outcomes in patients with VAP. Patients and Methods: A prospective cohort study was performed and included 152 patients with VAP treated in an ICU for more than 48 hours. The main outcomes of interest were all-cause ICU mortality and VAP-related mortality. Other outcomes considered were: intra-hospital mortality, VAP-related sepsis, relapse, re-infection, length of stay in ICU (ICU LOS), and number of days on mechanical ventilation (MV). Results: One-third of patients (35.5%) received inadequate antimicrobial therapy. Trauma (odds ratio [OR], 3.55; 95% confidence interval [CI], 1.25-10.06) and extensively drug-resistant (XDR) causative agent (OR, 3.09; 95% CI, 1.23-7.74) were independently associated with inadequate IAT. Inadequate IAT was associated with a higher mortality rate (OR, 3.08; 95% CI, 1.30-7.26), VAP-related sepsis (OR, 2.39; 95% CI, 1.07-5.32), relapse (OR, 3.25; 95% CI, 1.34-7.89), re-infection (OR, 6.06; 95% CI, 2.48-14.77), and ICU LOS (ß 4.65; 95% CI, 0.93-8.36). Acinetobacter spp., Pseudomonas aeruginosa and Klebsiella/Enterobacter spp. were the most common bacteria in patients with IAT and those with adequate antimicrobial therapy. Conclusions: This study demonstrated that inadequate IAT is associated with a higher risk of the majority of adverse outcomes in patients with VAP treated in ICUs. Trauma and XDR strains of bacteria are independent predictors of inadequate IAT of VAP in critically ill patients.

Development and Validation of a Multivariable Predictive Model for Mortality of COVID-19 Patients Demanding High Oxygen Flow at Admission to ICU: AIDA Score.

INTRODUCTION: Risk stratification is an important aspect of COVID-19 management, especially in patients admitted to ICU as it can provide more useful consumption of health resources, as well as prioritize critical care services in situations of overwhelming number of patients. MATERIALS AND METHODS: A multivariable predictive model for mortality was developed using data solely from a derivation cohort of 160 COVID-19 patients with moderate to severe ARDS admitted to ICU. The regression coefficients from the final multivariate model of the derivation study were used to assign points for the risk model, consisted of all significant variables from the multivariate analysis and age as a known risk factor for COVID-19 patient mortality. The newly developed AIDA score was arrived at by assigning 5 points for serum albumin and 1 point for IL-6, D dimer, and age. The score was further validated on a cohort of 304 patients admitted to ICU due to the severe form of COVID-19. RESULTS: The study population included 160 COVID-19 patients admitted to ICU in the derivation and 304 in the validation cohort. The mean patient age was 66.7 years (range, 20-93 years), with 68.1% men and 31.9% women. Most patients (76.8%) had comorbidities with hypertension (67.7%), diabetes (31.7), and coronary artery disease (19.3) as the most frequent. A total of 316 patients (68.3%) were treated with mechanical ventilation. Ninety-six (60.0%) in the derivation cohort and 221 (72.7%) patients in the validation cohort had a lethal outcome. The population was divided into the following risk categories for mortality based on the risk model score: low risk (score 0-1) and at-risk (score > 1). In addition, patients were considered at high risk with a risk score > 2. By applying the risk model to the validation cohort (n = 304), the positive predictive value was 78.8% (95% CI 75.5% to 81.8%); the negative predictive value was 46.6% (95% CI 37.3% to 56.2%); the sensitivity was 82.4% (95% CI 76.7% to 87.1%), and the specificity was 41.0% (95% CI 30.3% to 52.3%). The C statistic was 0.863 (95% CI 0.805-0.921) and 0.665 (95% CI 0.598-0.732) in the derivation and validation cohorts, respectively, indicating a high discriminative value of the proposed score. CONCLUSION: In the present study, AIDA score showed a valuable significance in estimating the mortality risk in patients with the severe form of COVID-19 disease at admission to ICU. Further external validation on a larger group of patients is needed to provide more insights into the utility of this score in everyday practice.

Predictors of Mortality in Critically Ill COVID-19 Patients Demanding High Oxygen Flow: A Thin Line between Inflammation, Cytokine Storm, and Coagulopathy.

INTRODUCTION: Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality. METHODS: We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients. RESULTS: The mean patient age was 65.6 years (range, 29-92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25th to 75th percentile: 6-18), while the median total number of hospital stay was 18 (25th to 75th percentile: 12-28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis. CONCLUSION: In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.

Restoring striatal WAVE-1 improves maze exploration performance of GluN1 knockdown mice.

NMDA receptors are important for cognition and are implicated in neuropsychiatric disorders. GluN1 knockdown (GluN1KD) mice have reduced NMDA receptor levels, striatal spine density deficits, and cognitive impairments. However, how NMDA depletion leads to these effects is unclear. Since Rho GTPases are known to regulate spine density and cognition, we examined the levels of RhoA, Rac1, and Cdc42 signaling proteins. Striatal Rac1-pathway components are reduced in GluN1KD mice, with Rac1 and WAVE-1 deficits at 6 and 12 weeks of age. Concurrently, medium spiny neuron (MSN) spine density deficits are present in mice at these ages. To determine whether WAVE-1 deficits were causal or compensatory in relation to these phenotypes, we intercrossed GluN1KD mice with WAVE-1 overexpressing (WAVE-Tg) mice to restore WAVE-1 levels. GluN1KD-WAVE-Tg hybrids showed rescue of striatal WAVE-1 protein levels and MSN spine density, as well as selective behavioral rescue in the Y-maze and 8-arm radial maze tests. GluN1KD-WAVE-Tg mice expressed normalized WAVE-1 protein levels in the hippocampus, yet spine density of hippocampal CA1 pyramidal neurons was not significantly altered. Our data suggest a nuanced role for WAVE-1 effects on cognition and a delineation of specific cognitive domains served by the striatum. Rescue of striatal WAVE-1 and MSN spine density may be significant for goal-directed exploration and associated long-term memory in mice.

Hemodynamic and cardiovascular problems during modified hyperthermic intraperitoneal perioperative chemotherapy.

BACKGROUND/AIMS: Cytoreductive surgery and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) significantly improves patients survival with peritoneal carcinomatosis especially in low-grade tumor e.g. ovarian and appendiceal adenocarcinoma, peritoneal pseudomyxoma and grade I gastric and colorectal cancer. METHODOLOGY: During a period of nine years, hemodynamic and cardiac functions combined with urinary output during hyperthermic intraoperative intraperitoneal chemotherapy were prospectively measured in 60 patients. RESULTS: Statistically significant hemodynamic and cardiac parameters were characterized by an increased heart rate and cardiac output as well as decreased systemic vascular resistance associated with an increased body temperature and decreased effective circulating volume. The tendency of urinary output was to decrease as the therapy progressed. CONCLUSIONS: HIPEC induces a hyperdynamic circulatory state requiring increased intravenous fluid administration, which avoids changes because of increased intra-abdominal pressure. Documented by normal blood pressure and adequate urinary output hemodynamic and intravenous fluids, titrated to frequent urinary output determination, can achieve cardiac stability.