Alterations In Levels Research Articles

Stress Markers, Executive Functioning, and Resilience Among Early Adolescents With Complex Congenital Heart Disease

Infants with complex congenital heart disease (cCHD) may experience prolonged and severe stress when undergoing open heart surgery. However, little is known about long-term stress and its role in neurodevelopmental impairments in this population. To investigate potential differences between early adolescents aged 10 to 15 years with cCHD and healthy controls in physiological stress markers by hair analysis, executive function (EF) performance, and resilience. This single-center, population-based case-control study was conducted at the University Children's Hospital Zurich, Switzerland. Patients with different types of cCHD who underwent cardiopulmonary bypass surgery during the first year of life and who did not have a genetic disorder were included in a prospective cohort study between 2004 and 2012. A total of 178 patients were eligible for assessment at ages 10 to 15 years. A control group of healthy term-born individuals was cross-sectionally recruited. Data assessment was between 2019 and 2021. Statistical analysis was performed from January to April 2023. Patients with cCHD who underwent infant open heart surgery. Physiological stress markers were quantified by summing cortisol and cortisone concentrations measured with liquid chromatography with tandem mass spectrometry in a 3-centimeter hair strand. EFs were assessed with a neuropsychological test battery to produce an age-adjusted EF summary score. Resilience was assessed with a standardized self-report questionnaire. The study included 100 patients with cCHD and 104 controls between 10 and 15 years of age (mean [SD] age, 13.3 [1.3] years); 110 (53.9%) were male and 94 (46.1%) were female. When adjusting for age, sex, and parental education, patients had significantly higher sums of hair cortisol and cortisone concentrations (β, 0.28 [95% CI, 0.12 to 0.43]; P < .001) and lower EF scores (β, -0.36 [95% CI, -0.49 to -0.23]; P < .001) than controls. There was no group difference in self-reported resilience (β, -0.04 [95% CI, -0.23 to 0.12]; P = .63). A significant interaction effect between stress markers and EFs was found, indicating a stronger negative association in patients than controls (β, -0.65 [95% CI, -1.15 to -0.15]; P = .01). The contrast effects were not significant in patients (β, -0.21 [95% CI, -0.43 to -0.00]; P = .06) and controls (β, 0.09 [95% CI, -0.11 to 0.30]; P = .38). This case-control study provides evidence for altered physiological stress levels in adolescents with cCHD and an association with poorer EF. These results suggest that future studies are needed to better understand the neurobiological mechanisms and timing of alterations in the stress system and its role in neurodevelopment.

Targeting the vivid facets of apolipoproteins as a cardiovascular risk factor in rheumatoid arthritis.

Mostly, cardiovascular diseases are blamed for casualties in rheumatoid arthritis (RA) patients. Customarily, dyslipidemia is probably the most prevalent underlying cause of untimely demise in people suffering from RA as it hastens the expansion of atherosclerosis. The engagement of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), etc., is crucial in the progression and proliferation of both RA and abnormal lipid parameters. Thus, lipid abnormalities should be monitored frequently in patients with both primary and advanced RA stages. An advanced lipid profile examination, i.e., direct role of apolipoproteins associated with various lipid molecules is a more dependable approach for better understanding of the disease and selecting suitable therapeutic targets. Therefore, studying their apolipoproteins is more relevant than assessing RA patients' altered lipid profile levels. Among the various apolipoprotein classes, Apo A1 and Apo B are primarily being focused. In addition, it also addresses how calculating Apo B:Apo A1 ratio can aid in analyzing the disease's risk. The marketed therapies available to control lipid abnormalities are associated with many other risk factors. Hence, directly targeting Apo A1 and Apo B would provide a better and safer option.

Association of Microalbuminuria with Glucose Levels, Microvascular and Macrovascular Complications in Relation with Blood Pressure in Diabetes Mellitus Type 2

Objectives: Determine the association of Microalbuminuria (MAU) with glucose markers, micro vascular and macrovascular complications in relation with blood pressure in patients with type 2 diabetes mellitus. Material and Method: This study was cross sectional study and data collected in Chemical laboratory of pathology department of Dr Akbar Niazi Teaching Hospital. It carried out during the time period of December 2021 to January 2022. Patients were divided into 2 groups which fulfill the inclusion and exclusion criteria patients having diabetes mellitus type 2 with good glucose control, HbA1c &lt; 7% (n=33) patients having diabetes mellitus type 2 with bad control HbA1c ≥7% (n=33) each group were further divided into 2 sub-groups Patients with Pre-hypertension (n) and patients with HTN (n). The sampling technique of this study was non-probability convenience sampling was done. Data/Documentation was collected by Performa and laboratory investigation. Spss version 21 used to analyze the data. Normality of data was assessed by KS test. Quantitative test was measured as mean and standard deviation. Qualitative variables were calculated as number percentage. ANCOVA test and chi square test were used for comparison of quantitative and qualitative variables respectively. Pearson correlation was applied to determine the association of MAU with glucose levels and diabetes related complications. Result: Among total 66 patients, the sample of patients were included 47 males (71.2%) and 19 females (28.8%). Patients of type 2 diabetes mellitus in HbAlc ≥7% group showed higher levels of Blood Glucose level, MAU, Systolic BP and Diastolic BP as compared to HbA1c &lt; 7% group. The comparison of the variables between 2 groups showed statistical differences in nephropathy and cardiovascular complications. In HbA1c ≥ 7% group, correlation of MAU with Systolic BP, Diastolic BP, Fasting Blood Glucose (FBG), HbA1c, Nephropathy, and Cardiovascular events were statistically significant. In Pre-HTN group, MAU was significantly correlated with Fasting blood glucose level, HbA1c, Nephropathy and cardiovascular complications. Patients of HTN showed more significant association with blood pressure (BP), Blood Glucose, HbA1c, Cardiovascular events with MAU as evident by higher r-values as compared to pre-HTN group. Regarding nephropathy, r-value was slightly higher in Prehypertensive group. Conclusion: Patients with uncontrolled diabetes mellitus have increased risk of developing HTN, MAU as well as diabetes related complication including nephropathy and cardiovascular events. More over MAU showed significant positive association with BP, blood glucose levels, nephropathy and cardiovascular events. Both pre- hypertensive and hypertensive patients showed significant positive association of MAU with blood glucose levels and diabetes related complication including nephropathy and cardiovascular events. This study suggested that Prehypertensive and hypertensive patients with altered blood glucose levels have increased risk of MAU, that why proper evaluation and treatment of MAU may lead to early diagnosis and decrease progression of HTN, diabetes mellitus type 2 and its related complications.

Perception of strigolactones and the coordinated phytohormonal regulation on rice (Oryza sativa) tillering is affected by endogenous ascorbic acid.

Phytohormones play a key role in regulating tiller number. Ascorbic acid (Asc)-phytohormone interaction plays a pivotal role in the regulation of senescence. We analysed the relationship between Asc and the enzyme concentrations and gene transcript abundances related to the signal perception of strigolactones (SLs), the contents of four phytohormones (abscisic acid, ABA; jasmonic acid, JA; indole acetic acid, IAA; cytokinin, CTK), the enzyme concentrations and gene transcript abundances related to the synthesis or transportation of these four phytohormones. Our results showed that Asc deficiency leads to the upregulation of enzyme concentrations, gene transcript abundances related to the SL signal perception, ABA synthesis and IAA transport. The altered level of Asc also leads to a change in the contents of ABA, JA, IAA and CTK. These findings support the conclusion that Asc or Asc/DHA play an important role in the signal perception and transduction of SLs, and Asc may affect the coordinated regulation of SL, IAA and CTK on rice (Oryza sativa ) tillering.

Epitranscriptomic regulation in fasting hearts: implications for cardiac health

ABSTRACT Cardiac tolerance to ischaemia can be increased by dietary interventions such as fasting, which is associated with significant changes in myocardial gene expression. Among the possible mechanisms of how gene expression may be altered are epigenetic modifications of RNA – epitranscriptomics. N6-methyladenosine (m6A) and N6,2’-O-dimethyladenosine (m6Am) are two of the most prevalent modifications in mRNA. These methylations are reversible and regulated by proteins called writers, erasers, readers, and m6A-repelled proteins. We analysed 33 of these epitranscriptomic regulators in rat hearts after cardioprotective 3-day fasting using RT-qPCR, Western blot, and targeted proteomic analysis. We found that the most of these regulators were changed on mRNA or protein levels in fasting hearts, including up-regulation of both demethylases – FTO and ALKBH5. In accordance, decreased methylation (m6A+m6Am) levels were detected in cardiac total RNA after fasting. We also identified altered methylation levels in Nox4 and Hdac1 transcripts, both of which play a role in the cytoprotective action of ketone bodies produced during fasting. Furthermore, we investigated the impact of inhibiting demethylases ALKBH5 and FTO in adult rat primary cardiomyocytes (AVCMs). Our findings indicate that inhibiting these demethylases reduced the hypoxic tolerance of AVCMs isolated from fasting rats. This study showed that the complex epitranscriptomic machinery around m6A and m6Am modifications is regulated in the fasting hearts and might play an important role in cardiac adaptation to fasting, a well-known cardioprotective intervention.

Functional and Transcriptome Analysis Reveal Specific Roles of Dimocarpus longan DlRan3A and DlRan3B in Root Hair Development, Reproductive Growth, and Stress Tolerance.

Ran GTPases play essential roles in plant growth and development. Our previous studies revealed the nuclear localization of DlRan3A and DlRan3B proteins and proposed their functional redundancy and distinction in Dimocarpus longan somatic embryogenesis, hormone, and abiotic stress responses. To further explore the possible roles of DlRan3A and DlRan3B, gene expression analysis by qPCR showed that their transcripts were both more abundant in the early embryo and pulp in longan. Heterologous expression of DlRan3A driven by its own previously cloned promoter led to stunted growth, increased root hair density, abnormal fruits, bigger seeds, and enhanced abiotic stress tolerance. Conversely, constitutive promoter CaMV 35S (35S)-driven expression of DlRan3A, 35S, or DlRan3B promoter-controlled expression of DlRan3B did not induce the alterations in growth phenotype, while they rendered different hypersensitivities to abiotic stresses. Based on the transcriptome profiling of longan Ran overexpression in tobacco plants, we propose new mechanisms of the Ran-mediated regulation of genes associated with cell wall biosynthesis and expansion. Also, the transgenic plants expressing DlRan3A or DlRan3B genes controlled by 35S or by their own promoter all exhibited altered mRNA levels of stress-related and transcription factor genes. Moreover, DlRan3A overexpressors were more tolerant to salinity, osmotic, and heat stresses, accompanied by upregulation of oxidation-related genes, possibly involving the Ran-RBOH-CIPK network. Analysis of a subset of selected genes from the Ran transcriptome identified possible cold stress-related roles of brassinosteroid (BR)-responsive genes. The marked presence of genes related to cell wall biosynthesis and expansion, hormone, and defense responses highlighted their close regulatory association with Ran.

A Narrative Review of Preclinical In Vitro Studies Investigating microRNAs in Myocarditis.

According to the World Health Organization's statement, myocarditis is an inflammatory myocardium disease. Although an endometrial biopsy remains the diagnostic gold standard, it is an invasive procedure, and thus, cardiac magnetic resonance imaging has become more widely used and is called a non-invasive diagnostic gold standard. Myocarditis treatment is challenging, with primarily symptomatic therapies. An increasing number of studies are searching for novel diagnostic biomarkers and potential therapeutic targets. Microribonucleic acids (miRNAs) are small, non-coding RNA molecules that decrease gene expression by inhibiting the translation or promoting the degradation of complementary mRNAs. Their role in different fields of medicine has been recently extensively studied. This review discusses all relevant preclinical in vitro studies regarding microRNAs in myocarditis. We searched the PubMed database, and after excluding unsuitable studies and clinical and preclinical in vivo trials, we included and discussed 22 preclinical in vitro studies in this narrative review. Several microRNAs presented altered levels in myocarditis patients in comparison to healthy controls. Moreover, microRNAs influenced inflammation, cell apoptosis, and viral replication. Finally, microRNAs were also found to determine the level of myocardial damage. Further studies may show the vital role of microRNAs as novel therapeutic agents or diagnostic/prognostic biomarkers in myocarditis management.

Maternal history of Alzheimer's disease predisposes to altered serum cholesterol levels in adult offspring.

Controversial findings regarding the association between serum cholesterol levels and Alzheimer's disease (AD) have been identified through observational studies. The genetic basis shared by both factors and the causality between them remain largely unknown. The objective of this study is to examine the causal impact of maternal history of AD on changes in serum cholesterol levels in adult offspring. By retrieving genetic variants from summary statistics of large-scale genome-wide association study of maternal history of AD (European-based: Ncase = 27 696, Ncontrol = 260 980). The causal association between genetically predicted maternal history of AD and changes in serum cholesterol levels in adult offspring was examined using the two-sample Mendelian randomization (MR) method. Causal impact estimates were calculated using single-nucleotide polymorphisms in both univariable MR (UMR) and multivariable MR (MVMR) analyses. Additionally, other approaches, such as Cochran's Q test and leave-one-out variant analysis, were employed to correct for potential biases. The results of UMR presented that genetically predicted maternal history of AD was positively associated with hypercholesterolemia (OR = 1.014; 95% CI: 1.009-1.018; p < 0.001), total cholesterol (OR = 1.29; 95% CI: 1.134-1.466; p < 0.001) and low-density lipoprotein (OR = 1.525; 95% CI: 1.272-1.828; p < 0.001) among adult offspring. Genetic predisposition for maternal history of AD to be negatively associated with high-density lipoprotein (OR = 0.889; 95% CI: 0.861-0.917; p < 0.001). The MVMR analysis remained robust and significant after adjusting for diabetes and obesity in offspring. Sufficient evidence was provided in this study to support the putative causal impact of maternal history of AD on the change of serum cholesterol profile in adult offspring. In clinical practice, priority should be given to the detection and monitoring of cholesterol levels in individuals with a maternal history of AD, particularly in the early stages.

A phase 1, first-in-human, dose-escalation and expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma.

TPS709 Background: High Expression of Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor-family transcription factor, drives the initiation and development of UC in luminal molecular subtype tumors. Genetic profiling of UC has identified recurrent oncogenic alterations in the PPARG transcriptional complex, including focal amplification, missense mutations, and fusions in the heterodimeric partner of PPARG, the retinoid X receptor alpha (RXRA). High levels of PPARG expression and recurrent oncogenic alterations are observed in other solid malignancies including colorectal, gastroesophageal, pancreatic and lung cancers. FX-909 is an oral, first-in-class, new molecular agent that specifically, potently, and covalently modifies PPARG to mediate basal and ligand-activated transcription. Treatment of genetically defined UC xenografts with FX-909 has shown an 84% tumor growth inhibition (TGI) at a dose expected to be equivalent to 50 mg dose in humans, which is the starting dose in this clinical study. Methods: FX-909-CLINPRO-1 (NCT05929235) is a first-in-human, multicenter, open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FX-909 given orally in patients with advanced solid malignancies. Patients enrolled in the trial must have ECOG performance status ≤2 and must be ≥ 18 years of age. Initially, FX-909 will be given once daily to patients with any advanced solid malignancy in a dose-escalation phase (Part A) utilizing a 3+3 design. Five dose cohorts of 3 to 6 patients are planned. At the time of submission, three patients are enrolled in Part A- cohort one, 50mg. Additional patients will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or evidence of clinical activity. Once a RP2D has been determined, a monotherapy expansion phase (Part B) will proceed in a Simon 2-stage design in patients with locally advanced (unresectable) or metastatic UC with measurable disease and tumors harboring defined genetic alterations in PPARG, RXRA and FGFR3 (Motley et al, 2022). In stage 1, up to 19 evaluable patients will be enrolled. If ≥4 objective responses are observed, enrollment will continue into Stage 2 with an additional 14 evaluable patients. One treatment cycle is 28 days. Dose expansion will evaluate the safety, PK/PD profile, and antitumor activity of FX-909 at the RP2D. Exploratory objectives include the evaluation patient selection biomarkers from tissue and blood samples. FX-909 clinical activity will be assessed using RECIST v1.1 criteria. The study is currently enrolling patients in the US. Clinical trial information: NCT05929235 .

Systematic pan-cancer analysis of RNF186 with potential implications in progression and prognosis in human cancer

AimsCancer remains a significant global public health issue. There is growing proof that Ring Finger Protein 186 (RNF186) may play a function in pan-cancer, however, this has not yet been thoroughly determined. This study aims to analyze RNF186 with potential implications in progression and prognosis in human cancer. Materials and methodsA comprehensive bioinformatics approaches combined with experimental verification were used across 33 types of cancers in this study to conduct a pan-cancer investigation of RNF186 from the perspectives of gene expression, prognosis, genomic alterations, immunological markers, gene set, and function. Key findingsRNF186 is a valuable prognostic biomarker in several cancer types, especially breast invasive carcinoma (BRCA) and uterine corpus endometrial carcinoma (UCEC). The levels of RNF186 promoter methylation and genetic alterations may be responsible for some cancers' abnormal expression. Furthermore, RNF186 expression was determined to be associated with immune checkpoint genes. Analysis of RNF186-related genes revealed that proteasome and PI3K-AKT signaling pathway were primarily involved in the cellular function of RNF186. Additionally, our research first confirmed that RNF186 may function as an oncogene and contribute to cancer proliferation, migration and invasion in UCEC. In contrast, RNF186 may play an inhibitory role in BRCA progression. This function depends on the ligase activity of RNF186. SignificanceThis study suggests that RNF186 is a novel critical target for tumor progression in BRCA and UCEC. It reveals that RNF186 may be associated with tumor immunotherapy, which may provide an effective predictive evaluation of the prognosis of immunotherapy.

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice.

Disturbances in the circadian rhythm are positively correlated with the processes of aging and related neurodegenerative diseases, which are also associated with brain iron accumulation. However, the role of brain iron in regulating the biological rhythm is poorly understood. In this study, we investigated the impact of brain iron levels on the spontaneous locomotor activity of mice with altered brain iron levels and further explored the potential mechanisms governing these effects invitro. Our results revealed that conditional knockout of ferroportin 1 (Fpn1) in cerebral microvascular endothelial cells led to brain iron deficiency, subsequently resulting in enhanced locomotor activity and increased expression of clock genes, including the circadian locomotor output cycles kaput protein (Clock) and brain and muscle ARNT-like 1 (Bmal1). Concomitantly, the levels of period circadian regulator 1 (PER1), which functions as a transcriptional repressor in regulating biological rhythm, were decreased. Conversely, the elevated brain iron levels in APP/PS1 mice inhibited autonomous rhythmic activity. Additionally, our findings demonstrate a significant decrease in serum melatonin levels in Fpn1cdh5 -CKO mice compared with the Fpn1flox/flox group. In contrast, APP/PS1 mice with brain iron deposition exhibited higher serum melatonin levels than the WT group. Furthermore, in the human glioma cell line, U251, we observed reduced PER1 expression upon iron limitation by deferoxamine (DFO; iron chelator) or endogenous overexpression of FPN1. When U251 cells were made iron-replete by supplementation with ferric ammonium citrate (FAC) or increased iron import through transferrin receptor 1 (TfR1) overexpression, PER1 protein levels were increased. Additionally, we obtained similar results to U251 cells in mouse cerebellar astrocytes (MA-c), where we collected cells at different time points to investigate the rhythmic expression of core clock genes and the impact of DFO or FAC treatment on PER1 protein levels. These findings collectively suggest that altered iron levels influence the circadian rhythm by regulating PER1 expression and thereby modulating the molecular circadian clock. In conclusion, our study identifies the regulation of brain iron levels as a potential new target for treating age-related disruptions in the circadian rhythm.

Heavy Metal Scavenger Metallothionein Rescues Against Cold Stress-Evoked Myocardial Contractile Anomalies Through Regulation of Mitophagy.

Cold stress prompts an increased prevalence of cardiovascular morbidity yet the underneath machinery remains unclear. Oxidative stress and autophagy appear to contribute to cold stress-induced cardiac anomalies. Our present study evaluated the effect of heavy metal antioxidant metallothionein on cold stress (4°C)-induced in cardiac remodeling and contractile anomalies and cell signaling involved including regulation of autophagy and mitophagy. Cold stress (3weeks) prompted interstitial fibrosis, mitochondrial damage (mitochondrial membrane potential and TEM ultrastructure), oxidative stress (glutathione, reactive oxygen species and superoxide), lipid peroxidation, protein injury, elevated left ventricular (LV) end systolic and diastolic diameters, decreased fractional shortening, ejection fraction, Langendorff heart function, cardiomyocyte shortening, maximal velocities of shortening/relengthening, and electrically stimulated intracellular Ca2+ rise along with elongated relaxation duration and intracellular Ca2+ clearance, the responses of which were overtly attenuated or mitigated by metallothionein. Levels of apoptosis, cell death (Bax and loss of Bcl2, IL-18), and autophagy (LC3BII-to-LC3BI ratio, Atg7 and Beclin-1) were overtly upregulated with comparable p62 under cold stress. Cold stress also evoked elevated mitophagy (decreased TOM20, increased Parkin and FUNDC1 with unaltered BNIP3). Cold stress overtly dampened phosphorylation of autophagy/mitophagy inhibitory molecules Akt and mTOR, stimulated and suppressed phosphorylation of ULK1 and eNOS, respectively, in the absence of altered pan protein levels. Cold stress-evoked responses in cell death, autophagy, mitophagy and their regulatory domains were overtly attenuated or ablated by metallothionein. Suppression of autophagy and mitophagy with 3-methyladenine, bafilomycin A1, cyclosporine A, and liensinine rescued hypothermia-instigated cardiomyocyte LC3B puncta formation and mechanical anomalies. Our findings support a protective nature for metallothionein in deep hypothermia-evoked cardiac abnormalities associated with regulation of autophagy and mitophagy.

7, 8-dihydroxyflavone Ameliorates Cholinergic Dysfunction, Inflammation, Oxidative Stress, and Apoptosis in a Rat Model of Vascular Dementia.

Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD.VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20mg/kg) and Donepezil (10mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1β, and NF-kβ), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats.Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus.These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD.

Leptin haploinsufficiency exerts sex-dependent partial protection in SOD1G93A mice by reducing inflammatory pathways in the adipose tissue.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant metabolic disruptions, including weight loss and hypermetabolism in both patients and animal models. Leptin, an adipose-derived hormone, displays altered levels in ALS. Genetically reducing leptin levels (Lepob/+) to maintain body weight improved motor performance and extended survival in female SOD1G93A mice, although the exact molecular mechanisms behind these effects remain elusive. Here, we corroborated the sexual dimorphism in circulating leptin levels in ALS patients and in SOD1G93A mice. We reproduced a previous strategy to generate a genetically deficient leptin SOD1G93A mice (SOD1G93ALepob/+) and studied the transcriptomic profile in the subcutaneous adipose tissue and the spinal cord. We found that leptin deficiency reduced the inflammation pathways activated by the SOD1G93A mutation in the adipose tissue, but not in the spinal cord. These findings emphasize the importance of considering sex-specific approaches in metabolic therapies and highlight the role of leptin in the systemic modulation of ALS by regulating immune responses outside the central nervous system.

Abstract TP177: Functional Outcome Prediction in Primary Angiitis of the Central Nervous System

Introduction: Predicting the probability of functional independence in patients with primary angiitis of the central nervous system (PACNS) may help guide treatment decisions and prognostication. We sought to develop a prediction model for functional independence in adults with PACNS. Methods: Adults with PACNS were included from an international, multicenter, retrospective, observational cohort (COVAC). Clinical and imaging variables were collected prior to immunosuppressant treatment. Univariable and multivariable logistic regression models were used to identify baseline variables associated with functional independence (modified Rankin Score 0-2), measured 12 months after diagnosis. Results: Among the 194 patients included, 60 (31%) were diagnosed with PACNS based on a positive biopsy. At 12 months, 124 (65%) patients were functionally independent and 12 (6%) were dead. In multivariable logistic regression models, variables predictive of functional independence at 12 months were presence of ≥ 1 intracranial stenosis on CT- or MR-angiogram (aOR 3.33, 95% CI: 1.34-8.77, p=0.01), headache (aOR 2.66, 95% CI: 1.29-5.62, p&lt;0.01), and absence of an altered level of consciousness (aOR 0.09, 95% CI: 0.02-0.28, p&lt;0.001), an acute brain infarct (aOR 0.13, 95% CI: 0.04-0.34, p&lt;0.001), or cognitive impairment (aOR 0.32, 95% CI: 0.15-0.68, p&lt;0.01). A predictive model including these five variables showed good discrimination (c-statistic: 0.79, 95% CI: 0.72-0.86). Purely lymphocytic PACNS (n=34) was not associated with higher odds of functional independence than granulomatous or necrotizing PACNS (n=26) (OR 0.97, 95% CI: 0.33-2.83, p=0.96). Conclusions: This study identified baseline clinical and imaging variables that may predict functional independence in adults with PACNS. Validation of these results is required in an independent cohort.

Modifications of the GH axis reveal unique sexually dimorphic liver signatures for Lcn13, Asns, Hamp2, Hao2, and Pgc1a

Abstract GH modifies liver gene transcription in a sexually dimorphic manner to meet liver metabolic demands related to sex; therefore GH dysregulation leads to sex-biased hepatic disease. We dissected the steps of the GH regulatory cascade modifying GH-dependent genes involved in metabolism, focusing on the male-predominant genes Lcn13, Asns and Cyp7b1, and the female-predominant genes Hao2, Pgc1a, Hamp2, Cyp2a4 and Cyp2b9. We explored mRNA expression in two settings a) intact liver GH receptor, but altered GH and IGF1 levels (NeuroDrd2KO, HiGH, aHepIGF1kd, and STAT5bCA mouse lines), and b) liver loss of GHR, with or without STAT5b reconstitution (aHepGHRkd, and aHepGHRkd + STAT5bCA). Lcn13 was downregulated in males in most models, while Asns and Cyp7b1 were decreased in males by low GH levels or action, or constant GH levels, but unexpectedly upregulated in both sexes by the loss of liver Igf1 or constitutive Stat5b expression. Hao, Cyp2a4 and Cyp2b9 were generally decreased in female mice with low GH levels or action (NeuroDrd2KO and/or aHepGHRkd mice), and increased in HiGH females, while in contrast, Pgc1a was increased in female NeuroDrd2KO but decreased in STAT5bCA and aHepIgf1kd females. Bioinformatic analysis of RNAseq from aHepGHRkd livers stressed the greater impact of GHR loss on wide gene expression in males and highlighted that GH modifies almost completely different gene signatures in each sex. Concordantly, we show that altering different steps of the GH cascade in the liver modified liver expression of Lcn3, Asns, Cyp7b1, Hao2, Hamp2, Pgc1a, Cyp2a4 and Cyp2b9 in a sex and gene specific manner.

Changes in Intrinsic Connectivity Networks Topology Across Levels of Dexmedetomidine-Induced Alteration of Consciousness.

Human consciousness is generally thought to emerge from the activity of intrinsic connectivity networks (resting-state networks [RSNs]) of the brain, which have topological characteristics including, among others, graph strength and efficiency. So far, most functional brain imaging studies in anesthetized subjects have compared wakefulness and unresponsiveness, a state considered as corresponding to unconsciousness. Sedation and general anesthesia not only produce unconsciousness but also phenomenological states of preserved mental content and perception of the environment (connected consciousness), and preserved mental content but no perception of the environment (disconnected consciousness). Unresponsiveness may be seen during unconsciousness, but also during disconnectedness. Deep dexmedetomidine sedation is frequently a state of disconnected consciousness. In this study, we were interested in characterizing the RSN topology changes across 4 different and steady-state levels of dexmedetomidine-induced alteration of consciousness, namely baseline (Awake, drug-free state), Mild sedation (drowsy, still responding), Deep sedation (unresponsive), and Recovery, with a focus on changes occurring between a connected consciousness state and an unresponsiveness state. A functional magnetic resonance imaging database acquired in 14 healthy volunteers receiving dexmedetomidine sedation was analyzed using a method combining independent component analysis and graph theory, specifically looking at changes in connectivity strength and efficiency occurring during the 4 above-mentioned dexmedetomidine-induced altered consciousness states. Dexmedetomidine sedation preserves RSN architecture. Unresponsiveness during dexmedetomidine sedation is mainly characterized by a between-networks graph strength alteration and within-network efficiency alteration of lower-order sensory RSNs, while graph strength and efficiency in higher-order RSNs are relatively preserved. The differential dexmedetomidine-induced RSN topological changes evidenced in this study may be the signature of inadequate processing of sensory information by lower-order RSNs, and of altered communication between lower-order and higher-order networks, while the latter remain functional. If replicated in an experimental paradigm distinguishing, in unresponsive subjects, disconnected consciousness from unconsciousness, such changes would sustain the hypothesis that disconnected consciousness arises from altered information handling by lower-order sensory networks and altered communication between lower-order and higher-order networks, while the preservation of higher-order networks functioning allows for an internally generated mental content (or dream).

Acute, but not repeated, cocaine exposure alters allopregnanolone levels in the midbrain of male and female rats.

Multiple psychiatric disorders are associated with altered brain and serum levels of neuroactive steroids, including the endogenous GABAergic steroid, allopregnanolone. Clinically, chronic cocaine use was correlated with decreased levels of pregnenolone. Preclinically, the effect of acute cocaine on allopregnanolone levels in rodents has had mixed results, showing an increase or no change in allopregnanolone levels in some brain regions. We hypothesized that cocaine acutely increases allopregnanolone levels, but repeated cocaine exposure decreases allopregnanolone levels compared to controls. We performed two separate studies to determine how systemic administration of 15mg/kg cocaine (1) acutely or (2) chronically alters brain (olfactory bulb, frontal cortex, dorsal striatum, and midbrain) and serum allopregnanolone levels in adult male and female Sprague-Dawley rats. Cocaine acutely increased allopregnanolone levels in the midbrain, but not in olfactory bulb, frontal cortex, or dorsal striatum. Repeated cocaine did not persistently (24h later) alter allopregnanolone levels in any region in either sex. However, allopregnanolone levels varied by sex across brain regions. In the acute study, we found that females had significantly higher allopregnanolone levels in serum and olfactory bulb relative to males. In the repeated cocaine study, females had significantly higher allopregnanolone levels in olfactory bulb, frontal cortex, and serum. Finally, acute cocaine increased allopregnanolone levels in the frontal cortex of females in proestrus, relative to non-proestrus stages. Collectively these results suggest that allopregnanolone levels vary across brain regions and by sex, which may play a part in differential responses to cocaine by sex.

Prenatal maternal glucocorticoid exposure modifies sperm miRNA profiles across multiple generations in the guinea-pig.

Maternal stress and glucocorticoid exposure during pregnancy have multigenerational effects on neuroendocrine function and behaviours in offspring. Importantly, effects are transmitted through the paternal lineage. Altered phenotypes are associated with profound differences in transcription and DNA methylation in the brain. In the present study, we hypothesized that maternal prenatal synthetic glucocorticoid (sGC) exposure in the F0 pregnancy will result in differences in miRNA levels in testes germ cells and sperm across multiple generations, and that these changes will associate with modified microRNA (miRNA) profiles and gene expression in the prefrontal cortex (PFC) of subsequent generations. Pregnant guinea-pigs (F0) were treated with multiple courses of the sGC betamethasone (Beta) (1mgkg-1; gestational days 40, 41, 50, 51, 60 and 61) in late gestation. miRNA levels were assessed in testes germ cells and in F2 PFC using the GeneChip miRNA 4.0 Array and candidate miRNA measured in epididymal sperm by quantitative real-time PCR. Maternal Beta exposure did not alter miRNA levels in germ cells derived from the testes of adult male offspring. However, there were significant differences in the levels of four candidate miRNAs in the sperm of F1 and F2 adult males. There were no changes in miRNA levels in the PFC of juvenile F2 female offspring. The present study has identified that maternal Beta exposure leads to altered miRNA levels in sperm that are apparent for at least two generations. The fact that differences were confined to epididymal sperm suggests that the intergenerational effects of Beta may target the epididymis. KEY POINTS: Paternal glucocorticoid exposure prior to conception leads to profound epigenetic changes in the brain and somatic tissues in offspring, and microRNAs (miRNAs) in sperm may mediate these changes. We show that there were significant differences in the miRNA profile of epididymal sperm in two generations following prenatal glucocorticoid exposure that were not observed in germ cells derived from the testes. The epididymis is a probable target for intergenerational programming. The effects of prenatal glucocorticoid treatment may span multiple generations.

Impact of hematocrit on pulsatile blood flow in stenosed arteries: a computational study in healthy, diabetic, and anemic models

In this study, researchers aim to enhance the realism of circulatory system simulations, focusing on factors affecting flow variations, particularly in stenotic arteries of individuals with altered hematocrit levels. Through extensive data collection and varied conditions, the goal is to attain more precise and valid results. The study conducts approximate simulations to comprehensively describe the dynamic motion of pulsatile flow. Different values of inlet velocity (UDF) are introduced, considering potential arterial distortion or occlusion due to plaque deposition, along with variations in hematocrit (Hct) levels commonly observed in patients. Three distinct types of pulsatile blood flow, corresponding to diabetes (Hct 65%), healthy (Hct 45%), and anemia (Hct 25%), are studied and compared. The research illuminates that stenosis in arteries with varying hematocrit levels significantly impacts hydrodynamic features, potentially predisposing individuals to cardiovascular diseases. Through meticulous analysis, several conclusions about hemodynamic characteristics are drawn. It is observed that both velocity and wall shear stress exhibit variation along the affected artery, influenced by stenosis and changes in hematocrit levels. Notably, the highest influence on velocity and wall shear stress is observed with Hct 65%, compared to Hct 45% and Hct 25% at the moment of stenosis. These findings hold substantial practical implications for the field of cardiovascular health, providing valuable insights into blood flow behavior in stenotic arteries with diverse hematocrit levels. Ultimately, this research contributes to more effective clinical interventions.