Responses In Central Nervous System Research Articles

Stress-induced obesity in mice causes cognitive decline associated with inhibition of hippocampal neurogenesis and dysfunctional gut microbiota

Effects of stress on obesity have been thoroughly studied in high-fat diet fed mice, but not in normal diet fed mice, which is important to clarify because even on a normal diet, some individuals will become obese under stress conditions. Here we compared mice that showed substantial weight gain or loss under chronic mild stress while on a normal diet; we compared the two groups in terms of cognitive function, hypothalamic–pituitary–adrenal signaling, neurogenesis and activation of microglia in hippocampus, gene expression and composition of the gut microbiome. Chronic mild stress induced diet-independent obesity in approximately 20% of animals, and it involved inflammatory responses in peripheral and central nervous system as well as hyperactivation of the hypothalamic–pituitary–adrenal signaling and of microglia in the hippocampus, which were associated with cognitive deficits and impaired hippocampal neurogenesis. It significantly increased in relative abundance at the phylum level (Firmicutes), at the family level (Prevotellaceae ucg − 001 and Lachnospiraceae NK4a136), at the genus level (Dubosiella and Turicibacter) for some enteric flora, while reducing the relative abundance at the family level (Lactobacillaceae and Erysipelotrichaceae), at the genus level (Bacteroidota, Alistipes, Alloprevotella, Bifidobacterium and Desulfovibrio) for some enteric flora. These results suggest that stress, independently of diet, can induce obesity and cognitive decline that involve dysfunctional gut microbiota. These insights imply that mitigation of hypothalamic–pituitary–adrenal signaling and microglial activation as well as remodeling of gut microbiota may reverse stress-induced obesity and associated cognitive decline.

Neuro-immune cell interactions in the regulation of intestinal immune homeostasis.

Bidirectional regulation between neurons and immune cells in the intestine governs essential physiological processes, including digestion, metabolism and motility, while also controlling intestinal inflammation and maintaining tissue homeostasis. This review covers recent advances and future research challenges focused on the regulatory molecules and potential therapeutic targets in neuron-immune interactions within the intestine. Recently identified molecular and cellular pathways have been shown to regulate neuron-immune cell cross talk in the context of maintaining tissue homeostasis, modulating inflammation, and promoting intestinal repair. Additionally, behaviors governed by the central nervous system, including feeding and stress responses, can play key roles in regulating intestinal immunity and inflammation. This review emphasizes recent progress in understanding the complex interplay between the nervous system and intestinal immune system and outlines future research directions. These advances have the potential to lead to innovative therapies targeting gastrointestinal disorders including inflammatory bowel diseases, allergic responses and cancer.

Negative auditory hallucinations are associated with increased activation of the defensive motivational system in schizophrenia

Auditory hallucinations (AH) are the most common symptom of psychosis. The voices people hear make comments that are benign or even encouraging, but most often voices are threatening and derogatory. Negative AH are often highly distressing and contribute to suicide risk and violent behavior. Biological mechanisms underlying the valence of voices (i.e., positive, negative, neutral) are not well delineated. In the current study, we examined whether AH voice valence was associated with increased activation of the Defensive Motivational System, as indexed by central and autonomic system response to unpleasant stimuli. Data were evaluated from two studies that used a common symptom rating instrument, the Psychotic Symptom Rating Scale (PSY-RATS), to measure AH valence. Participants included outpatients diagnosed with SZ. Tasks included: Study 1: Trier Social Stress Task while heart rate was recorded via electrocardiography (N = 27); Study 2: Passive Viewing Task while participants were exposed to pleasant, unpleasant, and neutral images from the International Affective Picture System (IAPS) library while eye movements, pupil dilation, and electroencephalography were recorded (N = 25). Results indicated that negative voice content was significantly associated with: 1) increased heart rate during an acute social stressor, 2) increased pupil dilation to unpleasant images, 3) higher neural reactivity to unpleasant images, and 4) a greater likelihood of having bottom-up attention drawn to unpleasant stimuli. Findings suggest that negative AH are associated with greater Defensive Motivational System activation in terms of central and autonomic nervous system response.

Blood-brain barrier damage accelerates the accumulation of micro- and nanoplastics in the human central nervous system

The widespread use of plastics has led to increased micro- and nanoplastics (MNPs) pollution, resulting in significant environmental challenges and concerns about potential harm to human health. This study investigated whether certain types of MNPs can accumulate in the human central nervous system (CNS) and trigger inflammatory responses, particularly after CNS infection. Our analysis of 28 cerebrospinal fluid (CSF) samples from 28 patients with or without CNS infection revealed that only polystyrene (PS), polyethylene (PE), polypropylene (PP), and polyvinyl chloride (PVC) were capable of selectively entering the human CNS. Concentrations of PP and PE were positively correlated with the CSF albumin index. The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) were significantly increased in patients with CNS infections. However, concentrations of MNPs were not significantly associated with CSF levels of IL-6 or IL-8. Overall, these findings suggest that specific MNPs can penetrate the human CNS, especially after impairment of the blood-brain barrier. Notably, MNPs derived from commonly used plastics did not significantly induce or exacerbate inflammation in the human CNS.

A Phase II Study of Atezolizumab, Pertuzumab, and High-Dose Trastuzumab for Central Nervous System Metastases in Patients with HER2-Positive Breast Cancer.

Patients with HER2-positive breast cancer brain metastases have few effective systemic therapy options. In a prior study, pertuzumab with high-dose trastuzumab demonstrated a high clinical benefit rate (CBR) in the central nervous system (CNS) in patients with brain metastases. The current trial evaluated whether the addition of atezolizumab to this regimen would produce further improvements in CNS response. This was a single-arm, multicenter, phase II trial of atezolizumab, pertuzumab, and high-dose trastuzumab for patients with HER2-positive breast cancer brain metastases. Participants received atezolizumab 1,200 mg i.v. every 3 weeks, pertuzumab (loading dosage 840 mg i.v., then 420 mg i.v. every 3 weeks), and high-dose trastuzumab (6 mg/kg i.v. weekly for 24 weeks, then 6 mg/kg i.v. every 3 weeks). The primary endpoint was CNS overall response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria. Key secondary endpoints included CBR, overall survival, and safety and tolerability of the combination. Among 19 enrolled participants, two had a confirmed intracranial partial response for a CNS overall response rate of 10.5% (90% confidence interval, 1.9%-29.6%). The study did not meet the prespecified efficacy threshold and was terminated early. The CBR was 42.1% at 18 weeks and 31.6% at 24 weeks. Seven patients (36.8%) required a dose delay or hold, and the most frequent any-grade adverse events were diarrhea (26.3%) and fatigue (26.3%). The addition of atezolizumab to pertuzumab plus high-dose trastuzumab does not result in improved CNS responses in patients with HER2-positive breast cancer brain metastases.

The effects of four hours of normobaric hypoxia on the vestibular control of balance.

Whole-body vestibular-evoked balance responses decrease following ~ 55min of normobaric hypoxia. It is unclear how longer durations of hypoxia affect the vestibular control of balance at the muscle and whole-body levels. This study examined how four hours of normobaric hypoxia influenced the vestibular control of balance. Fifteen participants (4 females; 11 males) stood on a force plate with vision occluded and head rotated rightward while subjected to three blocks of binaural, bipolar stochastic electrical vestibular stimulation (EVS; 0-25Hz, root mean square amplitude = 1.1mA) consisting of two, 90-s trials. The relationship between EVS and anteroposterior (AP) forces or medial gastrocnemius (MG) electromyography (EMG) was estimated in the time and frequency domains at baseline (BL; 0.21 fraction of inspired oxygen-FIO2) and following two (H2) and four (H4) hours of normobaric hypoxia (0.11 FIO2). The EVS-MG EMG short-latency peak and peak-to-peak amplitudes were smaller than BL at H2 and H4, but the medium-latency peak amplitude was only lower at H4. The EVS-AP force medium-latency peak amplitude was lower than BL at H4, but the short-latency peak and peak-to-amplitudes were unchanged. The EVS-MG EMG coherence and gain were reduced compared to BL at H2 and H4 across multiple frequencies ≥ 7Hz, whereas EVS-AP force coherence was blunted at H4 (≤ 4Hz), but gain was unaffected. Overall, the central nervous system's response to vestibular-driven signals during quiet standing wasdecreased forup to four hours of normobaric hypoxia, and vestibular-evoked responses recorded within postural muscles may be more sensitive than the whole-body response.

Embedded Hybrid-Dimensional Heterointerface for Filament Modulation in 2D Material-Based Artificial Nociceptor.

Nociceptors are key sensory receptors that transmit warning signals to the central nervous system in response to painful stimuli. This fundamental process is emulated in an electronic device by developing a novel artificial nociceptor with an ultrathin, nonstoichiometric gallium oxide (GaOx)-silicon oxide heterostructure. A large-area 2D-GaOx film is printed on a substrate through liquid metal printing to facilitate the production of conductive filaments. This nociceptive structure exhibits a unique short-term temporal response following stimulation, enabling a facile demonstration of threshold-switching physics. The developed heterointerface 2D-GaOx film enables the fabrication of fast-switching, low-energy, and compliance-free 2D-GaOx nociceptors, as confirmed through experiments. The accumulation and extrusion of Ag in the oxide matrix are significant for inducing plastic changes in artificial biological sensors. High-resolution transmission electron microscopy and electron energy loss spectroscopy demonstrate that Ag clusters in the material dispersed under electrical bias and regrouped spontaneously when the bias is removed owing to interfacial energy minimization. Moreover, 2D nociceptors are stable; thus, heterointerface engineering can enable effective control of charge transfer in 2D heterostructural devices. Furthermore, the diffusive 2D-GaOx device and its Ag dynamics enable the direct emulation of biological nociceptors, marking an advancement in the hardware implementation of artificial human sensory systems.

Joint Inflammation Correlates with Joint GPR30 Expression in Males and Hippocampal GPR30 Expression in Females in a Rat Model of Rheumatoid Arthritis.

It is not entirely clear how the interaction between joint inflammation and the central nervous system (CNS) response in rheumatoid arthritis (RA) works, and what pathophysiology underlies the sex differences in coexisting neuropsychiatric comorbidities. It is known that estrogen hormones reduce inflammation in RA and that this occurs mainly via the stimulation of G protein-coupled receptor-30 (GPR30), also known as G protein-coupled estrogen receptor (GPER) 1. However, changes in GPR30 expression and sex differences induced by local and systemic inflammation in RA are not yet known. Our aim was to reveal sex differences in the expression and association of joint GPR30 with local and systemic inflammation, clinical course and furthermore with hippocampal GPR30 expression during pristane-induced arthritis (PIA) in Dark Agouti (DA) rats, an animal model of RA. Furthermore, we demonstrated sex-specific differences in the association between joint and systemic inflammation and hippocampal microglia during PIA. Our results suggest sex-specific differences not only in the clinical course and serum levels of pro-inflammatory cytokines but also in the expression of GPR30. Female rats show greater synovial inflammation and greater damage to the articular cartilage compared to males during PIA attack. Male rats express higher levels of synovial and cartilaginous GPR30 than females during PIA, which correlates with a less severe clinical course. The correlation between synovial and cartilaginous GPR30 and joint inflammation scores (Krenn and Mankin) in male rats suggests that the more severe the joint inflammation, the higher the GPR30 expression. At the same time, there is no particular upregulation of hippocampal GPR30 in males. On the other hand, female rats express higher levels of neuroprotective GPR30 in the hippocampus than male rats at the basic level and during PIA attack. In addition, females have a higher number of Iba-1+ cells in the hippocampus during PIA attack that strongly correlates with the clinical score, serum levels of IL-17A, and Krenn and Mankin scores. These results suggest that male rats are better protected from inflammation in the joints and female rats are better protected from the inflammation in the hippocampus during a PIA attack, independently of microglia proliferation. However, in the remission phase, synovial GPR30 expression suddenly increases in female rats, as does hippocampal GPR30 expression in males. Further experiments with a longer remission period are needed to investigate the molecular background of these sex differences, as well as microglia phenotype profiling.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. ClinicalTrials.gov number, NCT03849768.

Rotavirus Sickness Symptoms: Manifestations of Defensive Responses from the Brain.

Rotavirus is infamous for being extremely contagious and for causing diarrhea and vomiting in infants. However, the symptomology is far more complex than what could be expected from a pathogen restricted to the boundaries of the small intestines. Other rotavirus sickness symptoms like fever, fatigue, sleepiness, stress, and loss of appetite have been clinically established for decades but remain poorly studied. A growing body of evidence in recent years has strengthened the idea that the evolutionarily preserved defensive responses that cause rotavirus sickness symptoms are more than just passive consequences of illness and rather likely to be coordinated events from the central nervous system (CNS), with the aim of maximizing the survival of the individual as well as the collective group. In this review, we discuss both established and plausible mechanisms of different rotavirus sickness symptoms as a series of CNS responses coordinated from the brain. We also consider the protective and the harmful nature of these events and highlight the need for further and deeper studies on rotavirus etiology.

Neurological manifestations of Flaviviridae, Togaviridae, and Peribunyaviridae as vector-borne viruses.

Vector-borne viruses pose a significant health problem worldwide, as they are transmitted to humans through the bite of infected arthropods such as mosquitoes and ticks. In recent years, emerging and re-emerging vector-borne diseases have gained attention as they can cause a wide spectrum of neurological manifestations. The neurological manifestations of vector-borne viruses encompass a board spectrum of clinical manifestations, ranging from mild and self-limiting symptoms to severe and life-threatening conditions. Common neurological complications include viral encephalitis, acute flaccid paralysis, aseptic meningitis, and various neuromuscular disorders. The specific viruses responsible for these neurological sequelae vary by geographic region and include Orthoflavivirus nilense, Zika virus, dengue virus, chikungunya virus, Japanese encephalitis virus, and tick-borne encephalitis virus. This review focuses on the pathogenesis of these neurologic complications and highlights the mechanisms by which vector-borne viruses invade the central nervous system and trigger neuroinflammatory responses. Diagnostic challenges and strategies for early detection of neurological manifestations are discussed, emphasising the importance of clinical suspicion and advanced laboratory testing.

Identification of endoplasmic reticulum stress genes in human stroke based on bioinformatics and machine learning

After ischemic stroke (IS), secondary injury is intimately linked to endoplasmic reticulum (ER) stress and body-brain crosstalk. Nonetheless, the underlying mechanism systemic immune disorder mediated ER stress in human IS remains unknown. In this study, 32 candidate ER stress-related genes (ERSRGs) were identified by overlapping MSigDB ER stress pathway genes and DEGs. Three Key ERSRGs (ATF6, DDIT3 and ERP29) were identified using LASSO, random forest, and SVM-RFE. IS patients with different ERSRGs profile were clustered into two groups using consensus clustering and the difference between 2 group was further explored by GSVA. Through immune cell infiltration deconvolution analysis, and middle cerebral artery occlusion (MCAO) mouse scRNA analysis, we found that the expression of 3 key ERSRGs were closely related with peripheral macrophage cell ER stress in IS and this was further confirmed by RT-qPCR experiment. These ERS genes might be helpful to further accurately regulate the central nervous system and systemic immune response through ER stress and have potential application value in clinical practice in IS.

Subclinical peripheral inflammation has systemic effects impacting central nervous system proteome in budgerigars

Regulation of neuroimmune interactions varies across avian species. Little is presently known about the interplay between periphery and central nervous system (CNS) in parrots, birds sensitive to neuroinflammation. Here we investigated the systemic and CNS responses to dextran sulphate sodium (DSS)- and lipopolysaccharide (LPS)-induced subclinical acute peripheral inflammation in budgerigar (Melopsittacus undulatus). Three experimental treatment groups differing in DSS and LPS stimulation were compared to controls. Individuals treated with DSS showed significant histological intestinal damage. Through quantitative proteomics we described changes in plasma (PL) and cerebrospinal fluid (CSF) composition. In total, we identified 180 proteins in PL and 978 proteins in CSF, with moderate co-structure between the proteomes. Between treatments we detected differences in immune, coagulation and metabolic pathways. Proteomic variation was associated with the levels of pro-inflammatory cytokine mRNA expression in intestine and brain. Our findings shed light on systemic impacts of peripheral low-grade inflammation in birds.

CNS efficacy of trastuzumab deruxtecan in metastatic breast cancer: A single-institution, real-world analysis.

e13117 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that revolutionized the management of patients with HER2+ (HER2 FISH+, IHC 3+) and HER2low (HER2 FISH-, IHC 1+/2+) metastatic breast cancer (MBC). Studies have shown that T-DXd may induce antitumor activity in HER2+ MBC with brain metastases (BM). However, data is limited on the central nervous system (CNS) efficacy of T-DXd in HER2low disease. The only report thus far is from the HER2low cohorts in the DEBBRAH study with 12 patients showing an intracranial overall response rate (ORR-IC) of 50% and progression free survival (PFS) of 5.7 months. Here, we provide a real-world, retrospective analysis of the CNS efficacy of T-DXd in HER2+, HER2low, and HER2null MBC with BM. Methods: This is a single institution, retrospective analysis of patients with MBC with BM who received T-DXd between January 2020 and November 2023. Patients with HER2+, HER2low, or HER2null MBC and BM, treated or untreated at the time of T-DXd initiation, were included. All patients had baseline brain magnetic resonance imaging before T-DXd initiation. Efficacy analyses were performed using the RECIST 1.1 criteria to CNS target lesions by investigator assessment. ORR-IC and intracranial clinical benefit rate (CBR-IC) were reported. CNS PFS, defined as time until CNS progression or death of any cause, and overall survival (OS) were also evaluated. Results: 29 patients were included in the study: 10 (35%) had HER2+, 16 (55%) had HER2low, and 3 (10%) had HER2null disease. The patients had ECOG performance status ranging from 0 to 3, and received a median of 3 prior lines of therapy (range 1-8). At baseline, 3 patients (10%) had untreated BM, 6 (21%) had prior surgery, and 23 (79%) had prior radiation. 28 (97%) had concurrent extra-cranial metastases. Best CNS response and duration of response are listed in the table below. ORR-IC was 10% overall and 6% in HER2low group. CBR-IC was 58% overall and 50% in HER2low group. Median OS in all patients was 65 weeks. Median CNS PFS was not statistically different in the overall group (24 weeks) compared to the HER2low group (21 weeks) with p=0.4661 via log rank test. Conclusions: This is the first real-world study reporting the CNS efficacy of T-DXd in patients with MBC across HER2 expression levels. The CNS efficacy of T-DXd in our institutional experience was similar in HER2+ and HER2low MBC, and was much lower than previously reported in prospective clinical trials. Performance status, extent of prior treatment, and systemic disease burden likely contributed to this difference. Larger cohort and prospective studies on patients with HER2low MBC with BM are warranted. [Table: see text]

A meta-analysis analyzing the efficacy of trastuzumab-deruxtecan (T-DXd) on central nervous system (CNS) disease in patients with metastatic breast cancer (mBC).

e14012 Background: CNS metastasis from mBC portends a poor prognosis. We sought to analyze CNS activity of T-DXd through a meta-analysis. Methods: A systematic search with terms encompassing BC and T-DXd was conducted in PubMed, Embase, Scopus, and Cochrane on November 23 2023. There were no search restrictions. A total of 2318 records were identified, and duplicates were removed using Mendeley. 1189 records that remained were imported into Rayyan, and the titles were screened independently by 2 reviewers. 47/75 full texts were relevant, of which 12 [7 clinical trials and 5 retrospective study] were included for analysis. Only studies that provided stratified CNS response data for mBC were included. RevMan was used to analyze the Risk Ratio (RR) and Odds Ratio (OR) with 95% Confidence Interval (CI), derived from Random Effects (RE) model with Mantel-Haenszel (MH) method. Binary RE Pooled Proportions (PP) using DerSimonian-Laird method were determined using OpenMeta. Visual inspection of our funnel plots revealed no bias. Results: The T-DXd cohort had a total of 377 patients with a median age of 54.2 years (42.5-69). Control group (T-DM1-1, Chemotherapy-2 studies) had 86 patients with a median age of 54.5 years (54.2-54.7). All studies had previously treated patients and most of the patients received local therapy. PP with T-DXd for CNS Complete Response (CR) was 4.8% (2-7.6%). Partial Response (PR) was 50.1% (32.4-67.7%) and Stable Disease (SD) was 28.9 (20.5-37.3%). PP of Objective Response Rate (ORR) (CR+PR) was 60.9% (48.3-73.5%). Drug discontinuation rate was 18% (12.2-23.9%) and pneumonitis rate was 14.5% (9.4-19.6%). RR for Event/Progressive Disease (PD) comparing T-DXd and control group was not significant [0.96 (0.77,1.2) p=0.74, I²=0%], nor was OR for Disease Control Rate (DCR) (CR+PR+SD) [1.11 (0.63,1.96) p=0.64, I²=0%] (Table). The median Progression Free Survival (PFS) was 14.1 (8.5-18.1) months for the T-DXd and 4.3 (3-5.6) months for the control group. Conclusions: Although direct comparison between the pooled T-DXd and control group failed to reveal a difference, the pooled ORR from 10/12 studies was clinically significant at 60.9%. The median PFS for T-DXd was also longer. T-DXd could be a viable treatment option for pretreated HER2+ and low mBC with CNS metastasis. Limitation of our study is the heterogeneity between the studies, entailing the need for future clinical trials in this setting. [Table: see text]

Reduced amplitude and slowed latency of the acoustic startle response in adolescents and adults with 22q11.2 deletion syndrome

Background22q11.2 deletion syndrome (22q11DS) is one of the most robust genetic predictors of psychosis and other psychiatric illnesses. In this study, we examined 22q11DS subjects' acoustic startle responses (ASRs), which putatively index psychosis risk. Latency of the ASR is a presumptive marker of neural processing speed and is prolonged (slower) in schizophrenia. ASR measures correlate with increased psychosis risk, depend on glutamate and dopamine receptor signaling, and could serve as translational biomarkers in interventions for groups at high psychosis risk. MethodsStartle magnitude, latency, and prepulse inhibition were assessed with a standard acoustic startle paradigm in 31 individuals with 22q11.2DS and 32 healthy comparison (HC) subjects. Surface electrodes placed on participants' orbicularis oculi recorded the electromyographic signal in ASR eyeblinks. Individuals without measurable startle blinks in the initial habituation block were classified as non-startlers. ResultsAcross the startle session, the ASR magnitude was significantly lower in 22q11DS subjects than HCs because a significantly higher proportion of 22q11DS subjects were non-startlers. Latency of the ASR to pulse-alone stimuli was significantly slower in 22q11DS than HC subjects. Due to the overall lower 22q11DS startle response frequency and magnitudes prepulse inhibition could not be analyzed. ConclusionsReduced magnitude and slow latency of 22q11DS subjects' responses suggest reduced central nervous system and neuronal responsiveness. These findings are consistent with significant cognitive impairments observed in 22q11DS subjects. Further research is needed to untangle the connections among basic neurotransmission dysfunction, psychophysiological responsiveness, and cognitive impairment.

Renal Afferent Nerve Activity and Association with Neurohumoral Dysregulation in a Model of Autosomal Recessive Polycystic Kidney Disease

Polycystic kidney disease (PKD) is a rare, genetic kidney disease characterized by cyst growth that leads to kidney failure. Renal nerves play an important role in the development and maintenance of hypertension and other renal diseases. Afferent (sensory) nerves convey information to the central nervous system in response to intrarenal stimuli. Our laboratory demonstrated that afferent renal nerve activity (ARNA) is elevated in 10-week-old PCK rats compared to non-cystic, age-matched Sprague-Dawley (SD) controls. Furthermore, ARNA positively correlated with cystic index (CI; a measure of cyst growth). To further elucidate the relationship between renal nerve activity, age, and cyst progression, we aimed to quantify both ARNA and renal sympathetic nerve activity (RSNA) in PCK and SD rats. We hypothesized that ARNA and RSNA would be greater in PCK than SD. Furthermore, arginine vasopressin (AVP) is elevated in PKD and increases cyst growth. There is evidence that activation of the afferent renal nerves can contribute to secretion of AVP. Thus, we propose that elevated ARNA increases AVP secretion, thereby increasing cyst growth. We also hypothesized that ARNA would positively correlate with age, CI, and copeptin (an indirect marker of AVP) in young PCK rats. To test our first hypothesis, we conducted direct renal nerve recordings in 10- to 12-week-old PCK (n=16;11M/5F) and 10-week-old SD (n=9;7M/2F) rats. For our second hypothesis, we conducted nerve recordings in 4- to 10-week-old PCK rats to evaluate the correlation of nerve activity with age, cystic index, and copeptin in animals ages 4- to 12-weeks-old (n=28;21M/7F). Multiunit nerve recording was performed under inactin anesthesia. As we previously published, a renal nerve bundle is isolated, placed on an iridium bipolar electrode, and encased in silicone. Resting RSNA was recorded following 10-minute stabilization period, then the nerve bundle was severed proximal to the electrode to isolate ARNA. ARNA recordings were normalized to maximal ARNA evoked by intrarenal 50 μM capsaicin. Comparisons between PCK and SD were analyzed by Student’s t-test (p&lt;.05). Linear regression analyses were used to assess variable correlation (p&lt;.05). Data presented as mean ± SEM. In contrast to our first hypothesis, RSNA did not differ between 10- to 12-week-old SD and PCK rats, whether measured via burst frequency (SD 6.92 ± 0.82; PCK *6.97 ± 0.34 Hz) or bursts/heart beat (SD 1.36±0.16; PCK 1.28 ± 0.06). ARNA was calculated as a percentage of maximal ARNA using either integrated ARNA (ARNAInt) or spikes/s (ARNASpikes). Baseline ARNAInt was greater in PCK rats (29.14±3.35%) than SD (13.46±2.08%, n=4), whereas PCK ARNASpikes trended (p=.06) higher than SD controls (SD 5.57±2.21; PCK 13.90±2.21%). In correlative analysis, RSNA trended (p=.05) to correlate with age in the PCK rat. However, there was no relationship between RSNA and (1) CI (p=0.29) or (2) copeptin (p=0.15). Similarly, there was no correlation detected between ARNA and age (ARNAInt: p=0.41; ARNASpikes: p=0.16) or serum copeptin (ARNAInt: p=0.96; ARNASpikes: p=0.20). ARNAInt trended (p=.07) to correlate with CI, but ARNASpikes did not correlate with CI (p=0.48). Overall, these data partially support our hypotheses. RSNA did not differ between SD and PCK rats, but ARNAInt was increased in PCK rats vs. SD. We failed to detect a correlation between either ARNA or RSNA and age, CI, or copeptin in PCK rats though, ARNAInt trended to correlate with CI. As ARNA does not appear to be correlated with serum copeptin, further studies are required to uncover the relationship between afferent renal nerves and cystogenesis in this model of PKD. PKD Foundation Research Award 1022534 (CB) NIDDK/PKD RRC Pilot and Feasibility Award U24DK126110 (CB) AHA 21PRE0000216068 (MG). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

CINCA/NOMID is a rare autoinflammatory syndrome in rheumatological practice. Experience of diagnosis, management and therapy with interleukin-1 inhibitors

Objective: to present the experience of diagnosis, management and therapy with interleukin-1 inhibitors (iIL1) in patients with Chronic Infantile Onset Neurologic Cutaneous Articular/Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID) according to the Russian Federal Rheumatological Center data.Material and methods. From 2007 to 2023, eight patients were included in the study (7 men) aged 10 months to 33 years, including 3 with a disease duration of more than 10 years (13, 17 and 33 years). Genetic testing was performed in all patients and mutations in the NLRP3 gene were identified in 6 cases.Results and discussion. The age of onset of the disease ranged from 0 to 6 months. The delay in diagnosis and prescription of therapy ranged from 10 months to 33 years. All patients had the classic manifestations of CINCA/NOMID, including fever, rash, central nervous system (CNS) involvement, elevated ESR and CRP levels, 6 patients had articular manifestations, 7 had ocular manifestations and 6 had sensorineural hearing loss. Amyloidosis was detected in 1 case. All patients were prescribed iIL1. Anakinra was used in 6 patients (in 5 as the first line, in 1 as the second line therapy) with a positive response; subsequently 2 of these patients were switched to canakinumab once every 4 weeks (1 patient deteriorated and was readministered anakinra). Five patients received canakinumab (3 as first-line therapy, 2 as second-line therapy), 1 patient was switched to anakinra due to insufficient CNS response. The response to iIL1 therapy was positive in all patients, but incomplete in some of them due to the severity of the manifestations and the presence of irreversible organ damage.Conclusion. Patients with CINCA/NOMID have a severe disease and a poor prognosis. In this context, early administration of iIL1 is necessary. In the case of CNS involvement, the use of anakinra is preferable, as it is characterized by better penetration of the blood-brain barrier and is therefore more effective. Later it is possible to switch the patient to canakinumab, however, to achieve a complete response, it is sometimes necessary to increase the dose of the drug and reduce the interval between doses.

Reactive gliosis in traumatic brain injury: a comprehensive review.

Traumatic brain injury (TBI) is one of the most common pathological conditions impacting the central nervous system (CNS). A neurological deficit associated with TBI results from a complex of pathogenetic mechanisms including glutamate excitotoxicity, inflammation, demyelination, programmed cell death, or the development of edema. The critical components contributing to CNS response, damage control, and regeneration after TBI are glial cells-in reaction to tissue damage, their activation, hypertrophy, and proliferation occur, followed by the formation of a glial scar. The glial scar creates a barrier in damaged tissue and helps protect the CNS in the acute phase post-injury. However, this process prevents complete tissue recovery in the late/chronic phase by producing permanent scarring, which significantly impacts brain function. Various glial cell types participate in the scar formation, but this process is mostly attributed to reactive astrocytes and microglia, which play important roles in several brain pathologies. Novel technologies including whole-genome transcriptomic and epigenomic analyses, and unbiased proteomics, show that both astrocytes and microglia represent groups of heterogenic cell subpopulations with different genomic and functional characteristics, that are responsible for their role in neurodegeneration, neuroprotection and regeneration. Depending on the representation of distinct glia subpopulations, the tissue damage as well as the regenerative processes or delayed neurodegeneration after TBI may thus differ in nearby or remote areas or in different brain structures. This review summarizes TBI as a complex process, where the resultant effect is severity-, region- and time-dependent and determined by the model of the CNS injury and the distance of the explored area from the lesion site. Here, we also discuss findings concerning intercellular signaling, long-term impacts of TBI and the possibilities of novel therapeutical approaches. We believe that a comprehensive study with an emphasis on glial cells, involved in tissue post-injury processes, may be helpful for further research of TBI and be the decisive factor when choosing a TBI model.

Treatment outcomes and prognostic factors of patients with lymphoblastic lymphoma in East Asia.

Lymphoblastic lymphoma (LBL) is a rare, aggressive non-Hodgkin lymphoma (NHL) that has no established therapeutic approaches. The aim of this study was to investigate optimal treatments and prognostic risk models for patients with LBL in East Asia. We retrospectively examined the clinical data and treatment courses of adult patients diagnosed as LBL by WHO 2017 classification system. Median overall survival (OS) of the 78 patients with LBL was 38.3 months. There was no significant difference in OS between the patients who were treated with acute lymphoblastic leukemia (ALL)-like protocols and with NHL-like protocols (72.4 months vs 37.5 months, respectively, P = .546). The patients treated with ALL-like protocols had significantly shorter progression-free survival (PFS) (median 11.7 months for ALL-like protocols vs 27.0 months for NHL-like protocols, P = .030). A multivariable analysis found that central nervous system (CNS) prophylaxis, relapse of CNS lesions, leukemic transformation, and response to initial treatment were risk factors for OS of patients with LBL. Hematopoietic stem cell transplantation had no survival benefit, compared with chemotherapy-only treatment. Less intensive chemotherapy may be more optimal for patients in East Asia. Prophylaxis and management of CNS lesions should be emphasized throughout the treatment of LBL.