Alterations In Central Nervous System Research Articles

Long-term effects of linear versus macrocyclic GBCAs on gene expression in the central nervous system of mice

BackgroundWe examined chronic gadolinium retention impact on gene expression in the mouse central nervous system (CNS) after injection of linear or macrocyclic gadolinium-based contrast agents (GBCAs).MethodsFrom 05/2022 to 07/2023, 36 female mice underwent weekly intraperitoneal injections of gadodiamide (2.5 mmol/kg, linear), gadobutrol (2.5 mmol/kg, macrocyclic), or saline. Mice were sacrificed on day 29 or 391 after a 1-year washout. Assessments included magnetic resonance imaging (MRI), mechanical hyperalgesia tests, and inductively coupled plasma mass spectrometry to measure gadolinium levels. Ribonucleic acid (RNA) sequencing and bioinformatic analyses identified differentially expressed genes (DEGs), with validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB).ResultsPost-gadodiamide, MRI showed increased signal intensity in the deep cerebellar nuclei (pre, 0.997 ± 0.006 versus post, 1.086 ± 0.013, p < 0.001). Mechanical hyperalgesia tests indicated transient sensory changes. After 1-year, gadolinium retention was noted in the brain (5.92 ± 0.32 nmol/kg) and spinal cord (1.23 ± 0.66 nmol/kg) with gadodiamide, compared to saline controls (0.06 ± 0.02 nmol/kg in brains and 0.28 ± 0.06 nmol/kg in spinal cords). RNA sequencing identified 17 shared DEGs between brain and spinal cord in the gadodiamide group on day 391, with altered Hmgb2 and Sgk1 expression confirmed by qRT-PCR and WB. Reactome pathway analysis showed enrichment in neuroinflammation pathways. No DEGs were detected in brains on day 29.ConclusionChronic gadolinium deposition from repeated linear GBCA but not macrocyclic administration causes significant gene expression alterations in the mouse CNS, particularly affecting neuroinflammation pathways.Relevance statementThis study examined the long-term impact of chronic gadolinium retention on gene expression in the mouse CNS, uncovering significant changes associated with neuroinflammation pathways after repeated administration of linear GBCA, but not with macrocyclic GBCA. These findings highlight the importance of further research on the long-term safety of linear GBCA in medical imaging.Key PointsChronic gadolinium retention alters gene expression in the mouse central nervous system.Significant neuroinflammatory pathway changes were observed after linear gadodiamide exposure.MRI showed increased signal intensity in deep cerebellar nuclei after gadodiamide injection.Graphical

Association between microcephaly and hearing disorders in children exposed or suspected of exposure to the Zika virus during the intrauterine period.

This study aimed to evaluate the association between microcephaly and hearing disorders in children with exposed or suspected exposure to Zika virus (ZIKV) during the intrauterine period. In this cross-sectional study, we enrolled children exposed or suspected of being exposed to ZIKV during intrauterine period, admitted to the hospital between April 2016 and July 2018, and followed up until September 2021. All children underwent at least one automated auditory brainstem response (AABR) test. For analysis, the patients were divided into four groups: those with microcephaly, without microcephaly, suspected ZIKV infection, and controls. Other causes of microcephaly were excluded. Hearing impairment was assessed using the AABR to determine associations with microcephaly or central nervous system (CNS) abnormalities. Of the 134 children included, 34 (25.4%) were diagnosed with congenital Zika syndrome (CZS), of whom 28 (82.4%) had microcephaly, and the remaining six (17.6%) without microcephaly. Among the 28 children with microcephaly, 3 (10.7%) had abnormal AABR. Among CZS children without microcephaly (n = 6), 1 (16.7%) had abnormal AABR (Fisher's exact test p = 0.56).Conclusion: In our study population, that hearing impairment assessed using the AABR test was not associated with microcephaly or severe CNS alterations.

Analysis of Analgesics and Adjuvant Medications on Psychiatric Comorbidities in Patients With Complex Regional Pain Syndrome 1.

Complex regional pain syndrome (CRPS) is a chronic pain disorder characterized by severe, disproportionate pain relative to an inciting event. The disorder's pathophysiology is complex, involving both central and peripheral nervous system alterations, alongside genetic, inflammatory, and psychological factors. Using data from TriNetX, this study investigated the impact of analgesic and adjuvant therapies on psychiatric outcomes in CRPS patients. The analysis included 1,029 patients treated with non-opioid versus opioid analgesics and those using antidepressants versus anticonvulsants. Results revealed no significant differences in major depressive disorder (MDD), anxiety, suicidal ideation, orpost-traumatic stress disorder (PTSD) between opioid and non-opioid analgesic groups. However, opioid analgesic was associated with a lower risk of behavioral disorders due to psychoactive substance use disorder (0.732; 95% confidence interval [CI] 0.555-0.899). Anticonvulsants, compared to antidepressants, were linked to significantly higher odds and hazards of psychiatric comorbidities: depression (odds ratio [OR] 5.475), anxiety (OR 1.87), PTSD (OR 1.551), and suicidal ideation (OR 2.718). Hazard ratios also showed higher risks for antidepressants in depression, anxiety, and PTSD. These findings highlight the risks and benefits associated with opioid analgesics and the potential therapeutic effects of antidepressantsin patients with CRPS. Treatment should consider physiological and psychiatric symptoms, as both are impactful on pain management.

Multisensory sensitivity in relation to pain: a scoping review of terminology and assessment.

Chronic pain is a debilitating health problem affecting 20 million Americans annually. Most patients with chronic pain report negative impacts on daily function and quality of life, which can result in devastating emotional and financial stress. Although the causes of chronic pain remain elusive, there is increasing interest in sensitivity to everyday sensory stimuli as it relates to chronic pain, potentially serving as an indirect marker of altered central nervous system sensory processing. However, sensitivity to multiple sensory inputs, eg, bright lights, certain fabrics, loud noises, etc, is described using multiple terminologies. The lack of a common vocabulary makes it difficult to find and summarize related discoveries, potentially inhibiting scientific progress. Thus, the purpose of this scoping review was to identify and characterize the terminology used in publications assessing some form of multisensory sensitivity as it relates to pain (eg, a pain cohort or pain sensitivity). Our review of 6 databases (PubMed, Scopus, Embase, CINAHL, PsycINFO+, and Cochrane) comprehensively cataloged peer-reviewed studies published through March 2023 in this domain. Of 12,841 possible studies identified, 92 met all inclusion criteria, with over 80% being published in the last decade. A wide range of terminology has been used for this construct, likely in part a result of the many different professional disciplines represented. These results provide valuable insights for future development of a standardized vocabulary and serve as a resource to aid future investigators of multisensory sensitivity and pain in their study design.

Current and Novel Therapies for Cluster Headache: A Narrative Review.

Cluster headache (CH) is an excruciating and debilitating primary headache disorder. The prevalence is up to 1.3%, and the typical onset is around age 30. Often misdiagnosed as migraine, particularly in children, the diagnosis rate of CH has been increasing among women. CH is characterized by intense unilateral pain and autonomic symptoms, significantly impacting patients' quality of life, mental health, and productivity.Genetic associations suggest a familial risk for developing CH, with lifestyle factors also potentially playing a role. The pathophysiology involves alterations in both central and peripheral nervous system, with the hypothalamus, trigeminocervical complex, and neuropeptides such as calcitonin gene-related peptide (CGRP) being implicated.Nonpharmacological treatments focus on patient education and lifestyle modifications, while pharmacological treatments include acute therapies such as oxygen and subcutaneous or nasal sumatriptan, as well as preventive therapies like verapamil, lithium, and CGRP monoclonal antibodies. Transitional options include oral corticosteroids and greater occipital nerve injections. Emerging interventional procedures offer new avenues for managing refractory cases. Noninvasive vagal nerve stimulation and occipital nerve stimulation show promise for both acute and preventive treatment. Careful consideration of safety profiles is crucial in specific populations such as pregnant patients and children.Current treatments still leave patients highly burdened by limited efficacy and side effects. Future research continues to explore novel pharmacological targets, interventional procedures, and the potential role of psychedelics in CH management. Comprehensive, multifaceted treatment strategies are essential to improve the daily functioning and quality of life for individuals with CH.

Gestational age assessment by ultrasound cerebellar measurements in fetal and perinatal deaths

BackgroundPerinatal mortality remains high in low- and middle-income countries. Accurate assessment of fetal gestational age (GA) is crucial to distinguish between prematurity and intrauterine growth restriction, two conditions commonly associated with perinatal mortality that require different preventive strategies and management. Ultrasound measurements of the cerebellum have been shown to be accurate in assessing GA during pregnancy, but their post-mortem performance has not yet been evaluated. ObjectiveWe aimed to explore the feasibility and validity of GA estimation in fetal and perinatal deaths by ultrasound measurements of the cerebellum. Study designThis is an observational cross-sectional study. Between August 2020 and November 2022 post-mortem cerebellar ultrasound measurements were conducted in a tertiary referral hospital in Barcelona, Spain. Extrauterine assessment included transcerebellar diameter, cerebellar vermis height and cerebellar vermis. Moreover, intrauterine ultrasound and autopsy direct cerebellar assessments were undertaken in a subset of cases. A total of 137 fetal and perinatal deaths [63 (46.0%) fetal deaths, 69 (50.4%) stillbirths and 5 (3.6%) neonates] were included. First, we correlated different types of transcerebellar diameter measurements between them (intrauterine, extrauterine and autopsy-based). Then, we evaluated the relationship between the extrauterine cerebellar ultrasound measurements and GA, and their performance across trimesters of gestation and in different abnormalities. ResultsGA ranged from 15.2 to 40.6 weeks. High correlation was observed between extrauterine, intrauterine, and autopsy transcerebellar measurements (p<0.001), and between all extrauterine cerebellar measurements and GA (p<0.001). Extrauterine transcerebellar diameter was identified as the strongest predictor of GA (R2=0.88; p<0.001), and its accuracy was not affected by the trimester of gestation, intrauterine growth restriction or central nervous system alterations. ConclusionsThis study shows the feasibility and accuracy of post-mortem GA evaluation by extrauterine ultrasound measurements of the cerebellum, especially of transcerebellar diameter. Implementation of this method as part of post-mortem assessment could improve cause of death attribution, especially in resource-constrained settings.

Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats

Parkinson’s disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk suggesting targeting the Pink1/Parkin pathway in the periphery might have therapeutic potential.

Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 versus 1010 ± 577 pg/ml, p = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic DHCR7 alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (p = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.

Affective and Cognitive Impairments in Rodent Models of Diabetes.

Diabetes and related acute and long-term complications have a profound impact on cognitive, emotional, and social behavior, suggesting that the central nervous system (CNS) is a crucial substrate for diabetic complications. When anxiety, depression, and cognitive deficits occur in diabetic patients, the symptoms and complications related to the disease worsen, contributing to lower quality of life while increasing health care costs and mortality. Experimental models of diabetes in rodents are a fundamental and valuable tool for improving our understanding of the mechanisms underlying the close and reciprocal link between diabetes and CNS alterations, including the development of affective and cognitive disorders. Such models must reproduce the different components of this pathological condition in humans and, therefore, must be associated with affective and cognitive behavioral alterations. Beyond tight glycemic control, there are currently no specific therapies for neuropsychiatric comorbidities associated with diabetes; animal models are, therefore, essential for the development of adequate therapies. To our knowledge, there is currently no review article that summarizes changes in affective and cognitive behavior in the most common models of diabetes in rodents. Therefore, in this review, we have reported the main evidence on the alterations of affective and cognitive behavior in the different models of diabetes in rodents, the main mechanisms underlying these comorbidities, and the applicable therapeutic strategy.

The synthetic cathinones MDPHP and MDPV: Comparison of the acute effects in mice, in silico ADMET profiles and clinical reports

The 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (MDPHP) is a synthetic cathinone closely related to 3,4-methylenedioxypyrovalerone (MDPV), one of the most common synthetic cathinones present in the “bath salts”. MDPHP has recently gained attention due to increasing seizures and involvement in human intoxications which occurred in Europe and Italy in the last years, but currently there is a lack of information about its pharmaco-toxicological effects. With the aim at filling this gap, the present study is endeavoured to (i) evaluate the effects of acute administration of MDPHP (0.01–20 mg/kg; i.p.) on behaviour, cardiorespiratory and cardiovascular parameters in CD-1 male mice, comparing them to those observed after administration of MDPV; (ii) predict the ADMET profile of the two analogues using the Plus ADMET Predictor®; (iii) present clinical data related to MDPHP and MDPV-induced intoxications recorded between 2011 and 2023 by the Pavia Poison Control Centre (PCC) − National Toxicology Information Centre (Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Italy). Our results substantiated that MDPHP and MDPV similarly affect sensorimotor and behavioural responses in mice, importantly increased locomotion and induced aggressive behaviour, and, at higher dosage, increased heart rate and blood pressure. These findings are in line with those observed in humans, revealing severe toxidromes typically characterized by Central Nervous System (CNS) alterations (behavioural/neuropsychiatric symptoms), including psychomotor agitation and aggressiveness, cardiovascular and respiratory disorders (e.g. tachycardia, hypertension, dyspnoea), and other peripheral symptoms (e.g. hyperthermia, acidosis, rhabdomyolysis).

Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats.

Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk, and venous thrombosis is a cause of sudden death in PD, suggesting targeting the Pink1/Parkin pathway in the periphery has therapeutic potential.

The Use of the RETeval Portable Electroretinography Device for Low-Cost Screening: A Mini-Review.

Electroretinography (ERG) provides crucial insights into retinal function and the integrity of the visual pathways. However, ERG assessments classically require a complicated technical background with costly equipment. In addition, the placement of corneal or conjunctival electrodes is not always tolerated by the patients, which restricts the measurement for pediatric evaluations. In this short review, we give an overview of the use of the RETeval portable ERG device (LKC Technologies, Inc., Gaithersburg, MD, USA), a modern portable ERG device that can facilitate screening for diseases involving the retina and the optic nerve. We also review its potential to provide ocular biomarkers in systemic pathologies, such as Alzheimer's disease and central nervous system alterations, within the framework of oculomics.

Neuromodulator hydrogen sulfide attenuates sickness behavior induced by lipopolysaccharide

Sickness behavior reflects a state of altered physiology and central nervous system function that occurs during systemic infection or inflammation, serving as an adaptive response to illness. This study aims to elucidate the role of hydrogen sulfide (H2S) in regulating sickness behavior and neuroinflammatory responses in a rat model of systemic inflammation. Adult male Wistar rats were treated with lipopolysaccharide (LPS) to induce sickness behavior. Intracerebroventricular (i.c.v.) pretreatments included aminooxyacetic acid (AOAA), an inhibitor of H2S synthesis, and sodium sulfide (NaHS), an H2S donor. Behavioral assays were conducted, along with the assessment of astrocyte activation, as indicated by GFAP expression in the hypothalamus. Pretreatment with NaHS mitigated LPS-induced behavioral changes, including hypophagia, social and exploratory deficits, without affecting peripheral cytokine levels, indicating a central modulatory effect. AOAA, conversely, accentuated certain behavioral responses, suggesting a complex role of endogenous H2S in sickness behavior. These findings were reinforced by a lack of effect on plasma interleukin levels but significant reduction in GFAP expression. Our findings support the central role of H2S in modulating neuroinflammation and sickness behavior, highlighting the therapeutic potential of targeting H2S signaling in neuroinflammatory conditions.

Implications of Inflammatory Processes on a Developing Central Nervous System in Childhood-Onset Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is increasingly affecting pediatric and adult populations. Neuropsychiatric manifestations (ie, cognitive dysfunction and mood disorders) appear to occur with greater severity and poorer prognosis in childhood-onset SLE (cSLE) versus adult-onset SLE, negatively impacting school function, self-management, and psychosocial health, as well as lifelong health-related quality of life. In this review, we describe pathogenic mechanisms active in cSLE, such as maladaptive inflammatory processes and ischemia, which are hypothesized to underpin central phenotypes in patients with cSLE, and the role of alterations in protective central nervous system (CNS) barriers (ie, the blood-brain barrier) are also discussed. Recent findings derived from novel neuroimaging approaches are highlighted because the methods employed in these studies hold potential for identifying CNS abnormalities that would otherwise remain undetected with conventional multiple resonance imaging studies (eg, T2-weighted or fluid-attenuated inversion recovery sequences). Furthermore, we propose that a more robust presentation of neuropsychiatric symptoms in cSLE is in part due to the harmful impact of a chronic inflammatory insult on a developing CNS. Although the immature status of the CNS may leave patients with cSLE more vulnerable to harboring neuropsychiatric manifestations, the same property may represent a greater urgency to reverse the maladaptive effects associated with a proneuroinflammatory state, provided that effective diagnostic tools and treatment strategies are available. Finally, considering the crosstalk among the CNS and other organ systems affected in cSLE, we postulate that a finer understanding of this interconnectivity and its role in the clinical presentation in cSLE is warranted.

Photobiomodulation regulates astrocyte activity and ameliorates scopolamine-induced cognitive behavioral decline.

The pathophysiological mechanism of Alzheimer's disease (AD) has not been clearly identified, and effective treatment methods have not yet been established. Scopolamine causes cholinergic dysfunction in the brain, including the accumulation of amyloid-beta plaques, thereby increasing oxidative stress and neuroinflammation, mimicking AD. Glial cells such as astrocytes have recently been identified as possible biomarkers for AD. Photobiomodulation (PBM) elicits a beneficial biological response in cells and tissues. PBM effects on the central nervous system (CNS) have been widely researched, including effects on astrocyte activity. In the present study, PBM was performed using light at the near-infrared wavelength of 825 nm. The Morris water maze and Y-maze tests were employed to evaluate cognitive function decline in a scopolamine-induced memory dysfunction model and its improvement with PBM. In addition, alteration of the mitogen-activated protein kinase (MAPK) pathway and immunofluorescence expression levels of active astrocytes were observed in the hippocampus, which is one of the areas affected by AD, to evaluate the mechanism of action of PBM. A reduction in the neuronal cell death in the hippocampus caused by scopolamine was observed with PBM. Moreover, alteration of a MAPK pathway-related marker and changes in glial fibrillary acidic protein (an active astrocyte marker) expression were observed in the PBM-treated group. Finally, significant correlations between functional and histological results were found, validating the results. These findings indicate the possibility of behavioral and histological improvement due to PBM in scopolamine-induced CNS alteration, which mimics AD. This improvement could be related to neuroinflammatory modulation and altered astrocyte activity.

The CNS Microenvironment Promotes Leukemia Cell Survival By Disrupting Tumour Suppression and Cell Cycle Regulation in Pediatric T-Cell Acute Lymphoblastic Leukemia

Although modern treatment has improved the overall survival of pediatric T-cell acute lymphoblastic leukemia (T-ALL) greatly, more than 20% of all children diagnosed with T-ALL relapse (Fattizzo et al., 2020). Approximately 30% of all relapse cases occur in the central nervous system (CNS) and CNS involvement is considered a major risk factor for treatment failure and increased mortality (Frishman-Levy &amp; Izraeli, 2017). To date, CNS directed therapy is considered essential for complete cure to prevent relapse in the CNS, leading to severe neurotoxic effects and long-term adverse complications (Thastrup et al., 2022). Due to lack of knowledge regarding the mechanisms promoting leukemia survival in the CNS and absence of reliable biomarkers to predict CNS involvement, the development of new therapeutic drugs able to eradicate leukemia cells in the CNS is not progressing, therefor limiting the overall survival of pediatric T-ALL patients (Thastrup et al., 2022). To identify genetic alterations in CNS involved T-ALL we performed an RNA-sequencing analysis coupled with a gene set enrichment analysis (GSEA) studying pediatric T-ALL patient samples obtained from the TARGET initiative. We included 30 samples from patients at initial diagnosis subdivided by degree of CNS involvement, ranging from CNS1 (no CNS disease) to CNS3 (advanced CNS disease), as well as 13 samples from patients who had relapsed in the CNS. Our analysis identified distinct genetic alterations in CNS involved T-ALL and CNS relapse compared to diagnosis samples without CNS implications, with dysregulation of genes involved in tumour suppression, apoptosis and self-renewal. CNS relapsed patients were distinguished from diagnosis patients by a distinct gene expression pattern, with an upregulation of many genes, including cell cycle inhibitor CDKN2A and transcription factor HOXA3 (Figure 1A). We also found disruption of many signaling pathways, including enrichment of the p53 pathway in patients who relapsed in the CNS compared to non-CNS involved diagnosis patients. To further study the effects of CNS implications in pediatric T-ALL, we established a co-culture of pediatric T-ALL cell lines (n=4) and a glioblastoma cell line (U87-MG). Following co-culture, changes to mRNA expression was evaluated by RT-qPCR, revealing dysregulation of many genes, including an upregulation of cancer stem cell marker and cell adhesion molecule CD44 (Chen et al., 2018). Moreover, T-ALL cells grown in CNS co-culture displayed a downregulation of tumour suppressor TP53 and an upregulation of its negative regulator, proto-oncogene MDM2 when compared to cells grown in suspension (Figure 1B) (Hernandez Borrero &amp; El-Deiry, 2021). Co-culture also induced pro-survival isoform switching of BCL2L1 (BCLX), part of the BCL family of apoptotic regulators (Daniel et al., 2013). Together, these results suggest an increased survival and loss of tumour suppression of T-ALL cells when grown in direct contact with CNS derived cells. To determine effects of the CNS microenvironment on therapy resistance, T-ALL cell lines grown in co-culture were exposed to 2µM methotrexate, a chemotherapeutic agent used during CNS directed therapy (Thastrup et al., 2022). Leukemia cells in co-culture displayed an increased survival compared to cells grown in suspension following 48 hours of methotrexate exposure, as well as dysregulation of several genes involved in cell survival, self-renewal and cell cycle regulation. Cyclins and CDKs involved in controlling cell cycle progression were differentially expressed in co-culture versus suspension, with a downregulation of CDK2 and cyclin A, crucial for S/G2 transition, as well as CDK1 and cyclin B, responsible for G2/M transition (Leal-Esteban &amp; Fajas, 2020). These results indicate a shift towards cell cycle arrest and senescence of T-ALL cells during methotrexate exposure in CNS co-culture, potentially promoting leukemia survival and chemoresistance. Taken together, our findings indicate a differential gene expression pattern in CNS involved T-ALL, which could potentially be utilized as predicative biomarkers to properly identify patients at risk of CNS relapse. CNS co-culture revealed cell cycle alterations and loss of proliferation markers, promoting senescence and therapy resistance, which could serve as potential therapeutic targets.

Otological symptoms in patients with rheumatoid arthritis of the temporomandibular joint

ABSTRACT Objective The aim of the current study was to describe the pattern of otological symptoms in patients with rheumatoid arthritis (RA), having clinical temporomandibular joint (TMJ) involvement. This issue had not been previously addressed. Methods A questionnaire and examination findings protocol was applied for 141 patients with RA and 141 control subjects. Results Otological symptoms (otalgia, hearing loss, tinnitus, and vertigo), all had a significantly higher incidence in RA patients, compared to control subjects (P = .001). Conclusion The onset and maintenance of otological symptoms in patients with TMJ involvement by RA probably result from peripheral, as well as central nervous system alterations in sensory stimuli programming.

Motor control differs for increasing and decreasing force production during ankle Isometric exercises in children

BackgroundPerformance of the central nervous system (CNS) in increased and decreasing muscle force around the ankle joint is essential for upright tasks of daily living. Previous studies have shown altered CNS control when they decrease force compared with when they increase force in young and older adults. But whether such alteration exists during childhood with incomplete maturation of CNS systems remain unclear. Therefore, this study aimed to evaluate the disparities in intramuscular EMG-EMG coherence, which serve as indicators of corticospinal drive to muscles during ankle isometric increasing and decreasing force generation in children.MethodsWe measured intramuscular EMG-EMG coherence activity of the tibialis anterior (TA) and the associated ability to perform isometric efforts at the ankle in 12 typically developing children (mean ± SD age = 5.91±1.37 years) and 12 healthy young adults (mean ± SD age = 23.16±1.52 years). The participants maintained isometric contractions at 20% of their maximal voluntary contractions (MVC) during ankle dorsiflexion to match a triangle trajectory for 7 s, including ramping up in 3.5 s (increasing force phase) and then linearly ramping down to rest in 3.5 s (decreasing force phase). The variability of force control was characterized by the coefficient of variance (CoV) of force output. Intramuscular EMG-EMG coherence from TA in two frequency bands, the beta band (15–30 Hz) and gamma band (30–45) that could reflect the corticospinal drive, were calculated for the comparison. A repeated measures ANOVA with the within-subjects factor of force generation phase (increasing force vs. decreasing force)x between-subjects factor of the group (children and young adults) was used for statistical analysis.ResultsRegarding the within-subjects difference, our results exhibited significantly higher CoV of force (p < 0.01) and lower EMG-EMG coherence of TA when they decrease force compared with when they increase force in both children and young adult groups. Regarding the between-subjects difference, the CoV of force was significantly higher (p < 0.01) in children compared to young adults, while the EMG-EMG coherence in children showed a significantly lower (p < 0.01) coherence compared with young adults. Furthermore, the EMG-EMG coherence measures were negatively correlated with the CoV of force.ConclusionsThe findings suggest that the age-related development would increase the corticospinal drive to TA muscle to deal with ankle isometric dorsiflexion during childhood, which could be also modulated with the force production phases, including increasing and decreasing force.

Understanding the molecular pathogenesis of primary central nervous system lymphoma by experimental animal models.

Primary central nervous system lymphoma (PCNSL) is a rare and invasive diffuse large B cell lymphomaconfined in central nervous system(CNS). The effort to press forward the translational progress has been frustrated by the insufficient understanding of immunophenotype of CNS and tumor genetic alterations of PCNSL, and the lack of validated diagnostic biomarkers. Researchers now have a variety of PCNSL animal models at their disposal that resemble the morphology and immunophenotype of PCNSL, however, a careful and detailed re-examination of these animal models is needed to clarify the differences in genetic alterations, migration capability, and immune status. In this review, we present the knowledge about the phenotypic and genotypic features of PCNSL tumor cells, and compile the preclinical animal models of PCNSL with regard to various injection sites, cell origins, recipient animals, and immune status, and elaborate on the tropism and migration of tumor cells and novel therapeutic strategies for PCNSL. We envisage that the selection of suitable animal models will serve as a well-defined preclinical system to understand the molecular pathogenesis of PCNSL, thereby galvanizing the development of novel and potent therapeutic approaches.

Gray Matter Changes Following Mild COVID-19: An MR Morphometric Study in Healthy Young People.

Although COVID-19 is primarily an acute respiratory infection, 5%-40% of patients develop late and prolonged symptoms with frequent neurological complaints, known as long COVID syndrome. The presentation of the disease suggests that COVID infection may cause functional and/or morphological central nervous system alterations, but studies published in the literature report contradictory findings. To investigate the chronic effects of COVID-19 on cerebral grey matter in a group of young patients without comorbidities, with mild course of COVID infection and no medical complaints at the time of examination. Prospective. Thirty-eight young (age = 26.6 ± 5.0 years; male/female = 14/24), adult participants who recovered from mild COVID infection without a history of clinical long COVID and 37 healthy control subjects (age = 25.9 ± 2.8 years; male/female = 14/23). Three Tesla, 3D T1-weighted magnetization-prepared rapid gradient-echo, 2D T2-weighted turbo spin-echo. MRI-based morphometry and volumetry along with neuropsychological testing and self-assessed questionnaire. Fisher's exact test, Mann-Whitney U-test, and multiple linear regression analyses were used to assess differences between COVID and healthy control groups. P < 0.05 was used as cutoff for significance. In the COVID group, significantly lower bilateral mean cortical thickness (left/right-hemisphere: 2.51 ± 0.06 mm vs. 2.56 ± 0.07 mm, η2 p = 0.102/2.50 ± 0.06 mm vs. 2.54 ± 0.07 mm, η2 p = 0.101), lower subcortical gray matter (57881 ± 3998 mm3 vs. 60470 ± 5211 mm3, η2 p = 0.100) and lower right olfactory bulb volume (52.28 ± 13.55 mm3 vs. 60.98 ± 15.8 mm3, η2 p = 0.078) were found. In patients with moderate to severe anosmia, cortical thickness was significantly lower bilaterally, as compared to patients without olfactory function loss (left/right-hemisphere: 2.50 ± 0.06 mm vs. 2.56 ± 0.05 mm, η2 = 0.173/2.49 ± 0.06 mm vs. 2.55 ± 0.05 mm, η2 = 0.189). Using further exploratory analysis, significantly reduced cortical thickness was detected locally in the right lateral orbitofrontal cortex in the COVID group (2.53 ± 0.10 mm vs. 2.60 ± 0.09 mm, η2 p = 0.112). Even without any subjective or objective neurological complaints at the time of the MR scan, subjects in the COVID group showed gray matter alterations in cortical thickness and subcortical gray matter volume. 2 TECHNICAL EFFICACY: Stage 3.