Targeting CNS myeloid infiltrates provides neuroprotection in a progressive multiple sclerosis model.

Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+ cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach.

The cytoplasmic localization of ADNP through 14-3-3 promotes sex-dependent neuronal morphogenesis, cortical connectivity, and calcium signaling.

Defective neuritogenesis is a contributing pathogenic mechanism underlying a variety of neurodevelopmental disorders. Single gene mutations in activity-dependent neuroprotective protein (ADNP) are the most frequent among autism spectrum disorders (ASDs) leading to the ADNP syndrome. Previous studies showed that during neuritogenesis, Adnp localizes to the cytoplasm/neurites, and Adnp knockdown inhibits neuritogenesis in culture. Here, we hypothesized that Adnp is localized in the cytoplasm during neurite formation and that this process is mediated by 14-3-3. Indeed, applying the 14-3-3 inhibitor, difopein, blocked Adnp cytoplasmic localization. Furthermore, co-immunoprecipitations showed that Adnp bound 14-3-3 proteins and proteomic analysis identified several potential phosphorylation-dependent Adnp/14-3-3 binding sites. We further discovered that knockdown of Adnp using in utero electroporation of mouse layer 2/3 pyramidal neurons in the somatosensory cortex led to previously unreported changes in neurite formation beginning at P0. Defects were sustained throughout development, the most notable included increased basal dendrite number and axon length. Paralleling the observed morphological aberrations, ex vivo calcium imaging revealed that Adnp deficient neurons had greater and more frequent spontaneous calcium influx in female mice. GRAPHIC, a novel synaptic tracing technology substantiated this finding, revealing increased interhemispheric connectivity between female Adnp deficient layer 2/3 pyramidal neurons. We conclude that Adnp is localized to the cytoplasm by 14-3-3 proteins, where it regulates neurite formation, maturation, and functional cortical connectivity significantly building on our current understanding of Adnp function and the etiology of ADNP syndrome.

The impact of submucosal PRP injection on wound healing after endoscopic sinus surgery: a randomized clinical trial.

PURPOSE: Chronic rhinosinusitis (CRS) is a prevalent chronic disease observed on a global scale. The utilization of endoscopic sinus surgery (ESS) has gained significant recognition as an effective intervention for individuals with CRS and nasal polyps who have not responded to conventional treatments. The need (or not) for revision surgery frequently relies on the promotion of optimal wound healing. The impact of platelet-rich plasma (PRP) on tissue healing has been extensively examined in various surgical fields. METHODS: The present prospective study involved 30 patients suffering with nasal polyposis who underwent endoscopic sinus surgery. 15 patients were assigned to the PRP group, and 15 patients to the control group. The clinical follow-up of the patients took place at specific intervals, at weeks 1, 2, 3, 4, 8, and 12 after the surgical procedure. The evaluator identified the existence of adhesions, crusting, bleeding, granulation and infection using a visual analogue scale score. The patients also completed the SNOT 22 questionnaire prior to surgery and at each postoperative visit. RESULTS: The present study observed a lower incidence of adhesion, infection, hemorrhage and granulation in the PRP group. Furthermore, a statistically significant difference was detected between the groups. CONCLUSION: Based on the findings of the present investigation, it seems that platelet-rich plasma (PRP) is beneficial on wound healing during the early stages following the surgical procedure. The technique is characterized by its limited invasiveness, which contributes to its low risk profile and the achievement of clinically good outcomes.

Cervical internal carotid artery fenestration: a rare cause of lumen "dissection''.

PURPOSE: To highlight the clinical and diagnostic importance of correctly identifying cervical internal carotid artery fenestration (fcICA), an extremely rare vascular anomaly, and to present a case where fcICA was initially misdiagnosed as a dissection in a patient with fibromuscular dysplasia (FMD). METHODS: A 47-year-old woman with pulsatile tinnitus underwent computed tomography angiography (CTA) and digital subtraction angiography (DSA) to differentiate between fenestration and dissection of the internal carotid artery. RESULTS: CTA revealed a fusiform dilatation of the distal C1 segment of the right internal carotid artery (ICA) with a linear filling defect, suggesting either fenestration or dissection. DSA confirmed the presence of a fenestrated right ICA segment composed of two symmetrical, smooth-walled limbs without a dissection flap, along with signs of FMD in the proximal vessel. The patient's symptoms were attributed to local flow perturbations induced by fcICA and FMD. CONCLUSION: This case illustrates that fcICA can be a true anatomical variant rather than a result of dissection, emphasizing the need for accurate imaging and diagnosis to avoid unnecessary treatments. The coexistence of fcICA with FMD increases the risk of dissection, necessitating careful monitoring. The distinction between fenestration and pseudofenestration remains challenging, requiring comprehensive imaging and close collaboration between radiologists and vascular neurologists.

The impact of SARS-CoV-2 immunization on COVID-19 disease course in people with myasthenia gravis.

INTRODUCTION/AIMS: There is limited knowledge regarding the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines οn coronavirus disease 2019 (COVID-19) disease course in people with myasthenia gravis. In this study, we aimed to investigate whether SARS-CoV-2 vaccination influences hospitalization and mortality due to COVID-19 in this population. METHODS: This is a retrospective analysis of administrative data extracted from the Greek nationwide database that holds the COVID-19 disease and vaccination registry, as well as all medical prescription records. The study period extended from the onset of the pandemic (February 2020) until the 10th of January 2022. RESULTS: We identified 278 people with myasthenia gravis (mean age 58.1 ± 17.2, 47.5% males) who tested positive for SARS-CoV-2. Of those, 139 (50%) were not vaccinated at the time of infection. Multivariable binary logistic regression analysis showed that the probability of hospitalization increased with age (odds ratio [OR]: 1.058; 95% confidence interval [CI], 1.036-1.080; p < .001) and immunosuppressive treatment (OR: 2.872; 95% CI 1.412-5.839; p = .004), and decreased with vaccination (OR: 0.244; 95% CI 0.132-0.453; p < .001). The probability of a fatal outcome increased with age (OR: 1.085; 95% CI 1.043-1.129; p < .001) and decreased with vaccination (OR: 0.315; 95% CI 0.125-0.791; p = .014). DISCUSSION: SARS-CoV-2 vaccination significantly reduces hospitalization and mortality due to COVID-19 in people with myasthenia gravis. This study regarding the efficacy of these vaccines, together with previous studies regarding their safety, provide evidence to support their use in people with myasthenia gravis.

Diagnosis and treatment of progressive multiple sclerosis: A position paper.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is an unpredictable disease characterised by a highly variable disease onset and clinical course. Three main clinical phenotypes have been described. However, distinguishing between the two progressive forms of MS can be challenging for clinicians. This article examines how the diagnostic definitions of progressive MS impact clinical research, the design of clinical trials and, ultimately, treatment decisions. METHODS: We carried out an extensive review of the literature highlighting differences in the definition of progressive forms of MS, and the importance of assessing the extent of the ongoing inflammatory component in MS when making treatment decisions. RESULTS: Inconsistent results in phase III clinical studies of treatments for progressive MS, may be attributable to differences in patient characteristics (e.g., age, clinical and radiological activity at baseline) and endpoint definitions. In both primary and secondary progressive MS, patients who are younger and have more active disease will derive the greatest benefit from the available treatments. CONCLUSIONS: We recommend making treatment decisions based on the individual patient's pattern of disease progression, as well as functional, clinical and imaging parameters, rather than on their clinical phenotype. Because the definition of progressive MS differs across clinical studies, careful selection of eligibility criteria and study endpoints is needed for future studies in patients with progressive MS.

The Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?

Multiple sclerosis (MS) is a heterogeneous disease of the central nervous system that is governed by neural tissue loss and dystrophy during its progressive phase, with complex reactive pathological cellular changes. The immune-mediated mechanisms that promulgate the demyelinating lesions during relapses of acute episodes are not characteristic of chronic lesions during progressive MS. This has limited our capacity to target the disease effectively as it evolves within the central nervous system white and gray matter, thereby leaving neurologists without effective options to manage individuals as they transition to a secondary progressive phase. The current review highlights the molecular and cellular sequelae that have been identified as cooperating with and/or contributing to neurodegeneration that characterizes individuals with progressive forms of MS. We emphasize the need for appropriate monitoring via known and novel molecular and imaging biomarkers that can accurately detect and predict progression for the purposes of newly designed clinical trials that can demonstrate the efficacy of neuroprotection and potentially neurorepair. To achieve neurorepair, we focus on the modifications required in the reactive cellular and extracellular milieu in order to enable endogenous cell growth as well as transplanted cells that can integrate and/or renew the degenerative MS plaque.

The Experience of a Tertiary Reference Hospital in the Study of Rare Neurological Diseases.

Background and Objectives: Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world's population. RDs are often called 'orphan' diseases, since people suffering from them attract little support from national health systems. Aim: The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND). Materials and Methods: Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system. Results: A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years. Conclusions: Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin.

The mammalian central nervous system (CNS) coordinates its communication through saltatory conduction, facilitated by myelin-forming oligodendrocytes (OLs). Despite the fact that neurogenesis from stem cell niches has caught the majority of attention in recent years, oligodendrogenesis and, more specifically, the molecular underpinnings behind OL-dependent myelinogenesis, remain largely unknown. In this comprehensive review, we determine the developmental cues and molecular drivers which regulate normal myelination both at the prenatal and postnatal periods. We have indexed the individual stages of myelinogenesis sequentially; from the initiation of oligodendrocyte precursor cells, including migration and proliferation, to first contact with the axon that enlists positive and negative regulators for myelination, until the ultimate maintenance of the axon ensheathment and myelin growth. Here, we highlight multiple developmental pathways that are key to successful myelin formation and define the molecular pathways that can potentially be targets for pharmacological interventions in a variety of neurological disorders that exhibit demyelination.

Translation, cross-cultural adaptation, and validation of the Greek version of the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19.

INTRODUCTION: Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) explores optimally impact of MS on sexual activity/satisfaction/intimacy. AIM: The present study aims to provide the only validation of the Greek Version of MSISQ-19, and compare results to validation studies in other languages. METHODS: The original/English version of the MSISQ-19 was translated into Greek according to standardized guidelines, while validity/reliability, correlations with other scales and sexual dysfunction prevalence were tested. Subjects were requested to complete all questionnaires and MSISQ-19, being re-tested three weeks later. Construct-validity of the Greek version of the MSISQ-19 was confirmed with principal-component-analysis. Bartlett's test assessed correlation-adequacy between items. Pearson's correlation explored internal-construct-validity between subscales and overall score, and external-construct-validity with disease-status variables, cognitive testing and patient-reported outcomes regarding fatigue, depression/anxiety, MS impact, and quality of life. RESULTS: 201 PwMS (130 female). Mean age was 39.3 ± 11.8 years with median disease-duration 11.7 ± 7.9 years. 79.1% RRMS, PPMS (10.4%) and SPMS (10.4%). Cronbach's alpha coefficient was 0.949. MSISQ-19 correlations between items were large. Significant associations of sexual dysfunction were identified with age (rho = 0.392, p < 0.01), years of education (rho=-0.199, p = 0.006), the Expanded Disability Status Scale (rho = 0.518, p < 0.01) and MS duration (rho = 0.354, p < 0.01). Correlations were disclosed with the Brief International Cognitive Assessment for MS (rho=-0.247, p < 0.05), Modified Fatigue Impact Scale (rho = 0.374, p < 0.05), Depression Anxiety Stress Scale (rho = 0.375, p < 0.05), Multiple Sclerosis Impact Scale (rho = 0.442, p < 0.05), and EuroQoL-five-dimensional instrument (rho = 0.375, p < 0.05). Internal consistency of the Greek version of the MSISQ-19 was confirmed with Cronbach's alpha. Test-retest reliability (31 PwMS) was excellent with intraclass-correlation-coefficients > 0.90. CONCLUSION: Besides Greek MSISQ-19 satisfactory validity/reliability/reproducibility and being first to include cognitive-testing, authors estimated sexual-dysfunction prevalence affecting half PwMS.HIGHLIGHTSThis study provides the only validation of the Greek Version of the MSISQ-19.The latter was found with satisfactory validity, reliability and reproducibility.50% of the Greek PwMS sample was found to be afflicted with sexual dysfunction.This is also the first validation study to examine associations with cognitive testing.Sexual function is still an underestimated functionality parameter upon examination.

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process.

Over the past two decades, the development of targeted immunotherapeutics for relapsing-remitting multiple sclerosis has been successfully orchestrated through the efficacious modulation of neuroinflammatory outcomes demonstrated in the experimental autoimmune encephalomyelitis (EAE) model. In this model, the focus of developing immunomodulatory therapeutics has been demonstrated through their effectiveness in modifying the pro-inflammatory Th1 and Th17-dependent neuropathological outcomes of demyelination, oligodendrocytopathy and axonal dystrophy. However, recent successful preclinical and clinical trials have advocated for the significance of B cell-dependent immunopathogenic responses and has led to the development of novel biologicals that target specific B cell phenotypes. In this context, a new molecule, B-cell activating factor (BAFF), has emerged as a positive regulator of B cell survival and differentiation functioning through various signaling pathways and potentiating the activity of various receptor complexes through pleiotropic means. One possible cognate receptor for BAFF includes the Nogo receptor (NgR) and its homologs, previously established as potent inhibitors of axonal regeneration during central nervous system (CNS) injury and disease. In this review we provide current evidence for BAFF-dependent signaling through the NgR multimeric complex, elucidating their association within the CNS compartment and underlying the importance of these potential pathogenic molecular regulators as possible therapeutic targets to limit relapse rates and potentially MS progression.

Neuropsychological correlates of cerebellar volumes in multiple sclerosis: an MRI volumetric analysis study.

The hallmark of Multiple Sclerosis (MS) pathophysiology is the damage to the myelin sheath around axons. The cerebellum is a predilection site for demyelination with a well-recognized role in motor and a rather understudied contribution to cognitive functions. The aim of this study is to investigate patterns of cerebellar grey and white matter pathology, expressed as reduced volume, as well as cortical thickness and their potential contribution to cognitive performance and disability status of patients with MS. 24 patients with MS underwent extensive neuropsychological assessment using paper and pencil tests and the Brain Health Assessment (BHA) tablet-based battery. Cerebellar lobular volumes and thickness were calculated using a volumetric analysis with automated segmentation of the cerebellum and its lobules. The main findings are a reduction of cerebellar grey matter (CGMV) and white matter volumes (CWMV) in lobule X and a widespread cerebellar cortical thinning in patients. Overall disease severity and neurological disability, assessed with the Expanded Disability Status Severity Scale, was correlated with fatigue and information processing speed tasks, but not with CGMV and CWMV. CWMV and CGMV of lobule I-II was negatively correlated with information processing speed, as well as visuospatial memory tests and, finally, inverse cortical thinning associations were noted between the whole cerebellum, lobule I-II, lobule III, lobule VI, Crus I, lobule VIIIA and information processing speed and verbal fluency tasks. The inverse associations observed may represent a compensatory mechanism activated in MS engaging additional high-level cortical areas functionally interconnected with the damaged cerebellum, in order to cope with the cognitive demands of a task.

What scans see when patients see defects: neuroimaging findings in body dysmorphic disorder.

Body dysmorphic disorder (BDD) is characterized by an individual's preoccupation with a perceived defect in their appearance which to others may be barely noticeable or even completely unnoticed. It confers significant disturbances of everyday functioning in affected persons. The present review study provides an overview of neuroimaging findings on BDD. Literature on three platforms, PubMed, Google Scholar and PsycArticles of APA PsycNet, was searched for studies on patients with BBD compared with healthy controls (HCs), with a focus on neuroimaging findings. Out of an initial yield of 414 articles, 23 fulfilled inclusion criteria and were reviewed. Among the most remarkable findings were functional abnormalities in visual processing, frontostriatal and limbic systems, reduced global efficiency of White Matter (WM) connectivity, reduced cortical thickness in temporal and parietal lobes, and correlations between these neuroimaging findings and clinical variables such as symptom severity and degree of insight. Structural, volumetric and functional neuroimaging findings in BDD affected persons may help shed light on the pathophysiology and neurobiological underpinnings of this condition. Future studies should further investigate the use of imaging findings as potential prognostic biomarkers of treatment efficacy and disease outcome.

Peripheral Inflammatory Markers TNF-α and CCL2 Revisited: Association with Parkinson's Disease Severity.

One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn-Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 (p = 0.01). Additionally, the UPDRS score was significantly associated with TNF-α levels. CCL2 levels, however, showed no significant associations.

Blood Metabolomics May Discriminate a Sub-Group of Patients with First Demyelinating Episode in the Context of RRMS with Increased Disability and MRI Characteristics Indicative of Poor Prognosis.

Biomarker research across the health-to-disease continuum is being increasingly applied. We applied blood-based metabolomics in order to identify patient clusters with a first demyelinating episode, and explored the prognostic potential of the method by thoroughly characterizing each cluster in terms of clinical, laboratory and MRI markers of established prognostic potential for Multiple Sclerosis (MS). Recruitment consisted of 11 patients with Clinically Isolated Syndrome (CIS), 37 patients with a first demyelinating episode in the context of Relapsing-Remitting MS (RRMS) and 11 control participants. Blood-based metabolomics and hierarchical clustering analysis (HCL) were applied. Constructed OPLS-DA models illustrated a discrimination between patients with CIS and the controls (p = 0.0014), as well as between patients with RRMS and the controls (p = 1 × 10−5). Hierarchical clustering analysis (HCL) for patients with RRMS identified three clusters. RRMS-patients-cluster-3 exhibited higher mean cell numbers in the Cerebro-spinal Fluid (CSF) compared to patients with CIS (18.17 ± 6.3 vs. 1.09 ± 0.41, p = 0.004). Mean glucose CSF/serum ratio and infratentorial lesion burden significantly differed across CIS- and HCL-derived RRMS-patient clusters (F = 14.95, p < 0.001 and F = 6.087, p = 0.002, respectively), mainly due to increased mean values for patients with RRMS-cluster-3. HCL discriminated a cluster of patients with a first demyelinating episode in the context of RRMS with increased disability, laboratory findings linked with increased pathology burden and MRI markers of poor prognosis.

Hereditary diffuse leukoencephalopathy with spheroids mimicking primary progressive aphasia: report of a Greek case.

INTRODUCTION: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult onset leukodystrophy, causally related to mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We report the unique case of a Greek HDLS patient, demonstrating an unusual phenotype, reminiscent of primary progressive aphasia (PPA). METHODS: A 63-year-old woman was referred with a 2-year history of deteriorating language and memory deficits, apathy, and two generalized tonic-clonic seizures. Neurological and neuropsychological examination revealed prominent aphasia with a pattern consistent with nonfluent variant of PPA. However, brain MRI disclosed confluent T2 and FLAIR white matter hyperintensities with frontal emphasis, whereas genetic testing corroborated the diagnosis of HDLS. DISCUSSION: PPA-like patterns may rarely develop in the context of HDLS. Prompt diagnosis of this leukoencephalopathy is essential, since preliminary data suggest that it could represent a potentially treatable disorder.

Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis.

BACKGROUND: Nerve growth factor (NGF) and its receptors, tropomyosin receptor kinase A (TrkA) and pan-neurotrophin receptor p75 (p75NTR), are known to play bidirectional roles between the immune and nervous system. There are only few studies with inconclusive results concerning the expression pattern and role of NGF, TrkA, and p75NTR (NGF system) under the neuroinflammatory conditions in multiple sclerosis (MS) and its mouse model, the experimental autoimmune encephalomyelitis (EAE). The aim of this study is to investigate the temporal expression in different cell types of NGF system in the central nervous system (CNS) during the EAE course. METHODS: EAE was induced in C57BL/6 mice 6-8 weeks old. CNS tissue samples were collected on specific time points: day 10 (D10), days 20-22 (acute phase), and day 50 (chronic phase), compared to controls. Real-time PCR, Western Blot, histochemistry, and immunofluorescence were performed throughout the disease course for the detection of the spatio-temporal expression of the NGF system. RESULTS: Our findings suggest that both NGF and its receptors, TrkA and p75NTR, are upregulated during acute and chronic phase of the EAE model in the inflammatory lesions in the spinal cord. NGF and its receptors were co-localized with NeuN+ cells, GAP-43+ axons, GFAP+ cells, Arginase1+ cells, and Mac3+ cells. Furthermore, TrkA and p75NTR were sparsely detected on CNPase+ cells within the inflammatory lesion. Of high importance is our observation that despite EAE being a T-mediated disease, only NGF and p75NTR were shown to be expressed by B lymphocytes (B220+ cells) and no expression on T lymphocytes was noticed. CONCLUSION: Our results indicate that the components of the NGF system are subjected to differential regulation during the EAE disease course. The expression pattern of NGF, TrkA, and p75NTR is described in detail, suggesting possible functional roles in neuroprotection, neuroregeneration, and remyelination by direct and indirect effects on the components of the immune system.

Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword.

Helicobacter pylori (H. pylori) infection affects an estimated 4.4 billion people globally. Moreover, H. pylori presents the most significant risk factor for gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and it is the first example of bacterial infection linked to carcinogenesis. Here, we contend that H. pylori research, which focuses on a cancer-causing pathogen resident in a relatively accessible organ, the stomach, could constitute an exemplar for microbial-related carcinogenesis in less tractable organs, such as the pancreas and lung. In this context, molecular biological approaches that could reap rewards are reviewed, including: (1) gastric cancer dynamics, particularly the role of stem cells and the heterogeneity of neoplastic cells, which are currently being investigated at the single-cell sequencing level; (2) mechanobiology, and the role of three-dimensional organoids and matrix metalloproteases; and (3) the connection between H. pylori and host pathophysiology and the gut microbiome. In the context of H. pylori's contribution to gastric cancer, several important conundrums remain to be fully elucidated. From among them, this article discusses (1) why H. pylori infection, which causes both gastric and duodenal inflammation, is only linked to gastric cancer; (2) whether a "precision oncomicrobiology" approach could enable a fine-tuning of the expression of only cancer-implicated H. pylori genes while maintaining beneficial H. pylori-mediated factors in extra-gastric tissues; and (3) the feasibility of using antibiotics targeting the microbial DNA damage system, which shares commonalities with mechanisms for human cell replication, as chemopreventives. Additional therapeutic perspectives are also discussed.

Cognitive Fatigability is Independent of Subjective Cognitive Fatigue and Mood in Multiple Sclerosis.

BACKGROUND: Sustained cognitive testing is used to detect cognitive fatigability and is often considered a substitute for subjective cognitive fatigue (CF). However, the relationship between cognitive fatigability and subjective CF in people with multiple sclerosis (PwMS) remains undetermined. OBJECTIVE: To explore potential associations between fatigability induced by sustained cognitive testing and subjective CF in PwMS. METHODS: We gave 120 PwMS and 60 demographically matched, healthy individuals the Beck Depression Inventory-FastScreen (BDI-FS) to measure mood and the Modified Fatigue Impact Scale to measure CF. In addition, we used the Quotient ADHD Test, a sustained attention test, to measure cognitive fatigability. We also explored potential correlations between the individuals' performance on the sustained attention test and thalamic volume using recent MRI scans. RESULTS: Forty-one (34.2%) of the PwMS exhibited cognitive fatigability. These 41 were found to be significantly older (P=0.006), had been diagnosed with the disease for longer (P=0.03), had higher scores (P<0.001) on the Expanded Disability Status Scale, and had reduced thalamic volume (P=0.04) compared with the 79 (65.8%) PwMS not exhibiting cognitive fatigability. The PwMS exhibiting cognitive fatigability scored similarly on the BDI-FS (P=0.21) and self-reported similar rates of CF (P=0.62) as the PwMS not exhibiting cognitive fatigability. CONCLUSION: Cognitive fatigability induced by sustained cognitive testing is not an accurate clinical alternative to subjective CF. This study provides evidence to support cognitive fatigability and CF in PwMS as two distinct concepts.

Computerized cognitive rehabilitation for treatment of cognitive impairment in multiple sclerosis: an explorative study.

In this explorative study, forty-seven patients with relapsing-remitting multiple sclerosis were randomized to a custom 6-week cognitive rehabilitation intervention (n = 23) using the BrainHQTM web-based platform and to a control group condition (n = 24). Cognitive rehabilitation intervention consisted of two 40-minute sessions per week. All patients were tested with the Brief International Cognitive Assessment for Multiple Sclerosis battery, the Stroop Color-Word Test, and the trail making test, while the Beck Depression Inventory - Fast Screen questionnaire was used as a measure of mood and the cognitive reserve index as a measure of cognitive reserve. We used the reliable change index, to calculate clinically meaningful changes of performance, and to discriminate between responders and non-responders of this intervention. Statistically significant improvement of the group receiving treatment was observed mainly on measures of verbal and non-verbal episodic memory and, to a lesser extent, on reading speed, selective attention/response inhibition, and visual attention. Verbal memory and visual attention improvements remained significant after considering the corrected for multiple comparisons level of significance. According to reliable change index scores, 12/23 (52.2%) of patients in the intervention group presented meaningful improvement in at least one measure (Greek Verbal Learning Test: 26%, Brief Visuospatial Memory Test-Revised: 17.4%, Stroop-Words test: 13%). This explorative study provides evidence that, at least in the short term, cognitive rehabilitation may improve the cognitive performance of multiple sclerosis patients.