Encephalopathy with cerebellar deficits in a context of hyponatremia.

BACKGROUND: Hyponatremia can present with various neurological manifestations ranging from altered mental status to cerebral herniation and death. However, cerebellar symptomatology has been rarely reported. CASE PRESENTATION: A 53-year-old male with a history of diabetes mellitus type 2, hypothyroidism, and anxiety disorder presented with impaired level of consciousness and ataxia. His laboratory tests were consistent with sepsis (staphylococcus aureus in blood culture), hyponatremia with euvolemia, low serum and high urine osmolarity. Brain computerized tomography revealed diffuse cerebral edema. Antibiotics and sodium replenishment were initiated. A lumbar puncture and subsequent investigations ruled out alternative etiologies (metabolic, autoimmune, paraneoplastic and other infectious causes). Repeated brain magnetic resonance imaging excluded osmotic demyelination syndromes. After serum sodium restoration his symptoms gradually improved. DISCUSSION: We highlight reversible cerebellar ataxia as a rare manifestation of hyponatremia, in the context of sepsis and possible syndrome of inappropriate antidiuretic hormone ADH release. Extensive diagnostic work-up is essential for the exclusion of other diagnoses.

Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer's disease.

COVID-19's effects on the human brain reveal a multifactorial impact on cognition and the potential to inflict lasting neuronal damage. Type I interferon signaling, a pathway that represents our defense against pathogens, is primarily affected by COVID-19. Type I interferon signaling, however, is known to mediate cognitive dysfunction upon its dysregulation following synaptopathy, microgliosis and neuronal damage. In previous studies, we proposed a model of outside-in dysregulation of tonic IFN-I signaling in the brain following a COVID-19. This disruption would be mediated by the crosstalk between central and peripheral immunity, and could potentially establish feed-forward IFN-I dysregulation leading to neuroinflammation and potentially, neurodegeneration. We proposed that for the CNS, the second-order mediators would be intrinsic disease-associated molecular patterns (DAMPs) such as proteopathic seeds, without the requirement of neuroinvasion to sustain inflammation. Selective vulnerability of neurogenesis sites to IFN-I dysregulation would then lead to clinical manifestations such as anosmia and cognitive impairment. Since the inception of our model at the beginning of the pandemic, a growing body of studies has provided further evidence for the effects of SARS-CoV-2 infection on the human CNS and cognition. Several preclinical and clinical studies have displayed IFN-I dysregulation and tauopathy in gene expression and neuropathological data in new cases, correspondingly. Furthermore, neurodegeneration identified with a predilection for the extended olfactory network furthermore supports the neuroanatomical concept of our model, and its independence from fulminant neuroinvasion and encephalitis as a cause of CNS damage. In this perspective, we summarize the data on IFN-I as a plausible mechanism of cognitive impairment in this setting, and its potential contribution to Alzheimer's disease and its interplay with COVID-19.

Role of Memantine in Limiting Cochleotoxicity in Rats.

Οur aim was to test whether amikacin's well-known cochleotoxic effects could be suppressed, depending on whether an NMDA-antagonist (memantine) was administered simultaneously with or after amikacin treatment. Forty Wistar rats were used in this experiment. Ten rats acted as controls and received no medication (group A). Amikacin (200 mg/kg) was administered intraperitoneally (i.p.) once daily for 14 days to 10 animals in group B; amikacin (200 mg/kg) was administered concurrently with memantine (10 mg/kg, i.p., once daily) to the same 10 animals in group C. Group D was given intraperitoneal memantine (10 mg/kg, once daily) for 14 days following a 2-week amikacin treatment. The cochlear activity of the right ear was tested using DPOAE in conscious animals. All animals were sacrificed at the conclusion of the experiment and both cochleae were collected for histological and immunohistochemical analysis. All groups treated with amikacin showed decreased cochlear activity, as testified by decreased DPOAE-amplitudes compared to the pre-treatment state. In the rats of group B, the DPOAE reduction was more pronounced. On histologic exam, the cochlear structures of group C rats and, although to a lesser extent, group D rats showed less severe cochlea damage. Memantine plays a protective role, resulting in restoring partially cochlear structures when administered either simultaneously with or after completion of amikacin i.p. treatment in rats.

Adult Neoneurogenesis and Oligodendrogenesis in Multiple Sclerosis: A Systematic Review of Human and Animal Studies.

Introduction: The subventricular zone promotes remyelination through activation differentiation of oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) into mature oligodendrocytes and thus in the adult brain. In multiple sclerosis (MS) this regenerative capability is halted resulting in neurodegeneration. We aimed to systematically search and synthesize evidence on mechanisms and phenomena associated with subventricular zone (SVZ) dysfunction in MS. Materials and Methods: Our systematic review was reported according to the PRISMA-ScR statement. MEDLINE, SCOPUS, ProQuest, and Google Scholar were searched using the terms "subventricular zone" and "multiple sclerosis," including English-written in vivo and postmortem studies. Results: Twenty studies were included. Thirteen studies on models of experimental autoimmune encephalomyelitis (EAE) reported among others strong stathmin immunoreactivity in the SVZ of EAE models, the role of MOG immunization in neurogenesis impairment, the effect of parenchymal OPCs and NSCs in myelin repair, and the importance of ependymal cells (E1/E2) and ciliated B1 cells in SVZ stem cell signaling. CXCR4 signaling and transcriptional profiles of SVZ microglia, Gli1 pathway, and galactin-3 were also explored. Studies in humans demonstrated microstructural SVZ damage in progressive MS and the persistence of black holes near the SVZ, whereas postmortem confirmed the generation of polysialic acid-neural cell adhesion molecule and NG2-positive progenitors through SVZ activation, SVZ stathmin immunoreactivity, Shh pathway, and Gal-3 upregulation. Discussion: Oligodendrogenesis defects translate to reduced remyelination, a hallmark of MS that determines its end-phenotype and disease course. Conclusion: The role of inflammation and subsequent SVZ microenvironment disruption is evident in MS pathology.

Loss of the "swallow tail sign" on susceptibility-weighted imaging in the diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis.

INTRODUCTION: Loss of dorsolateral nigral hyperintensity (DNH) on iron-sensitive brain MRI is useful for Parkinson's disease detection. DNH loss could also be of diagnostic value in dementia with Lewy bodies (DLB), an a-synuclein-related pathology. We aim to quantitatively synthesize evidence, investigating the role of MRI, a first-line imaging modality, in early DLB detection and differentiation from other dementias. METHODS: Our study was conducted according to the PRISMA statement. MEDLINE, Scopus, Web of Science, and Cochrane Library were searched using the terms like "dementia with Lewy bodies", "dorsolateral nigral hyperintensity", and "MRI". Only English-written peer-reviewed diagnostic accuracy studies were included. We used QUADAS-2 for quality assessment. RESULTS: Our search yielded 363 search results. Three studies were eligible, all with satisfying, high quality. The total population of 227 patients included 63 with DLB and 164 with other diseases (Alzheimer disease, frontotemporal dementia, mild cognitive impairment). Using a univariate random-effects logistic regression model, our meta-analysis resulted in pooled sensitivity, specificity and DOR of 0.82 [0.62; 0.92], 0.79 [0.70; 0.86] and 16.26 ([3.3276; 79.4702], p = 0.0006), respectively, for scans with mixed field strength (1.5 and 3 T). Subgroup analysis of 3 T scans showed pooled sensitivity, specificity and DOR of 0.82 [0.61; 0.93], 0.82 [0.72; 0.89] and 18.36 ([4.24; 79.46], p < 0.0001), respectively. DISCUSSION: DNH loss on iron-sensitive MRI might comprise a supportive biomarker for DLB detection, that could augment the value of the DLB diagnostic criteria. Further evaluation using standardized protocols is needed, as well as direct comparison to other supportive and indicative biomarkers.

Repetitive transcranial magnetic stimulation in murine models of epilepsy: A systematic review of methodological aspects and outcomes.

OBJECTIVES: Clinical studies of repetitive transcranial magnetic stimulation (rTMS) do not provide consistent efficacy results, possibly due to variability in methodological parameters. Our aim is to systematically review preclinical rTMS protocols in murine models of epilepsy, offering insights from might facilitate the optimization of clinical trials. METHODS: We searched MEDLINE, SCOPUS and Web of Science from inception until December 2023, including English-written and peer-reviewed studies with clinical or electroencephalographic (EEG) outcomes. RESULTS: Among 480 search results, in the 23 eligible studies both mice and rats were used. Epilepsy induction methods included injections of pentylenetetrazole, kainic acid, picrotoxin and lithium-pilocarpine, electrical kindling (amygdala/ventral hippocampus), electroconvulsive shock and genetic models of absence and temporal lobe epilepsy. For motor threshold (MT) definition electromyography with motor evoked potentials and single-pulse TMS were used. Stimulation intensity ranged between 40 % and 200 % of MT or 0.125-2.5 T. High-frequency rTMS (≥5 Hz) demonstrated either no effect on seizure suppression or a rather facilitatory effect, promoting ictogenesis, with the exception of 20-Hz-rTMS coupling with lorazepam for status epilepticus cessation. Low-frequency rTMS (<5 Hz), primarily at 0.5 and 1 Hz, exerted an inhibitory effect on both clinical and EEG parameters on various epilepsy models in most studies and also significantly ameliorated performance in behavioral tests. CONCLUSIONS: rTMS holds potential for effective neuromodulation, that is critically dependent on stimulation frequency and epilepsy type. Translational knowledge gained from preclinical protocols may inform and optimize rTMS application for epilepsy management in future clinical trials.

Identification of Key Genes Associated with Tumor Microenvironment Infiltration and Survival in Gastric Adenocarcinoma via Bioinformatics Analysis.

OBJECTIVE: Gastric carcinoma (GC) is the fifth most commonly diagnosed cancer and the third leading cause of cancer-related deaths globally. The tumor microenvironment plays a significant role in the pathogenesis, prognosis, and response to immunotherapy. However, the immune-related molecular mechanisms underlying GC remain elusive. Bioinformatics analysis of the gene expression of GC and paracancerous healthy tissues from the same patient was performed to identify the key genes and signaling pathways, as well as their correlation to the infiltration of the tumor microenvironment (TME) by various immune cells related to GC development. METHODS: We employed GSE19826, a gene expression profile from the Gene Expression Omnibus (GEO), for our analysis. Functional enrichment analysis of Differentially Expressed Genes (DEGs) was conducted using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database. RESULTS: Cytoscape software facilitated the identification of nine hub DEGs, namely, FN1, COL1A1, COL1A2, THBS2, COL3A1, COL5A1, APOE, SPP1, and BGN. Various network analysis algorithms were applied to determine their high connectivity. Among these hub genes, FN1, COL1A2, THBS2, COL3A1, COL5A1, and BGN were found to be associated with a poor prognosis for GC patients. Subsequent analysis using the TIMER database revealed the infiltration status of the TME concerning the overexpression of these six genes. Specifically, the abovementioned genes demonstrated direct correlations with cancer-associated fibroblasts, M1 and M2 macrophages, myeloid-derived suppressor cells, and activated dendritic cells. CONCLUSION: Our findings suggest that the identified hub genes, particularly BGN, FN1, COL1A2, THBS2, COL3A1, and COL5A1, play crucial roles in GC prognosis and TME cell infiltration. This comprehensive analysis enhances our understanding of the molecular mechanisms underlying GC development and may contribute to the identification of potential therapeutic targets and prognostic markers for GC patients.

Salicylate- and Noise-induced Tinnitus. Different Mechanisms Producing the same Result? An Experimental Model.

PURPOSE: Tinnitus, the generation of phantom sounds, can be the result of noise exposure, however, understanding of its underlying mechanisms is limited. Purpose of the study was is to determine whether different concentrations of salicylate can cause tinnitus of different intensity. METHODS: For the purposes of this study 50 male Wistar rats were used. The animals were divided into 5 groups (10 rats in each group). The animals that did not receive any substance were allocated to the control group (Group A). The second group (Group B) of rats received salicylate (Sigma Aldrich) intraperitoneally for 7 days (300 mg/Kg/day). The 3rd group (Group C) received salicylate intraperitoneally for 7 days, but at twice the concentration of the animals in the second group (600 mg/kg/d). The 4th group (Group D) simultaneously received salicylate (300 mg/Kg/day) and pure Memantine (Sigma Aldrich, 10 mg/kg/d) intraperitoneally for 7 days. The 5th group (Group E) did not receive any substance but was exposed for 168 consecutive hours (7 days) to sound to induce tinnitus. Cochlear activity was evaluated with the use of Distortion Product Otoacoustic Emissions (DPOAEs). At the end of the experimental period, the animals were sacrificed, and the right cochlea was removed and prepared for further histological and immunohistochemical studies. RESULTS: The DPOAEs of animals treated either with salicylate as monotherapy or salicylate combined with memantine were indistinguishable from the noise floor, did not differ significantly compared to the animals of the control group or those expose to constant noise. The cochlear structures of Group E remained anatomically and functionally unaffected from the exposure to constant noise. Memantine does not seem to offer substantial protection to the cochlear structures, according to histological examination and hearing tests, however, the rats receiving it exhibited better results in behavioral tests. CONCLUSIONS: The administration of memantine does not contribute significantly to the reduction of tinnitus.

Role of lipid-lowering agents in the management of diabetic retinopathy.

Diabetic retinopathy affects a substantial proportion of patients with diabetes mellitus (DM) and is the leading cause of blindness in working-aged adults. Even though the incidence of diabetic retinopathy has declined in the last decades, its prevalence increased and is expected to rise further as a result of the increasing incidence of type 2 DM (T2DM) and the longer life expectancy of patients with DM. The pathogenesis of diabetic retinopathy is multifactorial. Some observational studies suggested an association between dyslipidemia and the development and progression of retinopathy in patients with DM but others did not confirm this association. Regarding lipid-lowering agents, studies that evaluated the role of statins in the management of these patients are mostly small and yielded discrepant results. Large randomized studies with statins in patients with T2DM showed no benefit of these agents on diabetic retinopathy but were not designed to address this effect. In contrast, both preclinical data and two large randomized controlled studies, the FIELD and the ACCORD trial, showed that fenofibrate delays the progression of diabetic retinopathy. Even though the mechanisms underpinning this favorable effect are not entirely clear, these findings suggest that fenofibrate might represent a useful tool for the management of diabetic retinopathy.