Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells.

The aim of this study is to illuminate a novel therapeutic approach by identifying a functional binding target of salinomycin, an emerging anticancer stem cell (CSC) agent, and to help dissect the underlying action mechanisms. By utilizing integrated strategies, we identify that nucleolin (NCL) is likely a salinomycin-binding target and a critical regulator involved in human neuroblastoma (NB) CSC activity. Salinomycin markedly suppresses NB CD34 expression and reduces CD34+ cell population in an NCL-dependent manner via disruption of the interaction of NCL with CD34 promoter. The elevated levels of NCL expression in NB tumors are associated with poor patient survival. Altogether, these results indicate that NCL is likely a novel functional salinomycin-binding target that exhibits the potential to be a prognostic marker for NB therapy.

Neurological presentations of intravascular lymphoma (IVL): meta-analysis of 654 patients.

BACKGROUND: Patients with intravascular lymphoma (IVL) frequently have neurological signs and symptoms. Prompt diagnosis and treatment is therefore crucial for their survival. However, the spectrum of neurological presentations and their respective frequencies have not been adequately characterized. Our aim is to document the spectrum of clinical symptoms and their respective frequencies and to create a clinical framework for the prompt diagnosis of IVL. METHODS: A comprehensive meta-analysis of 654 cases of IVL published between 1957 and 2012 was performed to provide better insight into the neurological presentations of this disease. Neurologic complications were mainly divided into central nervous system (CNS) and peripheral nervous system (PNS) presentations. RESULTS: There were no differences in occurrences of CNS IVL based on gender or geographic locations (Asian Vs non-Asian). However, most patients with CNS IVL were younger than 70 years of age (p < 0.05). Our limited data do not support the treatment efficacy of methotrexate. CNS symptoms were seen in 42% of all cases. The most common CNS complications identified were cognitive impairment/dementia (60.9%), paralysis (22.2%), and seizures (13.4%). PNS complications were seen in 9.5% of cases. Out of these, muscle weakness (59.7%), neurogenic bladder (37.1%), and paresthesia (16.1%) were the most common presentations. CONCLUSIONS: CNS complications are more common among IVL patients. Out of these, dementia and seizures outnumber stroke-like presentations.

Multiple Sclerosis and COVID-19: An Overview on Risk, Severity, and Association With Disease Modifying Therapies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, emerged in December 2019, sparking a global health crisis. While initially recognized as a respiratory illness, it has become evident that Coronavirus disease 2019 (COVID-19) also affects the central nervous system. This comprehensive review focuses on the neurological manifestations of COVID-19 and its impact on patients with preexisting neurological disorders, particularly those with multiple sclerosis (MS) receiving disease-modifying therapies. Advancements in management, including vaccinations, antiviral therapy, and targeted prophylaxis, have led to a decline in the incidence and severity of COVID-19. Nevertheless, significant complications persist, particularly in patients with advanced MS, who are highly vulnerable to infectious agents like SARS-CoV-2. This review explores the evolving understanding of MS and its association with SARS-CoV-2, encompassing neuroinvasiveness, pathogenesis, disease severity, and outcomes. Research findings reveal substantial neurological implications for some MS patients with COVID-19, with a potential risk of disease relapse and severity. A notable proportion of MS patients experiencing COVID-19 may manifest new symptoms, experience exacerbation of existing symptoms, or encounter both simultaneously, underscoring the diverse neurological effects of the virus. While vaccination and therapeutics have mitigated the overall impact, specific subgroups, especially those on anti-CD20 therapy and with existing disability, remain at higher risk, necessitating ongoing vigilance and tailored care.

The Relationship Between COVID-19 and the Development of Depression: Implications on Mental Health.

Initially, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease-2019 (COVID-19), was predominantly considered to primarily affect the respiratory system. However, later studies revealed that it also affects brain function through its ability to bind to the angiotensin-converting enzyme type 2 (ACE2) receptors expressed on neural cells. Our study involved a comprehensive review of literature aiming to investigate the relationship between COVID-19 and the development of depression. Our analysis shows a connection between these 2 conditions, as a consequence of the inflammatory response in the nervous system to the COVID-19 virus and the psychophysiological effects of the pandemic. In COVID-19 patients, depression can arise either due to the direct viral infection of the brain or as a result of an indirect immune response triggering neuroinflammation after a cytokine storm. The resulting depression can be treated with non-pharmacological therapies such as psychotherapy, antidepressant medications, or a combination of these treatments depending on the severity of the symptoms.

Neuromuscular Disorders Associated With COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has had an enormous impact on practically every aspect of daily life, and those with neuromuscular disorders have certainly not been spared. The effects of COVID-19 infection are far-reaching, going well beyond respiratory symptoms alone. From simple myalgias to debilitating critical illness neuromyopathies, we continue to learn and catalog the diverse pathologies presented by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as it relates to the neuromuscular system. Complications have been documented both as a direct result of primary infection but also in those with pre-existing neuromuscular disorders from myasthenia gravis to devastating critical illness neuromyopathies. In this review, we will discuss the relationship between COVID-19 infection and critical illness neuromyopathy, peripheral nerve palsies, myalgias, positional compressive neuropathy, myasthenia gravis, and Guillain-Barré syndrome.

Neurological and Neurodegenerative Disorders: Novel Concepts and Treatment.

The journal "Aging and Disease" has released a special issue focused on novel concepts in understanding the pathophysiology and treatment of neurological and neurodegenerative disorders. The special issue comprises review and original research articles discussing the various disease mechanisms and/or treatment updates on aging, mild cognitive impairment, dementia, acute stroke, pediatric stroke, super-refractory status epilepticus, reflex epilepsy, drug-resistant epilepsy, Parkinson's disease, and traumatic brain injury. This editorial discusses the highlights from these articles.

Acute Stroke Management: Overview and Recent Updates.

Stroke is a leading cause of morbidity and mortality in the United States. Whether hemorrhagic or ischemic, stroke leads to severe long-term disability. Prior to the mid-1990s, the treatment offered to a patient who presented with an acute stroke was mainly limited to antiplatelets. The lack of adequate treatment, in particular, one without reperfusion contributed to the disability that ensued. There have been many advances in stroke care within the past two decades, especially with the acute management of ischemic stroke. Even with these advances, it is quite alarming that only a fraction of patients receives acute stroke treatment. Numerous trials were conducted to broaden treatment eligibility in hopes that more patients can be treated acutely and safely. These trials have tested both the time window for IV tPA and endovascular therapy (EVT). Acute stroke management is moving from a universal time window approach to a concept of tissue preservation. Specifically, preserving cerebral blood flow, the penumbra, and reducing the risk of a second event. This movement is being executed through the use of multimodal CT and MRI, as well as individualizing treatment to our patients. Minimizing the initial effect of stroke changes the outcome and leads to an increased likelihood of functional independence. In this review, we discuss the recent updates of acute ischemic stroke management in regards to mechanical thrombectomy as well as thrombolytics including tenecteplase.

Super-Refractory Status Epilepticus: Prognosis and Recent Advances in Management.

Super-refractory status epilepticus (SRSE) is a life-threatening neurological emergency with high morbidity and mortality. It is defined as "status epilepticus (SE) that continues or recurs 24 hours or more after the onset of anesthesia, including those cases in which SE recurs on the reduction or withdrawal of anesthesia." This condition is resistant to normal protocols used in the treatment of status epilepticus and exposes patients to increased risks of neuronal death, neuronal injury, and disruption of neuronal networks if not treated in a timely manner. It is mainly seen in patients with severe acute onset brain injury or presentation of new-onset refractory status epilepticus (NORSE). The mortality, neurological deficits, and functional impairments are significant depending on the duration of status epilepticus and the resultant brain damage. Research is underway to find the cure for this devastating neurological condition. In this review, we will discuss the wide range of therapies used in the management of SRSE, provide suggestions regarding its treatment, and comment on future directions. The therapies evaluated include traditional and alternative anesthetic agents with antiepileptic agents. The other emerging therapies include hypothermia, steroids, immunosuppressive agents, electrical and magnetic stimulation therapies, emergent respective epilepsy surgery, the ketogenic diet, pyridoxine infusion, cerebrospinal fluid drainage, and magnesium infusion. To date, there is a lack of robust published data regarding the safety and effectiveness of various therapies, and there continues to be a need for large randomized multicenter trials comparing newer therapies to treat this refractory condition.

Pediatric Stroke: Overview and Recent Updates.

Stroke can occur at any age or stage in life. Although it is commonly thought of as a disease amongst the elderly, it is important to highlight the fact that it also affects infants and children. In both populations, strokes have a high rate of morbidity and mortality. Arguably, it is more detrimental in the pediatric population given the occurrence at a younger age and therefore, a longer duration of disability, potentially over the entire lifespan. The high rate of morbidity and mortality in pediatrics is attributed to significant delays in diagnosis, as well as misdiagnosis. Acute stroke management is time dependent. Patients who receive acute treatment with either intravenous (IV) tissue plasminogen activator (tPA) or mechanical thrombectomy, have improved mortality and functional outcomes. Additionally, the earlier treatment is initiated, the higher the likelihood of preserving penumbra, restoring cerebral blood flow and potentially reversing symptoms, thereby limiting disability. Prompt identification is essential as it leads to improved patient care in such a narrow therapeutic window. It enhances the care received during hospitalization and reduces the risk of early stroke recurrence. Despite limited data and lack of large randomized clinical trials in pediatrics, both IV tPA and mechanical thrombectomy have been successfully used. Bridging the gap of acute stroke management in the pediatric population is an essential part of minimizing adverse outcomes. In this review, we discuss the epidemiology of pediatric stroke, the diverse etiologies, presentation as well as both acute and preventative management.

Management of Autoimmune Status Epilepticus.

Status epilepticus is a neurological emergency with increased morbidity and mortality. Urgent diagnosis and treatment are crucial to prevent irreversible brain damage. In this mini review, we will discuss the recent advances in the diagnosis and treatment of autoimmune status epilepticus (ASE), a rare form of the disorder encountered in the intensive care unit. ASE can be refractory to anticonvulsant therapy and the symptoms include subacute onset of short-term memory loss with rapidly progressive encephalopathy, psychiatric symptoms with unexplained new-onset seizures, imaging findings, CSF pleocytosis, and availability of antibody testing makes an earlier diagnosis of ASE possible. Neuroimmunomodulatory therapies are the mainstay in the treatment of ASE. The goal is to maximize the effectiveness of anticonvulsant agents and find an optimal combination of therapies while undergoing immunomodulatory therapy to reduce morbidity and mortality.

Identification of a panel of genes as a prognostic biomarker for glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a fatal disease without effective therapy. Identification of new biomarkers for prognosis would enable more rational selections of strategies to cure patients with GBM and prevent disease relapse. METHODS: Seven datasets derived from GBM patients using microarray or next generation sequencing in R2 online database (http://r2.amc.nl) were extracted and then analyzed using JMP software. The survival distribution was calculated according to the Kaplan-Meier method and the significance was determined using log-rank statistics. The sensitivity of a panel of GBM cell lines in response to temozolomide (TMZ), salinomycin, celastrol, and triptolide treatments was evaluated using MTS and tumor-sphere formation assay. FINDINGS: We identified that CD44, ATP binding cassette subfamily C member 3 (ABCC3), and tumor necrosis factor receptor subfamily member 1A (TNFRSF1A) as highly expressed genes in GBMs are associated with patients' poor outcomes and therapy resistance. Furthermore, these three markers combined with MGMT, a conventional GBM marker, can classify GBM patients into five new subtypes with different overall survival time in response to treatment. The four-gene signature and the therapy response of GBMs to a panel of therapeutic compounds were confirmed in a panel of GBM cell lines. INTERPRETATION: The data indicate that the four-gene panel can be used as a therapy response index for GBM patients and potential therapeutic targets. These results provide important new insights into the early diagnosis and the prognosis for GBM patients and introduce potential targets for GBM therapeutics. FUND: Baylor Scott & White Health Startup Fund (E.W.); Collaborative Faculty Research Investment Program (CFRIP) of Baylor University, Baylor Scott & White Health, and Baylor College of Medicine (E.W., T.S., J.H.H.); NIH R01 NS067435 (J.H.H.); Scott & White Plummer Foundation Grant (J.H.H.); National Natural Science Foundation of China 816280007 (J.H.H. and Fu.W.).

Role of Anticonvulsants in the Management of Posttraumatic Epilepsy.

Posttraumatic seizures (PTS) have been recognized as a major complication of traumatic brain injury (TBI). The annual incidence of TBI in the United States is 1.7 million. The role of anticonvulsants in the treatment of posttraumatic epilepsy (PTE) remains uncertain. Based on current studies, however, anticonvulsants have been shown to reduce early PTS occurring within the first 7 days, but little to no benefits have been shown in late PTS occurring after 7 days. In this paper, we provide a mini review of the role of anticonvulsants and current advances in the management of PTE.

Efficacy of N-Acetylserotonin and Melatonin in the EAE Model of Multiple Sclerosis.

Melatonin and N-acetylserotonin (NAS) are tryptophan metabolites that have potent anti-oxidant, anti-inflammatory and neuroprotective properties in several animal models of neurological injury and disease including multiple sclerosis (MS). The therapeutic effect of NAS has not been reported previously in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS. Using a MOG-peptide induced EAE mouse model we examined the effects of melatonin and NAS on clinical score, inflammatory markers, free radical generation, and sparing of axons, oligodendrocytes and myelin. We found that NAS and melatonin reduced clinical scores when administered prior to or after symptom onset. This effect was more pronounced when melatonin and NAS were administrated prior to symptom onset whereby the appearance of motor symptoms was significantly delayed. Activated microglia and CD4+ T-cells were increased in the white matter of untreated EAE mice, with a return to near control levels after melatonin or NAS treatment. The expression of the NADPH oxidase component p67phox and inducible nitric oxide synthase (iNOS) was increased in the EAE mice as compared with controls, and both drug treated groups had significant reductions in their expression. Melatonin and NAS treatment significantly reduced the loss of mature oligodendrocytes, demyelination and axonal injury. Both compounds also significantly attenuated iNOS induction and reactive oxygen species (ROS) generation in lipopolysaccharide-activated microglia in culture. Our results show for the first time the therapeutic effects of NAS and confirm previous reports on the effectiveness of melatonin in the EAE model of MS.

Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease.

Canavan disease is a devastating neurodegenerative childhood disease caused by mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to generate free acetate in the brain. Localization of aspartoacylase in different cell types in the rat brain was examined in an attempt to understand the pathogenesis of Canavan disease. In situ hybridization histochemistry with a riboprobe based on murine aspartoacylase cDNA was used in this study. The hybridization signal was detectable primarily in the myelin-synthesizing cells, namely oligodendroglia. These findings provide strong additional support for insufficient myelin synthesis as the pathogenic basis of Canavan disease and make a compelling case for acetate supplementation as a simple and noninvasive therapy for this fatal disease with no treatment.

Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination.

Canavan disease, an autosomal-recessive neurogenetic disorder, is caused by mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to generate free acetate in the brain. Earlier studies have shown that aspartoacylase is primarily restricted to myelin synthesizing cells (oligodendroglia) in the CNS. These findings have led us to investigate the developmental expression of aspartoacylase gene in the rat brain in an attempt to shed more light on the role of this enzyme in myelination. In situ hybridization using a 35S riboprobe based on murine aspartoacylase cDNA was used in this study. The probe hybridized mostly to the white matter tracts with different densities depending on the age of the animal and region of the brain examined. Little or no hybridization signals were detected in the 1-day-old rats, whereas the signal was clearly detectable in most of the white matter regions of the CNS in the 11-day-old rats. The signal density markedly increased at postnatal day 17, the peak of myelination. Thereafter, the hybridization signals decreased somewhat but still could be observed in the adult animals. Thus, the developmental expression pattern of aspartoacylase gene in the postnatal brain closely parallels myelination in the CNS. In the CNS, the hybridization signal of ASPA appeared to be restricted primarily to oligodendrocytes, the primary myelin synthesizing cell type in the CNS. However, the signal was not detectable in rat sciatic nerve (Schwann cells) of the peripheral nervous system. These findings indicate that the role of N-acetylaspartate in myelin synthesis is restricted to the CNS. Furthermore, they provide additional support for the acetate deficiency hypothesis of Canavan disease and also make a stronger case for acetate supplementation as an immediate and inexpensive therapy for Canavan disease.

Role of anticonvulsants in the management of AIDS related seizures.

Seventy percent of the AIDS patients have neurological complications. Seizures are one of the complications and can occur at any stage. Seizures can be life-threatening and treatment with anticonvulsants is warranted. The therapeutic dilemma occurs in this case because of the interactions between the anticonvulsants, especially the first generation anticonvulsants, with antiretroviral agents resulting in significant side-effects including toxicity. The non-availability of second-generation anticonvulsants and cost constraints further limit the choices for the physicians. In this mini-review, we discuss the management of AIDS related seizures with emphasis on the drug-drug interactions between anticonvulsants and antiretroviral agents. We will also address the future directions and the need for prospective studies with second-generation anticonvulsants.

Psychogenic nonepileptic spells in chronic epilepsy patients with moderate cognitive impairment: the need for video EEG monitoring for adequate diagnosis.

The objective of our study was to emphasize the importance of intensive video EEG monitoring in patients with a well-established diagnosis of epilepsy with moderate cognitive impairment. The idea was to diagnose new onset frequent atypical events prompting the need for frequent emergency room and clinic visits and hospital admissions. Retrospective chart reviews were conducted on patients with chronic epilepsy with moderate cognitive impairment who had an increased incidence of new onset episodes different from the baseline seizures. Data were acquired from electronic medical records. The hospital's Institutional Review Board gave approval for this retrospective analysis of patient records. We retrospectively analyzed data from three patients with an established diagnosis of epilepsy. Extensive chart reviews were performed with emphasis on type and duration of epilepsy and description of baseline seizures and description of new events. There were two men and one woman with moderate cognitive impairment. One subject had generalized epilepsy and other two had temporal lobe epilepsy. The patients were on an average of two to three antiepileptic medicines. The duration of follow-up in our neurology clinic ranged from 9 months to 5 years. The occurrence of increased frequency of these atypical events as described by the caregivers, despite therapeutic anticonvulsant levels, prompted the need for 5-day intensive video EEG monitoring. New atypical spells were documented in all three patients and the brain waves were normal during those episodes. The diagnosis of pseudoseizures was made based on the data acquired during the epilepsy monitoring unit stay. Our data analysis showed that intensive video EEG monitoring is an important tool to evaluate change in frequency and description of seizures even in cognitively impaired patients with an established diagnosis of epilepsy for adequate seizure management.

Selection of antiepileptic drugs in older people.

OPINION STATEMENT: Elderly people are one of the fastest-growing populations in the United States, and the incidence of epilepsy in older people is much higher than in other population subgroups. This age group is the most vulnerable because of the increased incidence of multiple medical comorbidities, including stroke. The diagnosis of epilepsy is extremely challenging and often delayed in this age group because of an atypical presentation. Seizures are manifest through extremely vague complaints, such as episodes of altered mental status or memory lapses. Once the diagnosis is established by careful history taking and diagnostic testing, anticonvulsants are the mainstay of treatment. The choice of anticonvulsants in elderly patients requires careful evaluation of medical comorbidities, which vary on an individual basis. This subgroup also is more susceptible to adverse effects because of the physiologic changes in the body due to older age, which affect the pharmacokinetics of most anticonvulsants. The ideal drug in this age group should have linear pharmacokinetics, fewer adverse effects, minimal or no drug-drug interactions, no enzyme induction/inhibition, a long half-life, and minimal protein binding, and should be cost-effective. As such, there is no ideal drug for this patient population, although both older- and newer-generation anticonvulsants are used for long-term treatment. Most newer anticonvulsants have the advantage of a favorable pharmacokinetic profile, minimal or no drug-drug interactions, and fewer adverse events, as well as being well tolerated. The older anticonvulsants still are widely used, because the newer anticonvulsants are much more expensive.

Importance of Video-EEG Monitoring in the Diagnosis of Epilepsy in a Psychiatric Patient.

Epilepsy is a chronic medical condition which is disabling to both patients and caregivers. The differential diagnosis of epilepsy includes psychogenic nonepileptic spells or "pseudoseizures." Epilepsy is due to abnormal electrical activity in the brain, and pseudoseizure is a form of conversion disorder. The brain waves remain normal in pseudoseizures. The problem arises when a patient with significant psychiatric history presents with seizures. Pseudoseizures become high on the differential diagnosis without extensive work up. This is a case of woman with significant psychiatric issues which resulted in a delay in the diagnosis of epilepsy.

Importance of Video-EEG Monitoring in the Diagnosis of Refractory Panic Attacks.

Partial seizures can be misdiagnosed as panic attacks. There is considerable overlap of symptoms between temporal lobe seizures and panic attacks making the diagnosis extremely challenging. Temporal lobe seizures can present with intense fear and autonomic symptoms which are also seen in panic disorders. This results in delay in diagnosis and management. We report an interesting case of a young woman who was diagnosed with right temporal lobe seizures with symptoms suggestive of a panic attack.