Mature B-cell lymphoma with acute myelitis as the first presentation: a case report and literature review.

BACKGROUND: Lymphomas are malignant tumors of the immune system that arise in lymphoid organs and can impact the central nervous system. However, lymphomas with acute myelitis as the first manifestation are exceedingly rare, and most of them are symptoms of spinal cord damage due to the lack of specificity in their clinical manifestations. The rate of early misdiagnosis is exceedingly high, and the prognosis is dire. Here, we report a case of mature B-cell lymphoma with acute myelitis as the first presentation and review the related literature. CASE PRESENTATION: In this study, We report a case of a 70-year-old male patient with bilateral lower extremity weakness, bowel and bladder dysfunction, and recurrent fever. A paraureteral mass was seen beneath the right kidney on imaging, and the final pathological biopsy revealed: CD20 ( +), mature B-cell tumor, The patient refused to undergo additional tests to ascertain the type of lymphoma and subsequent therapy and asked to be discharged. In mid-November 2020, the patient died. CONCLUSIONS: This case report shows that patients with lymphoma can present with acute myelitis as the first symptom, especially if they have recurrent fever, that conventional treatment for myelitis is ineffective, and that tumors are considered after other causes of myelitis have been ruled out. Furthermore, a focused search for tumor-related evidence, as well as early identification and therapy, may help patients live longer lives.

Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice.

In Alzheimer's disease and ischemic stroke, intranasal insulin can act as a neuroprotective agent. However, whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly understood. In this study, a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5, 1, or 2 IU insulin via intranasal delivery, twice per day, until 24 or 72 hours after surgery. Compared with saline treatment, 1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage, decreased blood-brain barrier permeability and neuronal degeneration damage, reduced neurobehavioral deficits, and improved the survival rate of mice. Expression levels of p-AKT and p-GSK3ß were significantly increased in the perihematoma tissues after intranasal insulin therapy. Our findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3ß signaling pathway. The study was approved by the Ethics Committee of the North Sichuan Medical College of China (approval No. NSMC(A)2019(01)) on January 7, 2019.

Diazepam Monotherapy or Diazepam-Ketamine Dual Therapy at Different Time Points Terminates Seizures and Reduces Mortality in a Status Epilepticus Animal Model.

BACKGROUND Being refractory to drugs remains an urgent treatment problem in status epilepticus (SE). The fact that γ-aminobutyric acid A receptors (GABAARs) become internalized and inactive, N-methyl-D-aspartate receptors (NMDARs) become externalized and active during SE may explain the refractoriness to benzodiazepine. However, the real-time dynamic efficacy of antiepileptic drugs remains unclear. Therefore, we propose a hypothesis that diazepam monotherapy or diazepam-ketamine dual therapy could terminate seizures and reduce mortality in the SE model at different time points during ongoing SE. MATERIAL AND METHODS An SE model was established in adult Sprague-Dawley rats with lithium and pilocarpine. The GABAAR agonist diazepam was injected at 5, 10, 20, or 30 min when SE continued. In addition, diazepam and the NMDAR antagonist ketamine were injected at 10 to 60 min at 6 different time points. We measured seizure-free rates, seizure duration, degree of behavioral seizure, and mortality. RESULTS Diazepam monotherapy at 5 min and 10 min from the beginning of SE was able to terminate seizures and improved survival rates. Diazepam-ketamine dual therapy at 10 min, 20 min, and 30 min from the beginning of SE terminated seizures and achieved high survival rates. CONCLUSIONS In this parallel randomized controlled trial with a rat model, we found that diazepam monotherapy was an effective antiepileptic strategy at the early stage of SE less than 10 min after SE onset. If SE lasts more than 10 min but less than 30 min, the diazepam-ketamine dual therapy strategy may be an appropriate choice.

Altered expression of DENND5B in patients with epilepsy and its regulation of seizures in mice.

Epilepsy is a high incidence neurological disease, and its repeated attacks cause serious physical and psychological damage to the patient. Differentially expressed in normal and neoplastic cells (DENN) domain containing 5B (DENND5B) is a lipoprotein binding protein that mediates synaptic vesicle transport and regulates neuroplasticity and lipid metabolism. Nevertheless, the effect of DENND5B on seizures remains unclear. We aimed to investigate the association of DENND5B with epilepsy, detect its expression and distribution in the nervous system, and explore its role in epileptogenesis through western blot, immunofluorescence staining, and behavioral studies. In this experiment, two C57BL/6 mice models, which induced seizures by pentylenetetrazole and kainic acid, were established. We observed that the expression of DENND5B was reduced in the brains of patients with temporal lobe epilepsy, and its expression was also similarly decreased in both chronic epileptic mice. The findings strongly suggest that DENND5B may be associated with epileptic seizures. Results of immunofluorescence showed that DENND5B was mainly expressed in the hippocampal region and co-located with neurons but not with astrocytes. Next, we used lentivirus to induce both lentiviral vector-mediated overexpression and knockdown of DENND5B in mice to test the change of susceptibility and severity of seizures in the two chronic seizure models. Knockdown of DENND5B was found to promote epileptic seizures, increase chronic spontaneous recurrent epileptic seizures and epileptic discharge, and reduce the incubation period. However, overexpression of DENND5B showed the opposite effect. These results suggest that DENND5B overexpression decreased the behavioral phenotype of epileptic seizures, but DENND5B downregulation had the opposite effect. In summary, our findings suggest that DENND5B can regulate epileptic seizures and may provide a new target for antiepileptic therapy.

Glucosamine promotes seizure activity via activation of the PI3K/Akt pathway in epileptic rats.

CONTEXT: Glucosamine is an amino monosaccharide with a small molecular weight and has a protective effect against various neurological diseases including multiple sclerosis and encephalomyelitis. Interestingly, low-dose glucosamine has exhibited anti-epilepsy activity. Recent studies have shown that the activation of the protein kinase B (Akt) signaling pathway may promote epilepsy. Glucosamine can increase the level of Akt phosphorylation in the brain tissue, which may aggravate epilepsy. Hence, we speculate that a higher dose of glucosamine may aggravate epilepsy via AKT signaling. OBJECTIVE: To investigate the effect of glucosamine on the behavior and electrophysiology of epileptic rats through PI3K/Akt pathway. METHODS: Glucose (2.0 g/kg) and glucosamine (0, 0.5, 1.0, and 2.0 g/kg) were added to 2 mL of drinking water, respectively. An acute seizure rat model of lithium-pilocarpine and PTZ-kindling were constructed to observe the effects of different doses of glucosamine on epileptic behavior and hippocampal electrical activity. Meanwhile, the changes in Akt were detected by western blot. RESULTS: Epileptic seizures were induced by a single dose of pilocarpine or PTZ and 2.0 g/kg of glucosamine significantly prolonged the duration and severity of epileptic seizures, enhanced hippocampal electrical activity energy density, and increased phosphorylated AKT levels. A glucosamine dose of 2.0 g/kg also significantly increased the total onset energy density. Furthermore, 2.0 g/kg glucosamine facilitated the development of the chronic PTZ-kindling process. CONCLUSIONS: Glucosamine may exacerbate acute and chronic epileptic seizures via activation of the PI3K/Akt pathway in rats with experimental epilepsy.

The multidisciplinary management of recurrent tracheoesophageal fistula after esophageal atresia: Experience with 135 cases from a tertiary center.

BACKGROUND & AIMS: Recurrent tracheoesophageal fistula (rTEF) after esophageal atresia requires complex management across different specialties. This study reviews our experience and discusses a multidisciplinary (MDT) approach adopted in the past 4 years. METHODS: We reviewed the medical records of 100 patients with rTEF managed by an MDT approach (post-MDT group) from 2016 to 2019. These cases were compared to a historical group of 35 patients with rTEF from 2012 to 2015 (pre-MDT group). RESULTS: Of the 135 patients with rTEF, 124 were referred from other hospitals. Preoperative examination found tracheomalacia in 23 patients, vocal fold immobility in 19 patients, and laryngomalacia in five patients. The incidence of postoperative anastomotic leak, anastomotic stricture, and repeat recurrences was 28.1%, 23.0%, and 8.9%, respectively. The overall mortality rate was 4.4%. No statistical difference in postoperative complications was noted between the two groups. The duration of stay in the pediatric intensive care unit (P = 0.038), the duration of intubation (P = 0.049), the postoperative hospital stay (P = 0.011), and the total length of hospital stay (P = 0.001) were significantly lower in the post-MDT group. Mid-term follow-up showed 23 patients had pathological gastroesophageal reflux. Five of them underwent fundoplication and recovered. CONCLUSION: The MDT approach by fostering coordination of surgical, medical, radiological, and nutritional management is beneficial in the management of rTEF and leads to a satisfactory outcome .

Type 2 diabetes mellitus worsens the prognosis of intermediate-stage hepatocellular carcinoma after transarterial chemoembolization.

AIMS: The aim of this study was to investigate the impact of type 2 diabetes mellitus (T2DM) on the prognosis of hepatocellular carcinoma (HCC) patients following transarterial chemoembolization (TACE). METHODS: Time to progression (TTP) and cancer-specific mortality (CSM) in competing risk model were compared in patients with (n = 289) or without (n = 763) T2DM. Propensity score matching (PSM) was used to reduce bias between the two groups. Multivariate competing risk regression was used to evaluate independent risk factors for TTP and CSM. RESULTS: The T2DM group showed significantly worse 5-year TTP and CSM rates than the non-T2DM group both in the whole cohort (n = 1052) and the PSM cohort (n = 514) (81.3% vs. 70.9%, P < 0.001, and 61.5% vs. 49.3%, P = 0.006; 81.4% vs. 68.6%, P = 0.003, and 61.7% vs. 43.2%, P = 0.014, respectively). Multivariate competing risk regression identified T2DM as an independent risk factor for TTP and CSM before and after PSM (hazard ratio: 1.37 [95% confidence interval: 1.07-1.77] and 1.36 [1.05-1.75]; 1.29 [1.04-1.60] and 1.24 [1.02-1.52], respectively). T2DM worsened the long-term outcomes of patients in the cirrhosis subgroup but not those in the noncirrhosis subgroup. CONCLUSIONS: T2DM worsened the long-term survival of intermediate-stage HCC patients who underwent TACE, especially in patients with cirrhosis.

Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model.

Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases in vitro using primary astrocytes isolated from mice and in vivo using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.

Low-dose intranasal insulin improves cognitive function and suppresses the development of epilepsy.

Intranasal insulin exerts neuroprotective effects in a variety of neurological diseases. Whether intranasal insulin affects epileptic activity and whether it has neuroprotective effects in epileptic diseases is however still unknown. In this study we show that low-dose intranasal insulin inhibited kainic acid (KA)- or pentylenetetrazole (PTZ)-induced acute seizures and reduced epileptic discharge activities in mice, potentially by alleviating the increase in seizure-induced glutamate in the hippocampus. Meanwhile, intranasal insulin increased GABA levels and the activities of hippocampal theta, which may affect the excitability of the hippocampus. In chronic KA-induced epilepsy, low-dose intranasal insulin reduces the frequency of spontaneous recurrent seizures and epileptic discharges, while it increases theta energy and thereby improves spatial memory. Larger doses of intranasal insulin increased the frequency of seizures but did not aggravate cognitive impairment, suggesting that the frequency of seizures may not be related to impaired cognitive function. Overall, our findings show that low-dose intranasal insulin inhibits epileptic events and improves cognitive impairment in epileptic mice, suggesting that learning and memory can be improved by intranasal insulin. However, larger doses might increase the risk of epileptic seizures.

Effects of repetitive magnetic stimulation on the growth of primarily cultured hippocampus neurons in vitro and their expression of iron-containing enzymes.

Background: The mechanism of action of repetitive transcranial magnetic stimulation (rTMS) involves the generation of neuronal and action potentials utilizing induced currents in time-varying magnetic fields. However, the long-lasting and effective biological impact of magnetic stimulation does not appear to be completely explained by the transient magnetic field pulses. In this context, we hypothesized magnetic stimulation may affect the expression of iron-containing enzymes in neurons, mediating the long-lasting biological effects associated with this stimulus. Methods: Primarily cultured hippocampus neurons from SD rats were used as the cell model in this study. These were randomly divided into control, sham, and magnetic stimulation groups to probe into the effect of the magnetic field directly. The latter group received 40%, 60%, and 100% maximal stimulator output Tesla (1.68, 2.52, and 4.2 T) with low-frequency rTMS (1 Hz). The expression of iron-containing enzymes (catalase and aconitase) and non-ferrous enzymes (protein kinase A) was measured with Western blotting and ELISA. Results: The survival rates of neurons in the 40%T and 60%T groups were significantly increased in comparison to the controls (P<0.05), while those in the 100%T group showed cell damage, with slightly disturbed neurite connections and decreased survival rate. Furthermore, catalase and aconitase expression was higher in all of the stimulated groups in comparison to controls (P<0.05). On the other hand, the expression of the iron-containing enzymes decreased in the 100%T group in comparison with the 40%T and 60%T groups (P<0.05). Meanwhile, the expression of protein kinase A was not significantly increased in the groups which underwent magnetic stimulation. Conclusion: rTMS may increase the expression of ferrous enzymes but does not have a strong effect on non-ferrous enzymes. Excessive intensity of magnetic stimulation may reduce neuronal survival rate and affect the expression of iron-containing enzymes. The mechanism underlying the lasting effect of rTMS may be related to the increase of ferriferous expression induced by magnetic stimulation, with a clear correlation with stimulation intensity.

Alpha-fetoprotein response following transarterial chemoembolization indicates improved survival for intermediate-stage hepatocellular carcinoma.

BACKGROUND: To investigate the clinical value of the alpha-fetoprotein (AFP) response following transcatheter arterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma (HCC). METHODS: Data on patients with Barcelona Clinic Liver Cancer B staging system were analyzed. An AFP response was defined as a decrease in AFP of more than 20% after a TACE session. The association between AFP response and treatment outcome regarding imaging response and overall survival (OS) was explored. Cox proportional hazards models were applied to identify independent risk factors for OS after TACE. RESULTS: Of the enrolled 376 patients with elevated serum AFP >20 ng/mL, 214 (57%) with AFP responses were identified. AFP responders had improved median survival than non-responders (20 vs. 12 months, P = 0.002). AFP response was significantly correlated with imaging response (P < 0.001). The Cox proportional hazards model revealed that AFP response was an independent factor for OS (hazard ratio, 0.59; 95% confidence interval, 0.45-0.78; P < 0.001). In stratified analyses, an AFP response achieved improved survival in patients with tumor diameters ≤5 cm, diameters >5 cm, tumor number ≤3 and without underlying cirrhosis. CONCLUSIONS: The AFP response indicates enhanced survival after TACE in patients with intermediate-stage BCLC.

Lithium affects rat hippocampal electrophysiology and epileptic seizures in a dose dependent manner.

Lithium, a classic mood stabilizer, prevents apoptosis-dependent cellular death and has garnered considerable interest as a neuroprotective agent that is efficacious in the treatment of many neurological diseases. However, the effects of lithium in epilepsy remain controversial. We found that different doses of lithium affect epileptic seizure activity and bidirectionally modulate the susceptibility to and severity of seizures induced by pilocarpine in rats. Recently, it has been demonstrated that systematically administered lithium affects the powers of hippocampal gamma and theta oscillations in baseline electroencephalograms. Low-dose lithium (10 mg/kg) administered to pilocarpine-treated rats markedly increased the powers of basal gamma (30-80 Hz) and theta (4-12 Hz) oscillations, decreased the proportion of Racine stage 4-5 seizures, extended latency until seizure onset, and significantly reduced the frequency of lower-class seizures (p < 0.05). Conversely, when the dose was increased to 40 mg/kg, lithium reduced the frequency of lower-class seizures compared to control treatment (p < 0.05). Further, at this high dose, lithium reduced the power of basal gamma oscillations and markedly increased the susceptibility to and severity of pilocarpine-induced seizures and enhanced ripple rhythms (80-200 Hz) postictally. Our results provide a framework for further investigations of the underlying electrophysiological mechanisms of lithium-induced imbalances in excitatory and inhibitory neural circuits that regulate seizure activity in rats. In conclusion, the observed in vivo changes in the powers of basal gamma and theta oscillations in response to different doses of lithium may reflect hippocampal neural network responsiveness.

The effects of berberine on a murine model of multiple sclerosis and the SPHK1/S1P signaling pathway.

Berberine (BBR) has shown neuroprotective properties. The present study aims to investigate the effects of BBR on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), and SphK1/S1P signaling, which plays a key role in MS. EAE was induced in mice, followed by treatment with BBR at 50, 100, or 300 mg/kg/d. Neurophysiological function was evaluated daily; inflammation, cell infiltration, and the severity of demyelination were also examined. The SphK1, SphK2, and S1P levels in the animals and primary astrocyte culture were measured. We found that treatment with BBR reduced the loss of neurophysiological function and the degree of demyelination. Moreover, BBR was associated with a decrease in SphK1 and S1P levels both in the animals and in culture. These results indicated that BBR suppresses demyelination and loss of neurophysiological function by inhibiting the SphK1/S1P signaling pathway. The use of BBR as a treatment of MS warrant further exploration.

Expression levels of microRNA-199 and hypoxia-inducible factor-1 alpha in brain tissue of patients with intractable epilepsy.

OBJECTIVES: During the last decade, experimental evidence has demonstrated an important role of hypoxia, which leads to neuronal cell death and angiogenesis, in the mechanisms of seizure precipitation and recurrence. MicroRNA-199 targets hypoxia-inducible factor-1alpha (HIF-1α), which has recently been implicated in the pathophysiology of the hypoxic state and brain injury. However, little is known about the roles of MicroRNA-199 and HIF-1α in the human epileptogenic process. DESIGN AND METHODS: In this study, we investigated the expression of miR-199a-5p, miR-199b-5p and HIF-1α using real-time PCR, immunohistochemistry and western blots in the temporal neocortex of twenty four patients with intractable epilepsy and twelve control subjects. RESULTS: Compared with the control group, the expression of miR-199a-5p and miR-199b-5p was significantly lower in epileptic brain tissues (p < 0.05). The levels of HIF-1α mRNA and protein were highly up-regulated in epileptic brain tissues compared with those of control subjects (p < 0.05). CONCLUSION: These data suggest that the abnormal expression of miR-199 and HIF-1α in epileptic brain tissue may be involved in the pathophysiology of human epilepsy and that the expression of HIF-1α may be regulated by miR-199. These findings may provide new insights into the treatment of epilepsy.

Identification of the Human SULT Enzymes Involved in the Metabolism of Rotigotine.

Sulfation has been reported to be a major pathway for the metabolism and inactivation of rotigotine in vivo. The current study aimed to identify the human cytosolic sulfotransferase (SULT) enzyme(s) capable of mediating the sulfation of rotigotine. Of the 13 known human SULTs examined, 6 of them (SULT1A1, 1A2, 1A3, 1B1, 1C4, 1E1) displayed significant sulfating activities toward rotigotine. pH dependence and kinetic parameters of the sulfation of rotigotine by relevant human SULTs were determined. Of the 6 human organ samples tested, small intestine and liver cytosols displayed considerably higher rotigotine-sulfating activity than did brain, lung, and kidney. Moreover, sulfation of rotigotine was shown to occur in HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells under metabolic conditions. Collectively, the results obtained provided a molecular basis underlying the previous finding of the excretion of sulfated rotigotine by patients undergoing treatment with rotigotine.

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Duliang Soft Capsule in Patients with Chronic Daily Headache.

Objective. To investigate the efficacy and safety of traditional Chinese medicine Duliang soft capsule (DSC) in prophylactic treatment for patients with chronic daily headache (CDH). Methods. A multicenter, double-blind, randomized, placebo-controlled clinical study was conducted at 18 Chinese clinical centers. The participants received either DSC or placebo for 4 weeks. The primary efficacy measure was headache-free rate (HFR) in a 4-week period between the pretreatment and posttreatment stages. The secondary efficacy measures were the decrease of headache days, the duration of headache attacks, the frequency of analgesic usage, quality of life, disability, and the headache severity (VAS scores). The accompanying symptoms and adverse events were also assessed. Results. Of 584 CDH patients assessed, 468 eligible patients were randomized. 338 patients received DSC, while 111 patients were assigned in the placebo group. Following treatment, there was a 16.56% difference in HFR favoring DSC over placebo (P < 0.01). Significant differences were also observed between DSC and placebo groups in the secondary measures. However, no statistical difference was found between the two groups in the associated symptoms. No severe adverse effects were observed in the study. Conclusions. DSC might be an effective and well-tolerated option for the prophylactic treatment of patients with CDH.

Genetic polymorphisms in pre-microRNAs and risk of ischemic stroke in a Chinese population.

Ischemic stroke is considered to be a complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. MicroRNAs participated in various physiopathological processes; common single-nucleotide polymorphisms (SNPs) in pre-miRNAs have been shown to be associated with susceptibility to several human diseases. We evaluated the associations of the hsa-mir-196-a2/rs11614913 T/C, hsa-mir-146a/rs2910164 C/G, and hsa-mir-499/rs3746444 A/G polymorphisms in pre-miRNAs with the risk of ischemic stroke in a Chinese population. The three polymorphisms were identified in 296 ischemic stroke patients and 391 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The frequency of the allele G of hsa-mir-499/rs3746444 A/G showed significant association with ischemic stroke when compared with controls (OR = 1.509, 95%CI = 1.151-1.978, P = 0.003). Increased ischemic stroke risks were associated with rs3746444 A/G genotypes in different genetic model (homozygote comparison: P = 0.045, OR = 2.084, 95%CI = 1.019-4.262; heterozygote comparison: P = 0.024, OR = 1.489, 95%CI = 1.063-2.087; dominant genetic model: P = 0.007, OR = 1.563, 95%CI = 1.135-2.153). Similar results were obtained by adjusted fully risk factors. However, we failed to find any association between the alleles and genotypes of rs2910164 C/G and rs11614913 T/C SNPs and ischemic stroke, respectively (p > 0.05). The present study provided evidence that hsa-mir-499/rs3746444 A/G polymorphism might be associated with a significantly increased risk of ischemic stroke in a Chinese population, indicating that the common genetic polymorphism in pre-microRNAs contributed to the pathogenesis of ischemic stroke.