Disruption of sphingomyelin synthase 2 gene alleviates cognitive impairment in a mouse model of Alzheimer's disease.

The membrane raft accommodates the key enzymes synthesizing amyloid ß (Aß). One of the two characteristic components of the membrane raft, cholesterol, is well known to promote the key enzymes that produce amyloid-ß (Aß) and exacerbate Alzheimer's disease (AD) pathogenesis. Given that the raft is a physicochemical platform for the sound functioning of embedded bioactive proteins, the other major lipid component sphingomyelin may also be involved in AD. Here we knocked out the sphingomyelin synthase 2 gene (SMS2) in 3xTg AD model mice by hybridization, yielding SMS2KO mice (4S mice). The novel object recognition test in 9/10-month-old 4S mice showed that cognitive impairment in 3xTg mice was alleviated by SMS2KO, though performance in the Morris water maze (MWM) was not improved. The tail suspension test detected a depressive trait in 4S mice, which may have hindered the manifestation of performance in the wet, stressful environment of MWM. In the hippocampal CA1, hyperexcitability in 3xTg was also found alleviated by SMS2KO. In the hippocampal dentate gyrus of 4S mice, the number of neurons positive with intracellular Aß or its precursor proteins, the hallmark of young 3xTg mice, is reduced to one-third, suggesting an SMS2KO-led suppression of syntheses of those peptides in the dentate gyrus. Although we previously reported that large-conductance calcium-activated potassium (BK) channels are suppressed in 3xTg mice and their recovery relates to cognitive amelioration, no changes occurred by hybridization. Sphingomyelin in the membrane raft may serve as a novel target for AD drugs.

Is the incident of once chronic obstructive pulmonary disease related admission a high risk for readmission in the future?

Background: Although it is known that a history of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the most important predictor of future risk of AECOPD and readmission to hospitals, there is no scientific evidence that an event of only one chronic obstructive pulmonary disease (COPD)-related admission is a high risk of future readmission. We retrospectively analyzed the association of an incident of one COPD-related admission with future readmission risk. Methods: This is a retrospective study. The data of AECOPD-related admissions and readmissions during 5 years were obtained and analyzed for the admission frequencies of patients with AECOPD and an association of the admission history with a future readmission risk. Results: The admission frequency of patients with frequent admission (3 or more admissions within 5 years) was 4.1 times that of those with non-frequent admission (0.95 vs. 0.23 times per person per year). In each calendar year during the 5-year study period, most patients (88.2%) were hospitalized only once, and 11.8% had two or more admissions. Nevertheless, their average number of admissions in each calendar year was 3.3 times that of those who only had one admission each year (3.33 vs. 1.00 times per person per year). More importantly, the positive predictive value for future readmission due to AECOPD was only 14.8% in those who had one admission in the previous year. The patients with the greater readmission risk were those with two or more admissions due to AECOPD in the previous year [crude odds ratio (OR): 4.10, 95% confidence interval (CI): 1.24-13.58 and 7.51, 95% CI: 3.81-16.68]. Conclusions: There is a subtype of frequent admission due to AECOPD, and it can be distinguished by having three or more admissions in the past 5 years or two or more admissions in the previous year. Nevertheless, an incident of admission once a year is not a good predictor of future readmission.

Antibacterial and anti-inflammatory activities of chitosan/copper complex coating on medical catheters: In vitro and in vivo.

Copper ions (Cu) grafted chitosan coating was prepared using the pneumatic spraying method on the silicone rubber surface. Coating's surface properties, morphology, composition, Cu releasing behavior, antibacterial, and anti-inflammatory activities are investigated and discussed. Surface properties, composition, and morphology were investigated by scanning electron microscopy (SEM) and contact angle measurements. The antibacterial activity has been tested with Escherichia coli and Staphylococcus aureus suspensions in vitro. Besides, the morphology of the biofilm was inspected with a field emission SEM. To evaluate the anti-inflammatory activity and biosafety of the coating in vivo, the optimized coating samples and control groups were implanted subcutaneously into the back of mice. The bacterial environment model was established by injection of the bacterial suspension. The morphology and bacterial adhered on the surface of catheters and the surrounding tissues were analyzed after 5 days of implantation. As in vitro results, the number of adhered bacterial on the surface of the silicon rubber surface was decreased, and the anti-inflammatory rate was increased by the intensify of the Cu content in chitosan coating. As for in vivo results, after 5 days of implantation, there was no evident inflammation in the surrounding tissues of all catheters in all without the S. aureus injected group. In the injected chitosan/Cu coated group; the inflammation, the number of the adhered bacteria were observed less than other injected samples without Cu; no inflammation were noticeable. Results indicate that the Cu-modified chitosan coating can confer excellent antibacterial and anti-inflammatory activity as applied on medical catheters.

MicroRNA-1298-3p inhibits proliferation and invasion of glioma cells by downregulating Nidogen-1.

Glioma is the most prevalent tumor of the central nervous system. To identify differentially expressed miRNAs (DEMs) in gliomas of different grades, bioinformatics analysis was performed. The DEMs between low-grade gliomas (LGGs) and high-grade gliomas (HGGs) were identified by screening the Gene Expression Omnibus and The Cancer Genome Atlas databases using the LIMMA package. Six overlapping DEMs were identified by comparing LGGs and HGGs. Downregulation of miR-1298-3p correlated with poor overall survival rates in glioma patients. Overexpression of miR-1298-3p induced apoptosis of glioma cells and inhibited glioma cell proliferation, migration, and invasion. The basement membrane protein Nidogen-1 (NID1) was identified as a direct binding target of miR-1298-3p in glioma cells. MiR-1298-3p agonist downregulated the NID1 and vimentin levels, but upregulated the level of E-cadherin in glioma cells. Importantly, overexpression of miR-1298-3p induced apoptosis and reduced tumor growth in a mouse xenograft model of glioma. Our results show that miR-1298-3p functions as a tumor suppressor in glioma cells, and suggest that it might serve as a potential biomarker and therapeutic target in glioma patients.

Effects of lycopene on vascular remodeling through the LXR-PI3K-AKT signaling pathway in APP/PS1 mice.

Alzheimer's disease (AD) is the commonest neurodegenerative disease and, in recent years, studies have increasingly shown that vascular lesions are involved in the pathology of AD onset and progression. Many vascular changes precede the pathological changes and clinical symptoms of AD, and vascular lesions and AD have many common risk factors. Understanding the relationship between vascular factors and the pathological process of AD may help us to identify novel prevention and treatment strategies as well as delay disease progress. Previous studies have shown that lycopene has neuroprotective, antioxidant, and anticancer effects; however, the specific molecular mechanism mediating these effects remains unknown. In the present study, we found: 1) lycopene improved learning and memory in an AD mouse model; 2) lycopene inhibited amyloid plaque aggregation and neuroinflammation; and 3) lycopene induced LXR expression and activated the LXR-PI3K-AKT signaling pathway. Our findings suggest that promotion of neurogenesis and improvement of the functions of the neurovascular unit could be a novel direction for the development of AD therapies.

Multiple secondary cauda equina non-Hodgkin's lymphoma: a case report and literature review.

BACKGROUND: Secondary central nervous system involvement of non-Hodgkin's lymphoma (NHL) is rare and with poor prognosis, the most common pathological type is diffuse large B cell lymphoma (DLBCL). Although it can occur in any part of central nervous system, it rarely directly infiltrates the spinal cord or cauda equina. CASE PRESENTATION: We present the case of 64-year-old immunocompetent man with a worsening pain of waist and left lower extremity, accompanied by numbness and paresis of bilateral lower extremity for 20 days. His previous medical history included a resection of painless mass in the left groin in another hospital 7 months ago, and the pathological diagnosis was non-Hodgkin small B cell lymphoma. Gd-enhanced MRI and F-18 FDG PET-CT scan demonstrated multiple infiltrations in the cauda equina. During the operation, we removed as many as 11 subdural-extramedullary bean-size lesions involving multiple nerve roots. The paralysis of his left leg recovered rapidly after the operation. During the follow-up period of more than one year, he underwent standard R-CHOP chemical therapy, no evidence of recurrence was noted until the 13th month, the patient died because of intracranial relapse. CONCLUSIONS: Imaging examination is important in the diagnosis of multiple secondary cauda equina non-Hodgkin's lymphoma, and we highlight the significance of gadolinium-enhanced MRI and F-18 FDG-PET/CT in preoperative diagnosis as well as the previous history.

Association between glaucoma and the risk of Alzheimer's disease: A systematic review of observational studies.

To address inconsistency as well as investigate the relationship between glaucoma and the risk of Alzheimer's disease (AD). We systematically conducted this meta-analysis based on observational studies published up to 15 January 2018, identified from PubMed and Web of Science. Two team members independently extracted the data and assessed the quality of each included study. Summary relative risk (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model. Eight observational studies with 6870 AD cases were included. The majority of these studies (n = 6) were graded as low risk according to the Newcastle-Ottawa Quality Assessment Scale. Individuals diagnosed with glaucoma, compared to those who were not, had an increased risk of AD (RR = 1.52; 95% CI: 1.41-1.63; I2  = 97%, p < 0.001). A significant finding was also observed for primary open-angle glaucoma (RR = 1.52; 95% CI: 1.41-1.63; I2  = 97%, p < 0.001). However, when stratified by study design, only the case-control studies (RR = 1.08; 95% CI: 0.89-1.31; I2  = 37.3%, p = 0.207) yielded significant results, while the cohort studies did not (RR = 1.08; 95% CI: 0.89-1.31; I2  = 97.7%, p < 0.001). Of note, our meta-regression analysis suggested that study design might be a source of heterogeneity (p = 0.009). Additionally, a significantly positive association was observed when the analyses were restricted to Asia (RR = 2.03; 95% CI: 1.02-4.07). There was no significant publication bias in these analyses. Recent evidence suggests that glaucoma may increase the risk of AD. Additional cohort studies are needed to confirm these findings and to have improved knowledge on the true nature of this association.

Stressful learning paradigm precludes manifestation of cognitive ability in sphingomyelin synthase-2 knockout mice.

Sphingomyelin synthases (SMSs) are enzymes converting ceramide to sphingomyelin. The behavioral phenotype attributed to their disruption has not been well described. We examined learning ability and hippocampal synaptic plasticity in mice deficient in SMS2 (SMS2 KO). In context-dependent fear learning and novel object recognition test, no difference in learning ability was detected in SMS2 KO and wild-type (WT) mice. By contrast, achievement of the Morris water maze (MWM) test was deteriorated in SMS2 KO mice. In the hippocampal CA1, while the basic synaptic transmission was normal, both short- and long-term synaptic plasticity was moderately suppressed. We interpret that the MWM test taking place in wet environment may represent learning paradigm under more stressful condition than those performed in dry conditions, and that the learning ability of SMS2 KO mice failed to manifest itself fully in stressful situations. In agreement, forced swimming induced depression-like behavior more easily in SMS2 KO mice. Mass spectrometry suggested a slightly altered species distribution of ceramide in the hippocampus of SMS2 KO mice. These findings support the proposal that altered synthesis of ceramide, which is the substrate of SMS2 and therefore expected to be modified in SMS2 KO mice, is associated with depression-like tendency in animal models and depressive disorder in humans.

Learning impairment by minimal cortical injury in a mouse model of Alzheimer's disease.

Brain injury accelerates amyloid-ß (Aß) deposits and exacerbates Alzheimer's disease (AD). Accumulation of intracellular soluble Aß impairs cognition prior to emergence of Aß plaques. However, it is not known whether brain injury affects learning impairment attributable to intracellular soluble Aß. We made a small injury by injecting glutamate into the parietal cortex in 3xTg AD mice of 4-5 months old, at which age soluble Aß is accumulated without Aß deposits. The size of glutamate-induced lesion was significantly larger than that of saline-injected control lesion. We reduced the relative difficulty of Morris water maze (MWM) task by repeating it twice, so that saline-injected 3xTg mice could perform as well as wild-type control mice. Under this condition, glutamate-injected 3xTg mice exhibited learning deficits. DNA microarray analysis revealed that 3 genes are upregulated, with one gene downregulated, more than 2 folds in the hippocampus. These 4 genes do not appear to be involved directly in learning but may be a part of signal cascade triggered by glutamate-induced small injury. Hippocampal content of soluble Aß1-42 was increased in the glutamate 3xTg group. Facilitation of large-conductance calcium-activated potassium (BK) channel accompanied learning recovery in the saline-control 3xTg group in agreement with our previous reports, in which learning deficits attributable to intracellular Aß were alleviated by facilitating BK channels. However, BK channel remained suppressed in the glutamate 3xTg group. It is suggested that glutamate-induced injury worsens learning by enhancing the toxicity of soluble Aß or increasing its content per se.

Cognitive Improvement by Photic Stimulation in a Mouse Model of Alzheimer's Disease.

We previously reported that activity of the large conductance calcium-activated potassium (big-K, BK) channel is suppressed by intracellular Aß in cortical pyramidal cells, and that this suppression was reversed by expression of the scaffold protein Homer1a in 3xTg Alzheimer's disease model mice. Homer1a is known to be expressed by physiological photic stimulation (PS) as well. The possibility thus arises that PS also reverses Aß-induced suppression of BK channels, and thereby improves cognition in 3xTg mice. This possibility was tested here. Chronic application of 6-hour-long PS (frequency, 2 Hz; duty cycle, about 1/10; luminance, 300 lx) daily for 4 weeks improved contextual and tone-dependent fear memory in 3xTg mice and, to a lesser extent, Morris water maze performance as well. Hippocampal long-term potentiation was also enhanced after PS. BK channel activity in cingulate cortex pyramidal cells and lateral amygdalar principal cells, suppressed in 3xTg mice, were facilitated. In parallel, neuronal excitability, elevated in 3xTg mice, was recovered to the control level. Gene expression of BK channel, as well as that of the scaffold protein Homer1a, was found decreased in 3xTg mice and reversed by PS. It is known that Homer1a is an activity-dependently inducible immediate early gene product. Consistently, our previous findings showed that Homer1a induced by electrical stimulation facilitated BK channels. By using Homer1a knockouts, we showed that the present PS-induced BK channel facilitation is mediated by Homer1a expression. We thus propose that PS might be potentially useful as a non-invasive therapeutic measure against Alzheimer's disease.

Patterning of robust self-assembled n-type hexaazatrinaphthylene-based nanorods and nanowires by microcontact printing.

The one-dimensional (1-D) self-assembly property of an n-type hexaazatrinaphthylene (HATNA) discotic pi-conjugated molecule was studied. Structurally robust unimolecular columnar stacks of HATNA with tunable length have been fabricated through a combination of supramolecular self-assembly and post-polymerization approach. Moreover, microcontact printing can be utilized to transfer the self-assembled nanostructures to the surface to create desired functional patterns.