Mediation of the APOE Associations With Cognition Through Cerebral Blood Flow: The CIBL Study.

Background: The ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for aging-related cognitive decline. However, the causal connection between ε4 alleles and cognition is not well understood. The objective of this study was to identify the roles of cerebral blood flow (CBF) in cognitive-related brain areas in mediating the associations of APOE with cognition. Methods: The multiple linear regression analyses were conducted on 369 subjects (mean age of 68.8 years; 62.9% of women; 29.3% of APOE ε4 allele carriers). Causal mediation analyses with 5,000 bootstrapped iterations were conducted to explore the mediation effects. Result: APOE ε4 allele was negatively associated with cognition (P < 0.05) and CBF in the amygdala, hippocampus, middle temporal gyrus, posterior cingulate, and precuneus (all P < 0.05). The effect of the APOE genotype on cognition was partly mediated by the above CBF (all P < 0.05). Conclusion: CBF partially mediates the potential links between APOE genotype and cognition. Overall, the APOE ε4 allele may lead to a dysregulation of the vascular structure and function with reduced cerebral perfusion, which in turn leads to cognitive impairment.

Meningioma preceding CASPR2 antibody limbic encephalitis with a stroke mimic: A case report.

RATIONALE: Todd paralysis (a stroke-like presentation in some patients with epilepsy) caused by limbic encephalitis (LE) is not easily distinguished from acute ischemic stroke by clinicians in the emergency room. PATIENT CONCERNS: We report a contactin-associated protein-like 2-antibody (CASPR2-Ab)-positive patient who presented with atypical LE. DIAGNOSES: CASPR2-Ab-positive LE was the presumed diagnosis. Re-evaluation of cerebrospinal fluid (CSF) samples revealed autoantibodies targeting CASPR2 at an immunoglobulin G titer of 1:1. The clinical presentation of subacute onset seizures, abnormal electroencephalography, hypermetabolism on positron emission tomography, good immunotherapy response, and the presence of specific antibodies in serum supports a diagnosis of autoimmune LE. INTERVENTION: The patient received glucocorticoids (1 g for 3 days and 500 mg for 3 days), immunoglobulin (25 g for 3 days), sodium valproate (1 g for 3 days), and clonazepam (1 mg for 3 days). OUTCOMES: Remission of temporal lobe epilepsy symptoms and cognitive dysfunction was observed. Follow-up analysis of CSF and serological examination were not approved by the patient. His Mini-Mental State Examination score improved to 21/30. Stable remission of symptoms was achieved throughout the follow-up period of 50 days. LESSONS: Autoimmune encephalitis (AE) should be considered in cases of late-onset epilepsy following meningioma peritumoral brain edema and resection. A diagnosis of AE should be considered in patients presenting with stroke-like symptoms if the magnetic resonance imaging abnormality does not match a known vascular territory. Early and correct diagnosis is crucial because immunotherapy is usually effective for this disease.

Methyl Jasmonate Protects Microglial Cells Against ß-Amyloid-Induced Oxidative Stress and Inflammation via Nrf2-Dependent HO-1 Pathway.

BACKGROUND: ß-Amyloid (Aß) induces oxidative stress and inflammation of microglial cells, thus leading to Alzheimer's disease. Methyl jasmonate (MeJA) is reported to have anti-inflammatory and anti-oxidant effects. However, the potential roles of MeJA in Aß-induced cell activities and the underlying mechanism are unclear. METHODS: Microglial cell line BV-2 was stimulated by 20 µM Aß and/or 20 µM MeJA and then divided into four groups (control, Aß, MeJA, and Aß+MeJA). Cell viability was detected by MTT assay. MDA, SOD activity, and ROS were detected by fluorescence spectrophotometry and immunofluorescence assay. Nrf2 and HO-1 were detected by qRT-PCR and Western blot. Furthermore, inflammatory cytokines (p-NFκB, TLR4, TNF-α, IL-1ß, and IL-6) and apoptosis factors (Bcl-2, Bax, and cl-casp-3) were detected by Western blot. TUNEL assay was applied to investigate apoptosis rate. Moreover, the mechanism of how MeJA played anti-oxidative stress and anti-inflammatory roles was investigated by silencing of Nrf2 via siRNA. RESULTS: The result of MTT assay showed that MeJA improved the decreased viability of BV-2 cells induced by Aß. The detection of MDA, SOD activity, and ROS showed the oxidative stress levels were decreased in Aß+MeJA group compared with Aß group. Nrf2, HO-1, and SOD were significantly up-regulated in Aß+MeJA group compared with Aß group (p<0.01). In contrast, inflammatory cytokines were significantly down-regulated in Aß+MeJA group compared with Aß group (p<0.05). Similarly, the expressions of apoptosis cytokines and TUNEL assay suggested a decreased apoptosis rate in Aß+MeJA group compared to Aß group (p<0.01). Finally, results of Nrf2 knockdown experiment showed down-regulations of anti-oxidative stress factors (Nrf2, HO-1 and SOD), up-regulations of inflammatory cytokines, and increased ratio of Bax to Bcl in Aß+MeJA+si-Nrf2 group compared with Aß+MeJA group (p<0.01). CONCLUSION: MeJA could relieve Aß-induced oxidative stress and inflammatory response in microglial cells by activating Nrf2/HO-1 pathway.

Clinical observation of regular intermittent epidural injection combined with different puncture points in suppressing breakthrough pain in labour analgesia.

The aim of the current study was to evaluate the clinical effects of the regular intermittent epidural injection combined with different puncture points (RIEI-dPP) in suppressing breakthrough pain during a labour analgesia. A total of 90 primipara were randomly divided into three groups (n = 30): Group L2-3 (A), Group L3-4 (B) and Group L4-5 (C). The analgesic pump parameters were set as: impact dose 8 mL, locking time 15 minutes, background dose 0, and the additional impact dose 8 mL after each hour intermittence. The pain's visual analogue scale (VAS), breakthrough pain, maximum block segment, modified Bromage score, labour duration and the neonatal Apgar score were recorded and compared. Compared with the pre-analgesia time, the VAS scores were found to be significantly decreased in the three groups (p < .05), but there were significant differences among the three groups (p > .05). During analgesia, the maximum block segment in Group C was more significantly reduced than in the other two groups (p > .05), but there was no significant difference in the breakthrough pain among the three groups (p > .05). The comparison of other indexes among the three groups showed there was no significant difference (p > .05). RIEI-dPP at L2-3, L3-4 and L4-5 during labour analgesia can effectively inhibit breakthrough pain. Impact Statement What is already known on this subject? According to human anatomical features, the injection speed and capacity are the prerequisite for obtaining the ideal block range. Experiments confirm that a more uniform and wider drug distribution can be achieved by epidural intermittent rapid infusion with higher injection pressure than a continuous infusion with low injection pressure. Compared with the continuous epidural administration mode, the regular intermittent epidural injection mode can better inhibit breakthrough pain with a lower amount of anaesthetic. What the results of this study add? Similar labour analgesic effects can be achieved by regular intermittent epidural injection mode with different puncture points. What the implications are of these findings for clinical practice and/or further research? Compared with a continuous infusion, a regular intermittent epidural injection can achieve a more uniform drug distribution in the epidural space, so the block range can be more extensive, which can not only reduce the amount of anaesthetic but also effectively reduce the incidence of breakthrough pain. However, the selection of an intervertebral puncture site still lacks a uniform standard. The outcomes of this study can directly verify that regular intermittent epidural injection at L2-3, L3-4 and L4-5 can effectively inhibit breakthrough pain and achieve good analgesic effects, so selecting the intervertebral space with clear anatomical structure positioning and easier puncture pathway can benefit a labour analgesia.

MicroRNA­296 targets AKT2 in pancreatic cancer and functions as a potential tumor suppressor.

Although microRNA-296 (miR-296) has been studied in various types of human cancer, its expression, biological role and mechanism of action in pancreatic cancer remains to be elucidated. The aim of the current study was to investigate the expression level, possible roles and underlying molecular mechanisms of miR­296 in pancreatic cancer. The present study revealed that miR­296 is significantly downregulated in tissue from patients with pancreatic cancer and in human pancreatic carcinoma cell lines, when compared with matched healthy tissue and normal human pancreatic cell lines, respectively. In addition, restoration of miR­296 expression was revealed to inhibit the proliferation, migration and invasive activity of pancreatic cancer cells. Furthermore, bioinformatics analysis and a luciferase reporter assay validated the AKT2 gene as a direct target of miR­296 in pancreatic cancer. Reverse transcription­quantitative polymerase chain reaction and western blot analysis revealed that miR­296 was able to decrease AKT2 expression at the post­transcriptional level. Notably, the effects of AKT2 knockdown were similar to miR­296 overexpression in pancreatic cancer. In conclusion, the present findings indicate a role for miR­296 as a tumor suppressor in pancreatic cancer through directly targeting AKT2, thus suggesting that miR­296 may serve as a potential therapeutic target for the treatment of pancreatic cancer.

Erythropoietin Modification Enhances the Protection of Mesenchymal Stem Cells on Diabetic Rat-Derived Schwann Cells: Implications for Diabetic Neuropathy.

Diabetes-triggered apoptosis of Schwann cells (SC) contributes to the degradation of diabetic peripheral neuropathy (DNP). In recent years, mesenchymal stem cells (MSC) were applied to DPN repair and it was demonstrated that paracrine secretion played a key role in neuroprotection exerted by MSC. Erythropoietin (EPO) is a potent cytokine capable of reducing apoptosis of SC. However, the expression of EPO in MSC is limited. In this study, we hypothesized that overexpression of EPO in MSC (EPO-MSC) may significantly improve their neuroprotective potentials. The EPO overexpression in MSC was achieved by lentivirus transduction. SC derived from the periphery nerve of diabetic rats were cocultured with MSC or EPO-MSC in normal or high glucose culture condition, respectively. In normal glucose culture condition, the overexpression of EPO in MSC promoted the MSC-induced restoration of SC from diabetic rats, including increases in GSH level and cell viability, decrease in TUNEL apoptosis, upregulation of antiapoptotic proteins, p-Akt, and Bcl-2, and downregulation of proapoptotic proteins, cleaved caspase-3, and Bax. The subsequent results in high glucose culture condition showed similar promotions achieved by EPO-MSC. Thus, it could be concluded that EPO-MSC possessed a potent potential in hampering apoptosis of SC, and the suppression was probably attributed to attenuating oxidative stress and regulating apoptosis related protein factors.

Simultaneous Determination of Salicylic Acid, Jasmonic Acid, Methyl Salicylate, and Methyl Jasmonate from Ulmus pumila Leaves by GC-MS.

Salicylic acid, jasmonic acid, methyl salicylate, and methyl jasmonate are important phytohormones and defensive signaling compounds, so it is of great importance to determine their levels rapidly and accurately. The study uses Ulmus pumila leaves infected by Tetraneura akinire Sasaki at different stages as materials; after extraction with 80% methanol and ethyl acetate and purification with primary secondary amine (PSA) and graphitized carbon blacks (GCB), the contents of signal compounds salicylic acid, jasmonic acid, methyl salicylate, and methyl jasmonate were determined by GC-MS. The results showed that the level of salicylic acid, jasmonic acid, methyl salicylate, and methyl jasmonate increased remarkably in U. pumila once infected by T. akinire Sasaki, but the maximums of these four compounds occurred at different times. Salicylic acid level reached the highest at the early stage, and jasmonic acid level went to the maximum in the middle stage; by contrast, change of content of methyl salicylate and methyl jasmonate was the quite opposite.

[Enzyme change in bronchoalveolar lavage fluid of pneumocystis pneumonia rats and the effect of garlicin treatment].

OBJECTIVE: To study the change of enzymes and effect of garlicin treatment on the change in bronchoalveolar lavage fluid (BALF) of rats with Pneumocystis carinii pneumonia (PCP). METHODS: Wistar rats were injected intramuscularly continually with dexamethasone to establish the rat model of PCP. The experimental rats (group A) were injected intramuscularly with garlicin at a dose of 10 mg/(kg x d) for 5 days in the 3rd, 6th and 9th week respectively, and SMZ/TMP therapy group (B), PCP infected group (C) and normal group (D) were established as controls. Three days after the last treatment, the rats of all groups were killed and BALF was collected without contamination and enzymes AST, ALF, CHE, ALP, LDH, CK, CKMB, HBDH, AFU, 5'NT, ADA were examined. RESULTS: The ALP level in group C [(573.41 +/- 350.63)U/L] was significantly higher than that in group D [(210.56 +/- 114.41) U/L] (q = 4.682, P < 0.01), group A [(392.07 +/- 217.57) U/L] (q = 3.851, P < 0.05), and group B [(325.21 +/- 180.65) U/L] (q = 4.380, P < 0.01); the level of CK, CKMB and 5'NT in group C [948.94 +/- 403.43, 489.47 +/- 254.46 and (6.76 +/- 3.11) U/L respectively] was higher than those in group D [426.22 +/- 319.00, 213.33 +/- 144.54 and (3.22 +/- 1.20) U/L] (q = 4.696, 3.784, 3.812, P< 0.05); there was no significant difference in the level of AST, ALT, CHE, LDH, HBDH, AFU and ADA among the four groups (F = 1.852, 0.958, 2.470, 1.423, 1.178, 1.342, 0.611, P > 0.05). CONCLUSIONS: The level of ALP, CK, CKMB but the ALP level decreases distinctly after the garlicin and 5'NT increases evidently in BALF of PCP infected rats, but the ALP level decreases distinctly after the garlicin treatment.

[A study on genetic epidemiology of cerebral infarction].

OBJECTIVE: To explore the genetic model of cerebral infarction and to examine the relationship between cerebral infarction and genetic factor. METHODS: A matched case-control study including 112 pairs pedigrees was carried out. Using the Li-Mantel-Gart method and the Falconer method to estimate the segregation ratio and the heritability of cerebral infarction. RESULTS: The prevalence rate of the first-degree and the second-degree relatives in cases was significantly higher than that in controls. The segregation ratio was 0.143 7 (0.113 0 - 0.174 4), significantly lower than 0.25, which showed that cerebral infarction did not possess the characteristics of monogenetic model. The results showed that the heritability of the first-degree and the second-degree relatives were 47.84% and 40.95% higher in male's than in female's. CONCLUSION: Cerebral infarction was a polygenetic disease, and the genetic factors played an important role in the occurrence of cerebral infarction, especially in males.