Glymphatic clearance function in patients with cerebral small vessel disease.

Few studies have focused on the connection between glymphatic dysfunction and cerebral small vessel disease (CSVD), partially due to the lack of non-invasive methods to measure glymphatic function. We established modified index for diffusion tensor image analysis along the perivascular space (mALPS-index), which was calculated on diffusion tensor image (DTI), compared it with the classical detection of glymphatic clearance function calculated on Glymphatic MRI after intrathecal administration of gadolinium (study 1), and analyzed the relationship between CSVD imaging markers and mALPS-index in CSVD patients from the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) (study 2). Among 39 patients included in study 1, mALPS-index were significantly related to glymphatic clearance function calculated on Glymphatic MRI ( r  = -0.772~-0.844, p < 0.001). A total of 330 CSVD patients were included in study 2. Severer periventricular and deep white matter hyperintensities (ß = -0.332, p < 0.001; ß = -0.293, p < 0.001), number of lacunas (ß = -0.215, p < 0.001), number of microbleeds (ß = -0.152, p = 0.005), and severer enlarged perivascular spaces in basal ganglia (ß = -0.223, p < 0.001) were related to mALPS-index. Our results indicated that non-invasive mALPS-index might represent glymphatic clearance function, which could be applied in clinic in future. Glymphatic clearance function might play a role in the development of CSVD.

Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human.

OBJECTIVE: Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain. METHODS: In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1-weighted imaging was performed to assess the function of the glymphatic pathway and head high-resolution T2-fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging. RESULTS: In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05). INTERPRETATION: We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357-369.

Comparison of various reconstructions derived from dual-energy CT immediately after endovascular treatment of acute ischemic stroke in predicting hemorrhage.

OBJECTIVES: Predicting 24-h hemorrhage immediately after endovascular treatment (EVT) of ischemic stroke is important but difficult for clinicians. We thus aimed to identify better image markers in predicting hemorrhage from different reconstructions derived from dual-energy CT. METHODS: We reviewed our prospectively collected database for anterior circulation ischemic stroke patients who received EVT and analyzed patients who underwent dual-energy CT immediately after EVT. Parenchymal hyperdensities were assessed on non-contrast CT and virtual non-contrast (VNC) which was constructed from dual-energy CT, respectively. Metallic hyperdensity sign was defined when a maximum density > 90 Hounsfield units was identified within the nonpetechial intracerebral hyperdense lesion in the basal ganglia on non-contrast CT. RESULTS: A total of 147 patients were included. Hemorrhagic transformation (HT) was identified in 81 (55.1%) patients, and parenchymal hemorrhage (PH) in 35 (23.8%) patients. The rate of HT at 24 h was higher in patients with parenchymal hyperdensities on non-contrast CT or VNC or with metallic hyperdensity sign than those without (72.4% vs 11.9%, p < 0.001; 82.0% vs 41.2%, p < 0.001; 100.0% vs 44.5%, p < 0.001). Parenchymal hyperdensities on non-contrast CT had a higher accuracy in predicting HT than those on VNC (76.9% vs 66.7%). Metallic hyperdensity sign on non-contrast CT also had a higher accuracy in predicting PH than parenchymal hyperdensities on VNC (88.4% vs 69.4%). CONCLUSIONS: Image markers on non-contrast CT (parenchymal hyperdensities and metallic hyperdensity sign) performed immediately post-EVT of ischemic stroke might be not inferior to dual-energy CT (parenchymal hyperdensities) to predict follow-up hemorrhage. KEY POINTS: • Image markers (parenchymal hyperdensities and metallic hyperdensity sign) on NCCT performed immediately post-EVT of ischemic stroke can predict follow-up hemorrhage. • Metallic hyperdensity sign on NCCT can accurately predict parenchymal hemorrhage. • Parenchymal hyperdensities on NCCT can accurately predict hemorrhagic transformation.

A prognostic nomogram in patients with distant metastasis of pancreatic neuroendocrine tumors: a population-based study.

Aim: Prognostic factors in patients with distant metastatic pancreatic neuroendocrine tumors (PNETs) remain uncertain. The purpose of our study is to establish a nomogram to predict survival outcomes in patients with metastatic PNETs. Methods: A total of 878 patients diagnosed with PNETs in the Surveillance, Epidemiology and End Results database between 2004 and 2016 were retrospectively identified. The Kaplan-Meier survival analysis with log-rank test was used to analyze survival outcomes. The nomogram was established after a univariate and multivariate Cox analysis. Results: The independent prognostic variables, including age, tumor grade and primary site surgery were applied to develop a nomogram. The original concordance index was 0.773 (95% CI: 0.751-0.795), and the bias-corrected concordance index was 0.769 (95% CI: 0.748-0.791). The internal calibration curves showed well consistency and veracity in predicting cancer-specific survival probabilities. Conclusion: A nomogram was constructed and verified to predict survival outcomes in patients with distant-stage PNETs.

Stress-Induced Hyperglycemia and Remote Diffusion-Weighted Imaging Lesions in Primary Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Stress-induced hyperglycemia (SIH) is the relative transient increase in glucose during a critical illness such as intracerebral hemorrhage (ICH) and is likely to play an important role in the pathogenesis of remote diffusion-weighted imaging (DWI) lesion (R-DWIL) in primary ICH. We sought to determine the association between SIH and the occurrence of R-DWILs. METHODS: We prospectively enrolled primary ICH patients within 14 days after onset from November 2016 to May 2018. In these patients, cerebral magnetic resonance imaging was performed within 14 days after ICH onset. R-DWIL was defined as a hyperintensity signal in DWI with corresponding hypointensity in apparent diffusion coefficient, and at least 20 mm apart from the hematoma. SIH was measured by stress-induced hyperglycemia ratio (SHR). SHR was calculated by fasting blood glucose (FBG) divided by estimated average glucose derived from glycosylated hemoglobin. The included patients were dichotomized into two groups by the 50th percentile of SHR, and named as SHR (-P50) group and SHR (P50+) group, respectively. We evaluated the association between SHR and R-DWIL occurrence using multivariable logistic regression modeling adjusted for potential confounders. RESULTS: Among the 288 patients enrolled, forty-six (16.0%) of them had one or more R-DWILs. Compared with the patients in the lower 50% of SHR (SHR [-P50]), the odds ratio (OR) [95% confidence interval (CI)] for the higher 50% of SHR (SHR [P50+]) group for R-DWIL occurrence was 3.13 (1.39-7.07) in the total population and 6.33 (2.19-18.30) in population absent of background hyperglycemia after adjusting for potential covariates. Similar results were observed after further adjusted for FBG. CONCLUSIONS: Our study demonstrated that SIH was associated with the occurrence of R-DWILs in patients with primary ICH within 14 days of symptom onset.

Different mechanisms in periventricular and deep white matter hyperintensities in old subjects.

Objective: Although multiple pieces of evidence have suggested that there are different mechanisms in periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs), the exact mechanism remains uncertain. Methods: We reviewed clinical and imaging data of old participants from a local She Ethnic group. We assessed the cerebral blood flow of white matter (WM-CBF) on arterial spin-labeling, deep medullary veins (DMVs) visual score on susceptibility-weighted imaging, and index for diffusion tensor image analysis along the perivascular space (ALPS index), indicating glymphatic function on diffusion tensor imaging. Furthermore, we investigated their relationships with volumes of PWMHs and DWMHs. Results: A total of 152 subjects were included, with an average age of 63 ± 8 years old. We found that higher age and history of hypertension were independently related to higher volumes of both PWMHs and DWMHs (all p < 0.05). Lower ALPS index was independently associated with higher PWMHs volumes (ß = 0.305, p < 0.001), and this relationship was accounted for by the indirect pathway via DMVs score (ß = 0.176, p = 0.017). Both lower ALPS index and WM-CBF were independent risk factors for higher DWMHs volumes (ß = -0.146, p = 0.041; ß = -0.147, p = 0.036). Conclusions: Our study indicated that there were different mechanisms in PWMHs and DWMHs. PWMHs were mainly attributed to the damage of veins due to the dysfunction of the glymphatic pathway, while DWMHs could be affected by both ischemia-hypoperfusion and dysfunction of the glymphatic pathway. Advances in knowledge: The relationship between glymphatic dysfunction and PWMHs might be accounted for by the indirect pathway via venous abnormalities, a glymphatic dysfunction, and lower CBF in white matter were independent risk factors for DWMHs.

The neuroprotective effect of propofol against brain ischemia mediated by the glutamatergic signaling pathway in rats.

Several mechanisms are involved in the neuroprotection of propofol against ischemia, but influences of propofol on the binding properties of glutamate receptors and the uptake of glutamate in brain ischemia are not known. The present study was undertaken to investigate these issues in rat global brain ischemic model using methods of neuropathological evaluation, radioligand binding assay with and uptake test for L-(3)H-glutamate. It was shown that propofol used in anesthetic doses protected pyramidal neurons in the hippocampal CA1 subfield against delayed neuronal death normally induced by global brain ischemia. Simultaneously, the propofol decreased the value of maximal number of binding sites (Bmax), increased the value of equilibrium dissociation constant (Kd), and increased the glutamate uptake in the CA1 subfield. These findings indicate that it is, at least partly, via modulating the binding properties of glutamate receptors and the uptake of glutamate that propofol protects neurons against ischemic injury.

Reduced field-of-view diffusion-weighted imaging (DWI) in patients with gastric cancer: Comparison with conventional DWI techniques at 3.0T: A preliminary study.

To evaluate the qualitative image quality and quantitative apparent diffusion coefficient (ADC) value of reduced field-of view (rFOV) and full field-of-view (fFOV) diffusion-weighted imaging (DWI) sequences at 3.0 T in patients with gastric cancer.Fifty-three patients (37 males, 16 females; mean age, 63.3 ±â€Š10.3 years) with 60 lesions with gastric cancer who underwent magnetic resonance (MR) scans, including both rFOV-DWI and fFOV-DWI, were retrospectively analyzed. Two observers subjectively evaluated image quality for both the fFOV-DWI and rFOV-DWI sequences regarding the anatomic details, distortion, lesion conspicuity, artifacts, and overall image quality. The mean ADC values of gastric cancer were calculated. The Wilcoxon test and paired samples t test were used. Interobserver agreement was assessed using kappa statistics.The mean scores based on the 2 observers demonstrated significant differences in image quality in terms of anatomic details, distortion, lesion conspicuity, artifacts and overall image quality at both b values between rFOV-DWI and fFOV-DWI (P < .05) in the whole gastric area. rFOV-DWI yielded significantly better scores in image quality at b = 800 seconds/mm (P < .05) in patients with esophagogastric junction cancers, but there were no significant differences in the gastric corpus and gastric antrum region. The mean tumor ADC values of rFOV-DWI were significantly lower than those of fFOV-DWI (1.237 ±â€Š0.228 × 10-3 mm/second vs 1.683 ±â€Š0.322 × 10-3 mm/second, P < .001).rFOV-DWI yielded significantly better image quality (anatomic details, distortion, lesion conspicuity, artifacts, overall image quality) and more accurate ADC measurements than fFOV-DWI did.

Dual-Effect of Magnetic Resonance Imaging Reporter Gene in Diagnosis and Treatment of Hepatocellular Carcinoma.

PROPOSE: The early diagnosis of hepatocellular carcinoma (HCC) with ferritin heavy chain (Fth) modified by alpha-fetoprotein (AFP) promoter has been studied. However, no study has focused on the considerable upregulation and specific targeting effects of transferrin receptors (TfR) caused by the transfection of plasmids encoded with the AFP promoter. Thus, the objective of our study was to investigate whether the transfection of Fth gene modified with AFP promoter (AFP@Fth) could be used for early diagnosis and enhanced treatment of HCC. METHODS: The AFP@Fth plasmid was transfected into AFP positive cells. The expression of intracellular Ferritin was verified by Western blot, and the upregulation of TfR was confirmed by immunofluorescence and flow cytometry analysis. Cellular iron accumulation resulting in decreased imaging signals was examined by magnetic resonance imagining. Doxorubicin liposome modified with transferrin (Tf-LPD) was prepared to investigate the efficiency of the subsequent treatment after transfection. The enhanced drug distribution and effects were investigated both in vitro and in vivo. RESULTS: Both Ferritin and TfR were overexpressed after transfection. The transfected cells showed higher intracellular iron accumulation and resulted in a lower MR T2-weighted imaging (T2WI) intensity, suggesting that the transfection of AFP@Fth could be a potential strategy for early diagnosis of liver cancer. The following treatment efficacy was revealed by Tf-LPD. As compared with un-transfected cells, transfected cells exhibited higher uptake of transferrin-modified liposomes (Tf-LP), which was due to the specific interaction between Tf and TfR overexpressed on the transfected cells. This is also the reason why Tf-LPD showed better in vitro and in vivo anticancer ability than doxorubicin loaded liposome (LPD). These results suggested that transfection of AFP@Fth could result in enhanced therapy of liver cancer. CONCLUSION: Transfection of AFP@Fth could be used for early diagnosis and for enhanced treatment of live cancers.

Early elevated neutrophil-to-lymphocyte ratio associated with remote diffusion-weighted imaging lesions in acute intracerebral hemorrhage.

AIMS: To explore the relationship between the circulating neutrophil-to-lymphocyte ratio (NLR) and the remote diffusion-weighted imaging lesions (R-DWILs) after spontaneous intracerebral hemorrhage (ICH). METHODS: Consecutive patients with spontaneous ICH were prospectively collected from November 2016 to May 2018 and retrospectively analyzed. We included subjects who presented within 24 hours after symptom onset and were free of detectable infections on admission or in hospital. Blood samples were obtained at 24-48 hours after ICH ictus, while all complete MRI scans were performed at 5-8 days. R-DWILs were defined as focal hyperintensities remote from the site of the ICH or the peri-hematoma regions. NLR was calculated by dividing the absolute neutrophil counts by the absolute lymphocyte counts. Multivariate binary logistic regression models were generated to evaluate the relationship between NLR and R-DWILs. RESULTS: One hundred sixty-three subjects met eligibility criteria (age 62.3 ± 13.6 years, 60.7% males), of whom 31(19.0%) experienced R-DWILs. Higher circulating NLR was documented in patients with R-DWILs. With the best cutoff value of 6.01, elevated NLR was independently associated with the presence of R-DWILs (OR = 3.170, 95% CI 1.306-7.697, P = .011) in the bivariate logistic regression analysis with adjustment for age, sex, atrial fibrillation, previous ischemic stroke/TIA, SBP on admission, hematoma volume, and IVH. CONCLUSIONS: This study provides significant evidence of the association between circulating NLR and R-DWILs in spontaneous ICH patients. Patients with NLR > 6.01 at 24-48 hours after ICH ictus should be paid more attention to when evaluating R-DWILs.

Fluorocitrate, an inhibitor of glial metabolism, inhibits the up-regulation of NOS expression, activity and NO production in the spinal cord induced by formalin test in rats.

Previous experiments have suggested that nitric oxide plays an important role in nociceptive transmission in the spinal cord. In order to explore the involvement of glia in the NO-mediated nociceptive transmission, the present study was undertaken to investigate the effect of fluorocitrate (FC), an inhibitor of glial metabolism, on NOS expression and activity and NO production in the spinal cord during the process of peripheral inflammatory pain and hyperalgesia induced by formalin test in rats. Sixty adult male Sprague-Dawley rats were randomly assigned into sham, formalin, formalin + normal saline (NS), and formalin + FC groups. The NOS expression, NOS activity and NO production was detected by NADPH-d histochemistry staining, NOS and NO assay kit, respectively. It was found that formalin test significantly up-regulated NOS expression and activity and NO production in the laminae I-II of the dorsal horn and the grey matter around the central canal in the lumbar spinal cord at 1 h after the formalin test. Selective inhibition of glia metabolism with intrathecal administration of FC (1 nmol) significantly inhibited the up-regulation in NOS expression and activity and NO production normally induced by the formalin test, which was represented with decreases in the number and density of the NADPH-d positive cells in the dorsal horn and grey matter around the central canal, and decrease in density of NADPH-d positive neuropil in the dorsal horn in formalin + FC group compared with formalin group. The results suggested that glia may be involved in the NO-mediated nociceptive transmission in the spinal cord.

Brain Iron Deposits in Thalamus Is an Independent Factor for Depressive Symptoms Based on Quantitative Susceptibility Mapping in an Older Adults Community Population.

Objectives: With the trend of an aging population, an increasing prevalence of late-life depression has been identified. Several studies demonstrated that iron deposition was significantly related to the severity of symptoms in patients with depression. However, whether brain iron deposits influence depressive symptoms is so far unclear in the community of older adults. We measured iron deposition in deep intracranial nucleus by quantitative susceptibility mapping (QSM) and aimed to explore the relationship between iron deposition and depressive symptoms. Methods: We reviewed the data of a community population from CIRCLE study, which is a single-center prospective observational study that enrolled individuals above 40 years old with cerebral small vessel disease (SVD), while free of known dementia or stroke. We evaluated regional iron deposits on QSM, measured the volume of white matter hyperintensities (WMHs) on T2 fluid-attenuated inversion recovery, and assessed depressive symptoms by Hamilton depression scale (HDRS). We defined depressive symptom as HDRS > 7. Results: A total of 185 participants were enrolled. Participants in depressive symptom group had higher QSM value in thalamus than control group (18.79 ± 14.94 vs 13.29 ± 7.64, p = 0.003). The QSM value in the thalamus was an independent factor for the presence of depressive symptoms (OR = 1.055; 95% CI: 1.011-1.100; p = 0.013). The regional QSM values in other areas were not associated with HDRS score (all p > 0.05). No significant correlations were observed between WMHs volume and HDRS score (p > 0.05), or regional QSM values and WMHs volume (all p > 0.05). Conclusions: Our study demonstrated that iron deposits in the thalamus were related to the depressive symptoms in older adults.

[Antisense oligodeoxynucleotides of glial glutamate transporter-1 inhibits the neuro-protection of cerebral ischemic preconditioning in rats].

The present study was undertaken to investigate the role of glial glutamate transporter-1 (GLT-1) in the brain ischemic tolerance induced by cerebral ischemic preconditioning (CIP) by observing the effect of GLT-1 antisense oligodeoxynucleotides (AS-ODNs) on the neuro-protection of CIP against brain ischemic insult in rats. Wistar rats with permanently occluded bilateral vertebral arteries were randomly assigned to 7 groups: (1) Sham group: the bilateral common carotid arteries (BCCA) were separated, but without occluding the blood flow; (2) CIP group: the BCCA were clamped for 3 min; (3) Brain ischemic insult group: the BCCA were clamped for 8 min; (4) CIP+brain ischemic insult group: 3 min CIP was preformed 2 d prior to 8 min ischemic insult; (5) Double distilled water group: 5 muL double distilled water was injected into the right lateral cerebral ventricle 12 h before, 12 h and 36 h after the BCCA was separated (but without occluding the blood flow), respectively; (6) AS-ODNs group: 5 microL AS-ODNs solution was injected into the right lateral cerebral ventricle 12 h before, 12 h and 36 h after the BCCA was separated (but without occluding the blood flow), respectively. This group was further divided into 9 nmol and 18 nmol subgroups according to the doses of AS-ODNs; (7) AS-ODNs+CIP+brain ischemic insult group: 5 microL AS-ODNs solution was injected into the right lateral cerebral ventricle 12 h before, 12 h and 36 h after CIP, respectively. This group was also further divided into 9 nmol and 18 nmol subgroups according to the doses of AS-ODNs. The other treatments were the same as those in CIP+brain ischemic insult group. The effect of the AS-ODNs on the expression of GLT-1 was assayed by using Western blot analysis. The profile of delayed neuronal death (DND) of pyramidal neurons in the CA1 hippocampus was evaluated by using thionin staining under light microscope by determining the neuronal density (ND) and histological grade (HG). Western blot analysis showed that AS-ODNs injected into the lateral cerebroventricle inhibited the expression of GLT-1 in the CA1 hippocampus in a dose-dependent manner. Neuropathological evaluation showed that there was no apparent DND in sham and CIP groups. Obvious DND of pyramidal neurons was found in brain ischemic insult group, which was represented by an increase in HG and a decrease in ND. CIP effectively protected the pyramidal neurons in the CA1 hippocampus against DND normally induced by ischemic insult, which indicating that CIP induced ischemic tolerance on the pyramidal neurons in the CA1 hippocampus. However, the injection of AS-ODNs into the lateral cerebroventricle blocked the neuro-protection of CIP against DND induced by brain ischemic insult. These results further proved the role of GLT-1 in the brain ischemic tolerance induced by CIP in rats.

Factors Associated With Remote Diffusion-Weighted Imaging Lesions in Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Remote diffusion-weighted imaging lesions (R-DWILs) have been detected in patients with spontaneous intracerebral hemorrhage (ICH) and may be correlated with clinical outcome. However, the mechanisms and characteristics of R-DWILs have not been fully elucidated. In this study, we sought to demonstrate the clinical characteristics of R-DWILs in spontaneous ICH. METHODS: We prospectively collected data with spontaneous ICH patients from November 2016 to December 2017. In these patients, cerebral magnetic resonance imaging was performed within 28 days after ICH onset. R-DWIL was defined as a hyperintensity signal in diffusion-weighted imaging with corresponding hypointensity in apparent diffusion coefficient, and at least 20 mm apart from the hematoma. We compared two groups of patients with or without R-DWIL with the demographic and clinical characteristics, laboratory parameters, and imaging characteristics, by using univariate and multivariate analysis. RESULTS: Of the 222 patients enrolled, a total of 75 R-DWILs were observed in 41 patients (18.5%). Among these lesions, the cortical and subcortical areas were the predominant locations with a proportion of 77.3%. The median diameter of R-DWILs was 7 mm (range 2-20 mm). Twelve patients were found having more than one lesion, with five among which showed R-DWILs in multiple cerebral arterial territories. In multivariate modeling, higher fasting glucose (OR 1.231; 95% CI 1.035-1.465; p = 0.019) and more severe white matter hyperintensity (WMH) (OR 6.589; 95% CI 2.975-14.592; p < 0.001) were independent factors related to the presence of R-DWILs. CONCLUSION: In our study, approximately one-fifth of ICH patients showed coexistence of R-DWIL. Higher fasting glucose and more severe WMH were associated with R-DWIL occurrence in spontaneous ICH.

Association of Renal Dysfunction With Remote Diffusion-Weighted Imaging Lesions and Total Burden of Cerebral Small Vessel Disease in Patients With Primary Intracerebral Hemorrhage.

Objective: Remote diffusion-weighted imaging (DWI) lesions (R-DWIL) found in intracerebral hemorrhage (ICH) patients are considered as an additional marker of cerebral small vessel disease (cSVD). This study aimed to investigate the association of renal dysfunction and R-DWIL, as well as the total burden of cSVD on magnetic resonance imaging among patients with primary ICH. Methods: One hundred and twenty-six consecutive patients were prospectively enrolled. R-DWIL on DWI, as well as other imaging markers of cSVD, including lacunes, white matter lesions, cerebral microbleeds, and enlarged perivascular spaces were rated using validated scales. Renal dysfunction was evaluated either by reduced estimated glomerular filtration rate (eGFR) or the presence of proteinuria or increased cystatin C. Results: After adjustments for potential confounders by logistic regression, impaired eGFR [odds ratio (OR) 6.00, 95% confidence interval (CI) 1.73-20.78], proteinuria (OR 3.07, 95% CI 1.25-7.54) and increased cystatin C (OR 2.73, 95% CI 1.11-6.72) were correlated with presence of R-DWIL. A similar association was also found between cystatin C levels (OR 3.16, 95% CI 1.39-7.19), proteinuria (OR 2.79, 95% CI 1.34-5.83) and the comprehensive cSVD burden. Conclusions: Renal dysfunction are associated with the presence of R-DWIL, and total burden of cSVD in patients with primary ICH.

The PI3K-AKT-mTOR pathway activates recovery from general anesthesia.

We investigated roles of PI3K-AKT-mTOR pathway in recovery from general anesthesia. Sprague-Dawley rats divided into five groups: saline+artificial cerebrospinal fluid (ACSF; Group A), ketamine+ACSF (Group B), ketamine+IGF-1 (Group C), ketamine+PI3K inhibitor (Group D), and PI3K/Akt agonists (Group E). Proportion of δ waves on ECoGs was recorded. Rats were tested for duration of loss of righting reflex (LORR), ataxic period and behavior in Morris water maze. mRNA and protein expression of members of PI3K-AKT-mTOR pathway were measured by RT-qPCR and Western blots. Histopathologic changes in hippocampal tissues observed by HE staining. We found that the proportion of δ waves decreased in Group C, while increased in Group D compared with Group B; the durations of LORR and ataxic period were shorter in Group C, but longer in Group D. In Morris water maze, escape latency (EL) and duration and frequency of staying on platform was shorter in Group C and longer in Group D than in Group B. Group A exhibited low expression of proteins in PI3K-AKT-mTOR pathway, while p-AKT, p-mTOR and p-P70S6K expression increased in cerebral cortex, brain stem, and thalamus in Group C. By contrast, expression of those proteins was lower in Group D than Group B. Those proteins expressions were higher in Group E than in Group A. HE staining showed that anesthesia may induce cell apoptosis in rat hippocampal CA1 areas, and PI3K/Akt agonists could inhibit apoptosis. Our results suggest that activation of PI3K-AKT-mTOR pathway may promote recovery from general anesthesia and enhance spatial learning and memory.

Learning gene functional classifications from multiple data types.

In our attempts to understand cellular function at the molecular level, we must be able to synthesize information from disparate types of genomic data. We consider the problem of inferring gene functional classifications from a heterogeneous data set consisting of DNA microarray expression measurements and phylogenetic profiles from whole-genome sequence comparisons. We demonstrate the application of the support vector machine (SVM) learning algorithm to this functional inference task. Our results suggest the importance of exploiting prior information about the heterogeneity of the data. In particular, we propose an SVM kernel function that is explicitly heterogeneous. In addition, we describe feature scaling methods for further exploiting prior knowledge of heterogeneity by giving each data type different weights.

An anti-nociceptive role for ceftriaxone in chronic neuropathic pain in rats.

Glial glutamate transporter-1 (GLT-1) plays an essential role in the maintenance of glutamate homeostasis and is involved in the development and maintenance of pathological pain. The present study was undertaken (1) to observe the anti-nociceptive effects of ceftriaxone (Cef) in a chronic neuropathic pain model induced by chronic constrictive nerve injury (CCI) of the sciatic nerve and (2) to identify the role of spinal GLT-1 in the process. CCI induced significant thermal hyperalgesia and mechanical allodynia, which began from postoperative day 3 and lasted to day 21. This long-term hyperalgesia was accompanied by significant down-regulation of GLT-1 expression in the L4-L6 segments of the spinal dorsal horn, as revealed by immunohistochemistry and Western blot. Intraperitoneal preventive and therapeutic administration of Cef effectively prevented or reversed, respectively, the development of thermal hyperalgesia, mechanical allodynia, and GLT-1 down-regulation in the spinal dorsal horn. To further determine whether the above anti-nociceptive effects of Cef are a result of the up-regulation of spinal GLT-1 expression and its function, we further observed the effects of intrathecal administration of Cef in the same model. It was found that intrathecal administration of Cef led to the specific up-regulation of GLT-1 expression and glutamate uptake ((3)H-glutamate) in the spinal dorsal horn, and similar anti-nociceptive effects to those of intraperitoneal administration of Cef. The above effects of intrathecal Cef administration were all significantly inhibited by intrathecal administration of GLT-1 antisense oligodeoxynucleotides (As-ODNs). These results indicate that Cef plays an anti-nociceptive role by up-regulating spinal GLT-1 expression and its function.