Altered white matter structural connectivity in primary Sjögren's syndrome: a link-based analysis.

PURPOSE: Cognitive impairment has been revealed in primary Sjögren's syndrome (pSS). However, the underlying white matter structural connectivity (SC) changes have not been studied. This study aimed to investigate the altered white matter brain network in patients with pSS using diffusion tensor imaging (DTI). METHODS: Forty-one pSS patients and sixty matched healthy controls (HCs) underwent neuropsychological tests and the subsequent MRI examinations. The clinical data were gathered from the medical record. The structural brain network was established using DTI, and a link-based comparison was performed between patients with pSS and HCs (false discovery rate correction, P < 0.05). Furthermore, the mean fractional anisotropy (FA) of the altered SCs was correlated with the neuropsychological tests and clinical data in patients with pSS (Bonferroni correction, P < 0.05). RESULTS: Compared with HCs, patients with pSS mainly exhibited decreased SC in the frontal and parietal lobes and some parts of the temporal and occipital lobes. In addition, increased SC was found between the right caudate nucleus and right median cingulate/paracingulate gyri. Specifically, the reduced SC between the left middle temporal gyrus and left middle occipital gyrus was negatively correlated with white matter high signal intensity (WMH). CONCLUSIONS: Patients with pSS showed diffusely decreased SC mainly in the frontoparietal network and exhibited a negative correlation between the reduced SC and WMH. SC represents a potential biomarker for preclinical brain impairment in patients with pSS.

Different cerebral functional segregation in Sjogren's syndrome with or without systemic lupus erythematosus revealed by amplitude of low-frequency fluctuation.

BACKGROUND: Sjögren's syndrome (SjS) associated with systemic lupus erythematosus (SjS-SLE) was considered a standalone but often-overlooked entity. PURPOSE: To assess altered spontaneous brain activity in SjS-SLE and SjS using amplitude of low-frequency fluctuation (ALFF). MATERIAL AND METHODS: Sixteen patients with SjS-SLE, 17 patients with SjS, and 17 matched controls underwent neuropsychological tests and subsequent resting-state functional magnetic resonance imaging (fMRI) examinations. The ALFF value was calculated based on blood oxygen level dependent (BOLD) fMRI. Statistical parametric mapping was utilized to analyze between-group differences and multiple comparison was corrected with Analysis of Functional NeuroImages 3dClustSim. Then, the ALFFs of brain regions with significant differences among the three groups were correlated to corresponding clinical and neuropsychological variables by Pearson correlation. RESULTS: ALFF differences in the bilateral precuneus/posterior cingulate cortex (PCC), right parahippocampal gyrus/caudate/insula, and left insula were found among the three groups. Both SjS-SLE and SjS displayed decreased ALFF in the right parahippocampal gyrus, right insula, and left insula than HC. Moreover, SjS-SLE showed wider decreased ALFF in the bilateral precuneus and right caudate, while the SjS group exhibited increased ALFF in the bilateral PCC. Additionally, patients with SjS-SLE exhibited lower ALFF values in the bilateral PCC and precuneus than SjS. Moreover, ALFF values in the right parahippocampal gyrus and PCC were negatively correlated to fatigue score and disease duration, respectively, in SjS-SLE. CONCLUSION: SjS-SLE and SjS exhibited common and different alteration of cerebral functional segregation revealed by AlFF analysis. This result appeared to indicate that SjS-SLE might be different from SjS with a neuroimaging standpoint.

Renormalization of Thalamic Sub-Regional Functional Connectivity Contributes to Improvement of Cognitive Function after Liver Transplantation in Cirrhotic Patients with Overt Hepatic Encephalopathy.

OBJECTIVE: The role of preoperative overt hepatic encephalopathy (OHE) in the neurophysiological mechanism of cognitive improvement after liver transplantation (LT) remains elusive. This study aimed to explore changes in sub-regional thalamic functional connectivity (FC) after LT and their relationship with neuropsychological improvement using resting-state functional MRI (rs-fMRI) data in cirrhotic patients with and without a history of OHE. MATERIALS AND METHODS: A total of 51 cirrhotic patients, divided into the OHE group (n = 21) and no-OHE group (n = 30), and 30 healthy controls were enrolled in this prospective study. Each patient underwent rs-fMRI before and 1 month after LT. Using 16 bilateral thalamic subregions as seeds, we conducted a seed-to-voxel FC analysis to compare the thalamic FC alterations before and after LT between the OHE and no-OHE groups, as well as differences in FC between the two groups of cirrhotic patients and the control group. Correction for multiple comparisons was conducted using the false discovery rate (p < 0.05). RESULTS: We found abnormally increased FC between the thalamic sub-region and prefrontal cortex, as well as an abnormally decreased FC between the bilateral thalamus in both OHE and no-OHE cirrhotic patients before LT, which returned to normal levels after LT. Compared with the no-OHE group, the OHE group exhibited more extensive abnormalities prior to LT, and the increased FC between the right thalamic subregions and right inferior parietal lobe was markedly reduced to normal levels after LT. CONCLUSION: The renormalization of FC in the cortico-thalamic loop might be a neuro-substrate for the recovery of cognitive function after LT in cirrhotic patients. In addition, hyperconnectivity between thalamic subregions and the inferior parietal lobe might be an important feature of OHE. Changes in FC in the thalamus might be used as potential biomarkers for recovery of cognitive function after LT in cirrhotic patients.

Neuromarkers from Whole-Brain Functional Connectivity Reveal the Cognitive Recovery Scheme for Overt Hepatic Encephalopathy after Liver Transplantation.

Neurocognitive impairment is present in cirrhosis and may be more severe in cirrhosis with overt hepatic encephalopathy (OHE). Liver transplantation (LT) can restore liver function, but how it reverses the impaired brain function is still unclear. MRI of resting-state functional connectivity can help reveal the underlying mechanisms that lead to these cognitive deficits and cognitive recovery. In this study, 64 patients with cirrhosis (28 with OHE; 36 without OHE) and 32 healthy control subjects were recruited for resting-state fMRI. The patients were scanned before and after LT. We evaluated presurgical and postsurgical neurocognitive performance in cirrhosis patients using psychomotor tests. Network-based statistics found significant disrupted connectivity in both groups of cirrhotic patients, with OHE and without OHE, compared with control subjects. However, the presurgical connectivity disruption in patients with OHE affected a greater number of connections than those without OHE. The decrease in functional connectivity for both OHE and non-OHE patient groups was reversed after LT to the level of control subjects. An additional hyperconnected network (i.e., higher connected than control subjects) was observed in OHE patients after LT. Regarding the neural-behavior relationship, the functional network that predicted cognitive performance in healthy individuals showed no correlation in presurgical cirrhotic patients. The impaired neural-behavior relationship was re-established after LT for non-OHE patients, but not for OHE patients. OHE patients displayed abnormal hyperconnectivity and a persistently impaired neural-behavior relationship after LT. Our results suggest that patients with OHE may undergo a different trajectory of postsurgical neurofunctional recovery compared with those without, which needs further clarification in future studies.

Altered Brain Function in Young HIV Patients with Syphilis Infection: A Voxel-Wise Degree Centrality Analysis.

OBJECTIVE: This study assessed the possible effect of syphilis co-infection in the brain function in young HIV patients by using voxel-wise degree centrality (DC) analysis. METHODS: Forty-four syphilis-co-infected HIV patients (HIV+/syphilis+), 45 HIV patients without syphilis history (HIV+/syphilis-) and 43 matched healthy controls (HC) underwent resting-state fMRI examinations. Laboratory tests and a battery of neuropsychological tests were performed before each MRI examination. One-way ANOVA was used to compare the differences of DC among the three groups. The correlations between MRI metrics and laboratory/neuropsychological tests in each patient's group were performed by Pearson correlation analysis. RESULTS: Compared with HIV+/syphilis-, worse performance in complex motor skills was found in HIV+/syphilis+. Compared with HC, HIV+/syphilis+ and HIV+/syphilis- groups showed attenuated DC in the right orbital frontal cortex and increased DC in the left parietal/temporal cortex. Besides, we also found increased DC in the left inferior frontal cortex and bilateral posterior cingulated cortex/precuneus in HIV+/syphilis+ compared with HC. Moreover, compared with HIV+/syphilis-, HIV+/syphilis+ displayed decreased DC in the left middle occipital cortex. Additionally, in HIV+/syphilis+ group, the mean z value of DC was correlated to the CD4+ cell counts and the learning and delayed recall score. CONCLUSION: Syphilis co-infection might be related to more brain functional reorganization in young HIV patients which could be reflected by DC value.

Microstructural brain abnormalities correlate with neurocognitive dysfunction in minimal hepatic encephalopathy: a diffusion kurtosis imaging study.

PURPOSE: To investigate the diffusion kurtosis imaging (DKI) in early minimal hepatic encephalopathy (MHE) diagnosis and evaluate the correlations between changes in DKI metrics and cognitive performance. METHODS: We enrolled 116 cirrhosis patients, divided into non-HE (n = 61) and MHE (n = 55), and 46 normal controls (NCs). All patients underwent cognitive testing before magnetic resonance imaging. DKI metrics were calculated through whole-brain voxel-based analysis (VBA) and differences between the groups were assessed. Pearson correlation between the DKI metrics and cognitive performance was analysed. The receiver operating characteristic (ROC) curve was used to analyse the diagnostic efficiency of DKI metrics for MHE. RESULTS: MHE patients had significantly altered DKI metrics in a wide range of regions; lower fractional anisotropy (FA) and higher mean diffusivity (MD) are mainly located in the corpus callosum, left temporal white matter (WM), and right medial frontal WM. Furthermore, significantly altered kurtosis metrics included lower mean kurtosis (MK) in the corpus callosum and left thalamus, lower radial kurtosis (RK) in the corpus callosum, and lower axial kurtosis (AK) in the right anterior thalamic radiation. Alterations in axial diffusivity (AD), radial diffusivity (RD), and MD were closely correlated with cognitive scores. The ROC curves indicated AD in the forceps minor had the highest predictive performance for MHE in the cirrhosis patients (area under curve = 0.801, sensitivity = 77.05%, specificity = 74.55%). CONCLUSIONS: Altered DKI metrics indicate brain microstructure abnormalities in MHE patients, some of which may be used as neuroimaging markers for early MHE diagnosis.

Inhibition of protein phosphatase 2A with a small molecule LB100 radiosensitizes nasopharyngeal carcinoma xenografts by inducing mitotic catastrophe and blocking DNA damage repair.

Nasopharyngeal carcinoma (NPC), while uncommon worldwide, is a major health problem in China. Although local radiation and surgery provide good control of NPC, better treatments that permit reductions in radiation dosing are needed. Inhibition of protein phosphatase 2A (PP2A), a ubiquitous multifunctional enzyme with critical roles in cell cycle regulation and DNA-damage response, reportedly sensitizes cancer cells to radiation and chemotherapy. We studied PP2A inhibition with LB100, a small molecule currently in a Phase I clinical trial, on radiosensitization of two human nasopharyngeal cell lines: CNE1, which is reportedly radioresistant, and CNE2. In both cell lines, LB100 exposure increased intracellular p-Plk1, TCTP, and Cdk1 and decreased p53, changes associated with cell cycle arrest, mitotic catastrophe and radio-inhibition of cell proliferation. Mice bearing subcutaneous xenografts of either cell line were administered 1.5 mg/kg LB100 daily for three days and a single dose of 20 Gy radiation (day 3), which produced marked and prolonged tumor mass regression (dose enhancement factors of 2.98 and 2.27 for CNE1 and CNE2 xenografts, respectively). Treatment with either LB100 or radiation alone only transiently inhibited xenograft growth. Our results support further exploration of PP2A inhibition as part of radiotherapy regimens for NPC and potentially other solid tumors.

Expression and prognosis of FOXO3a and HIF-1α in nasopharyngeal carcinoma.

PURPOSE: The Forkhead Box O3a transcription factor (FOXO3a) and hypoxia-inducible factor-1α (HIF-1α) have been reported to play important roles in the development and prognosis of human cancers. However, their exact roles are not clear. Therefore, we investigated the expression status and clinical significance of FOXO3a and HIF-1α expression in nasopharyngeal carcinoma. METHODS: The expression of FOXO3a and HIF-1α proteins was detected in nasopharyngeal carcinoma tissues and normal nasopharyngeal tissues by immunohistochemistry and western blot. Furthermore, we analyzed the association of FOXO3a and HIF-1α expression with various clinicopathologic factors including survival status of nasopharyngeal carcinoma patients. RESULTS: FOXO3a was low expressed and HIF-1α was high expressed in nasopharyngeal carcinoma tissues, compared with normal nasopharyngeal tissues (both P < 0.05). The low expression of FOXO3a was significantly correlated with clinical stage (P = 0.003), T stage (P = 0.011), lymph node metastasis (P = 0.003), and distant metastasis (P = 0.030), and over expression of HIF-1α was significantly correlated with T stage (P = 0.026), lymph node metastasis (P = 0.002), and distant metastasis (P = 0.010). The Spearman analysis indicated that FOXO3a expression was inversely correlated with HIF-1α expression(rs = -0.598, P < 0.001). Overall survival curves estimated by Kaplan-Meier showed that tumor patients with low FOXO3a or high HIF-1α expression had significantly poorer prognosis compared with patients with high FOXO3a or low HIF-1α levels (P < 0.001, and P = 0.012, respectively). In addition, multivariate Cox regression analysis showed that T stage, distant metastasis, and FOXO3a were significant independent prognostic factors for overall survival (P = 0.011, P = 0.008, and P = 0.047, respectively). CONCLUSIONS: Our results suggested that FOXO3a and HIF-1α may be considered to be important prognostic markers in nasopharyngeal carcinoma.

[Study on anti-atherosclerotic mechanisms of divided functional recipes of dahuang zhechong pill in rabbits].

OBJECTIVE: To study anti-atherosclerotic mechanisms of divided functional recipes of Dahuang Zhechong pill (DHZCP) in rabbits. METHOD: The atherosclerotic rabbit model was established by high fat feeding combined with immune endothelial injury. Male New Zealand rabbits were divided into 9 groups: normal control group, model control group, Danshen positive control group, and 6 DHZCP-divided groups including divided functional recipes No. 1, 2, 3 with low and high doses for each divided recipe. After intragastric administration for 60 days, blood lipids and serum MDA and NO levels and SOD activity and plasma ET concentration, and contents of hydroxyproline and proteins in the vascular wall were determined. RESULT: Compared with the model group, the level of blood lipids did not significantly change, serum MDA and ET levels, and the contents of hydroxyproline and proteins in the vascular wall significantly decreased (P < 0.05), and SOD activity and NO level increased in the divided functional recipes (all P < 0.05). CONCLUSION: The divided functional recipes of DHZCP can inhibit development of atherosclerosis via a non-lowering lipid mechanisms, including anti-peroxidation of lipids, protection of endothelial function, and decrease of formation of extracellular matrix by reducing synthesis of collage and protein on the vascular wall. Among them, the divided functional recipe No. 1 exhibits the most obvious effect.

[Effect of the disassembled recipes of dahuang zhechong pill on proliferation and apoptosis of vascular smooth muscle cells in atherosclerotic rabbits].

OBJECTIVE: To study the effects of the disassembled recipes of Dahuang Zhechong Pill (DRDZP) on proliferation and apoptosis of vascular smooth muscle cell (VSMC) of thoracic aorta in atherosclerotic rabbits. METHODS: The atherosclerotic rabbit model was induced by high-cholesterol diet and immune injury of endothelium. Expression of proliferating cell nuclear antigen (PCNA) in VSMC was detected by SP immunohistochemical technique, and VSMC apoptosis was observed with TUNEL technique. RESULTS: Compared with the model control, PCNA expression in VSMC decreased, while apoptotic cells increased significantly in all the groups treated by DR-DZP (P < 0.01). CONCLUSION: All the DR-DZP could inhibit VSMC proliferation and promote its apoptosis to modulate the balance between cell proliferation and apoptosis, so as to exert antiatherosclerotic action, among which the disassembled-recipe I is the main composition to contribute to antiatherosclerotic action of Dahuang Zhechong Pill.