Altered hippocampal functional connectivity in primary Sjögren syndrome: a resting-state fMRI study.

Structural and metabolic abnormalities in the hippocampus have been associated with the pathophysiological mechanism of central nervous system involvement in primary Sjögren syndrome (pSS). Nevertheless, how hippocampal function is altered in pSS remains unknown. The purpose of our study is to investigate the alterations in hippocampal functional connectivity (FC) in pSS by using resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-eight patients with pSS and 38 age- and education level-matched healthy controls (HCs) underwent magnetic resonance imaging examination. Prior to each MRI examination, neuropsychological tests were performed. Left and right hippocampal FCs were analyzed by using seed-based whole-brain correlation and compared between pSS and HCs. Spearman correlation analysis was performed between the z-value of hippocampal FC in brain regions with significant difference between the two groups and neuropsychological tests/clinical data in pSS. Compared with the controls, the patients with pSS showed decreased hippocampal FC between the left hippocampus and the right inferior occipital gray (IOG)/inferior temporal gray (ITG), as well as between the right hippocampus and right IOG/middle occipital gray (MOG), left MOG, and left middle temporal gray. In addition, increased hippocampal FCs were detected between the left hippocampus and left putamen, as well as between the right hippocampus and right cerebellum posterior lobe. Moreover, the visual reproduction score positively correlated with the FC between right hippocampus and right IOG/MOG. The white matter hyperintensity score negatively correlated with the FC between left hippocampus and right IOG/ITG. In conclusion, patients with pSS suffered decreased hippocampal FC mainly sited in the occipital and temporal cortex with right hippocampal laterality. Altered hippocampal FC might be a potential biomarker in detecting brain function changes and guiding neuroprotection in pSS.

[AKR1B10 inhibitor enhances the inhibitory effect of sorafenib on liver cancer xenograft].

Objective: To investigate the inhibitory effect of AKR1B10 inhibitor combined with sorafenib on hepatocellular carcinoma (HCC) xenograft growth. Methods: HepG2 xenograft model was established in nude mice. The mice were then randomly divided into four groups: control group, epalrestat monotherapy group, sorafenib monotherapy group and combination treatment group. Tumor volume, tumor weight, T/C ratio and the change in body weight of nude mice in each group were compared to evaluate the curative effect. Immunohistochemistry staining was used to detect the expression of Ki-67 in tumor tissues to evaluate the proliferation status of tumor cells. One-way analysis of variance was used to compare the differences between the groups. Student's t-test was used to test means of two groups and chi-square test was used for multiple samples. Results: The differences of the grafted tumor volume before and after treatment between the control group, epalrestat group, sorafenib group and combined therapy group was 238.940 ± 39.813, 124.991 ± 84.670, -26.111 ± 11.518, and -54.072 ± 17.673(mm(3)), respectively, (F = 37.048, P < 0.001). The tumor mass were 0.273 ± 0.140, 0.158 ± 0.078, 0.079 ± 0.054, 0.045 ± 0.024 (g), (F = 16.594, P < 0.001); T/C ratio were 100%, 57.9%, 28.9%, 16.5%, and Ki-67 positive rate were 23.295 ± 6.218, 13.503 ± 3.392, 7.325 ± 2.257, 4.664 ± 1.189 (%), (χ(2) = 822.203, P < 0.001) . The tumor volume (t = -3.579, P = 0.002) and Ki-67 positive rate (t = -10.003, P < 0.001) in epalrestat monotherapy group were significantly lower than control group. The tumor volume (t = 2.056, P = 0.025), tumor mass (t = 2.101, P = 0.043), and Ki-67 positive rate (t = -2.850, P = 0.005) in combination treatment group were significantly lower than sorafenib monotherapy group. Compared with the control group, the body weight of nude mice in the treatment group decreased to a certain extent, but there was no statistically significant difference between epalrestat monotherapy group and control group (t = -1.599, P = 0.262), and combined therapy and sorafenib monotherapy group (t = -0.051, P = 0.96). Conclusion: AKR1B10 inhibitor enhanced the inhibitory effect of sorafenib on hepatocellular carcinoma xenograft.

[The comparison of liver inflammation and fibrosis between chronic HBV and HCV infection].

Objective: To explore the difference of liver inflammation and fibrosis in patients with chronic hepatitis B virus (HBV) infection and chronic hepatitis C virus (HCV) infection, and to investigate the relationship between hepatic pathology and alanine aminotransferase (ALT). Methods: 57 patients with chronic HCV infection and 346 patients with chronic HBV infection who were hospitalized at Shengjing Hospital of China Medical University from January 2012 to September 2016 were enrolled. In chronic HBV infection, including 88 cases whose ALT were more than two times of upper limited of normal (ALT≥2×ULN) and 258 cases whose ALT were less than two times of upper limited of normal (ALT < 2×ULN).All the patients were underwent liver biopsy. Chronic HBV infection (ALT≥2×ULN and ALT < 2×ULN) and chronic HCV infection were compared respectively. Statistical analyses were performed using a Univariate χ²-test and Mann-Whitney U test for comparison. Correlations between variables were analyzed using Spearman's rank correlation. Results: In chronic HBV infection group, 169 cases (48.8%) had inflammation grade≥2 (G≥2), 98 cases (28.3%) had fibrosis stage≥2 (S≥2), 81 cases (23.4%) with G≥2 and S≥2.In the ALT < 2×ULN group, there were 109 cases (42.2%) with G≥2, 62 cases (24%) with S≥2, 49 cases (19%) with G≥2 and S≥2. In the ALT≥2×ULN group, 60 cases (68.2%) with G≥2, 35 cases (39.8%) with S≥2, 31 cases (35.2%) with G≥2 and S≥2. The grade of inflammation and fibrosis have significantly different between ALT≥2×ULN group and ALT < 2×ULN group (χ² = 17.66, χ² = 8.06, P < 0.01). In chronic HCV infection group, 47 cases (82.5%) with G≥2, 20 cases (35.1%) with S≥2, 20 cases (35.1%) with G≥2 and S≥2. ALT had no correlation with inflammation and fibrosis (P > 0.05). The grade of inflammation was significantly different between chronic HCV infection and chronic HBV infection whose ALT < 2×ULN (χ² = 30.19, P < 0.01) but the fibrosis have no difference (χ² = 2.96, P > 0.05). Compared with chronic HBV infection whose ALT≥2×ULN, both inflammation and fibrosis had no significantly different (χ² = 3.65, χ² = 0.32, P > 0.05 respectively). Conclusion: In chronic HBV infection whose ALT < 2×ULN, about 30%-40% liver tissue with significant necroinflammation and /or fibrosis. About 80% chronic HCV infection with significant necroinflammation, and the grade of inflammation has no correlation with ALT. The grade of inflammation has significantly different between chronic HCV infection group and chronic HBV infection group whose ALT < 2×ULN.

Bisphosphonates therapy for osteoarthritis: a meta-analysis of randomized controlled trials.

High-turnover type bone metabolism derangement has been considered to be one of the major causes of osteoarthritis (OA). Bisphosphonates can attach to hydroxyapatite binding sites on bony surfaces, particularly those which are undergoing active bone resorption. To evaluate the effectiveness of bisphosphonates in OA treatment, literature databases were searched from inception to February 28, 2016 for clinical studies of bisphosphonates for OA treatment. All randomized controlled trials in which bisphosphonates therapy was compared with a placebo or a conventional medication, were selected. 15/1145 studies were eligible for analysis, which included 3566 participants. Bisphosphonates therapy improved pain, stiffness and function significantly in OA assessed by the Western Ontario and McMaster Universities Arthritis Index scale (MD = 4.59; 95 % CI 2.83-6.34; P < 0.00001; MD = 1.43; 95 % CI 0.83-2.23; P = 0.0005; MD = 2.01; 95 % CI 1.27-2.75; P < 0.00001). Bisphosphonates also reduced osteophyte score significantly (MD = -0.51; 95 % CI -0.84 to -0.19; P = 0.002). However, no significant differences were found in subjective improvement, osteoarthritis progression, the number of required acetaminophen treatment or joint replacement. In conclusion, bisphosphonates therapy is effective in relieving pain,stiffness and accelerating functional recovery in OA. Limitations of the studies we analysed included the differences in duration of bisphosphonates use, the doses and types of bisphosphonates and the lack of long-term data on OA joint structure modification after bisphosphonates therapy. More targeted studies are required to evaluate on the effectiveness of bisphosphonates for OA treatment.

Association between PPARγ2 Pro12Ala polymorphism and myocardial infarction and obesity in Han Chinese in Hohhot, China.

Activation of the peroxisome proliferator-activated receptor g (PPARg) improves insulin sensitivity and inhibits atherosclerosis. Whether PPARg2 Pro12Ala polymorphism affects myocardial infarction is not clearly understood. We investigated a possible association of PPARg2 Pro12Ala polymorphism with obesity and myocardial infarction in Han Chinese in Hohhot, Inner Mongolia, China. We included 121 subjects with myocardial infarction and 137 healthy controls in our study. Triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured. The following information was recorded for each subject: age, gender, body height, body weight, systolic blood pressure, and diastolic blood pressure; the body mass index was calculated. PCR-RFLP was used to examine Pro12Ala polymorphism. There were significant differences in clinical characteristics between myocardial infarction patients and healthy controls, except for diastolic blood pressure and triglycerides. The PP, PA/AA genotype frequencies were 88.4 and 11.6% in myocardial infarction patients and 95.6 and 4.4% in controls, respectively (P = 0.031). Individuals with the A allele had a significantly higher risk of myocardial infarction. The A allele was not an independent risk factor for obesity. We conclude that PPARg2 Pro12Ala polymorphisms are associated with increased risk for myocardial infarction in Han Chinese in Hohhot.

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease.

We have recently shown that intrastriatal injection of recombinant human erythropoietin (EPO) protects dopaminergic (DA) neurons in the substantia nigra (SN) from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of Parkinson's disease. However, systemic administration of EPO did not protect nigral DA neurons, suggesting that the blood-brain barrier limits the passage of EPO protein into the brain. In the present study, we used an adeno-associated viral (AAV) serotype 9 (AAV9) vector to deliver the human EPO gene into the brain of 6-OHDA-lesioned rats. We observed that expression of the human EPO gene was robust and stable in the striatum and the SN for up to 10 weeks. EPO-immunoreactive (IR) cells were widespread throughout the injected striatum, and EPO-IR neurons and fibers were also found in the ipsilateral SN. Enzyme-linked immunosorbent assay and western blot analyses exhibited dramatic levels of EPO protein in the injected striatum. As a result, nigral DA neurons were protected against 6-OHDA-induced toxicity. Amphetamine-induced rotational asymmetry and spontaneous forelimb use asymmetry were both attenuated. Interestingly, we also observed that intrastriatal injection of AAV9-EPO vectors led to increased numbers of red blood cells in peripheral blood. This highlights the importance of using an inducible gene delivery system for EPO gene delivery.

Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson's disease.

Erythropoietin (EPO), a hematopoietic cytokine, has recently been demonstrated to protect nigral dopaminergic neurons in a mouse model of Parkinson's disease (PD). In the present study, we tested the hypothesis that recombinant human erythropoietin (rhEPO) could protect dopaminergic neurons and improve neurobehavioral outcome in a rat model of PD. rhEPO (20 units in 2 microl of vehicle) was stereotaxically injected into one side of the striatum. 6-hydroxydopamine (6-OHDA) was injected into the same side 1 day later. Another group of rats received rhEPO (5000 u/kg, i.p.) daily for 8 days, and unilateral injection of 6-OHDA in the striatum 3 days after systemic administration of rhEPO. We observed that intrastriatal administration, but not systemic administration of rhEPO significantly reduced the degree of rotational asymmetry. The rhEPO-treated rats also showed an improvement in skilled forelimb use when compared with control rats. The number of tyrosine hydroxylase (TH)-immunoreactive (IR) neurons in the ipsilateral substantia nigra (SN) was significantly larger in intrastriatal rhEPO-treated rats than that in control rats. TH-IR fibers in the 6-OHDA-lesioned striatum were also increased in the intrastriatal rhEPO-treated rats when compared with control rats. In addition, there were lower levels of expression of major histocompatibility complex (MHC) class II antigens and a smaller number of activated microglia in the ipsilateral SN in intrastriatal rhEPO-treated rats than that in control rats at 2 weeks, suggesting that intrastriatal injection of rhEPO attenuated 6-OHDA-induced inflammation in the ipsilateral SN. Our results suggest that intrastriatal administration of rhEPO can protect nigral dopaminergic neurons from cell death induced by 6-OHDA and improve neurobehavioral outcome in a rat model of PD. Anti-inflammation may be one of mechanisms responsible for rhEPO neuroprotection.

Enriched environment influences brain-derived neurotrophic factor levels in rat forebrain after focal stroke.

Tissue levels of brain-derived neurotrophic factor (BDNF) protein were studied using enzyme immunoassay in different forebrain regions in the ipsi- and contralateral hemispheres of rats housed under enriched or standard conditions after the middle cerebral artery ligation. BDNF levels in the ipsilateral to ligation side was significantly higher only in the frontal cortex of standard as compared to enriched rats. However, BDNF overall was more abundant in standard than in enriched group. In addition, BDNF levels detected in the hippocampus and frontal cortex on the ischemic side of standard rats was higher as compared to contralateral side. The present study shows that housing conditions after permanent middle cerebral artery ligation leads to differential regulation of BDNF protein levels in forebrain regions which might have important implication for post-ischemic recovery.

Enhancement of nigral graft survival in rat brain with the systemic administration of synthetic fibronectin peptide V.

A major obstacle in neural transplantation is a severe loss of neurons in grafts soon after implantation. In the present study, we have investigated whether the systemic administration of synthetic fibronectin peptide V can increase the survival of neural grafts. Synthetic fibronectin peptide V is derived from the 33,000 mol. wt carboxyl-terminal heparin-binding domain of fibronectin. Previous studies have shown that these polypeptides possess anti-inflammatory properties. However, it is currently unknown whether this peptide has anti-apoptotic properties. Dissociated neural grafts were prepared from the ventral mesencephalon of pregnant Sprague-Dawley rats and were stereotaxically injected as a cell suspension into the striatum of adult Sprague-Dawley rats. A group of recipient rats received i.v. injections of peptide V (5mg/kg, dissolved in saline) at 24 and 4h prior to transplantation, at the time of transplantation, and 24, 48 and 72h post-transplantation. Saline-treated rats served as controls. The rats were killed at two, four and 42 days post-grafting and the brain tissue was immunologically processed for tyrosine-hydroxylase, major histocompatibility complex class I and class II antigens, complement receptor type 3 and leukocyte common antigen immunocytochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. We found a significant increase (approximately twofold) in the number of dopamine neurons in the grafts for the peptide-treated group at four and 42 days compared with the controls. In contrast, there was no significant difference in the patterns of inflammation using different immunocytochemical markers in the two different groups. The levels of expression for these markers, however, were reduced over time. Interestingly, the number of apoptotic cells in the graft areas was significantly smaller in the peptide-treated group than in the control group two days after grafting. The results demonstrate that the systemic administration of synthetic fibronectin peptide V can dramatically increase the survival of nigral grafts in the brain and substantially reduce the number of apoptotic cells in the graft site, suggesting that this peptide may exert a beneficial effect on survival of nigral grafts through an anti-apoptotic mechanism.

Environmental influence on brain-derived neurotrophic factor messenger RNA expression after middle cerebral artery occlusion in spontaneously hypertensive rats.

Enriched environment significantly enhances postischemic functional outcome. We have tested the hypothesis that housing in enriched environment stimulates gene expression for brain-derived neurotrophic factor. After ligation of the middle cerebral artery in male spontaneously hypertensive rats, they were housed in individual cages for 30h, then housed either in standard cages or in an enriched environment. The rats were killed two to 30days after the ischemic event. Cryostat coronal sections through the dorsal hippocampus (Bregma -3.3) were processed for in situ hybridization using a rat-brain-derived neurotrophic factor messenger RNA antisense oligonucleotide probe. Postischemic gene expression was significantly higher in standard rats than in enriched rats in contralateral and peri-infarct cortex and in most parts of the hippocampus two, three and 12days after the ischemic event, with a trend for higher-than-baseline levels in standard rats and lower-than-baseline levels in enriched rats. At 20 and 30days the values for both groups were below baseline levels. Contrary to our hypothesis, gene expression in rats postoperatively housed in enriched environment was significantly lower than in standard rats at a time when other studies have reported hyperexcitability in the ipsilateral and contralateral cortex. Should the low messenger RNA levels correspond to low protein synthesis, this might indicate that dampening of the early postischemic hyperexcitability may be beneficial. Low levels in both groups at 20 and 30days may correspond to loss of callosal connections in the opposite hemisphere and to horizontal cortical connections in the lesioned hemisphere.

Are neuronal markers and neocortical graft-host interface influenced by housing conditions in rats with cortical infarct cavity?

The aim was to study if exposure to an enriched environment influenced graft-host interface and neuronal markers in neocortical grafts implanted in cortical infarct cavities 3 weeks after distal ligation of the middle cerebral artery in adult hypertensive rats. Half the rats were exposed to an enriched environment for 2 h daily 5 days a week starting 1 week after the arterial ligation. The brain was fixed by perfusion 4 weeks postgrafting. The immunoreactivity to glial fibrillary acidic protein, microtubule associated protein 2, and synaptophysin was studied in coronal paraffin-embedded sections. A distinct glial border separated the infarct cavity from the surrounding brain in sham-transplanted rats. Most grafts filled the larger part of the infarct cavity. In 8 of 18 transplants, 4 in each experimental group, part of the transplants protruded through the thin glial membrane that delineated the transplant-host interface into the adjacent host brain tissue. Microtubule associated protein 2 immunostained sections indicated bridging of dendrites in the host-transplant interface. Synaptophysin immunoreactivity was significantly higher in grafts than in contralateral cortex. However, graft morphology and neuronal marker immunoreactivity did not differ between rats housed in standard and activity stimulating cages.

[Treatment of advanced and recurrent gynecologic cancer with chemotherapy by cannula perfusion into both internal iliac arteries].

This paper reports fourteen cases of advanced and recurrent gynecologic cancers treated with prolonged arterial perfusion chemotherapy by catheterization of both internal iliac arteries through femoral arteriopuncture under X-ray. The immediate effective rate was 78.5%, follow-up rate 100%. By this technique anticancer drugs can be selectively injected into vessels supplying the tumors. The drug is concentrated within the tumor resulting in longterm better local effects, and fewer general side reactions, and a much higher dose than that which could be given conventionally. This technique is considered as a new route of treatment in gynecologic tumors.