Neuroprotective effect of aldose reductase knockout in a mouse model of spinal cord injury involves NF-κB pathway.

The inflammatory response following spinal cord injury (SCI) involves the activation of resident microglia and the infiltration of macrophages. Activated microglia/macrophages have either detrimental or beneficial effects on neural regeneration based on their functional polarized M1/M2 subsets. Aldose reductase (AR) has recently been shown to be a key component of the innate immune response. However, the mechanisms involved in AR and innate immune response remain unclear. In this study, wild-type (WT) or AR-deficiency (KO) mice were subjected to SCI by a spinal crush injury model. AR KO mice showed better locomotor recovery and smaller injury lesion areas after spinal cord crushing compared with WT mice. Here, we first demonstrated that AR deficiency repressed the expression level of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide (LPS) in vitro via the activation of autophagy. AR deficiency caused 4-hydroxy-2-(E)-nonenal (4-HNE) accumulation in LPS-induced macrophages. We also found that exogenous addition of low concentrations of 4-HNE in LPS-induced macrophages had the effect of promoting further activation of NF-κB pathway, whereas high concentrations of 4-HNE had inhibitory effects. Together, these results indicated that autophagy as a mechanism underlying AR and 4-HNE in LPS-induced macrophages.

Endoscopic submucosal dissection versus transanal local excision for rectal carcinoid: a comparative study.

AIM: The aim of this study is to compare the short-term clinical outcomes between endoscopic submucosal dissection and transanal local excision for rectal carcinoid tumors. METHODS: Between 2007 and 2012, 31 patients with rectal carcinoid underwent endoscopic submucosal dissection at our hospital. They were compared with a matched cohort of 23 patients who underwent transanal local excision for rectal carcinoid between 2007 and 2012. Short-term clinical outcomes including surgical parameters, postoperative recovery, and oncologic outcomes were compared between the two groups. RESULTS: The mean size of tumors was significantly bigger in the transanal local excision group (0.8 ± 0.2 versus 1.1 ± 0.5 cm; P = 0.018). En bloc resection was achieved for 30 patients (97 %) in the endoscopic submucosal dissection group and all the patients in the transanal local excision group. The operation time was longer in the transanal local excision than that in the endoscopic submucosal dissection group (40.0 ± 22.7 min versus 12.2 ± 5.3 min; P < 0.001). Complications in the transanal local excision group were five cases of acute retention of urine. There was no local recurrence or distant metastasis in either group during the follow-up period. CONCLUSION: For the treatment of rectal carcinoid tumors with diameter <1 cm, endoscopic submucosal dissection has better short-term clinical outcomes than transanal local excision in terms of faster recovery and possibly a lower morbidity rate. Transanal local excision may be the first therapeutic choice of scar-embedded rectal carcinoid tumors.

Malignant Intracranial High Grade Glioma and Current Treatment Strategy.

Malignant high-grade glioma (HGG) is the most common and extremely fatal type of primary intracranial tumor. These tumors recurred within 2 to 3 cm of the primary region of tumor resection in the majority of cases. Furthermore, the blood-brain barrier significantly limited the access of many systemically administered chemotherapeutics to the tumor, pointing towards a stringent need for new therapeutic patterns. Therefore, targeting therapy using local drug delivery for HGG becomes a priority for the development of novel therapeutic strategies. The main objectives to the effective use of chemotherapy for HGG include the drug delivery to the tumor region and the infusion of chemotherapeutic agents into the vascular supply of a tumor directly, which could improve the pharmacokinetic profile by enhancing drug delivery to the neoplasm tissue. Herein, we reviewed clinical and molecular features, different methods of chemotherapy application in HGGs, especially the existing and promising targeting therapies using local drug delivery for HGG which could effectively inhibit tumor invasion, proliferation and recurrence of HGG to combat the deadly disease. Undoubtedly, novel chemical medicines targeting these HGG may represent one of the most important directions in the Neuro-oncology.

Toll-like receptor 4 (TLR4) deficiency aggravates dextran sulfate sodium (DSS)-induced intestinal injury by down-regulating IL6, CCL2 and CSF3.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair role of TLR4 in the intestinal epithelium is still unknown. METHODS: By comparing to wild-type (WT) mice, Toll-like receptor 4 (TLR4)-knockout mice (TLR4-KO) were used as dextran sulfate sodium (DSS)-induced colitis models to explore the role of TLR4 signaling in intestinal injury. High-throughput RNA-Seq, RT-qPCR and ELISA were performed to screen and verify key differences in gut genes between WT and TLR4-KO mice. Functional study of core dysregulated factors was performed in intestinal cell lines. RESULTS: We found that DSS-induced intestinal injury was aggravated by LPS (TLR4 agonist) and TLR4-KO. When compared to WT mice, IL6, CCL2, CSF3, IL11, Ccnb1, Ccnd1 and TNF-α significantly decreased and Fas and FasL have increased in the gut of TLR4-KO mice. IL6, CCL2, CSF3, Fas and FasL have all increased in CT-26 cells treated with LPS. Combined with the above data and KEGG enrichment, it can be assumed that TLR4-KO might aggravate DSS-induced intestinal damage by attenuating cell cycle, cytokine-cytokine receptor interaction, and Toll-like receptor signaling pathway, and enhancing the apoptosis pathway. In the functional study of core dysregulated factors, it was found that LPS, IL6, IL11, CSF3, CCL2, S100A8, S100A9 and Mmp3 have improved viability of colon cancer cell lines and decreased apoptosis rate of mouse colon cancer cells when these were treated with DSS. However, Jo-2 (Fas agonistic monoclonal antibody) played the opposite role in colon cancer cells treated with DSS. CONCLUSIONS: TLR4 had a repairing effect on DSS-induced intestinal damage and it up-regulate IL6, CCL2 and CSF3. Fas and FasL enhanced DSS-induced colon injury in mice, but might have little to do with TLR4 signaling.

[Diagnosis and treatment of patients with cholangiocarcinoma].

OBJECTIVE: To explore the diagnosis and treatment of the cholangiocarcinoma. METHODS: Forty one patients with cholangiocarcinoma who were enrolled in our hospital from January 1970 to January 2005 were retrospectively analyzed. RESULTS: Among these 41 patients, the 1, 3, and 5-year survival rate was 82.3%, 45.8%, 45.8%, respectively, with radical operation, and was 11.0%, 0, 0 with non-radical operation (chi2 = 21.38, P < 0.01). The 1-year and 3-year survival rate was 11.0% and 0 in 9 patients treated with laparatomy, which was not significantly different from those treated with non-radical operation (chi2 = 0.02, P = 0.89). Four patients did not receive operation and all died within one year. Among 25 patients who did not experience lymph node metastasis, the 1, 3, and 5-year survival rate was 58.4%, 27.3%, and 27.3%. Among 16 patients who were found lymph node metastasis, the 1-year and 3-year survival rate was 61.8% and 0 (chi2 = 13.85, P < 0.01). CONCLUSION: Operation is the most effective treatment for cholangiocarcinoma. Radical operation is the only curative treatment.

[Inhibition of growth and angiogenesis of U251 cell xenograft in vivo by short hairpin RNA targeting survivin gene].

OBJECTIVE: To observe the impact of specific short hairpin RNA (shRNA) targeting survivin gene on tumorigenesis and angiogenesis of human brain glioblastoma U251 cells in vivo of nude mice. METHODS: U251 cells, U251-SR cells transfected stably with shRNA eukaryotic expression vector pWH1-SR targeting survivin gene, and U251-P cells transfected stably with blank pWH1 vector, were inoculated respectively into subcutaneous tissue in flank of 15 nude mice (each group 5 mice), and the tumor growth status was observed and measured. Protein expressions of survivin, proliferating cell nuclear antigen (PCNA) and factor VIII related antigen (F VIII RAg) were investigated by immunohistochemistry SABC method, apoptotic cells were screened by TUNEL method, furthermore proliferative index (PI), apoptotic index (AI) and microvessel density (MVD) were measured respectively in each group of tumor specimens. RESULTS: Comparing with those in U251 and U251-P groups, in U251-SR group, the tumorigenesis time delayed, tumor grew slowly, both tumor volume and tumor weight decreased significantly (P < 0.01 for both); Survivin protein expression was down-regulated markedly; PI and MVD decreased significantly, whereas AI increased remarkably (P < 0.01 for all). CONCLUSIONS: The specific shRNA targeting survivin gene can inhibit significantly tumorigenesis and angiogenesis of U251 cells in vivo.

Predictive Factors for Surgical Intervention in Patients over the Age of 80 with Adhensive Small-Bowel Obstruction.

Adhensive small-bowel obstruction (SBO) remains a common cause of admission to surgical wards around the world. Given the growing elderly population, the number of elderly patients with adhensive SBO can be expected to increase substantially. Timely and appropriate treatment would improve morbidity and mortality rates in elderly patients with adhensive SBO. However, accurately determining which patients should undergo surgical treatment during the hospitalization remains difficult. The aim of this study was to identify predictive factors for surgical intervention in patients aged over 80 years presenting with SBO due to postoperative adhesions. A clinical and radiological data for the assessment of patients presenting with adhensive SBO were collected. A logistic regression model was applied to identify risk factors that would predict the need of surgical intervention. A total of 21 patients (13 males, 8 females) were treated during a 3.5-year period. The mean age was 85.5 ± 4.7 years, ranging from 80 to 97 years. There is no significant difference in age (group 1 87.6 ± 5.9 years vs. group 2 84.8 ± 4.3 years, p = 0.262) between two groups. Serious coexisting diseases were noted in 13 (61.9 %, 13/21) patients. Primary hypertension, cardiac diseases, and diabetes mellitus were common coexisting conditions. However, there is no significant difference in comorbidities (40 vs. 68.8 %, p = 0.325) between group 1 and group 2. Adhensive SBO was successfully treated with conservative treatment in 16 patients (76.2 %, 16/21, group 2), whereas conservative treatment failed in 5 patients (23.8 %, 5/21, group 1), who subsequently underwent laparotomy. Postoperative complication rate was 14.3 % (wound infection, 1/5) and mortality was 0 % (0/5) in group 1. One patient death was recorded in group 2 (1/16, 6.3 %). The overall mean hospital stay was 10.0 ± 5.9 days (range 3-27 days). Group 1 had a longer hospital stay than group 2. However, the difference did not reach the significant level (12.8 ± 8.2 vs. 9.1 ± 5.9 days, p = 0.274). On univariate analysis, the need for surgical intervention was significantly associated with granulocyte percentage (2.768, 0.961-7.975, p = 0.059), CT findings of free intraabdominal fluid (28.000, 1.988-394.405, p = 0.014), and level of albumin (0.265, 0.073-0.970, p = 0.045). On multivariate analysis, the predictive factor was free intraabdominal fluid (28.000, 1.988-394.405, p = 0.014). Conservative treatment remains a major consideration in patients over the age of 80. Although major cases of adhensive SBO are successfully treated with conservative methods, some fail to respond, and the independent risk factor for surgical indication is free intraabdominal fluid.

Effects of total lignans from Eucommia ulmoides barks prevent bone loss in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: The present study systematically investigate the in vivo and in vitro effect of total lignans (TL) extracted from Eucommia ulmoides Oliv. barks on bone formation using ovariectomy rat model and primary cultures of rat osteoblasts. MATERIALS AND METHODS: Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (SHAM) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17α-ethinylestradiol (E2, 25 µg/kg/day); OVX with TL of graded doses (20, 40, or 80 mg/kg/day). The treatment began 4 weeks after the surgery and lasted for 16 weeks. in vitro experiments were performed to determine the potential mechanisms of the anti-osteoporotic effect of TL. RESULTS: Treatment with TL significantly prevent OVX-induced decrease in biomechanical quality of femur such as maximum stress and Young׳s modulus. The mechanical changes were associated with the prevention of a further BMD decrease or even with some improvements in microarchitecture. TL inhibited BMD decrease in the femur caused by OVX, which was accompanied by a significant decrease in skeletal remodeling, as was evidenced by the decreased levels of the bone turnover markers. µCT analysis of the femoral metaphysis showed how to prevent the deterioration of trabecular microarchitecture. TL induced primary osteoblastic cell proliferation and differentiation, inhibition of osteoclastogenesis through an increase in osteoprotegrin (OPG) and a decrease in NF-κB ligand (RANKL) expression in vitro. CONCLUSIONS: We concluded that TL treatment can effectively suppress the loss of bone mass induced by OVX and in vitro evidence suggests this could be through actions on both osteoblasts and osteoclasts.

Use of electrical impedance tomography to monitor regional cerebral edema during clinical dehydration treatment.

OBJECTIVE: Variations of conductive fluid content in brain tissue (e.g. cerebral edema) change tissue impedance and can potentially be measured by Electrical Impedance Tomography (EIT), an emerging medical imaging technique. The objective of this work is to establish the feasibility of using EIT as an imaging tool for monitoring brain fluid content. DESIGN: a prospective study. SETTING: In this study EIT was used, for the first time, to monitor variations in cerebral fluid content in a clinical model with patients undergoing clinical dehydration treatment. The EIT system was developed in house and its imaging sensitivity and spatial resolution were evaluated on a saline-filled tank. PATIENTS: 23 patients with brain edema. INTERVENTIONS: The patients were continuously imaged by EIT for two hours after initiation of dehydration treatment using 0.5 g/kg intravenous infusion of mannitol for 20 minutes. MEASUREMENT AND MAIN RESULTS: Overall impedance across the brain increased significantly before and after mannitol dehydration treatment (p = 0.0027). Of the all 23 patients, 14 showed high-level impedance increase and maintained this around 4 hours after the dehydration treatment whereas the other 9 also showed great impedance gain during the treatment but it gradually decreased after the treatment. Further analysis of the regions of interest in the EIT images revealed that diseased regions, identified on corresponding CT images, showed significantly less impedance changes than normal regions during the monitoring period, indicating variations in different patients' responses to such treatment. CONCLUSIONS: EIT shows potential promise as an imaging tool for real-time and non-invasive monitoring of brain edema patients.

A randomized controlled study comparing omeprazole and cimetidine for the prophylaxis of stress-related upper gastrointestinal bleeding in patients with intracerebral hemorrhage.

OBJECT: Patients with intracerebral hemorrhage (ICH) are at high risk for severe stress-related upper gastrointestinal (UGI) bleeding, which is predictive of higher mortality. The aim of this study was to evaluate the effectiveness of omeprazole and cimetidine compared with a placebo in the prevention and management of stress-related UGI bleeding in patients with ICH. METHODS: In a single-center, randomized, placebo-controlled study, 184 surgically treated patients with CT-proven ICH within 72 hours of ictus and negative results for gastric occult blood testing were included. Of these patients, 165 who were qualified upon further evaluation were randomized into 3 groups: 58 patients received 40 mg intravenous omeprazole every 12 hours, 54 patients received 300 mg intravenous cimetidine every 6 hours, and 53 patients received a placebo. Patients whose gastric occult blood tests were positive at admission (n = 70) and during/after the prophylaxis procedure (n = 48) were treated with high-dose omeprazole at 80 mg bolus plus 8 mg/hr infusion for 3 days, followed by 40 mg intravenous omeprazole every 12 hours for 7 days. RESULTS: Of the 165 assessable patients, stress-related UGI bleeding occurred in 9 (15.5%) in the omeprazole group compared with 15 patients (27.8%) in the cimetidine group and 24 patients (45.3%) in the placebo group (p = 0.003). The occurrence of UGI bleeding was significantly related to death (p = 0.022). Nosocomial pneumonia occurred in 14 patients (24.1%) receiving omeprazole, 12 (22.2%) receiving cimetidine, and 8 (15.1%) receiving placebo (p > 0.05). In patients with UGI bleeding in which high-dose omeprazole was initiated, UGI bleeding arrested within the first 3 days in 103 patients (87.3%). CONCLUSIONS: Omeprazole significantly reduced the morbidity of stress-related UGI bleeding in patients with ICH due to its effective prophylactic effect without increasing the risk of nosocomial pneumonia, but it did not reduce the 1-month mortality or ICU stay. Further evaluation of high-dose omeprazole as the drug of choice for patients presenting with UGI bleeding is warranted. Clinical trial registration no.: ChiCTR-TRC-12001871, registered at the Chinese clinical trial registry (http://www.chictr.org/en/proj/show.aspx?proj=2384).

[Differentiation of ectomesenchymal stem cells into dendritic cells in vitro induced by cytokines].

AIM: To induce the differentiation of ectomesenchymal stem cells (EMSCs) into dentritic cells (DCs) in vitro. METHODS: The EMSCs were cultured for 17 days continuously in RPMI1640 medium containing 100 ng/mL rat recombinant GM-CSF and 200 U/mL rat recombinant IL-3. On the 19th day, they were induced by rat recombinant TNF-α. The characteristics of the induced EMSCs were observed in aspects of morphology, ultrastructure, surface marker, mixed lymphocyte reaction and secretion of IL-12. The bone marrow-derived mesenchymal stem cells (BMSCs) of Sprague Dawley rat were used as controls. RESULTS: The induced EMSCs exhibited slender pseudopodia, burr and partial adherent growth. Scanning electron microscopy showed that the cells displayed processes and pseudopodia. The expressions of surface markers of induced EMSCs were similar to those of BMSCs-induced DCs. The mixed lymphocyte reaction assay revealed that the EMSCs stimulated the proliferation of lymphocytes. The induced EMSCs displayed the ability of IL-12 secretion. CONCLUSION: EMSCs can be differentiated into DCs by induction in vitro.

Achyranthes bidentata root extract prevent OVX-induced osteoporosis in rats.

AIM: The objective of the present study was to systematically investigate the effects of Achyranthes bidentata root extract (ABRE) on postmenopausal osteoporosis. MATERIALS AND METHODS: Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (SHAM) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17 ß-ethinylestradiol (E(2), 25 µg/kg/day); OVX with ABRE of graded doses (100, 300, or 500 mg/kg/day). Daily oral administration of ABRE or E(2) started on week 4 after OVX for 16 weeks. Bone mass, bone turnover and strength were analyzed by dual-energy X-ray absorptiometry (DEXA), biochemical markers and three-point bending test. The trabecular bone microarchitecture was evaluated by microcomputed tomography (µCT). RESULTS: 16 weeks treatment of ABRE slowed down the body weight gain and prevented the loss of bone mass induced by the OVX. The prevention effect on bone loss was due to altering the rate of bone remodeling, which could be inferred from the decreased level of bone turnover markers, such as serum alkaline phosphatase (ALP), osteocalcin (OC) and urinary deoxypyridinoline (DPD). The changes of urinary calcium and phosphorus excretion provided the same evidence. The treatment could also enhance the bone strength and prevent the deterioration of trabecular microarchitecture. CONCLUSIONS: We conclude that 16 weeks of ABRE treatment improve bone biomechanical quality through modifications of bone mineral density (BMD), and trabecular microarchitecture without hyperplastic effect on uterus, and it might be a potential alternative medicine for treatment of postmenopausal osteoporosis.