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991.
Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia 下载免费PDF全文
Shakkottai VG Chou CH Oddo S Sailer CA Knaus HG Gutman GA Barish ME LaFerla FM Chandy KG 《The Journal of clinical investigation》2004,113(4):582-590
Cerebellar ataxia, a devastating neurological disease, may be initiated by hyperexcitability of deep cerebellar nuclei (DCN) secondary to loss of inhibitory input from Purkinje neurons that frequently degenerate in this disease. This mechanism predicts that intrinsic DCN hyperexcitability would cause ataxia in the absence of upstream Purkinje degeneration. We report the generation of a transgenic (Tg) model that supports this mechanism of disease initiation. Small-conductance calcium-activated potassium (SK) channels, regulators of firing frequency, were silenced in the CNS of Tg mice with the dominant-inhibitory construct SK3-1B-GFP. Transgene expression was restricted to the DCN within the cerebellum and was detectable beginning on postnatal day 10, concomitant with the onset of cerebellar ataxia. Neurodegeneration was not evident up to the sixth month of age. Recordings from Tg DCN neurons revealed loss of the apamin-sensitive after-hyperpolarization current (IAHP) and increased spontaneous firing through SK channel suppression, indicative of DCN hyperexcitability. Spike duration and other electrogenic conductance were unaffected. Thus, a purely electrical alteration is sufficient to cause cerebellar ataxia, and SK openers such as the neuroprotective agent riluzole may reduce neuronal hyperexcitability and have therapeutic value. This dominant-inhibitory strategy may help define the in vivo role of SK channels in other neuronal pathways. 相似文献
992.
Giuseppe Bazzo Laura Nota Salvatore Soresi Lea Ferrari Patricia Minnes 《Journal of Applied Research in Intellectual Disabilities》2007,20(2):110-115
Background The sexual lives of people with intellectual disability is made complex by the involvement and influence of social service providers, whose beliefs and values have a great impact on the support they provide. We hypothesized that social service providers’ role, educational level and service in which they worked could affect attitudes towards the sexual behaviour of individuals with intellectual disability. Materials and methods The current study describes attitudes of social service providers towards the sexuality of individuals with disability measured by 20 items of Sexuality and Mental Retardation Attitudes Inventory (SMRAI). This instrument was devised by Brantlinger [Mental Retardation (1983) Vol. 21, pp. 17–22] to assess the attitudes of the staff employed by organizations that supplied services to individuals with intellectual disability. Specifically, analysis of variance (type of service × professional role × education) was performed on participants’ scores. Results Results suggested that the social service providers participating in this research study tended to have moderately liberal attitudes. Educational level and role carried out did not produce differences in their attitudes. A significant difference emerged between those who operated in different services. It was especially the staff of the outpatient treatment services who revealed the most liberal and positive attitudes towards the sexuality of individuals with intellectual disability. Conclusions The data reported in the present study seem to underline some differences between the data collected from the Italian and the Anglo‐Saxon social service providers. Failure to record influences associated with the role carried out and previous training could be related to the different contextual differences. Results suggest that particular attention should be paid to the training of those who hold managerial posts in Italian residential services. 相似文献
993.
Ferroni P Di Filippo F Martini F Spila A D'Alessandro T Cavaliere F Anzà M Garinei R Aloe S Carone MD Gazzaniga PP Guadagni F 《Journal of immunotherapy (Hagerstown, Md. : 1997)》2001,24(4):354-362
Hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor-a (TNFalpha) and cytotoxic drugs is currently used for treatment of melanoma and sarcoma of the limbs. Tumor necrosis factor-alpha is involved in the systemic inflammatory response syndrome as a result of activation of inflammatory cells and production of bioactive substances. The goal of this study was to determine the circulating levels of proinflammatory cytokines and soluble adhesion molecules in 19 patients with limb melanoma or sarcoma undergoing ILP with (n = 9) or without TNFalpha (n = 10). The results obtained demonstrated that ILP with TNFalpha was responsible for a leakage of TNFalpha in the systemic circulation, followed by a rise in interleukin (IL)-6 and IL-8 levels within I h. Elevated soluble (s)P-selectin levels were found 1-3 h after ILP. Plasma sE-selectin peaked 6-9 h after ILP, and soluble vascular cell adhesion molecule (sVCAM) levels reached a maximum after 24 h. Significant correlations were observed among these variables, confirming the interdependence of all changes observed. On the other hand, ILP with cytotoxic drugs alone induced only a modest release of TNFalpha, which was not followed by an immediate rise in IL-6 and IL-8. Four of the 9 patients undergoing ILP with TNF had severe systemic toxicity. No association was found between systemic TNF levels and the clinical outcome, whereas elevated TNF perfusion levels as well as systemic IL-6 and IL-8 levels were constantly elevated in patients with severe toxicity. These results are suggestive of an important role of TNFalpha levels in the perfusion system (more than leakage of perfusate) in causing postoperative toxicity, although other ILP-related factors should not be excluded. 相似文献
994.
Reduction in the development of cerulein-induced acute pancreatitis by treatment with M40401, a new selective superoxide dismutase mimetic 总被引:3,自引:0,他引:3
Cuzzocrea S Genovese T Mazzon E Di Paola R Muià C Britti D Salvemini D 《Shock (Augusta, Ga.)》2004,22(3):254-261
Oxidative stress plays an important role in the early stage of acute pancreatitis, as well as in the associated multiple organ injury. This study tests the hypothesis that M40401, a new superoxide dismutase mimetic, attenuates experimental acute pancreatitis. Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis that was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis, as well as increases in the serum levels of amylase and/or lipase. The infiltration of the pancreatic tissue of these animals with neutrophils (measured as an increase in myeloperoxidase activity) was associated with expression of intercellular adhesion molecule-1, as well as signs of enhanced lipid peroxidation (e.g., increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for nitrotyrosine and poly (ADP-ribose) polymerase in the pancreas of cerulein-treated mice. In contrast, the degree of pancreatic inflammation and tissue injury (histological score), the expression of intercellular adhesion molecule-1, the staining for nitrotyrosine and poly (ADP-ribose) polymerase, and lipid peroxidation were markedly reduced in pancreatic tissue sections obtained from cerulein-treated mice administered with M40401. These results confirm our hypothesis that superoxide anions play an important role in cerulein-mediated acute pancreatitis and support the possible clinical use of low-molecular-weight synthetic superoxide dismutase mimetics in those conditions that are associated with overproduction of superoxide. 相似文献
995.
996.
997.
Quiros-Roldan E Torti C Pirovano S Moretti F Casari S Carosi G Soriano V Imberti L 《Intervirology》2004,47(6):350-354
SEN virus (SENV) is a new family of single-stranded DNA viruses with eight different strains, A-H. The modifications in SENV DNA detection and subtype distribution were studied over a long-term follow-up (48 +/- 32.5 months) in 52 HIV-infected patients. 46% of the patients in the first sample and 34.6% in the second sample were found to have detectable SENV viremia. While the most prevalent variant in the first sample was found to be genotype A (83.3%), the second sample revealed a broader subtype diversification. Several epidemiological and clinical variables were tested in univariate model for clearance of detectable SENV viremia, but none of them reached statistical significance. In conclusion, a high degree of instability of both SENV DNA detection and subtype distribution in a cohort of HIV-infected patients was suggested, which may have important implications for further studies on both SENV epidemiology and its clinical impact. 相似文献
998.
Andrea Necchi Salvatore Lo Vullo Daniele Raggi Federica Perrone Patrizia Giannatempo Giuseppina Calareso Elena Togliardi Nicola Nicolai Luigi Piva Davide Biasoni Mario Catanzaro Tullio Torelli Silvia Stagni Maurizio Colecchia Adele Busico Marzia Pennati Nadia Zaffaroni Luigi Mariani Roberto Salvioni 《Urologic oncology》2018,36(1):8.e1-8.e8
Background
Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676).Patients and methods
After transurethral resection of the bladder, T2–T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400 mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively.Results
From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9–58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0–69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6–NR), nor was median overall survival (interquartile range: 30.3–NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response (P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution.Conclusions
SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy. 相似文献999.
1000.
Marco Fiore Samuel Ford Dario Callegaro Claudia Sangalli Chiara Colombo Stefano Radaelli Anna Maria Frezza Salvatore L. Renne Paolo G. Casali Alessandro Gronchi 《Annals of surgical oncology》2018,25(6):1536-1543