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1.
Transgenic and Natural Mouse Models of Proteolipid Protein (PLP)-Related Dysmyelination and Demyelination 总被引:2,自引:0,他引:2
I.R. Griffiths A. Schneider J. Anderson K-A. Nave 《Brain pathology (Zurich, Switzerland)》1995,5(3):275-281
The X chromosome-linked PLP/DM-20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus-Merzbacher disease, X-linked Spastic Paraplegia). The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death. In most mutants, residual myelin structures have an abnormal ultrastructure and periodicity. Surprisingly, transgenic mice which carry extra copies of the wild type PLP gene show dysmyelination, demonstrating that the PLP gene is dosage sensitive. Pathological changes of transgenic mice vary from the phenotype of natural mutants. Specifically, many Golgi saccules of oligodendrocytes are vacuolated and the cytoplasm contains autophagic vacuoles hinting at a perturbation in protein trafficking. In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment. Surprisingly, transgenic animals which overexpress PLP/DM-20 at a low level appear normal during early development, but later spontaneously demyelinate. The mechanisms underlying this demyelination phenotype is unknown but an immune-mediated process has been suggested. All attempts to correct the phenotype of natural PLP mutants, such as jimpy mice, with a wild type transgene have had little effects, indicating a dominant-negative effect of the mutant gene product. On the other hand, mice with a targeted disruption of the PLP/DM-20 gene have suprisingly minor clinical signs. This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain-of-function effects of a mutant myelin protein. 相似文献
2.
Sebastian Gabrielsson Git‐Marie E. Looi Karin Zingmark Stefan Svenstedt 《Scandinavian journal of caring sciences》2014,28(4):784-792
Challenging situations in psychiatric inpatient settings call for interprofessional collaboration, but the roles and responsibilities held by members of different professions is unclear. The aim of this study was to describe staff members' perceptions of interprofessional collaboration in the context of challenging situations in psychiatric inpatient care. Prior to the study taking place, ethical approval was granted. Focus group interviews were conducted with 26 physicians, ward managers, psychiatric nurses, and nursing assistants. These interviews were then transcribed and analysed using qualitative content analysis. Results described participants' perceptions of shared responsibilities, profession‐specific responsibilities and professional approaches. In this, recognising knowledge of the patient as decision‐making power was understood to be a recurring theme. This is a delimited qualitative study that reflects the specific working conditions of the participants at the time the study was conducted. The findings suggest that nursing assistants are the most influential professionals due to their closeness to and first‐hand knowledge of patients. The results also point to the possibility of other professionals gaining influence by getting closer to patients and utilising their professional knowledge, thus contributing to a more person‐centred care. 相似文献
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Savonenko AV Melnikova T Laird FM Stewart KA Price DL Wong PC 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(14):5585-5590
beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders. 相似文献
5.
Ku JL Yoon KA Kim IJ Kim WH Jang JY Suh KS Kim SW Park YH Hwang JH Yoon YB Park JG 《British journal of cancer》2002,87(2):187-193
Human cell lines established from biliary tract cancers are rare, and only five have been reported previously. We report the characterisation of six new six biliary tract cancer cell lines (designated SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079 and SNU-1196) established from primary tumour samples of Korean patients. The cell lines were isolated from two extrahepatic bile duct cancers (one adenocarcinoma of common bile duct, one hilar bile duct cancer), two adenocarcinomas of ampulla of Vater, one intrahepatic bile duct cancer (cholangiocarcinoma), and one adenocarcinoma of the gall bladder. The cell phenotypes, including the histopathology of the primary tumours and in vitro growth characteristics, were determined. We also performed molecular characterisation, including DNA fingerprinting analysis and abnormalities of K-ras, p15, p16, p53, hMLH1, hMSH2, DPC4, beta-catenin, E-cadherin, hOGG1, STK11, and TGF-betaRII genes by PCR-SSCP and sequencing analysis. In addition, we compared the genetic alterations in tumour cell lines and their corresponding tumour tissues. All lines grew as adherent cells. Population doubling times varied from 48-72 h. The culture success rate was 20% (six out of 30 attempts). All cell lines showed (i) relatively high viability; (ii) absence of mycoplasma or bacteria contamination; and (iii) genetic heterogeneity by DNA fingerprinting analysis. Among the lines, three lines had p53 mutations; and homozygous deletions in both p16 and p15 genes were found three and three lines, respectively; one line had a heterozygous missense mutation in hMLH1; E-cadherin gene was hypermethylated in two lines. Since the establishment of biliary tract cancer cell lines has been rarely reported in the literature, these newly established and well characterised biliary tract cancer cell lines would be very useful for studying the biology of biliary tract cancers, particularly those related to hypermethylation of E-cadherin gene in biliary tract cancer. 相似文献
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Al-Saktawi K McLaughlin M Klugmann M Schneider A Barrie JA McCulloch MC Montague P Kirkham D Nave KA Griffiths IR 《Journal of neuroscience research》2003,72(1):12-24
The rumpshaker mutation of the proteolipid protein (Plp) gene causes dysmyelination in man and mouse. We show that the phenotype in the mouse depends critically on the genetic background in which the mutation is expressed. On the C3H background there is normal longevity whereas changing to a C57BL/6 strain results in seizures and death at around postnatal day 30. The more severe phenotype is associated with less myelin and reduced levels of major myelin proteins. There are also more apoptotic cells, including oligodendrocytes, increased numbers of proliferating cells, increased numbers of NG2+ oligodendrocyte progenitors and increased microglia compared to the milder phenotype. The number of mature oligodendrocytes is similar to wild-type in both strains of mutant, however, suggesting that increased oligodendrocyte death is matched by increased generation from progenitors. The dichotomy of phenotype probably reflects the influence of modifying loci. The localization of these putative modifying genes and their mode of action remain to be determined. 相似文献
8.
BackgroundAlmost half of the global traffic crashes involve vulnerable groups such as pedestrian, cyclists and two-wheeler users. The main objective of this study was to determine the factors that influence standard of the safety helmets used amongst food delivery workers by presence of Standard and Industrial Research Institute of Malaysia (SIRIM) certification label.MethodsA cross sectional study was conducted amongst 150 food delivery workers from fast food outlets in the vicinity of Selangor and Kuala Lumpur. During observation, safety helmets were classified as standard safety helmet in the presence of SIRIM label and non-standard in the absence of the label. They were approached for questionnaire participation once consent was obtained and were requested to exchange their safety helmet voluntarily with a new one after the interview. Data analysis was carried out using SPSS. Chi square and logistic regression analysis was applied to determine the significance and odds ratio of the variables studied, respectively (penetration test, age, education level, knowledge, crash history, types of safety helmet, marital status and years of riding experience) against the presence of SIRIM label.ResultsThe response rate for this study was 85.2%. The prevalence of non-standard helmets use amongst fast food delivery workers was 55.3%. Safety helmets that failed the penetration test had higher odds of being non-standard helmets compared with safety helmets passing the test. Types of safety helmet indicated half-shell safety helmets had higher odds to be non-standard safety helmets compared to full-shell safety helmets. Riders with more years of riding experience were in high odds of wearing non-standard safety helmets compared to riders with less riding experience.ConclusionNon-standard (non-SIRIM approved) helmets were more likely to be half-shell helmets, were more likely to fail the standards penetration test, and were more likely to be worn by older, more experienced riders. The implications of these findings are discussed. 相似文献
9.
Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). 总被引:8,自引:0,他引:8
S Faderl M J Keating K-A Do S-Y Liang H M Kantarjian S O'Brien G Garcia-Manero T Manshouri M Albitar 《Leukemia》2002,16(6):1045-1052
It has been suggested that the expansion of the leukemic cells in chronic lymphocytic leukemia (CLL) is due to dysregulation of pathways of programmed cell death (apoptosis) rather than cell proliferation, although differences may exist in early vs late and treated vs untreated patients. In the present study, we analyzed the expression of 11 proteins in CLL cells that are implicated in the control of apoptosis, proliferation, and differentiation, and correlated this expression profile with survival. Using a quantitative solid-phase radioimmunoassay (RIA), we measured the cellular protein levels of Bcl-2, cyclin D1, PCNA, ATM, Fas, Bax, retinoic acid receptor alpha (RARalpha), retinoic acid receptor beta (RXRbeta), Flt1, VEGF, and cellular beta2-microglobulin in 230 samples of CLL. Univariate analysis using the Cox proportional hazard model showed a correlation with survival of only the following proteins: Bcl-2 (P < 0.001), cyclin D1 (P = 0.027), Fas (P = 0.055), PCNA (P < 0.001), and ATM (P = 0.028). In a multivariate analysis using classification and regression tree analysis (CART), five groups of patients (nodes) could be generated with significant differences of survival expectation (P < 0.0001) based on levels of expression of the above proteins. Based on CART analysis, Bcl-2 levels emerge as the most important protein in predicting survival between all 11 proteins studied. Patients with marked elevation in Bcl-2 levels had the worst outcome while patients with intermediate levels, but with high levels of PCNA and cyclin D1 or abnormal ATM expression had intermediate survival. These data indicate that intracellular levels of proteins such as Bcl-2, ATM, cyclin D1, and PCNA can be used as markers to predict clinical behavior and survival in patients with CLL. The pathways in which these proteins are involved may also represent possible targets for future therapeutic trials in CLL. 相似文献
10.
Characteristics and outcome among children suffering from out of hospital cardiac arrest in Sweden 总被引:8,自引:0,他引:8
AIM: To evaluate the characteristics, outcome and prognostic factors among children suffering from out of hospital cardiac arrest in Sweden. METHODS: Patients aged below 18 years suffering from out of hospital cardiac arrest which were not crew witnessed and included in the Swedish cardiac arrest registry were included in the survey. This survey included the period 1990-2001 and 60 ambulance organisations covering 85% of the Swedish population (8 million inhabitants). RESULTS: In all 457 children participated in the survey of which 32% were bystander witnessed and 68% received bystander CPR. Ventricular fibrillation was found in 6% of the cases. The overall survival to 1 month was 4%. The aetiology was sudden infant death syndrome in 34% and cardiac in 11%. When in a multivariate analysis considering age, sex, witnessed status, bystander CPR, initial rhythm, aetiology and the interval between call for, and arrival of, the ambulance and place of arrest only one appeared as an independent predictor of an increased chance of surviving cardiac arrest occurring outside home (adjusted odds ratio 8.7; 95% CL 2.2-58.1). CONCLUSION: Among children suffering from out of hospital cardiac arrest in Sweden that were not crew witnessed, the overall survival is low (4%). The chance of survival appears to be markedly increased if the arrest occurs outside the patients home compared with at home. No other strong predictors for an increased chance of survival could be demonstrated. 相似文献