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81.
Delivery of a hammerhead ribozyme specifically down-regulates the production of fibrillin-1 by cultured dermal fibroblasts 总被引:4,自引:1,他引:4
Kilpatrick MW; Phylactou LA; Godfrey M; Wu CH; Wu GY; Tsipouras P 《Human molecular genetics》1996,5(12):1939-1944
The hammerhead ribozyme is a small catalytic RNA molecule. Potential
hammerhead ribozymes that possess a catalytic domain and flanking sequence
complementary to a target mRNA can cleave in trans at a putative cleavage
site within the target molecule. We have investigated the potential of
hammerhead ribozymes to down-regulate the product of the fibrillin-1 gene
(FBN1). Fibrillin is a 347 kDa glycoprotein that is a major constituent of
the elastin-associated microfibrils. Mutations in the FBN1 gene are
responsible for Marfan syndrome (MFS), a common systemic disorder of the
connective tissue. Many FBN1 mutations responsible for MFS appear to act in
a dominant-negative fashion, raising the possibility that reduction of the
amount of product from the mutant FBN1 allele might be a valid therapeutic
approach for MFS. A trans-acting hammerhead ribozyme (FBN1-RZ1) targeted to
the 5' end of the human FBN1 mRNA has been designed and synthesized, and
shown to cleave its target efficiently in vitro. FBN1-RZ1 cleavage is
magnesium dependent and efficient at both 37 and 50 degrees C. Delivery of
the FBN1-RZ1 ribozyme into cultured dermal fibroblasts, by receptor-
mediated endocytosis of a ribozyme-transferrin-polylysine complex,
specifically reduces both cellular FBN1 mRNA and the deposition of
fibrillin in the extracellular matrix. These results suggest that the use
of hammerhead ribozymes is a valid approach to the study of fibrillin gene
expression and possibly to the development of a therapeutic approach to
MFS.
相似文献
82.
JUAN C. DE LA TORRE MARGARET MALLORY MICHELLE BROT LISA GOLD GEORGE KOOB MICHAEL B. A. OLDSTONE ELIEZER MASLIAH 《Virology》1996,220(2):508
Neurons have a restricted expression of MHC heavy chain molecules which prevents presentation of antigens of infecting viruses. As a result, such infected cells escape immune surveillance and allow the establishment of noncytolytic persistent infection. Here we show that a chronic noncytolytic viral infection bothin vitroandin vivoselectively perturbed the expression of GAP-43, a protein that plays a central role in neuronal plasticity processes accompanying learning and memory. GAP-43 expression was greatly decreased in the hippocampus, an area of heightened viral replication, while synaptic density was preserved. Concurrently, the ability to learn tasks was significantly impaired in these persistently infected mice. Yet, infected neurons remained free from structural injury. 相似文献
83.
Lee JI Verhagen Metman L Ohara S Dougherty PM Kim JH Lenz FA 《Journal of neurophysiology》2007,97(4):2627-2641
The neuronal basis of hyperkinetic movement disorders has long been unclear. We now test the hypothesis that changes in the firing pattern of neurons in the globus pallidus internus (GPi) are related to dyskinesias induced by low doses of apomorphine in patients with advanced Parkinson's disease (PD). During pallidotomy for advanced PD, the activity of single neurons was studied both before and after administration of apomorphine at doses just adequate to induce dyskinesias (21 neurons, 17 patients). After the apomorphine injection, these spike trains demonstrated an initial fall in firing from baseline. In nine neurons, the onset of on was simultaneous with that of dyskinesias. In these spike trains, the initial fall in firing rate preceded and was larger than the fall at the onset of on with dyskinesias. Among the three neurons in which the onset of on occurred before that of dyskinesias, the firing rate did not change at the time of onset of dyskinesias. After injection of apomorphine, dyskinesias during on with dyskinesias often fluctuated between transient periods with dyskinesias and those without. Average firing rates were not different between these two types of transient periods. Transient periods with dyskinesias were characterized by interspike interval (ISI) independence, stationary spike trains, and higher variability of ISIs. A small but significant group of neurons demonstrated recurring ISI patterns during transient periods of on with dyskinesias. These results suggest that mild dyskinesias resulting from low doses of apomorphine are related to both low GPi neuronal firing rates and altered firing patterns. 相似文献
84.
Bregje Thoonsen Yvonne Engels Eric van Rijswijk Stans Verhagen Chris van Weel Marieke Groot Kris Vissers 《The British journal of general practice》2012,62(602):e625-e631
Background
According to the World Health Organization (WHO) definition, palliative care should be initiated in an early phase and not be restricted to terminal care. In the literature, no validated tools predicting the optimal timing for initiating palliative care have been determined.Aim
The aim of this study was to systematically develop a tool for GPs with which they can identify patients with congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cancer respectively, who could benefit from proactive palliative care.Design
A three-step procedure, including a literature review, focus group interviews with input from the multidisciplinary field of palliative healthcare professionals, and a modified Rand Delphi process with GPs.Method
The three-step procedure was used to develop sets of indicators for the early identification of CHF, COPD, and cancer patients who could benefit from palliative care.Results
Three comprehensive sets of indicators were developed to support GPs in identifying patients with CHF, COPD, and cancer in need of palliative care. For CHF, seven indicators were found: for example, frequent hospital admissions. For COPD, six indicators were found: such as, Karnofsky score ≤50%. For cancer, eight indicators were found: for example, worse prognosis of the primary tumour.Conclusion
The RADboud indicators for PAlliative Care Needs (RADPAC) is the first tool developed from a combination of scientific evidence and practice experience that can help GPs in the identification of patients with CHF, COPD, or cancer, in need of palliative care. Applying the RADPAC facilitates the start of proactive palliative care and aims to improve the quality of palliative care in general practice. 相似文献85.
A Heim D Wagner T Roth?mel U Hartmann J Flik W Verhagen 《Journal of medical virology》1999,58(3):291-295
Human corneas are explanted for grafting as late as 72 h after death, for example, from medical examiner cases. Currently, infection of the donor with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) is excluded in most cornea banks by serological testing of the cadaveric serum only. The reliability of this strategy was investigated by testing paired cadaveric and premortem sera of 33 potential donors. Results were discordant in 17 of 33 donors by at least one assay. Most frequently, HBsAg enzyme-linked immunosorbent assay (ELISA) yielded false-positive results with the cadaveric serum (16 of 33 serum pairs). Virus safety of the graft was affected in a single case, which was HCV antibody negative in the cadaveric serum, but positive in the premortem serum (confirmed by HCV-RIBA strip immunoassay). Forensic DNA profiling by polymerase chain reaction (PCR) of both serum samples confirmed that these were derived from the same individual. In conclusion, the results indicate that serological testing of cadaveric sera is not a reliable method for screening of potential cornea donors, and may not be sufficient for the virus safety of cornea grafts. Therefore, other screening strategies such as detection of viral nucleic acids by PCR should be evaluated. 相似文献
86.
High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons
Klöckener T Hess S Belgardt BF Paeger L Verhagen LA Husch A Sohn JW Hampel B Dhillon H Zigman JM Lowell BB Williams KW Elmquist JK Horvath TL Kloppenburg P Brüning JC 《Nature neuroscience》2011,14(7):911-918
Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K(ATP) channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(ΔIR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(ΔIR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(ΔIR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development. 相似文献
87.
Verhagen JM Schrander-Stumpel CT Krapels IP de Die-Smulders CE van Lint FH Willekes C Weber JW Gavilanes AW Macville MV Stegmann AP Engelen JJ Bakker J Vos YJ Frints SG 《European journal of medical genetics》2011,54(6):e542-e547
Congenital hydrocephalus is a common and often disabling disorder. The etiology is very heterogeneous. Little is known about the genetic causes of congenital hydrocephalus.A retrospective survey was performed including patients with primary congenital hydrocephalus referred to the Department of Clinical Genetics between 1985 and 2010 by perinatologists, (child) neurologists or pediatricians. Patients with hydrocephalus secondary to other pathology were excluded from this survey. We classified patients with primary congenital hydrocephalus into two main groups: non-syndromic hydrocephalus (NSH) and syndromic hydrocephalus (SH). Seventy-five individuals met the inclusion criteria, comprising 36% (27/75) NSH and 64% (48/75) SH. In 11% (8/75) hydrocephalus was familial. The cause of hydrocephalus was unknown in 81% (61/75), including all patients with NSH. The male–female ratio in this subgroup was 2.6:1, indicating an X-linked factor other than the L1CAM gene. In the group of SH patients, 29% (14/48) had a known cause of hydrocephalus including chromosomal abnormalities, L1 syndrome, Marden–Walker syndrome, Walker–Warburg syndrome and hemifacial microsomia.We performed this survey in order to evaluate current knowledge on the genetic etiology of primary congenital hydrocephalus and to identify new candidate genes or regulatory pathways for congenital hydrocephalus. Recommendations were made concerning the evaluation and genetic workup of patients with primary congenital hydrocephalus. We conclude that further molecular and functional analysis is needed to identify new genetic forms of congenital hydrocephalus. 相似文献
88.
Excessive dorsiflexion (dorsal tilting) of the lunate on a lateral wrist radiograph can be an important sign of carpal injury. Lunate dorsiflexion is a well-recognized sign of an intercarpal ligamentous injury pattern known as dorsal intercalated segment instability (DISI). It is less well recognized that excessive dorsal tilting of the lunate (DISI configuration) can also be produced by displacement of a scaphoid waist fracture. Since the management and prognosis of displaced scaphoid fractures may be quite different from those for nondisplaced fractures, radiologists can make an important contribution by recognizing dorsal tilting of the lunate and appreciating that it may be an important, indirect sign of scaphoid fracture displacement, which may not be directly visualized with standard wrist radiography. In this setting, computed tomography or complex motion tomography may be helpful for further evaluation of the scaphoid fracture. 相似文献
89.
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