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排序方式: 共有1426条查询结果,搜索用时 187 毫秒
1.
Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas. 相似文献
2.
Balloon dacryocystoplasty: indications and contraindications 总被引:3,自引:0,他引:3
3.
OBJECTIVES--To assess how the opinions of cardiologists, physicians, and general practitioners on the indications for permanent pacing compare with published guidelines, and to determine whether resources, pacing experience, and position influence referral practices. DESIGN--Anonymous postal survey by questionnaire from St Bartholomew's Hospital, London and the King's Fund Institute, London. The questionnaire established the respondent's position, resources, and previous pacing experience. Eleven clinical and electrocardiographic situations were described and respondents were asked to decide on whether pacing was indicated. The responses received were compared with the guidelines provided by the 1984 American College of Cardiology/American Heart Association task force. PARTICIPANTS--The 630 members of the British Cardiac Society, 1370 randomly selected general physicians, and 2000 general practitioners. RESULTS--Patients with symptoms were more likely to be referred for pacing than symptom free patients regardless of underlying aetiology. In relatively symptom free patients the frequency with which pacing was recommended was low, even when it was unequivocally indicated on prognostic grounds. Failure to recommend pacing was unrelated to diagnostic facilities or referral difficulties. Respondents with pacing experience were more likely to recommend pacing. CONCLUSIONS--The physicians surveyed had a conservative approach towards recommending pacing. Most physicians were influenced predominantly by symptoms and the prognostic indications for pacing were not well appreciated. 相似文献
4.
J S Judge V Low H Gajraj A K House 《The Australian and New Zealand journal of surgery》1992,62(4):261-265
The results of technetium renography were compared with arteriography to determine whether this is a satisfactory screening test for renal artery stenosis (RAS). Sixty-three patients were studied before aortic surgery. All were investigated by aortography and isotope renography. These tests were assessed blind and all arteriograms were graded by a single independent radiologist. Renal artery stenosis was detected by arteriography in 34 (54%) patients. Twenty-three (37%) had mild (less than 50%) stenosis, seven (11%) had moderate (50-80%) stenosis and four (6%) had severe (greater than 80%) stenosis. Of these 34 patients, only 6 (18%) were correctly diagnosed by isotope renography. None of the four with severe stenosis were identified. Isotope renography resulted in six true positives, six false positives, 23 true negatives and 28 false negatives. It was concluded that isotope renography did not fulfil the criteria for a screening test for the detection of RAS and appeared to be of no value in those patients undergoing aortic surgery in whom arteriography was not indicated. 相似文献
5.
Duncan WC; Illingworth PJ; Young FM; Fraser HM 《Human reproduction (Oxford, England)》1998,13(9):2532-2540
The molecular mechanisms involved in luteolysis are still unclear in the
primate. This study aimed to investigate the effect of induced luteolysis
on the ovarian luteinizing hormone (LH) receptor and the steroidogenic
enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the marmoset
monkey. Luteolysis was induced in the mid-luteal phase either directly by
systemic prostaglandin F2alpha (PGF2alpha), or indirectly by LH withdrawal
using systemic gonadotrophin releasing hormone antagonist (GnRHant)
treatment. The LH receptor was studied by isotopic mRNA in-situ
hybridization and in-situ ligand binding and 3beta-HSD expression was
studied using isotopic mRNA in-situ hybridization and immunohistochemistry.
Induced luteolysis was associated with a reduction in the expression of LH
receptor (P < 0.0001) and 3beta-HSD mRNA, closely followed by a
reduction in the LH receptor (P < 0.05) and 3beta-HSD protein
concentrations within 24 h. There were no differences in the findings
whether luteolysis was induced with PGF2alpha or GnRHant. This study shows
that disparate mechanisms to induce luteolysis in the primate result in an
identical rapid loss of the LH receptor and 3beta-HSD. In conclusion,
induced luteolysis leads to rapid loss of the steroidogenic pathway in
luteal cells.
相似文献
6.
HM Clink 《Journal of clinical pathology》1980,33(8):799-800
7.
8.
An X-linked pattern of transmission observed in four families with familial mental retardation in several generations was associated with a probable secondary constriction at the distal end of the q arms of the X chromosome. Twenty retarded males and no retarded females were observed. All available live retarded males and most of their normal mothers were found to have the abnormal X chromosome. The marker chromosome was shown to be the X chromosome in each case by Giemsa banding. In affected male and female carriers the marker chromosome varied in appearance and was not present in all metaphases. The significance of this study in relation to previously reported pedigrees showing non-specific X-linked mental retardation is discussed. 相似文献
9.
Cloning, expression, and occurrence of the Brucella Cu-Zn superoxide dismutase. 总被引:7,自引:3,他引:7
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B J Bricker L B Tabatabai B A Judge B L Deyoe J E Mayfield 《Infection and immunity》1990,58(9):2935-2939
Recently, the complete amino acid sequence of a protein expressed in Escherichia coli from cloned Brucella abortus DNA was reported. On the basis of amino acid homology, this protein was identified as a copper-zinc superoxide dismutase (Cu-Zn SOD) (B. L. Beck, L. B. Tabatabai, and J. E. Mayfield, Biochemistry 29:372-376, 1990). We demonstrate in this paper that the sequenced protein is the same as the previously studied salt-extractable protein BCSP20. The plasmid-encoded protein expressed from recombinant E. coli is identical to the Brucella-derived BCSP20 in molecular mass, N-terminal amino acid sequence, and cross-reactivity with homologous and heterologous rabbit sera against either the recombinant gene product or the Brucella-derived protein. A survey of the expression of the Cu-Zn SOD protein in Brucella biovars representing all species was done by Western blotting (immunoblotting) using antisera raised against the recombinant E. coli-derived protein. With the exception of B. neotomae and B. suis biovar 2, the Cu-Zn SOD protein was detectable in all Brucella species and biovars tested, including eight biovars of B. abortus. 相似文献
10.
Direct cytotoxic action of Shiga toxin on human vascular endothelial cells. 总被引:12,自引:17,他引:12
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T G Obrig P J Del Vecchio J E Brown T P Moran B M Rowland T K Judge S W Rothman 《Infection and immunity》1988,56(9):2373-2378
To help explain a role of the Shiga toxin family in hemorrhagic colitis and hemolytic-uremic syndrome in humans, it has been hypothesized that these toxins cause direct damage to the vascular endothelium. We now report that Shiga toxin purified from Shigella dysenteriae 1 does indeed have a direct cytotoxic effect on vascular endothelial cells in cultures. Human umbilical vein endothelial cells (HUVEC) in confluent monolayers were reduced 50% by 10(-8) M Shiga toxin after a lag period of 48 to 96 h. In comparison, nonconfluent HUVEC were reduced 50% by 10(-10) M Shiga toxin within a 24-h period. These data suggest that dividing endothelial cells are more sensitive to Shiga toxin than are quiescent cells in confluent monolayers. Both confluent and nonconfluent HUVEC specifically bound 125I-Shiga toxin. However, in response to the toxin, rates of incorporation of [3H]leucine into protein were more severely reduced in nonconfluent cells than in confluent cells. Toxin inhibition of protein synthesis preceded detachment of cells from the substratum. The specific binding of 125I-Shiga toxin to human endothelial cells and the cytotoxic response were both toxin dose dependent and neutralized by anti-Shiga toxin antibody. Heat-denatured Shiga toxin was without the cytotoxic effect. In addition, the complete culture system contained less than 0.1 ng of bacterial endotoxin per ml, as measured by the Limulus amoebocyte lysate test. 相似文献