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81.
82.
Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability 总被引:1,自引:15,他引:1
La Spada AR; Peterson KR; Meadows SA; McClain ME; Jeng G; Chmelar RS; Haugen HA; Chen K; Singer MJ; Moore D; Trask BJ; Fischbeck KH; Clegg CH; McKnight GS 《Human molecular genetics》1998,7(6):959-967
X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG
repeat expansion in the first exon of the androgen receptor (AR) gene.
Disease-associated alleles (37-66 CAGs) change in length when transmitted
from parents to offspring, with a significantly greater tendency to shift
size when inherited paternally. As transgenic mice carrying human AR cDNAs
with 45 and 66 CAG repeats do not display repeat instability, we attempted
to model trinucleotide repeat instability by generating transgenic mice
with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions
in their genomic context. Studies of independent lines of AR YAC transgenic
mice with CAG 45 alleles reveal intergenerational instability at an overall
rate of approximately 10%. We also find that the 45 CAG repeat tracts are
significantly more unstable with maternal transmission and as the
transmitting mother ages. Of all the CAG/CTG repeat transgenic mice
produced to date the AR YAC CAG 45 mice are unstable with the smallest
trinucleotide repeat mutations, suggesting that the length threshold for
repeat instability in the mouse may be lowered by including the appropriate
flanking human DNA sequences. By sequence-tagged site content analysis and
long range mapping we determined that one unstable transgenic line has
integrated an approximately 70 kb segment of the AR locus due to
fragmentation of the AR YAC. Identification of the cis - acting elements
that permit CAG tract instability and the trans -acting factors that
modulate repeat instability in the AR YAC CAG 45 mice may provide insights
into the molecular basis of trinucleotide repeat instability in humans.
相似文献
83.
Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy 总被引:1,自引:0,他引:1 下载免费PDF全文
Gardiner TA Gibson DS de Gooyer TE de la Cruz VF McDonald DM Stitt AW 《The American journal of pathology》2005,166(2):637-644
The present study was undertaken to test whether inhibition of the proangiogenic inflammatory cytokine tumor necrosis factor (TNF)-alpha can modulate retinal hypoxia and preretinal neovascularization in a murine model of oxygen-induced retinopathy (OIR). OIR was produced in TNF-alpha-/- and wild-type (WT) control C57B6 neonatal mice by exposure to 75% oxygen between postnatal days 7 and 12 (P7 to P12). Half of each WT litter was treated with the cytokine inhibitor semapimod (formerly known as CNI-1493) (5 mg/kg) by daily intraperitoneal injection from the time of reintroduction to room air at P12 until P17. The extent of preretinal neovascularization and intraretinal revascularization was quantified by image analysis of retinal flat-mounts and retinal hypoxia correlated with vascularization by immunofluorescent localization of the hypoxia-sensitive drug pimonidazole (hypoxyprobe, HP). HP adducts were also characterized by Western analysis and quantified by competitive enzyme-linked immunosorbent assay. TNF-alpha-/- and WT mice showed a similar sensitivity to hyperoxia-induced retinal ischemia at P12. At P13 some delay in early reperfusion was evident in TNF-alpha-/- and WT mice treated with semapimod. However, at P17 both these groups had significantly better vascular recovery with less ischemic/hypoxic retina and preretinal neovascularization compared to untreated retinopathy in WT mice. Immunohistochemistry showed deposition of HP in the avascular inner retina but not in areas underlying preretinal neovascularization, indicating that such aberrant vasculature can reduce retinal hypoxia. Inhibition of TNF-alpha significantly improves vascular recovery within ischemic tissue and reduces pathological neovascularization in OIR. HP provides a useful tool for mapping and quantifying tissue hypoxia in experimental ischemic retinopathy. 相似文献
84.
Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts 总被引:18,自引:0,他引:18 下载免费PDF全文
Inai T Mancuso M Hashizume H Baffert F Haskell A Baluk P Hu-Lowe DD Shalinsky DR Thurston G Yancopoulos GD McDonald DM 《The American journal of pathology》2004,165(1):35-52
Angiogenesis inhibitors are receiving increased attention as cancer therapeutics, but little is known of the cellular effects of these inhibitors on tumor vessels. We sought to determine whether two agents, AG013736 and VEGF-Trap, that inhibit vascular endothelial growth factor (VEGF) signaling, merely stop angiogenesis or cause regression of existing tumor vessels. Here, we report that treatment with these inhibitors caused robust and early changes in endothelial cells, pericytes, and basement membrane of vessels in spontaneous islet-cell tumors of RIP-Tag2 transgenic mice and in subcutaneously implanted Lewis lung carcinomas. Strikingly, within 24 hours, endothelial fenestrations in RIP-Tag2 tumors disappeared, vascular sprouting was suppressed, and patency and blood flow ceased in some vessels. By 7 days, vascular density decreased more than 70%, and VEGFR-2 and VEGFR-3 expression was reduced in surviving endothelial cells. Vessels in Lewis lung tumors, which lacked endothelial fenestrations, showed less regression. In both tumors, pericytes did not degenerate to the same extent as endothelial cells, and those on surviving tumor vessels acquired a more normal phenotype. Vascular basement membrane persisted after endothelial cells degenerated, providing a ghost-like record of pretreatment vessel number and location and a potential scaffold for vessel regrowth. The potent anti-vascular action observed is evidence that VEGF signaling inhibitors do more than stop angiogenesis. Early loss of endothelial fenestrations in RIP-Tag2 tumors is a clue that vessel phenotype may be predictive of exceptional sensitivity to these inhibitors. 相似文献
85.
E. George Hunter T. F. McDonald Don P. MacLeod 《Pflügers Archiv : European journal of physiology》1972,335(4):266-278
Summary The action potential duration (APD) of guinea pig atrial muscle responded qualitatively to metabolic depression and altered glucose concentration as shown previously for papillary muscle. Both preparations lost potassium and gained sodium during 8 h anoxic incubations and these changes were partially prevented by 50 mM glucose. Experiments with potassium42 indicated that anoxia-induced loss of potassium was not primarily due to an increased efflux but to a decreased influx. Stimulation did not increase potassium42 efflux from atria but caused some increase in potassium loss. The ATP content of atria and ventricular muscle decreased rapidly during anoxic incubation but was maintained at a significantly higher level in the presence of 50 mM glucose. Since muscle potassium levels following 8 h of anoxic incubation were incompatible with observed resting potentials, the results support the concept of either an electrogenic sodium pump or the intracellular compartmentalization of potassium. In addition, the anoxia-induced reduction of action potential duration does not appear to be associated with an increase in potassium42 efflux.This work was supported by grants from the Medical Research Council of Canada and the Canadian Heart Foundation. 相似文献
86.
Neutrophil activity in abscess-bearing mice: comparative studies with neutrophils isolated from peripheral blood, elicited peritoneal exudates, and abscesses. 总被引:1,自引:5,他引:1 下载免费PDF全文
P H Hart L K Spencer M F Nulsen P J McDonald J J Finlay-Jones 《Infection and immunity》1986,51(3):936-941
Intraabdominal abscesses were induced in mice by intraperitoneal inoculation of Bacteroides fragilis and Escherichia coli plus bran as the abscess-potentiating agent. Six- or seven-day-old abscesses were mechanically disaggregated in buffer, and the cells obtained were fractionated on discontinuous Percoll density gradients. Neutrophil populations of different density, each approximately 90% pure, were isolated. When the abscess-derived neutrophils were subsequently incubated with normal serum in vitro under aerobic conditions, the viability of the gram-negative bacteria that had been phagocytosed within the abscess did not change significantly. This anergy to intracellular bacteria (on subsequent incubation in vitro under optimal conditions for phagocytic killing) was also found for neutrophils that had been obtained from abscesses induced by a mixture that included Proteus mirabilis plus B. fragilis and from those induced by E. coli plus P. mirabilis. While unable to significantly kill intracellular organisms that had been phagocytosed in vivo, the abscess-derived neutrophils could engulf and kill organisms to which they were exposed in vitro. Neutrophils from abscesses induced by P. mirabilis only plus bran killed that organism introduced in vitro significantly more effectively than the organisms that had been engulfed in vivo. In contrast, neutrophils from abscesses induced by the gram-positive organism Staphylococcus aureus plus bran were able to kill their intracellular organisms on subsequent incubation in vitro as effectively as they could kill added S. aureus. Neutrophils isolated from the peripheral blood and from induced peritoneal exudates of abscess-bearing mice were able to phagocytose and kill organisms in vitro with greater efficiency than abscess-derived neutrophils. The mechanism whereby neutrophils from abscesses induced by the gram-positive organism S. aureus can kill the organisms phagocytosed in vivo on subsequent in vitro incubation, in contrast to the relative anergy to their intracellular organisms displayed by neutrophils derived from abscesses induced by combinations of gram-negative bacteria, is not known. 相似文献
87.
Agglutinating antibody titers to members of the family Legionellaceae in cystic fibrosis patients as a result of cross-reacting antibodies to Pseudomonas aeruginosa. 总被引:3,自引:0,他引:3 下载免费PDF全文
The objective of this study was to evaluate the prevalence and significance of antibody titers to organisms in the family Legionellaceae in 128 serum samples collected from cystic fibrosis patients at routine examinations. Antibody titers were determined for 10 antigenic types of Legionellaceae; Legionella pneumophila serogroups 1 to 6, Fluoribacter (Legionella) bozemanae, Fluoribacter (Legionella) dumoffii, Fluoribacter (Legionella) gormanii, and Tatlockia (Legionella) micdadei. The method of antibody titer determination was the microagglutination test. Elevated titers (greater than or equal to 1:64) to one or more antigens were found in 41.3% of cystic fibrosis patients but in only 9.7% of 103 normal control subjects (P less than 0.01). Titers to 8 of the 10 antigens were directly correlated with the number of Pseudomonas aeruginosa precipitating antibodies in patient sera, as determined by crossed immunoelectrophoresis (correlation coefficients, greater than or equal to 0.74). Cross-reactions between P. aeruginosa and L. pneumophila were substantiated by crossed immunoelectrophoresis of hyperimmune rabbit serum as well as patient sera against P. aeruginosa and Legionellaceae antigens. Monospecific antibody to the "common antigen" of P. aeruginosa was used to demonstrate the presence of this antigen in L. pneumophila. The presence of cross-reacting antibodies in cystic fibrosis patients chronically infected with P. aeruginosa emphasizes the need for cautious interpretation of antibody titers to members of the family Legionellaceae. 相似文献
88.
In vitro parasite-monocyte interactions in human leishmaniasis: possible role of fibronectin in parasite attachment. 总被引:5,自引:7,他引:5 下载免费PDF全文
Leishmania spp. must attach to mononuclear phagocyte surfaces before entering this host cell. We investigated the potential role of fibronectin in facilitating parasite attachment. Human plasma fibronectin bound to axenically cultured promastigotes, and promastigotes and amastigotes preferentially bound to fibronectin-coated cover slips. Promastigotes grown in the absence of fibronectin were strikingly deficient in their ability to attach to human monocytes compared with promastigotes grown in the presence of fibronectin. Rabbit anti-human plasma fibronectin antiserum decreased promastigote and amastigote attachment to monocytes. Immunoglobulin G F(ab')2 and Fab fragments also reduced the ability of amastigotes to bind to monocytes. Antiserum pretreatment of amastigotes followed by washing resulted in reduced parasite binding, whereas antibody pretreatment of monocytes did not. Addition of exogenous fibronectin did not enhance parasite attachment to monocytes. These findings suggest that Leishmania spp. can bind fibronectin and may utilize this glycoprotein to facilitate attachment to the mononuclear phagocytes that they infect. 相似文献
89.
Comparison of BACTEC MYCO/F LYTIC and WAMPOLE ISOLATOR 10 (lysis-centrifugation) systems for detection of bacteremia, mycobacteremia, and fungemia in a developing country 总被引:2,自引:0,他引:2 下载免费PDF全文
Archibald LK McDonald LC Addison RM McKnight C Byrne T Dobbie H Nwanyanwu O Kazembe P Reller LB Jarvis WR 《Journal of clinical microbiology》2000,38(8):2994-2997
In less-developed countries, studies of bloodstream infections (BSI) have been hindered because of the difficulty and costs of culturing blood for bacteria, mycobacteria, and fungi. During two study periods (study period I [1997] and study period II [1998]), we cultured blood from patients in Malawi by using the BACTEC MYCO/F LYTIC (MFL), ISOLATOR 10 (Isolator), Septi-Chek AFB (SC-AFB), and Septi-Chek bacterial (SC-B) systems. During study period I, blood was inoculated at 5 ml into an MFL bottle, 10 ml into an Isolator tube for lysis and centrifugation, and 10 ml into an SC-B bottle. Next, 0.5-ml aliquots of Isolator concentrate were inoculated into an SC-AFB bottle and onto Middlebrook 7H11 agar slants, chocolate agar slants, and Inhibitory Mold Agar (IMA) slants. During study period II, the SC-B and chocolate agar cultures were discontinued. MFL growth was detected by fluorescence caused by shining UV light (lambda = 365 nm) onto the indicator on the bottom of the bottle. During study period I, 251 blood cultures yielded 44 bacterial isolates. For bacteremia, the MFL was similar to the Isolator concentrate on chocolate agar (34 of 44 versus 27 of 44; P, not significant [NS]), but more sensitive than the SC-B bottle (34 of 44 versus 24 of 44; P = 0.05). For both study periods combined, 486 blood cultures yielded 37 mycobacterial and 13 fungal isolates. For mycobacteremia, the sensitivities of the MFL and Isolator concentrate in the SC-AFB bottle were similar (30 of 37 versus 29 of 37; P, NS); the MFL bottle was more sensitive than the concentrate on Middlebrook agar (30 of 37 versus 15 of 37; P = 0.002). For fungemia, the MFL bottle was as sensitive as the SC-B bottle or Isolator concentrate on chocolate agar or IMA slants. We conclude that the MFL bottle, inoculated with just 5 ml of blood and examined under UV light, provides a sensitive and uncomplicated method for comprehensive detection of BSI in less-developed countries. 相似文献
90.
Controlled comparison of BacT/ALERT FAN aerobic medium and BATEC fungal blood culture medium for detection of fungemia 下载免费PDF全文
McDonald LC Weinstein MP Fune J Mirrett S Reimer LG Reller LB 《Journal of clinical microbiology》2001,39(2):622-624
Yeasts are an increasingly common cause of nosocomial bloodstream infections. Methods for their detection are many; controlled comparisons are few. The vented FAN aerobic blood culture medium has been shown to be superior to the standard BacT/ALERT aerobic medium for the detection of fungemia as well as bacteremia. The BACTEC selective fungal medium (FM) (BD Biosciences, Sparks, Md.) allowed detection of more episodes of fungemia than did a resin-containing medium with equal volumes of blood cultured. Therefore, we compared vented FAN to FM for the ability to recover fungi from the blood of patients who were at increased risk of having fungemia. From 5,109 cultures processed for which both FAN and FM bottles were adequately filled, fungi were recovered from 87 cultures. Of these, 47 were detected with both bottles, 12 were detected with FAN only, and 28 were detected with FM only (P < 0.05). FAN was the first bottle positive for 36 of the 47 cultures for which both bottles yielded the same fungus, whereas the FM bottle was the first bottle positive for 11 cultures (P < 0.001). A total of 54 episodes of fungemia were identified, with 40 detected by both media, 4 detected only by FAN, and 10 detected only by FM (P value, not significant). We conclude that the vented FAN aerobic bottle is comparable to the FM bottle for detection of episodes of yeast infection but has the added benefit of detecting bacteria. 相似文献