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61.
Migliaccio AR Rana RA Sanchez M Lorenzini R Centurione L Bianchi L Vannucchi AM Migliaccio G Orkin SH 《The Journal of experimental medicine》2003,197(3):281-296
Here it is shown that the phenotype of adult mice lacking the first enhancer (DNA hypersensitive site I) and the distal promoter of the GATA-1 gene (neo Delta HS or GATA-1(low) mutants) reveals defects in mast cell development. These include the presence of morphologically abnormal alcian blue(+) mast cells and apoptotic metachromatic(-) mast cell precursors in connective tissues and peritoneal lavage and numerous (60-70% of all the progenitors) "unique" trilineage cells committed to erythroid, megakaryocytic, and mast pathways in the bone marrow and spleen. These abnormalities, which were mirrored by impaired mast differentiation in vitro, were reversed by retroviral-mediated expression of GATA-1 cDNA. These data indicate an essential role for GATA-1 in mast cell differentiation. 相似文献
62.
A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties 下载免费PDF全文
Olsen DB Eldrup AB Bartholomew L Bhat B Bosserman MR Ceccacci A Colwell LF Fay JF Flores OA Getty KL Grobler JA LaFemina RL Markel EJ Migliaccio G Prhavc M Stahlhut MW Tomassini JE MacCoss M Hazuda DJ Carroll SS 《Antimicrobial agents and chemotherapy》2004,48(10):3944-3953
Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2'-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5'-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2'-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2'-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2'-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection. 相似文献
63.
Treatment of compulsive behaviour in eating disorders with intermittent ketamine infusions 总被引:2,自引:0,他引:2
Mills IH; Park GR; Manara AR; Merriman RJ 《QJM : monthly journal of the Association of Physicians》1998,91(7):493-503
We have previously shown that eating disorders are a compulsive behaviour
disease, characterized by frequent recall of anorexic thoughts. Evidence
suggests that memory is a neocortical neuronal network, excitation of which
involves the hippocampus, with recall occurring by re-excitement of the
same specific network. Excitement of the hippocampus by glutamate-NMDA
receptors, leading to long-term potentiation (LTP), can be blocked by
ketamine. Continuous block of LTP prevents new memory formation but does
not affect previous memories. Opioid antagonists prevent loss of
consciousness with ketamine but do not prevent the block of LTP. We used
infusions of 20 mg per hour ketamine for 10 h with 20 mg twice daily
nalmefene as opioid antagonist to treat 15 patients with a long history of
eating disorder, all of whom were chronic and resistant to several other
forms of treatment. Nine (responders) showed prolonged remission when
treated with two to nine ketamine infusions at intervals of 5 days to 3
weeks. Clinical response was associated with a significant decrease in
Compulsion score: before ketamine, mean +/- SE was 44.0 +/- 2.5; after
ketamine, 27.0 +/- 3.5 (t test, p = 0.0016). In six patients
(non-responders) the score was: before ketamine, 42.8 +/- 3.7; after
ketamine, 44.8 +/- 3.1. There was no significant response to at least five
ketamine treatments, perhaps because the compulsive drive was
re-established too soon after the infusion, or because the dose of opioid
antagonist, nalmefene, was too low.
相似文献
64.
ANDERSON G; COLES ET; CRANE M; DOUGLAS AC; GIBBS AR; GEDDES DM; PEEL ET; WOOD JB 《QJM : monthly journal of the Association of Physicians》1992,83(3):427-438
In order to describe the British experience of Wegener's granuiomatosisHospital Activity Analysis was used to collect cases diagnosedin England, Wales and Scotland between 1975 and 1985. Wherepossible clinical details, histological material and chest radiographswere obtained. Two hundred and sixty five patients were consideredto have Wegener's granuiomatosis. In 109 a single pathologistconfirmed the diagnosis by finding both granulomas and vasculitisin biopsy material. The diagnosis was made on clinical groundsor clinical grounds together with histological diagnosis inthe local hospital in 156 patients. Wegener's granuiomatosiswas confined to the lung or upper respiratory tract in 22 percent of patients and renal disease occurred in 58 per cent.Laboratory tests showed a pattern of mild anaemia, polymorphleucocytosis, eosinophilia and an elevated ESR and hypergammaglobulinaemia,with no specific pattern of changes. Histological confirmation was most frequently obtained by examinationof nasal biopsy specimens, but multiple biopsies were oftenrequired. Renal biopsies showed focal proliferative glomerulonephritisbut granulomatous glomerulonephritis was uncommon. Of availablechest radiographs 61 per cent were abnormal, large opacitiesbeing most common. Small irregular opacities were found lessoften and other abnormalities were uncommon. Treatment varied widely and 10 per cent of patients receivedno drug therapy. This large series illustrates that even withoutspecific treatment, patients with Wegener's granuiomatosis cansurvive for several years and with modern treatment survivalfor more than a decade is possible. Conclusions about the effectivenessof the various therapies cannot be drawn from this restrospectivestudy. Renal failure and disseminated vasculities were the commonestcauses of death; death was considered to result from complicationsof treatment with cytotoxic drugs or prednisolone in 6 per centof patients. 相似文献
65.
To determine the cost of expanding blood product operations, the concept of marginal cost must be used. This article reports the development and implementation of a method of costing increases in collecting plasma using apheresis operations. The model takes into account the fact that certain resource inputs--notably, direct labor and machines--increase in discrete steps rather than in a continuous manner. To address this fact, a stepwise cost analysis function was developed, which related operating costs to the volume of apheresis collections. This function was used to predict the marginal costs of potential increases in the supply of plasma at a blood center in Canada. Differences were noted in the cost of plasma in Canada and the United States, much of which could be attributed to different standards regarding the volume of plasma per collection and to differences in pricing materials. 相似文献
66.
67.
LD Petz ; L Calhoun ; P Yam ; M Cecka ; G Schiller ; AR Faitlowicz ; R Herron ; D Sayah ; RB Wallace ; A Belldegrun 《Transfusion》1993,33(9):742-750
A patient without evident immune deficiency who received a transfusion of blood from a second-degree family member developed fatal transfusion- associated graft-versus-host disease (TA-GVHD). The donor was homozygous for an HLA haplotype for which the recipient was heterozygous (one-way HLA match). All 39 reported cases of TA-GVHD in immunocompetent patients were reviewed to ascertain the predisposing factors and to define the indications for irradiating blood for this population. HLA typing was described in 15 cases; in 13, including seven related and six unrelated donors, a one-way HLA match was present. Thirty-one (79%) of the 39 cases were reported from Japan (and 196 other cases are cited in the Japanese literature), but a one-way HLA match among unrelated donors at HLA-A, -B, -DR loci is only approximately two to four times more likely in Japanese persons than in whites. Fresh blood (< 96 hours old) was used in 29 (94%) of the 31 cases reported from Japan and in 33 (87%) of 38 cases overall (in one case, the age of the blood used was not reported). Thus, factors that appear to predispose to TA-GVHD in immunocompetent patients are a one- way HLA match, fresh blood, and, possibly, Japanese ancestry. Irradiating cellular blood components from all blood relatives of transfusion recipients will not completely eliminate the risk of TA- GVHD. 相似文献
68.
We compared the erythroid burst-promoting activity (BPA) and colony-stimulating activity (CSA) released under serum-deprived conditions by stromal cells derived from nine normal subjects and from nine patients after bone marrow transplantation. BPA and CSA were defined according to the capacity of the conditioned media (CM) to stimulate formation of erythroid bursts and granulocyte/macrophage (GM) colonies in serum-deprived cultures of nonadherent marrow cells. Six patients (group A) failed to establish or maintain successful allografts during the study. The remaining three (group B) did not experience problems with engraftment. CM from all stromal cell cultures contained detectable levels of BPA. Preincubation of the CM with an anti-GM colony-stimulating factor (GM-CSF) monoclonal antibody (MoAb), but not with a rabbit anti-interleukin-3 (IL-3) serum, reduced BPA by an average of 94%. CM from normal and group B stromal cell cultures contained detectable CSA, and the levels correlated with the amounts of granulocyte-CSF (G-CSF) detected by a specific bioassay. G-CSF was not detectable in medium conditioned by stromal cells from transplanted patients with poor marrow function. These results indicate that CM from stromal cells from normal subjects and transplanted patients with good marrow function contain both GM-CSF and G-CSF, while CM from stromal cells from transplanted patients with poor marrow function contain detectable levels of GM-CSF only. The reduced capacity of these stromal cells to produce G-CSF is associated with a reduced capacity of the CM to sustain GM colony formation and may be associated with the inability of these patients to sustain their neutrophil counts in vivo. 相似文献
69.
Hayden R Sawyer S Frey E Mori S Migliaccio AA Della Santina CC 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2011,210(3-4):623-640
To facilitate design of a multichannel vestibular prosthesis that can restore sensation to individuals with bilateral loss of vestibular hair cell function, we created a virtual labyrinth model. Model geometry was generated through 3-dimensional (3D) reconstruction of microMRI and microCT scans of normal chinchillas (Chinchilla lanigera) acquired with 30-48 μm and 12 μm voxels, respectively. Virtual electrodes were positioned based on anatomic landmarks, and the extracellular potential field during a current pulse was computed using finite element methods. Potential fields then served as inputs to stochastic, nonlinear dynamic models for each of 2,415 vestibular afferent axons with spiking dynamics based on a modified Smith and Goldberg model incorporating parameters that varied with fiber location in the neuroepithelium. Action potential propagation was implemented by a well validated model of myelinated fibers. We tested the model by comparing predicted and actual 3D angular vestibulo-ocular reflex (aVOR) axes of eye rotation elicited by prosthetic stimuli. Actual responses were measured using 3D video-oculography. The model was individualized for each animal by placing virtual electrodes based on microCT localization of real electrodes. 3D eye rotation axes were predicted from the relative proportion of model axons excited within each of the three ampullary nerves. Multiple features observed empirically were observed as emergent properties of the model, including effects of active and return electrode position, stimulus amplitude and pulse waveform shape on target fiber recruitment and stimulation selectivity. The modeling procedure is partially automated and can be readily adapted to other species, including humans. 相似文献
70.
Migliaccio AA Meierhofer R Della Santina CC 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2011,210(3-4):489-501
We characterized the three-dimensional angular vestibulo-ocular reflex (3D aVOR) of adult C57BL6 mice during static tilt testing, sinusoidal, and high-acceleration rotations and compared it with that of another lateral-eyed mammal with afoveate retinae (chinchilla) and two primate species with forward eye orientation and retinal foveae (human and squirrel monkey). Noting that visual acuity in mice is poor compared to chinchillas and even worse compared to primates, we hypothesized that the mouse 3D aVOR would be relatively low in gain (eye-velocity/head-velocity) compared to other species and would fall off for combinations of head rotation velocity and frequency for which peak-to-peak position changes fall below the minimum visual angle resolvable by mice. We also predicted that as in chinchilla, the mouse 3D aVOR would be more isotropic (eye/head velocity gain independent of head rotation axis) and better aligned with the axis of head rotation than the 3D aVOR of primates. In 12 adult C57BL6 mice, binocular 3D eye movements were measured in darkness during whole-body static tilts, 20-100°/s whole-body sinusoidal rotations (0.02-10 Hz) and acceleration steps of 3,000°/s2 to a 150°/s plateau (dominant spectral content 8-12 Hz). Our results show that the mouse has a robust static tilt counter-roll response gain of ~0.35 (eye-position Δ/head-position Δ) and mid-frequency aVOR gain (~0.6-0.8), but relatively low aVOR gain for high-frequency sinusoidal head rotations and for steps of head rotation acceleration (~0.5). Due to comparatively poor static visual acuity in the mouse, a perfectly compensatory 3D aVOR would confer relatively little benefit during high-frequency, low-amplitude movements. Therefore, our data suggest that the adaptive drive for maintaining a compensatory 3D aVOR depends on the static visual acuity in different species. Like chinchillas, mice have a much more nearly isotropic 3D aVOR than do the primates for which comparable data are available. Relatively greater isotropy in lateral-eyed species without retinal foveae (e.g., mice and chinchillas in the present study) compared to forward-eyed species with retinal foveae (e.g., squirrel monkeys and humans) suggests that the parallel resting optic axes and/or radially symmetric retinal foveae of primates underlie their characteristically low 3D aVOR gain for roll head rotations. 相似文献