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1.

Trial Design

This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.

Methods

Males aged 5–18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13–17 years), renal function, and glycolipid levels (plasma, urine).

Results

Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m2 (range 90.4–161.0 mL/min/1.73 m2) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0–27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.

Conclusions

These data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.

Trial Registration

ClinicalTrials.gov NCT00701415  相似文献   
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RU 486 is known primarily as an antagonist to progestins and glucocorticoids. However, RU 486 has also been shown to have agonistic progestational properties in biochemical and behavioral studies. In the current study, RU 486 was implanted directly into tim ventromedial hypothalamus (VMH) to test for facilitative action on the receptive behavior of female ovariectomized Long-Evans rats primed with 5 μg of estradiol benzoate. Cannulae containing RU 486, progesterone (P), or empty cannulae were implanted 48 hr after estrogen priming. The lordosis quotient and the lordosis score were assessed 4 hr after the cannulae were lowered by a standardized test consisting of 10 mounts by a stimulus male. P and RU 486 significantly facilitated receptivity compared to blank implants in terms of lordosis quotient and lordosis score, with no significant difference between the hormone treatments. While only a single dose of each treatment was given in the current study, RU 486 facilitated lordosis when implanted to the VMH as well as progesterone in contrast to our previous results where the steroids were administered systemically.  相似文献   
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Abstract. The in vitro proliferation [uptake of 5-bromo-2'-deoxyuridine (BrdU)] and the degree of differentiation (presence of desmin) of myosatellite cells isolated from white axial muscle of carp between 3 cm and 27 cm standard length (SL) were examined 17 h after isolation. The fraction of the myosatellite cells that were both desmin positive and BrdU positive never exceeded 2% of the total number of isolated myosatellite cells, irrespective of the standard length of the donor(s). This indicates that, for carp, the temporal relationship between replication and desmin expression of myosatellite cells is different from that described for myogenic cells of mammals and birds. The percentage of BrdU positive myosatellite cells was significantly correlated with standard length: it increased from 10% for carp of about 5 cm SL to 40–50% for carp between 20 cm and 27 cm SL. The percentage of desmin positive myosatellite cells was about 50–60%; it was not significantly correlated with standard length. The percentage of myosatellite cells that were both BrdU negative and desmin negative showed a stepwise difference in this percentage with increasing length. Fish smaller than 10 cm SL, had more of these cells (10–40%), than larger fish (which had 0–12%). So, apparently the composition of the myosatellite cell population changes during growth. The low percentage of proliferating cells, and the relatively high percentage of differentiated (desmin positive) myosatellite cells obtained from 3–6 cm large carp, suggests that, in these small fish, muscle growth strongly depends on the use of a pool of myogenic cells that has been formed at an earlier stage of their development.  相似文献   
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Curvularia lunata was found causing (disseminated phaeohyphomycosis among a group of Nezara viridula (Insecta:Heteroptera) parasitizing vegetable crop Vigna unguiculata. Dark lesions were seen on pronotum and abdominal sterna. Experimental lesions were produced by applying 0.1 ml of 6.2 × 108cfu/ml–1 on abdominal sterna. Histopathology revealed that almost all internal organs and tissues showed extensive damage. It is interesting to note that C. lunata exhibited predeliction for chitinous tissues and elicited cellular immune response by granulocytes (phagocytosis). This is the first report of phaeohyphomycosis of an insect, extending the disease to invertebrates.A promising research career of one of the authors (Mrs. Vinita Dubey) was cut short by untimely death. This paper is dedicated to her memory.  相似文献   
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Shewanella colwelliana (strain D) is a periphytic estuarine bacterium that forms biofilms beneficial to oyster set. Our study examined whether these and other films concentrated two hydrophobic, organophosphate pesticides, Abate and malathion, that are detected in Chesapeake Bay oyster waters. Both biofilms and purified exopolysaccharide of S. colwelliana did not adsorb more of the Abate or malathion than could be accounted for by adsorption to control surfaces. Similar results were obtained by using Deleya marina, Hyphomonas MHS3, and autochthonous biofilms. Conversely, decapsulated S. colwelliana D cells, prepared in the laboratory, bioconcentrated Abate. Significantly, the S. colwelliana D biofilms exposed to Abate did not inhibit the settlement and metamorphosis of Crassostrea gigas larvae.  相似文献   
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Varicella Zoster Virus (VZV), the alphaherpesvirus that causes varicella upon primary infection and Herpes zoster (shingles) following reactivation in latently infected neurons, is known to be fusogenic. It forms polynuclear syncytia in culture, in varicella skin lesions and in infected fetal human ganglia xenografted to mice. After axonal infection using VZV expressing green fluorescent protein (GFP) in compartmentalized microfluidic cultures there is diffuse filling of axons with GFP as well as punctate fluorescence corresponding to capsids. Use of viruses with fluorescent fusions to VZV proteins reveals that both proteins encoded by VZV genes and those of the infecting cell are transferred in bulk from infecting non-neuronal cells to axons. Similar transfer of protein to axons was observed following cell associated HSV1 infection. Fluorescence recovery after photobleaching (FRAP) experiments provide evidence that this transfer is by diffusion of proteins from the infecting cells into axons. Time-lapse movies and immunocytochemical experiments in co-cultures demonstrate that non-neuronal cells fuse with neuronal somata and proteins from both cell types are present in the syncytia formed. The fusogenic nature of VZV therefore may enable not only conventional entry of virions and capsids into axonal endings in the skin by classical entry mechanisms, but also by cytoplasmic fusion that permits viral protein transfer to neurons in bulk.  相似文献   
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