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Biomedical subjects

S M Evans

Publications and source records attributed to S M Evans.

At least 37 records · Page 2Linked to original sources
PubMed2001

Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles.

OBJECTIVES: Pharmacokinetic studies were performed on the first 28 patients enrolled in a phase I trial to determine the ability of EF5 [2-(2-nitro-1-H-imidazolI-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] to detect hypoxia in human tumors in the absence of patient toxicity. METHODS: EF5 was made in purified form and formulated for intravenous injection by the National Cancer Institute. After obtaining consent from the patients, EF5 was administered and blood samples were drawn at various times over approximately 48 h. For most patients it was possible to collect total urine at approximately 8-h intervals. EF5 in plasma and urine was analyzed by high-performance liquid chromatography. RESULTS: EF5's plasma concentration followed a simple exponential decay following infusion. The plasma half-life was 11.7 +/- 2.6 h (+/- SD) and was not affected by drug dose (9 to 28 mg/kg), fractional urine recovery, patient weight or gender. Absolute plasma values suggested even biodistribution of the drug throughout the soft tissue with a volume of distribution equal to 0.56 l/ kg. Despite the relatively high lipid partition coefficient (logP = 0.6), EF5 was excreted primarily (up to 70%) via kidney clearance. No drug metabolites (e.g. retaining the 2-nitroimidazole chromophore) were detected in either plasma or urine. No toxicity was found at drug doses adequate to detect tumor hypoxia. CONCLUSIONS: Currently held paradigms of 2-nitroimidazole metabolism (e.g. clearance rate and toxicity as affected by octanol/ water partition coefficient) are discussed. The results reported herein suggest that EF5 is biologically stable with predictable pharmacokinetics. EF5's consistent half-life and clearance properties will allow quantitative analysis of EF5 binding relative to tissue oxygen levels.

Area Under Curve↗
PubMed2001

Low pO2 and beta-estradiol induce VEGF in MCF-7 and MCF-7-5C cells: relationship to in vivo hypoxia.

Previous work from this laboratory demonstrated that MCF-7 breast carcinoma cells grown in nude mice contained minimal hypoxia but that tamoxifen treatment of these tumors resulted in increased hypoxia (Evans S. et al., Cancer Research, 1997). These findings led to studies exploring the link between estrogen signaling and tumor oxygenation and determining the role of VEGF in this process. The stimulation of estrogen-dependent MCF-7 breast carcinoma cells in vitro with beta-estradiol resulted in a two-fold induction of VEGF mRNA and 1.3-2-fold increase in protein, similar to what was observed when these cells were exposed to 0. 1% oxygen. Furthermore, the two stimuli given together had an additive effect on (increasing) VEGF expression, suggesting that the combination of hypoxia and estrogen may be important in upregulating VEGF in some breast cancers. Estrogen-independent MCF-7-5C cells, developed by growing MCF-7 cells in long-term culture in estrogen-free media, were also studied. Using EF5, a fluorinated 2-nitroimidazole which localizes to hypoxic cells, MCF-7-5C tumors grown in nude mice were found to contain lower pO2 levels and more hypoxic regions than similarly grown MCF-7 tumors. We tested the hypothesis that this might be the result of defective expression of VEGF in MCF-7-5C cells in response to beta-estradiol and/or hypoxia. However, MCF-7-5C and MCF-7 cells showed a similar induction of VEGF in vitro in response to either beta-estradiol or hypoxia. Therefore, although these two cell lines grown as tumors have substantial differences in the presence and patterns of hypoxia, this could not be explained by a difference in VEGF induction.

Animals↗
PubMed2001

Training in infrainguinal bypass surgery for severe leg ischaemia.

BACKGROUND: Recent changes in surgical training in the UK mean that operative experience must be gained more efficiently. However, it is important to demonstrate that improved training opportunities are not associated with inferior patient outcomes. The aim was to examine changes in training in infrainguinal bypass surgery and to compare the outcomes of operations performed by consultants and trainees. METHODS: A prospectively gathered, computerized database of 1077 consecutive infrainguinal bypasses performed on 1003 patients for chronic severe leg ischaemia between 1 January 1983 and 31 December 1998 was analysed. RESULTS: Consultants performed 733 (68 per cent) infrainguinal bypasses to the following distal sites: 347 (47 per cent) above-knee popliteal artery, 257 (35 per cent) below-knee popliteal artery, 121 (17 per cent) to a crural artery and eight (1 per cent) other. Trainees performed 344 operations: 170 (49 per cent) were to the above-knee popliteal artery, 122 (35 per cent) to the below-knee popliteal artery, 48 (14 per cent) crural and four (1 per cent) other. The operative mortality rate was 27 (4 per cent) of 733 for consultants and 11 (3 per cent) of 344 for trainees (P > 0.05, chi2 test). There were no significant differences in patency or limb salvage at 36 months after operation between consultants and trainees, regardless of the site of distal anastomosis and the type of conduit used. CONCLUSION: With appropriate case selection and supervision, training in infrainguinal bypass grafting does not compromise early or long-term patient outcomes.

Blood Vessel Prosthesis Implantation↗
PubMed2001

Plasma endothelin levels and outcome in patients undergoing repair of ruptured infrarenal abdominal aortic aneurysm.

BACKGROUND: Endothelin-1 (ET-1) is the most potent known vasoconstrictor. Elevated plasma levels have been demonstrated in patients with myocardial infarction, cardiogenic and septic shock, and respiratory, heart, and kidney failure, as well as in those undergoing elective abdominal aortic aneurysm (AAA) repair. However, endothelin levels have not previously been examined in patients undergoing repair of ruptured AAA. We hypothesized that hemorrhagic shock, lower torso ischemia, and reperfusion associated with ruptured AAA repair lead to increased synthesis and secretion of ET-1, which, in turn, predispose to organ failure, one of the principal causes of death in this condition. METHODS: Fourteen patients were studied. Plasma levels of big ET-1 and ET-1 were measured immediately before operation and immediately before, 5 minutes, and 6 hours after aortic clamp release. RESULTS: All patients survived for at least 24 hours after operation. Big ET-1 levels were above the normal range at one or more sample points in all patients, and the ET-1 levels were above the normal range in all survivors and four of five nonsurvivors. Five patients who died of organ failure had significantly lower big ET-1 levels at all sample points and significantly lower ET-1 levels after 5 minutes of reperfusion when compared with survivors. Preoperative ET-1 levels were significantly lower in eight patients who subsequently developed kidney failure than in six patients who did not. CONCLUSION: Contrary to our original hypothesis, these novel data demonstrate that patients with ruptured AAA in whom fatal postoperative organ failure develops have significantly lower perioperative endothelin levels than survivors.

Aged↗
PubMed2001

Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation.

We evaluated the levels and distribution of hypoxia in 31 human tumors using fluorescent immunohistochemical detection of binding by the 2-nitroimidazole, EF5. Hypoxia was found to be a heterogeneous property of human tumors. Necrosis was usually found adjacent to the highest level of binding in an individual patient's tumor. However, hypoxia often occurred without necrosis. In the group of tumors studied, the most common relationship between blood vessels (PECAM/CD31) and EF5 staining was consistent with diffusion-limited hypoxia; acute hypoxia occurred infrequently. Within a given patient's tumor, there was an inverse correlation between regions of proliferation (Ki-67) and regions of hypoxia. Again, however, when these parameters were examined in a group of patients, the absence of proliferation did not predict the presence of hypoxia. The relationships between hypoxia and other biologic endpoints are complex, but, within a given tumor's spatial relationships, they are in accord with known physiologic principles. Thus, our data emphasize that the relationships between hypoxia and other biologic parameters vary between patients. Necrosis, proliferation, and blood vessel distribution cannot predict the level or presence of hypoxia in an individual patient's tumor.

Antineoplastic Agents↗
PubMed2001

Efficacy and tolerability of a low microparticle diet in a double blind, randomized, pilot study in Crohn's disease.

BACKGROUND: Ultrafine and fine particles are potent adjuvants in antigen-mediated immune responses, and cause inflammation in susceptible individuals. Following recent findings that microparticles accumulate in the phagocytes of intestinal lymphoid aggregates, this study is the first investigation of whether their reduction in the diet improves the symptoms of Crohn's disease. METHODS: In a double blind study, 20 patients with active corticosteroid-treated ileal or ileo-colonic Crohn's disease randomly received either a low microparticle diet (trial group; n = 10) or a control diet (n = 10) for 4 months. Crohn's disease activity index (CDAI) and corticosteroid requirements were compared. RESULTS: One patient in each group was withdrawn. In the trial group there was a progressive decrease in CDAI from entry (392 +/- 25) to month 4 (145 +/- 47) (P = 0.002 vs control group) and seven patients were in remission (CDAI <150). In contrast, the control group had returned to baseline levels (302 +/- 28 on entry and 295 +/- 25 at month 4), with none in remission. Corticosteroid intake was reduced more in the trial group although this did not reach significance. CONCLUSIONS: A low microparticle diet may be effective in the management of ileal Crohn's disease and could explain the efficacy of elemental diets, which similarly are low in microparticles.

Adult↗
PubMed2001

Volunteers assess marine biodiversity.

Much less is known about marine biodiversity than that of terrestrial and freshwater environments. There is surprisingly little information about even the most common of organisms that live on the seashore. Science has limited resources to study them and volunteers can therefore make significant contributions. This article considers the value of a project in which volunteers are mapping the distribution and abundance of littoral animals and plants of the Northumberland coast.

Animals↗
PubMed2000

Regulation of the tinman homologues in Xenopus embryos.

Vertebrate homologues of the Drosophila tinman transcription factor have been implicated in the processes of specification and differentiation of cardiac mesoderm. In Xenopus three members of this family have been isolated to date. Here we show that the XNkx2-3, Xnkx2-5, and XNkx2-10 genes are expressed in increasingly distinctive patterns in endodermal and mesodermal germ layers through early development, suggesting that their protein products (either individually or in different combinations) perform distinct functions. Using amphibian transgenesis, we find that the expression pattern of one of these genes, XNkx2-5, can be reproduced using transgenes containing only 4.3 kb of promoter sequence. Sequence analysis reveals remarkable conservation between the distalmost 300 bp of the Xenopus promoter and a portion of the AR2 element upstream of the mouse and human Nkx2-5 genes. Interestingly, only the 3' half of this evolutionarily conserved sequence element is required for correct transgene expression in frog embryos. Mutation of conserved GATA sites or a motif resembling the dpp-response element in the Drosophila tinman tinD enhancer dramatically reduces the levels of transgene expression. Finally we show that, despite its activity in Xenopus embryos, in transgenic mice the Xenopus Nkx2-5 promoter is able to drive reporter gene expression only in a limited subset of cells expressing the endogenous gene. This intriguing result suggests that despite evolutionary conservation of some cis-regulatory sequences, the regulatory controls on Nkx2-5 expression have diverged between mammals and amphibians.

Animals↗
PubMed2000

The use of imposex to assess tributyltin contamination in coastal waters and open seas.

Imposex in muricid gastropods has been used to monitor tributyltin (TBT) contamination worldwide. Pollution was severe during the 1980s but regulations prohibiting the use of TBT-based antifoulants on vessels < 25 m in length have been highly effective in reducing TBT levels in coastal waters. Large vessels are still sources of TBT and major ports, especially those with dry docking and repair facilities, continue to be hot-spots of contamination. Measures of imposex suggest that severe pollution is normally localised to within a few kilometres of them. Mild imposex, possibly as a result of TBT pollution (although other causes have not been ruled out), has been described in whelks Buccinum undatum from offshore waters of the southern and central North Sea. However, the species is still abundant there and the occurrence of imposex does not seem to have affected its breeding performance. Imposex was mild or absent in populations of dogwhelks from open oceanic sites around the north Atlantic Ocean, suggesting that the oceans are free of contamination at biologically significant levels.

Animals↗
PubMed2000

NMDA-induced changes in a cortical network in vivo are prevented by AMPA.

Analogues of glutamic acid including N-methyl-D-aspartic acid (NMDA) depolarise neurones of the cerebral cortex in vivo and thus change the size of the somatosensory evoked potentials (SEPs). The potentials recover rapidly despite maintained superfusion with NMDA, suggesting a form of neuronal desensitisation or network adaptation. In this study potentials were evoked at the cortical surface by electrical stimulation of the contralateral forepaw and compounds applied topically to the cortical surface by a cortical cup. NMDA at 50-250 microM caused a concentration-dependent decrease in the amplitude of the SEPs, with the highest concentration always abolishing them. AMPA at 50 microM did not affect evoked potentials when applied alone, but prevented the NMDA. Such AMPA-NMDA interactions were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and enhanced by cyclothiazide (which prevents AMPA desensitisation). Superfusion with potassium did not change sensitivity to NMDA. These results suggest that, in the rat cerebral cortex in vivo, activation of AMPA receptors can induce a loss of the network response to activation of NMDA receptors. Such a phenomenon may have physiological and therapeutic implications.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

Depletion of tumor oxygenation during photodynamic therapy: detection by the hypoxia marker EF3 [2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl)acetamide ].

Photodynamic therapy (PDT) of tumors can create hypoxia when oxygen is depleted by photochemical consumption or the oxygen supply is compromised by microvascular damage. However, oxygen is a requirement for PDT, and hypoxia during illumination can lead to poorer tumor response. As such, sensitive methods of quantifying tumor oxygen and evaluating its distribution may help in the development and optimization of treatment protocols. In this study, the hypoxia marker EF3 [2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl)acetam ide] was used to evaluate the oxygenation of PDT-treated radiation-induced fibrosarcoma tumors. Tumor-bearing mice were administered Photofrin (5 mg/kg) 24 h before PDT illumination at 75 mW/cm2, 135 J/cm2 (30 min). EF3 (52 mg/kg) was injected either within 3 min before PDT illumination, with tumor excision at the conclusion of illumination, or within 3 min after illumination, with tumor excision 30 min later. Control animals received EF3 alone, EF3 plus Photofrin, or EF3 plus illumination. After tumor disaggregation, staining with a fluorochrome-conjugated monoclonal antibody, and flow cytometric analysis, control tumors demonstrated an averaged median fluorescence intensity (+/- SE) of 17.1 +/- 2.8. EF3 binding significantly (P = 0.007) increased during PDT to a median fluorescence intensity of 48.9 +/- 8.3. In the 30 min after PDT, EF3 binding returned to control levels (median, 18.3 +/- 3.3). To evaluate the oxygen concentrations corresponding to these fluorescence intensities, an in vitro standard curve was created based on the in vivo exposure conditions. From this curve, the oxygen tensions of tumors exposed to EF3 under control conditions, during PDT, or after PDT were calculated to be 3.1-5.3, 1.2-2.4, and 3.0-5.2 mm Hg, respectively. Detection of EF3 binding using a monoclonal antibody correlated well with direct detection of binding using a radioactive assay. EF3 binding was linear with drug incubation for times from 1.5 to 60 min. Overall, this work demonstrates that hypoxia during PDT illumination of radiation-induced fibrosarcoma tumors can be detected by the hypoxia marker EF3. Hypoxia during illumination can be labeled separately from that found before or after PDT. Tissue oxygen tensions corresponding to EF3 binding levels can be calculated.

Animals↗
PubMed2000

Detection of hypoxia in human squamous cell carcinoma by EF5 binding.

Localization and quantitation of 2-nitroimidazole drug binding in low pO2 tumors is a technique that can allow the assessment of hypoxia as a predictive assay. EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] is such a drug, and it has been shown to be predictive of radiation response in rodent tumors. Using fluorescence immunohistochemical techniques, we provide data on the presence, distribution, and levels of EF5 binding as a surrogate for hypoxia in human head and neck and uterine cervix squamous cell cancers (SCCs). Six patients with SCC were studied. Four patients had head and neck tumors, and two had uterine cervix cancers. The incubation of fresh tissue cubes in EF3 under hypoxic conditions ("reference binding") demonstrated that all tumors were capable of binding drug, and that this binding varied by a factor of 2.9-fold (174.5-516.1) on an absolute fluorescence scale. In the five patients treated at the lowest drug doses (9 mg/kg), in situ binding was quantitatable. For all six patients, the maximum rate of in situ binding varied by a factor of 6.7 between the lowest and highest binding tumor (24.8-160.3) on an absolute fluorescence scale. In tumors with high binding regions, intratumoral heterogeneity was large, extending from minimal fluorescence (<1%) up to 88.6% of reference binding. In tumors with minimal binding, there was little intratumoral heterogeneity. These studies demonstrate substantial heterogeneity of in situ binding between and within individual squamous cell tumors.

Adult↗
PubMed2000

Hypoxia and necrosis in rat 9L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and the Eppendorf needle electrode.

PURPOSE: The purpose of this study was to assess the presence of tumor hypoxia using two independent techniques: binding of the 2-nitroimidazole EF5 and Eppendorf needle electrode measurements. The distribution of tumor hypoxia was assessed with respect to tumor necrosis in corresponding histological studies. METHODS AND MATERIALS: Each of several rats bearing a subcutaneous 9L glioma or Morris 7777 hepatoma tumor was given EF5 i.v. to a final, whole-body concentration of 100 microM. About 2.5 h later, each rat was anesthetized, and needle electrode measurements were made in the tumor along 1-5 tracks (30-200 individual measurements). At 3 h post-EF5 injection, the tumor was excised and frozen. Frozen sections were analyzed for the presence and distribution of binding of EF5 and necrosis using immunohistochemical techniques followed by staining with hematoxylin and eosin (H&E). The histochemical analysis and electrode readings in similar regions of the tumor were compared. RESULTS: Electrode measurements were taken at 0.4-mm intervals along one-dimensional tracks, whereas EF5 binding measurements from tissue sections contained two-dimensional information at high spatial resolution ( approximately 2.5 micro). The EF5 measurements showed greater spatial heterogeneity than did the electrode measurements. In tumor regions with minimal necrosis, needle tracks with relatively high pO(2) readings were usually found to contain relatively low EF5 binding, and vice versa. Because EF5 binding is inversely related to tissue pO(2), this result was expected. The expected inverse correlation of the two techniques was most disparate in necrotic tumor regions (confirmed by H&E staining), where needle electrode measurements showed low to zero pO(2) values, but little or no EF5 binding was found. CONCLUSION: The two methods compared in this study operate in fundamentally different ways and provide substantially different information. EF5 binding provided detailed spatial information on the distribution of hypoxia in viable tumor tissue. There was no EF5 binding in necrotic tumor tissue because cells in such tissue were unable to metabolize the drug. In contrast, output from the needle electrode method appeared to represent a "track-average" tissue pO(2) and did not distinguish between extreme hypoxia and either macroscopic or microscopic necrosis. At the present time, the importance of tumor necrosis in determining treatment response is unknown. However, our data suggest that the Eppendorf needle electrode technique will overestimate the presence of hypoxia. Both techniques are potentially limited by sampling errors in tumors with heterogeneous distributions of hypoxia.

Animals↗
PubMed2000

Site-specific lesion formation, inflammation and inducible nitric oxide synthase expression by indomethacin in the rat intestine.

The involvement of nitric oxide (NO) formed by the inducible isoform of NO synthase (iNOS) has been investigated in the development of rat intestinal lesions following indomethacin administration. Over a 72-h period, indomethacin (10 mg kg(-1), s.c.) provoked a time-dependent increase in expression of iNOS (assessed by the conversion of radiolabelled L-arginine to citrulline) and enhancement of vascular leakage of radiolabelled human serum albumin in the jejunum which commenced 18 h after indomethacin. Similar effects were not observed in the ileum, colon or caecum. In addition, macroscopic lesions were detectable and myeloperoxidase activity (an index of neutrophil recruitment) were increased in the rat jejunum 18-24 h after indomethacin, but remained at basal levels in the ileum and colon. These findings suggest that indomethacin provokes a site-selective expression of iNOS in the rat jejunum which correlates with lesion formation and vascular leakage, whereas both the ileum and colon are spared.

Animals↗
PubMed2000

Increased sensitivity to alprazolam in females with a paternal history of alcoholism.

RATIONALE: Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. OBJECTIVES: To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). METHODS: The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. RESULTS: Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. CONCLUSIONS: In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.

Affect↗
PubMed2000

Effects of external beam radiation on the allograft dermal implant.

OBJECTIVE: The purpose of this study was to define the effects of external beam radiation (EBR) on AlloDerm (LifeCell Corp) through the analysis of graft thickness, fibroblast recellularization, and neovascularization as a function of time. METHODS AND MATERIAL: Thirty-six male Sprague-Dawley rats (n = 36) were randomly assigned to 1 of 4 groups (A, B, C, and D). AlloDerm was implanted subcutaneously into the hind legs of each rat, and 20 Gy of EBR was administered to one side. Grafts harvested 1, 2, 4, and 12 weeks after radiation were subjected to blinded histologic analysis. RESULTS: In groups A, B, and C, the irradiated grafts showed a significant decrease in recellularization versus nonirradiated (P < 0.001). At 12 weeks (group D), recellularization equalized, but neovascularization was significantly less (P = 0.048) in the irradiated group. Graft thickness was unaffected. CONCLUSIONS: In the rat model, EBR of the implanted AlloDerm graft hinders recellularization in the early posttreatment period. However, EBR did not adversely affect graft thickness, recellularization or ultimate graft survival.

Animals↗
PubMed2000

Effects of bone marrow transplantation on the cardiovascular abnormalities in canine mucopolysaccharidosis VII.

The genetic mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting from defective catabolism of glycosaminoglycans (GAGs). Echocardiographic abnormalities in dogs with MPS type VII (Sly syndrome, beta-glucuronidase deficiency) included mitral valve thickening and insufficiency, large aortic dimensions in both the long and short axes, and thickened aortic valves. Grossly, at post mortem examination, there was nodular thickening of the mitral valve, a prominent ductus diverticulum, and a dilated aorta with thickened walls. Histologically, cytoplasmic vacuolation was seen in cells of the mitral valves, coronary arteries, and aorta. By electron microscopy, the cells of the mitral valve were packed with electron-lucent cytoplasmic vacuoles. The mean residual activity of beta-glucuronidase in the aorta and myocardium was <1% of normal, the mean hexosaminidase A activity >2. 5 times normal, and the mean GAG concentrations more than twice normal. In three MPS VII dogs that received heterologous BMT at 6 weeks of age, the echocardiographic abnormalities were improved, and the histopathologic and ultrastructural pathology was reduced. In the aorta and myocardium, the mean beta-glucuronidase activity of the BMT group was 4.5% and 11% of normal, respectively, and the hexosaminidase A activity and GAG concentrations were normalized. Bone Marrow Transplantation (2000) 25, 1289-1297.

Animals↗