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Martin Charron

Publications and source records attributed to Martin Charron.

15 recordsLinked to original sources
PubMed2004

Biodistribution of post-therapeutic versus diagnostic (131)I-MIBG scans in children with neuroblastoma.

BACKGROUND: To evaluate the biodistribution of therapeutic (131)I-metaiodobenzylguanidine (MIBG) and assess the sensitivity of diagnostic versus therapeutic (131)I-MIBG scans to detect metastatic disease. PROCEDURE: This retrospective study included 44 diagnostic and post-therapy scans (PTS) in 18 children with neuroblastoma treated with (131)I-MIBG (2.0-33.1 GBq). The findings of diagnostic scans (DS) (2.6-44.4 MBq) were compared to those of corresponding PTS. RESULTS: In terms of biodistribution, the PTS identified (131)I-MIBG activity in one or more patients in the following regions not detected on the DS: nasal mucosa, cerebellum, central brain, adrenals, spleen, kidneys, thyroid, salivary glands, lower halves of the lungs, bladder, bowel, and an incisional scar. Conversely, the DS identified activity in the thorax, heart, kidneys, and bladder each in one patient without being visualized on the PTS. In terms of sensitivity to detect metastatic disease, 210 lesions were seen on the PTS compared to 151 on the DS. The PTS demonstrated sites of disease not evident in the DS in 16 cases. CONCLUSIONS: The biodistribution of (131)I-MIBG is different using therapeutic doses as compared to pre-therapy doses. (131)I-MIBG imaging following high therapeutic doses often reveals sites of occult metastatic disease that may be clinically relevant.

3-Iodobenzylguanidine↗
PubMed2003

Nuclear factor-kappaB activates transcription of the androgen receptor gene in Sertoli cells isolated from testes of adult rats.

The androgen receptor (AR) in Sertoli cells mediates the actions of testosterone on spermatogenesis. However, the transcription factors responsible for AR gene regulation in Sertoli cells remain unknown. In this study, we determined that nuclear factor-kappaB (NF-kappaB) regulates transcription of AR in primary cultures of Sertoli cells isolated from testes of adult rats. Electrophoretic mobility shift and antibody supershift assays with nuclear extracts prepared from Sertoli cells identified two binding sites, termed kappaB1 at -491/-482 bp and kappaB2 at -574/-565 bp, upstream of the transcription start site of the AR gene that bind the NF-kappaB subunits, p50 and p65. DNAse I footprint analyses showed that binding of the p50 NF-kappaB subunit protected the same regions on the rat AR promoter. Analyses of AR promoter-luciferase reporter gene activity after transfection of primary cultures of Sertoli cells demonstrated that mutation of the kappaB2 site or combined mutation of the kappaB1 and kappaB2 sites reduced activity by 40%. Preferential binding of the transcriptionally active p65/p50 heterodimer to the kappaB2 site rather than to the kappaB1 site supported these observations. Overexpression of the NF-kappaB p65 and p50 subunits in Sertoli cells increased activity from the wild-type AR promoter and the promoter with mutation of the kappaB1 site, but not the kappaB2 site. Activity was further stimulated by CBP (CREB binding protein), a coactivator of p65 transcriptional activity. Taken together, our data show that NF-kappaB is an activator of AR gene transcription in Sertoli cells and may be an important determinant of androgen activity during spermatogenesis.

Animals↗
PubMed2003

Pinhole imaging of 131I-metaiodobenzylguanidine (131I-MIBG) in an animal model of neuroblastoma.

PURPOSE: To evaluate (131)I-MIBG scintigraphic localization of xenotransplanted and spontaneously arising neuroblastomas in murine models of high-risk neuroblastoma. METHODS: Neuroblastoma xenografts were created by inoculation of human neuroblastoma cell suspensions into the subcutaneous flanks of athymic nude mice. In addition, spontaneous paraspinal neuroblastomas were detected by direct palpation in MYCN transgenic mice. After measured tumor volumes exceeded 200 mm(3), each mouse received an intraperitoneal injection of 18 muCi/g (131)I-metaiodobenzylguanidine ((131)I-MIBG). Pinhole scintigraphy was performed to evaluate the MIBG biodistribution and to attempt to visualize the tumors. Each mouse was imaged on a gamma camera equipped with a 3-mm pinhole on one head and an HEGP collimator on the other. RESULTS: Images demonstrated absorption of radiolabeled MIBG and visualization of tumors. Analysis of the images allowed for quantification of relative MIBG uptake and for determination of linear and area measurements of the tumors. CONCLUSION: High-energy pinhole imaging effectively demonstrates uptake of radiolabeled MIBG by human neuroblastoma tumors in murine laboratory models. This technique allows for in vivo assessment of tumor burden. In the future, we plan to use this method to evaluate sensitivity for detecting metastatic spread as well as investigating the therapeutic efficacy of high-dose (131)I-MIBG in combination with radiosensitizing agents.

3-Iodobenzylguanidine↗
PubMed2003

Imaging studies after a first febrile urinary tract infection in young children.

BACKGROUND: Guidelines from the American Academy of Pediatrics recommend obtaining a voiding cystourethrogram and a renal ultrasonogram for young children after a first urinary tract infection; renal scanning with technetium-99m-labeled dimercaptosuccinic acid has also been endorsed by other authorities. We investigated whether imaging studies altered management or improved outcomes in young children with a first febrile urinary tract infection. METHODS: In a prospective trial involving 309 children (1 to 24 months old), an ultrasonogram and an initial renal scan were obtained within 72 hours after diagnosis, contrast voiding cystourethrography was performed one month later, and renal scanning was repeated six months later. RESULTS: The ultrasonographic results were normal in 88 percent of the children (272 of 309); the identified abnormalities did not modify management. Acute pyelonephritis was diagnosed in 61 percent of the children (190 of 309). Thirty-nine percent of the children who underwent cystourethrography (117 of 302) had vesicoureteral reflux; 96 percent of these children (112 of 117) had grade I, II, or III vesicoureteral reflux. Repeated scans were obtained for 89 percent of the children (275 of 309); renal scarring was noted in 9.5 percent of these children (26 of 275). CONCLUSIONS: An ultrasonogram performed at the time of acute illness is of limited value. A voiding cystourethrogram for the identification of reflux is useful only if antimicrobial prophylaxis is effective in reducing reinfections and renal scarring. Renal scans obtained at presentation identify children with acute pyelonephritis, and scans obtained six months later identify those with renal scarring. The routine performance of urinalysis, urine culture, or both during subsequent febrile illnesses in all children with a previous febrile urinary tract infection will probably obviate the need to obtain either early or late scans.

Antibiotic Prophylaxis↗
PubMed2003

Mice that express enzymatically inactive cathepsin L exhibit abnormal spermatogenesis.

The finding of large, stage-specific changes in secretion of procathepsin L by rat Sertoli cells has led to the hypothesis that this proenzyme promotes the survival, replication, or differentiation of spermatogenic cells. Experiments described herein used a mouse model to test this hypothesis. To prove that mice are appropriate for this purpose, we first demonstrate that mature mouse Sertoli cells express cathepsin L mRNA in the same stage-specific manner as rat Sertoli cells and they also secrete procathepsin L. To test whether catalytically active cathepsin L is required for normal spermatogenesis, we examined the testes of 110- to 120-day-old furless mice, which express catalytically inactive cathepsin L. Morphologic examination of testes of furless mice revealed both normal and atrophic seminiferous tubules. Enumeration of atrophic tubules in furless and control mice demonstrates that lack of functional cathepsin L results in a 12-fold increase in seminiferous tubule atrophy. To determine whether lack of functional cathepsin L affects the production of male germ cells in apparently normal, nonatrophic tubules, we compared numbers in control and furless mice of preleptotene spermatocytes, pachytene spermatocytes, and round spermatids per Sertoli cell. Results demonstrate that the lack of functional cathepsin L causes a 16% reduction in formation of preleptotene spermatocytes and a 25% reduction in differentiation of these cells into pachytene spermatocyte. These results suggest that procathepsin L either directly or indirectly has two distinct functions in the testis. This proenzyme prevents atrophy of seminiferous tubules and promotes the formation of preleptotene spermatocytes and the differentiation of these meiotic cells into pachytene spermatocytes.

Animals↗
PubMed2003

Targeted radiotherapy with submyeloablative doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma.

PURPOSE: Treatment of refractory neuroblastoma remains a significant clinical problem. Targeted radiotherapy with 131I-MIBG has demonstrated antitumor activity in heavily pretreated neuroblastoma patients with recurrent disease. Response rates may be correlated with total radionuclide dose per kilogram body weight delivered, but higher dose levels are associated with protracted grade 4 hematologic toxicity. The optimal method for using single-agent 131I-MIBG for patients with relapsed high-risk neuroblastoma has not been defined. This study was designed to retrospectively determine the clinical response to 131I-MIBG therapy at submyeloablative doses in patients with refractory neuroblastoma and to describe the toxicities. PATIENTS AND METHODS: A retrospective chart review of 20 patients with neuroblastoma treated with 131I-MIBG at the Children's Hospital of Philadelphia from 1988 to 2000 was performed. Demographic data, 131I-MIBG dose delivered, toxicities, and clinical responses were reviewed. RESULTS: A median dose of 9.5 mCi/kg of 131I-MIBG was delivered in 32 courses to 20 patients. Three patients were treated in first complete response, and the remaining 17 patients for residual and/or progressive disease. The objective response rate to the first therapy was 31%, and the remaining patients achieved disease stabilization. In addition, 9 of 11 patients with pain at study entry had significant improvement. Disease response was not correlated with 131I-MIBG dose delivered. No unanticipated toxicities were observed. CONCLUSIONS: Submyeloablative-dose 131I-MIBG is an effective and relatively nontoxic method for neuroblastoma disease palliation. Most patients show subjective improvement in pain and/or performance status. Increased availability and experience with 131I-MIBG therapy would benefit a large number of children with end-stage neuroblastoma and no realistic hope for cure.

3-Iodobenzylguanidine↗
PubMed2003

Temporal correlation of the erythrocyte sedimentation rate with Tc-99m WBC uptake on children with inflammatory bowel diseases.

The goal of this study was to evaluate the temporal correlation of Tc-99m WBC studies with the erythrocyte sedimentation rate, a commonly used index of intensity of inflammation, in a large population of children with inflammatory bowel diseases. Over a 6-year period, 313 Tc-99m WBC studies were performed and the hospital charts of these consecutive children were reviewed. In each set of scans (0.5-1 hour and 2-3 hours) from the 313 patients, the bowel was divided into 8 segments resulting in 5008 bowel segments for scoring. The intensity of uptake on the planar images was graded on a scale of 0 to 6 and compared with the erythrocyte sedimentation rate obtained within 3 days, 1 week, 2 weeks, 1 month, 3 months, 6 months, or 1 year of the Tc-99m WBC scan, when available. A dataset of 508 erythrocyte sedimentation rates was available for computation. In children with Crohn's disease, when erythrocyte sedimentation rate is obtained within 3 days of the Tc-99m WBC scan, the correlation coefficient is R=0.314 (P<0.005), within 1 week R=0.358 (P<0.05), within 2 weeks R=0.254 (P=0.129), within 1 month R=-0.029 (P=0.84), within 3 months R=-0.002 (P=0.989), within 6 months R=0.241 (P=0.145), and within 1 year R=0.068 (P=0.759). In children with Crohn's disease, the uptake of Tc-99m WBC correlates well with the erythrocyte sedimentation rate during the flare of inflammation, and the correlation progressively subsides after a few weeks. No such correlation was noted in children with ulcerative colitis.

Adolescent↗
PubMed2003

Inflammatory bowel disease activity assessment with biologic markers and 99mTc-WBC scintigraphy: are there different trends in ileitis versus colitis?

UNLABELLED: To evaluate whether scintigraphy with (99m)Tc-labeled white blood cells (WBC) can assess the intensity of bowel inflammation, a large dataset of laboratory values and clinical activity indices was correlated with (99m)Tc-WBC scintigraphy in children with Crohn's disease (CD), ulcerative colitis (UC), and miscellaneous colitis (MC). Also evaluated was whether stratification of children with CD as ileitis versus colitis results in different correlation coefficients for laboratory values versus (99m)Tc-WBC scintigraphy. METHODS: Over a 6-y period, 313 (99m)Tc-WBC studies were performed. A dataset of 2,714 laboratory values is available for analysis. RESULTS: There is a positive correlation between the erythrocyte sedimentation rate (ESR) and large bowel uptake of (99m)Tc-WBC (P < 0.05) and a negative trend with small bowel uptake of (99m)Tc-WBC in children with CD. Similarly, there is a correlation between WBC counts and scintigraphy in most segments of the large bowel and a negative correlation with the small bowel (R = -0.32, P = 0.01) in children with CD. There is a correlation between platelets and (99m)Tc-WBC in children with CD or UC. There is no correlation between the ESR and (99m)Tc-WBC in children with UC or MC. Many clinical activity indices correlate (P < 0.001) with (99m)Tc-WBC in children with CD, but none correlates in children with UC. Numerous laboratory values correlate with each other. There is a negative correlation between protein, albumin, hemoglobin, and hematocrit versus (99m)Tc-WBC scintigraphy in children with CD. In children with UC, there is a negative correlation between hemoglobin and hematocrit versus (99m)Tc-WBC. CONCLUSION: (99m)Tc-WBC scintigraphy, ESR, and WBC counts are good indicators of the inflammatory activity in CD if the inflammation is limited to the large bowel. There is a trend toward an inverse relationship when the inflammation is limited to the small bowel; thus, scintigraphy and the aforementioned markers may be of limited value. This report also demonstrates that (99m)Tc-WBC scintigraphy correlates with clinical activity indices in CD and with numerous biologic markers. In children with UC, scintigraphy with (99m)Tc-WBC and most laboratory markers are of limited value in assessing disease activity.

Adolescent↗
PubMed2003

An analytic study of the effects of attenuation on tumor detection in whole-body PET oncology imaging.

UNLABELLED: There has been considerable debate about the desirability of attenuation correction in whole-body PET oncology imaging. The advantages of attenuation correction are quantitative accuracy, whereas the perceived disadvantages are loss of contrast, noise amplification, and increased scanning time. In this work, we explain contrast changes between images reconstructed with and without attenuation correction. METHODS: To analytically explain both well-known and surprising phenomena in images reconstructed without attenuation correction, we performed a series of simulation studies, a phantom experiment, and a patient experiment. RESULTS: We showed that it is possible to calculate a priori the appearance of images reconstructed without attenuation correction. Compared with attenuation-corrected images, images without attenuation correction may have locally enhanced contrast in the abdomen or other regions of uniform attenuation, although the amount of enhancement varies with position in a complex manner. In regions of nonuniform attenuation, such as the thorax, it is possible that foci of increased tracer uptake disappear in images reconstructed without attenuation correction. The critical tracer concentration for this zero-contrast effect depends on the size, location, and density of the foci. Above the critical value, foci are visible in images with and without attenuation correction, whereas below the critical value, foci are visible in attenuation-corrected images but appear as photopenic regions in images without attenuation correction. CONCLUSION: Even though images without attenuation correction may be desired, these results suggest that all studies should at least be reconstructed with attenuation correction to avoid missing regions of elevated tracer uptake.

Female↗
PubMed2002

A 3-kilobase region derived from the rat cathepsin L gene directs in vivo expression of a reporter gene in sertoli cells in a manner comparable to that of the endogenous gene.

During mammalian spermatogenesis, the transcription of several genes in Sertoli cells is turned on and off as the adjacent male germ cells progress through the stages of the cycle of the seminiferous epithelium. A requirement for defining how germ cells regulate this process is the identification of a promoter that confers, in vivo, accurate, stage-specific gene expression in Sertoli cells. To date, such a promoter has not been identified. Using transgenic mice, we show that the 3-kilobase genomic fragment immediately upstream of the rat cathepsin L translation start site directs expression of the reporter gene, beta-galactosidase, only in Sertoli cells. The expression pattern of the reporter gene recapitulated that of the endogenous gene in Sertoli cells as 75% of the seminiferous tubules that contained X-gal positive Sertoli cells were at stages VI-VIII and beta-galactosidase enzymatic activity was 4-fold higher in mature testes compared with immature testes. This is, to our knowledge, the first identification of a promoter region that contains all of the regulatory elements required for accurate, stage-specific gene expression in Sertoli cells.

Animals↗
PubMed2002

A GC-box within the proximal promoter region of the rat cathepsin L gene activates transcription in Sertoli cells of sexually mature rats.

It has been proposed that stage-specific gene expression in Sertoli cells results from sequential activation and repression of transcription. However, the exact molecular mechanisms are unknown. As a first step in addressing this fundamental issue, we recently demonstrated that a 3-kilobase (kb) genomic fragment immediately upstream of the rat cathepsin L translation start site directed stage-specific expression of a reporter gene only in Sertoli cells of transgenic mice in a manner comparable to that of the endogenous gene (predominantly in stages VI-VIII tubules). Supporting the activation/repression model of regulation, an upstream domain that mediated an inhibitory effect by male germ cells was identified within this 3-kb promoter region. In the present study, we localized and characterized the regulatory elements that activate transcription. Analyses of a series of 5' deletion constructs demonstrated that a 120-base pair (bp) region that spans the transcription start site of the rat cathepsin L gene was sufficient to activate transcription in Sertoli cells isolated from sexually mature rats. Within this region, electrophoretic mobility shift assays showed that one member of the Sp/XKLF family of factors, Sp3, specifically bound to a GC-box. Furthermore, Sp1-binding activity was not detected in nuclear extracts from Sertoli cells of sexually mature rats. Finally, the GC-box was shown to be essential for promoter activity since mutating this binding motif abolished promoter activity. Collectively, these results suggest that the GC-box is a critical regulatory element for the cathepsin L promoter in mature Sertoli cells.

Animals↗
PubMed2002

CT and 99mTc-WBC vs colonoscopy in the evaluation of inflammation and complications of inflammatory bowel diseases.

BACKGROUND: The goal of this study was to evaluate the accuracy of computerized tomography (CT) and 99mTc-white blood cell (WBC) scintigraphy versus colonoscopy in assessing inflammatory bowel diseases (IBD) in a large population of children. METHODS: In a patient population of 313 consecutive children who had a 99mTc-WBC scan, 106 colonoscopies were done within a median time interval of 8 days of the 99mTc-WBC scan. One hundred and three CT scans were performed on 84 patients. RESULTS: Of the 42 CT scans obtained within a short time interval after the 99mTc-WBC scan, 21 (50%) were normal. In the 21 children with a positive 99mTc-WBC scan, 62% (13/21) of the CT scans underestimated the bowel wall inflammation in at least one segment. In the children with a negative 99mTc-WBC study, there were 17 negative CT examinations and 4 examinations showing an abnormal terminal ileum. When CT was compared with colonoscopy in assessing inflammation, there were five true-negative CT, two true-positive CT, no false-positive, and seven false-negative CT examinations. When 99mTc-WBC scintigraphy was compared with colonoscopy in assessing inflammation, there were seven true-positive, two false-negative, five true-negative, and no false-positive 99mTc-WBC studies. The 99mTc-WBC scan was positive in five patients with a false-negative CT examination. Of the total 103 CT scans obtained, 53 (51%) were normal. Four abscesses (3.8%) were demonstrated by CT. CONCLUSIONS: 99mTc-WBC scintigraphy is more sensitive than CT for detecting inflammation of the bowel wall. The incidence of complications from IBD in this retrospective study was much lower than had been previously reported.

Adolescent↗
PubMedDate not supplied

Determination of the half-life of the murine beta4-galactosyltransferase-1 mRNA in somatic cells using the tetracycline-controlled transcriptional regulation system.

The glycosyltransferases are recognized as a functional family of an estimated 300 distinct, intracellular, membrane-bound enzymes that are positioned along the secretory pathway and participate coordinately in the biosynthesis of the carbohydrate moieties on glycoconjugates. The full-length cDNA sequence for many of these proteins is now available yet little is known about the transcriptional or translational regulation of a given transcript or its decay rate in the cell. These issues are made more complex by the observations that transcription of a glycosyltransferase gene in different cells/tissues results in mRNAs with significantly different structures. For example, transcription of the murine beta4-galactosyoltransferase-1 gene in somatic cells yields two transcripts of 3.9 and 4.1 kb. In contrast transcription of this gene in developing male germ cells results in transcripts of 2.9 and 3.1 kb which are distinguished from their somatic cell counterparts primarily by the deletion of approximately 1.7 kb of sequence in the 3'-untranslated region (UTR). With the long range goal of determining the role that the 3'-UTR serves in mRNA decay we have taken advantage of a recently developed methodology, the Tet-Off system, to determine the half-life of the mRNA encoding beta4-galactosyltransferase-1 in the murine NIH 3T3 somatic cell line. We show that the beta4-galactosyltransferase-1 mRNA has a half-life of approximately 84 min (range of 82-85 min) in 3T3 cells and that substitution of the galactosyltransferase coding sequence with the coding sequence of luciferase does not significantly alter the decay rate (approximately 87 min; range of 84-91 min). This latter observation suggests that the beta4-galactosyltransferase-1 coding sequence does not contain functional elements that affect the intrinsic stability of this mRNA.

3' Untranslated Regions↗