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R J Coffey

Publications and source records attributed to R J Coffey.

At least 73 records · Page 4Linked to original sources
PubMed1996

Synergistic interaction of the Neu proto-oncogene product and transforming growth factor alpha in the mammary epithelium of transgenic mice.

Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-alpha) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-alpha, we examined whether coexpression of TGF-alpha and Neu in mammary epithelium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring either a mouse mammary tumor virus/TGF-alpha or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-alpha and neu in the mammary epithelium. Female mice coexpressing TGF-alpha and neu developed multifocal mammary tumors which arose after a significantly shorter latency period than either parental strain alone. The development of these mammary tumors was correlated with the tyrosine phosphorylation of Neu and the recruitment of c-Src to the Neu complex. Immunoprecipitation and immunoblot analyses with EGFR- and Neu-specific antisera, however, failed to detect physical complexes of these two receptors. Taken together, these observations suggest that Neu and TGF-alpha cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.

Aging↗
PubMed1996

Identification of an EGF/TGF-alpha receptor in primary cultures of guinea pig gastric mucous epithelial cells.

Binding and localization of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) were assessed using in vitro primary cultures of guinea pig gastric mucous epithelial cells (GMEC). GMEC were isolated and cultured in six-well plates with Dulbecco's modified Eagle's medium + 10% serum and then changed to serum-free medium for 24 h for binding studies. The binding time course of 125I-labeled EGF and 125I-TGF-alpha in GMEC cultures at 4 degrees C was saturable, reaching a plateau within 4-6 h. Competition-binding curves revealed that the amount of unlabeled EGF and TGF-alpha to reduce 125I-EGF binding by 50% was 0.35 and 0.23 nM, respectively. The amount of unlabeled EGF and TGF-alpha to decrease 125I-TGF-alpha binding by 50% was 0.30 and 0.21 nM, respectively. A Scatchard analysis of the data disclosed that a single class of high-affinity binding sites (dissociation constant = 0.24 nM) was present. The maximal binding capacity was approximately 20 fmol/10(6) cells or approximately 12,000 receptors per cell. The binding of 125I-EGF and 125I-TFG-alpha to GMEC cultures was maximal between pH 7.0 and 8.5. No specific binding of EGF or TGF-alpha could be detected below pH 5.0. The half-maximal pH dissociation value for EGF and TGF-alpha was pH 5.89 and pH 6.83, respectively. We found no difference in the final amounts of membrane-bound or internalized 125I-EGF and 125I-TGF-alpha. However, there was a significant difference (P < 0.05) at 5-30 min in the rate of dissociated and internalized 125I-EGF- and 125I-TGF-alpha. Immunofluorescence microscopy of GMEC cultures for EGF/TGF-alpha receptors showed increased fluorescence at the leading edges and around the perimeter of cells. Detection of an EGF/TGF-alpha receptor was also confirmed by Western blotting. Our findings demonstrate that guinea pig GMEC possess a specific EGF/TGF-alpha receptor, which further supports a physiological role for EFG and TFG-alpha as mitogens in these cells.

Animals↗
PubMed1996

Expression of trefoil peptides in the gastric mucosa of transgenic mice overexpressing transforming growth factor-alpha.

Overexpression of transforming growth factor-alpha (TGF-alpha) in the gastric mucosa of metallothionein-TGF alpha (MT-TGF alpha) transgenic mice leads to a marked alteration in the ontogeny of the fundic cellular lineages. Induction of the transgene leads to the over-production of mucous cells with a concomitant diminution in the development of parietal cell and chief cell lineages. We have sought to define more precisely the mucous cell lineages involved in the mucous cell hyperplasia in MT-TGF alpha mice by investigating the expression of trefoil peptides in MT-TGF alpha mice. MT-TGF alpha mice and their non-transgenic littermates were treated with cadmium sulfate beginning at 13 days of age. Animals were then sacrificed at intervals over the following 2 weeks and gastric mucosa was examined for expression of trefoil peptides and TGF alpha by immunohistochemistry and in situ hybridization. No TGF alpha mRNA expression could be demonstrated by in situ hybridization in non-transgenic mice. In MT-TGF alpha mice, in situ grains for TGF alpha mRNA were detected at the base of fundic glands in 13 day old animals, whereas the expression was observed more widely in the mucosa of older animals (28 days). TGF alpha immunoreactivity was observed in foveolar mucous cells and residual parietal cells in MT-TGF alpha mice at all ages. By in situ hybridization, pS2 mRNA was detected in the surface mucous cells in normal gastric mucosa. In MT-TGF alpha mice, pS2 mRNA was found throughout the expanded foveolar region. By in situ hybridization, spasmolytic peptide (SP) expression was observed in the region of the progenitor zone in both groups of mice. By immunohistochemistry, SP expression was noted in a broad band of mucous neck cells deep to the progenitor zone. No gastric expression of intestinal trefoil factor (ITF) was noted in either group of mice. The results demonstrate that the expansion of the foveolar mucous cell compartment in MT-TGF alpha mice is due to the hyperplasia of normal surface cells expressing their particular mucin-associated trefoil peptide, pS2.

Animals↗
PubMed1996

The role of radiosurgery and particulate embolization in the treatment of dural arteriovenous fistulas.

Over the past 5 years 29 patients with dural arteriovenous fistulas (AVFs) were treated by the authors using the Leksell radiosurgical gamma knife unit. Within 2 days after radiosurgery, 17 patients with AVFs that exhibited retrograde pial or cortical venous drainage (12 patients) and/or produced intractable bruit (eight patients) underwent particulate embolization of external carotid feeding vessels. The rationale for this treatment strategy was that radiosurgery was expected to cause obliteration of most fistulas after 12 to 36 months. In patients with bruit, ocular symptoms, or in those at risk for hemorrhage, treatment with embolization after radiosurgery kept the fistulas angiographically visible for radiosurgical targeting yet offered palliation of symptoms and temporary, partial protection from hemorrhage during the latency period. In 12 patients, preobliteration embolization immediately reduced (10 patients) or eliminated (two patients) retrograde pial venous drainage. To date, no lesion has hemorrhaged after treatment. Angiography 1 to 3 years posttreatment in 18 patients showed total obliteration of 13 fistulas (72%) and partial obliteration of five (28%). Radiosurgery, followed by embolization when retrograde pial venous drainage, intractable bruit, and/or major external carotid artery supply is present, appears to be a promising treatment for selected patients with symptomatic dural AVFs.

Adult↗
PubMed1995

Stereotactic radiosurgery using the gamma knife for acoustic neuromas.

PURPOSE: To assess the efficacy and toxicity of stereotactic radiosurgery using the gamma knife for acoustic neuromas. METHODS AND MATERIALS: Between January 1990 and January 1993, 36 patients with acoustic neuromas were treated with stereotactic radiosurgery using the gamma knife. The median maximum tumor diameter was 21 mm (range: 6-32 mm). Tumor volumes encompassed within the prescribed isodose line varied from 266 to 8,667 mm3 (median: 3,135 mm3). Tumors < or = 20 mm in maximum diameter received a dose of 20 Gy to the margin, tumors between 21 and 30 mm received 18 Gy, and tumors > 30 mm received 16 Gy. The dose was prescribed to the 50% isodose line in 31 patients and to the 45%, 55%, 60%, 70%, and 80% isodose line in one patient each. The median number of isocenters per tumor was 5 (range: 1-12). RESULTS: At a median follow-up of 16 months (range: 2.5-36 months), all patients were alive. Thirty-five patients had follow-up imaging studies. Nine tumors (26%) were smaller, and 26 tumors (74%) were unchanged. No tumor had progressed. The 1- and 2-year actuarial incidences of facial neuropathy were 52.2% and 66.5%, respectively. The 1- and 2-year actuarial incidences of trigeminal neuropathy were 33.7% and 58.9%, respectively. The 1- and 2-year actuarial incidence of facial or trigeminal neuropathy (or both) was 60.8% and 81.7%, respectively. Multivariate analysis revealed that the following were associated with the time of onset or worsening of facial weakness or trigeminal neuropathy: (a) patients < age 65 years, (b) dose to the tumor margin, (c) maximum tumor diameter > or = 21 mm, (d) use of the 18 mm collimator, and (e) use of > five isocenters. The 1- and 2-year actuarial rates of preservation of useful hearing (Gardner-Robertson class I or II) were 100% and 41.7% +/- 17.3, respectively. CONCLUSION: Stereotactic radiosurgery using the gamma knife provides short-term control of acoustic neuromas when a dose of 16 to 20 Gy to the tumor margin is used. Preservation of useful hearing can be accomplished in a significant proportion of patients.

Adult↗
PubMed1995

Mammary tumor suppression by transforming growth factor beta 1 transgene expression.

In cell culture, type alpha transforming growth factor (TGF-alpha) stimulates epithelial cell growth, whereas TGF-beta 1 overrides this stimulatory effect and is growth inhibitory. Transgenic mice that overexpress TGF-alpha under control of the mouse mammary tumor virus (MMTV) promoter/enhancer exhibit mammary ductal hyperplasia and stochastic development of mammary carcinomas, a process that can be accelerated by administration of the chemical carcinogen 7,12-dimethylbenz[a]anthracene. MMTV-TGF-beta 1 transgenic mice display mammary ductal hypoplasia and do not develop mammary tumors. We report that in crossbreeding experiments involving the production of mice carrying both the MMTV-TGF-beta 1 and MMTV-TGF-alpha transgenes, there is marked suppression of mammary tumor formation and that MMTV-TGF-beta 1 transgenic mice are resistant to 7,12-dimethylbenz[a]anthracene-induced mammary tumor formation. These data demonstrate that overexpression of TGF-beta 1 in vivo can markedly suppress mammary tumor development.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Autocrine transforming growth factor alpha is dispensible for v-rasHa-induced epidermal neoplasia: potential involvement of alternate epidermal growth factor receptor ligands.

Autocrine epidermal growth factor receptor activation by transforming growth factor alpha (TGF alpha) has been implicated in growth stimulation during epithelial neoplasia. Using keratinocytes isolated from mice with genetic defects in TGF alpha expression, we tested whether TGF alpha is required for transformation by the v-rasHa oncogene. Introduction of v-rasHa into primary epidermal cultures using a retroviral vector stimulated growth of both control (TGF alpha +/+, BALB/c) and TGF alpha-deficient (TGF alpha -/-, wa-1) keratinocytes. Moreover, v-rasHa elicited characteristic changes in marker expression (keratin 1 was suppressed; keratin 8 was induced), previously shown to be associated with epidermal growth factor (EGF) receptor activation, in both TGF alpha +/+ and TGF alpha -/- keratinocytes. v-rasHa markedly increased secreted (> 10-fold) and cell-associated (2-3-fold) TGF alpha levels in keratinocytes from TGF alpha +/+ and BALB/c mice, but not TGF alpha -/- or wa-1 mice. Based on Northern blot analysis, v-rasHa induced striking up-regulation of transcripts encoding the additional EGF family members amphiregulin, heparin-binding EGF-like growth factor, and betacellulin in cultured keratinocytes from all four mouse strains. Interestingly, in addition to the normal 4.5-kilobase TGF alpha transcript, wa-1 keratinocytes expressed two additional TGF alpha transcripts, 4.7 and 5.2 kilobases long. All three transcripts were up-regulated in response to v-rasHa, as well as exogenous TGF alpha or keratinocyte growth factor treatment, and were also detected in RNA isolated from wa-1 brain and skin. In vivo, v-rasHa keratinocytes from control as well as TGF alpha-deficient mice produced squamous tumors when grafted onto nude mice, and these lesions expressed high levels of amphiregulin, heparin-binding EGF-like growth factor, and betacellulin mRNA, regardless of their TGF alpha status. These findings indicate that TGF alpha is not essential for epidermal neoplasia induced by the v-rasHa oncogene and suggest that another EGF family member(s) may contribute to autocrine growth stimulation of ras-transformed keratinocytes.

Animals↗
PubMed1995

Decreased tumor formation in 7,12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis.

To determine the role of a specific member of the metalloproteinase family, stromelysin-1, in mammary carcinogenesis and tumor progression, transgenic mice expressing activated rat stromelysin-1 under the control of the mouse mammary tumor virus promoter/enhancer were treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA) to induce mammary tumors. Surprisingly, the expression of stromelysin-1 during the time of DMBA treatment reduced the number of mice developing mammary tumors, in particular adenoacanthomas, from 65 to 32% (P = 0.02). In contrast, when transgenic mice expressing both transforming growth factor alpha and stromelysin-1 under the control of the mouse mammary tumor virus long terminal repeat were treated with DMBA, there was no significant difference in the number of mice that developed tumors compared to transforming growth factor alpha controls. A 4-fold increase in the number of apoptotic cells was detected in stromelysin-1 transgenic mice compared to littermate controls at the time of DMBA administration, suggesting that the reduction in DMBA-induced tumorigenicity is likely to be due, at least in part, to an increased rate of cell turnover in stromelysin-1 transgenic mice. When malignant adenocarcinomas developed in the stromelysin-expressing mice, there was no detectable alteration in the extent of invasion or in the metastatic potential of these tumors compared to tumors from control mice. These results suggest that the expression of a single metalloproteinase, stromelysin-1, is insufficient for the progression of mammary adenocarcinomas to an invasive and metastatic phenotype, but that matrix degradation by metalloproteinases can alter basic processes of cell proliferation and apoptosis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Regional distribution of transforming growth factor-alpha and epidermal growth factor in normal and portal hypertensive gastric mucosa in humans.

This study was designed to evaluate the concentration and the regional distribution of TGF-alpha and EGF in normal and portal hypertensive human gastric mucosa. To this end we measured by RIA the gastric and duodenal concentration of TGF-alpha and EGF in subjects with chronic hepatitis, who had normal gastric endoscopic appearance, and in patients with liver cirrhosis with and without congestive gastropathy. Our results show that TGF-alpha concentration is significantly higher than EGF concentration in both the stomach and duodenum. No significant regional differences in the distribution of the two peptides were found. Moreover, the gastroduodenal tissue levels of TGF-alpha were comparable in subjects with and without hypertensive gastropathy. EGF gastric concentration was not altered in patients with congestive gastropathy. However, EGF duodenal tissue levels were significantly lower in patients with liver cirrhosis than in noncirrhotic subjects. We speculate that the higher level of TGF-alpha in the gastroduodenal mucosa may support the hypothesis that TGF-alpha and not EGF is the major physiological ligand for TGF-alpha/EGF receptor in the intact gut. Furthermore, the lower duodenal concentration of EGF in cirrhotics might partially explain the increased susceptibility of cirrhotic patients to duodenal ulcer.

Adult↗
PubMed1995

Immunolocalization of transforming growth factor-alpha in normal and diseased human gastric mucosa.

Roles for transforming growth factor-alpha (TGF alpha) in the stomach include cell migration and proliferation, inhibition of acid secretion, and cytoprotection. The authors have previously shown increased TGF alpha expression in rat gastric mucosa in response to acute gastric injury. They also have shown that TGF alpha immunoreactivity is increased in the gastric mucosa of four patients with Ménétrier's disease. To further characterize TGF alpha immunoreactivity in human gastric mucosa, the authors have performed immunohistochemical analysis with an anti-TGF alpha monoclonal antibody on human gastric biopsies (n = 25) showing either normal (n = 8), mild reactive/reparative change in common conditions with or without associated gastritis (n = 13), and exaggerated mucosal change in proliferative conditions (Ménétrier's disease, hypertrophic lymphocytic gastritis, and hyperplastic polyps) (n = 17). All normal biopsies showed a predictable pattern of TGF alpha immunostaining, with significant positivity found only in foveolar cells at the luminal surface and parietal cells, sparing foveolar cells in the gastric pits, mucous neck cells and chief cells of the gastric glands. Three patients with mild foveolar hyperplasia without associated inflammation did not deviate from the normal pattern except in foci of reactive epithelial change. Ten of 11 patients with chronic active gastritis, in addition to this normal staining pattern, demonstrated significant immunoreactivity in deeper foveolar cells and mucous neck cells showing reactive epithelial changes, defined as the presence of nuclear enlargement and nucleolar prominence with or without mucin depletion. Three cases of ulceration with associated reactive epithelial changes also showed increased immunoreactivity. Furthermore, five cases of Ménétrier's disease with massive foveolar hyperplasia and minimal inflammation (MFH) and six cases with hypertrophic lymphocytic gastritis (HLG) have been studied, and both show full-thickness TGF alpha immunoreactivity restricted to the gastric epithelium. This pattern of staining is indistinguishable from that observed in two cases of hyperplastic polyps but differs significantly from that observed in cases of mild foveolar hyperplasia. These results further define patterns of TGF alpha immunostaining in normal, reactive/reparative and exaggerated proliferative human gastric biopsies, confirm participation of TGF alpha in the response to gastric mucosal injury, and provide additional support for a possible role for TGF alpha in the pathogenesis of proliferative gastric disorders including Ménétrier's disease, hypertrophic lymphocytic gastritis, and hyperplastic gastric polyps.

Gastric Mucosa↗
PubMed1995

Extracellular matrix regulates whey acidic protein gene expression by suppression of TGF-alpha in mouse mammary epithelial cells: studies in culture and in transgenic mice.

Whey acidic protein (WAP) is an abundant rodent milk protein. Its expression in mouse mammary epithelial cell cultures was previously found to require the formation of an extracellular matrix (ECM)-induced three-dimensional alveolar structure. In the absence of such structures, cells were shown to secrete diffusible factors leading to suppression of WAP expression. We demonstrate here that (a) TGF-alpha production and secretion by mammary cells is downregulated by the basement membrane-dependent alveolar structure, and (b) compared with beta-casein, WAP expression is preferentially inhibited both in culture and in transgenic mice when TGF-alpha is added or overexpressed. Thus, (c) the enhanced TGF-alpha production when cells are not in three-dimensional structures largely accounts for the WAP-inhibitory activity found in the conditioned medium. Since this activity can be abolished by incubating the conditioned medium with a function blocking antibody to TGF-alpha. The data suggest that ECM upregulates WAP by downregulating TGF-alpha production. We also propose that changes in TGF-alpha activity during mouse gestation and lactation could contribute to the pattern of temporal expression of WAP in the gland. These results provide a clear example of cooperation among lactogenic hormones, ECM, and locally acting growth factors in regulation of tissue-specific gene expression.

Animals↗
PubMed1995

Extending the application of critical path methods.

Most health care organizations are using critical pathways in an attempt to reduce the variation in patient care, improve quality, enhance communication, and reduce costs. Virtually all of the critical path efforts to date have developed tables of treatments, medications, and so forth by day and have displayed them in a format known as a Gantt chart. This article presents a methodology for identifying the true "time-limiting" critical path, describes three additional methods for presenting the information--the network, precedent, and resource formats--and shows how these can significantly enhance current critical path efforts.

Academic Medical Centers↗
PubMed1995

Basic actions of transforming growth factor-alpha and related peptides.

Transforming growth factor-alpha (TGF-alpha) and related peptides have been implicated in a wide range of biological activities, including cell growth, differentiation and acid inhibition. This chapter reviews the roles of TGF-alpha in the stomach, the insights gained into the action of the TGF-alpha family of growth factors from the study of polarized epithelial cells and the confirmation of events mediated by the epidermal growth factor receptor (EGFR) by the study of mice in which the EGFR has been disrupted by homologous recombination.

Animals↗
PubMed1995

Induction of heparin-binding epidermal growth factor-like growth factor mRNA in rat kidney after acute injury.

Previous studies have suggested that EGF or other members of the EGF family of mitogenic proteins are involved in proliferation of renal tubular epithelial cells occurring during recovery from injury to the kidney. The present studies examined whether expression of mRNA for the recently identified heparin-binding EGF-like growth factor (HB-EGF) is regulated in response to renal injury induced by either ischemia/reperfusion or mercuric chloride. Increased expression of HB-EGF mRNA was demonstrated in the post-ischemic kidney within 45 min of unilateral ischemia/reperfusion in the rat. Induction of HB-EGF mRNA occurred only when ischemia was followed by reperfusion, and was not eliminated by removal of blood cells from the post-ischemic kidney by saline perfusion. In situ hybridization with 35S-labeled antisense riboprobes of HB-EGF indicated that compared with control, there was increased HB-EGF mRNA expression in the 6 h post-ischemic kidney in the inner cortex and outer medulla in a patchy distribution, with the greatest expression in the inner stripe of the outer medulla. Expression occurred primarily in tubular epithelial cells. Recombinant human HB-EGF stimulated [3H]-thymidine incorporation in both primary cultures of rabbit proximal tubule cells and NRK 52E normal rat kidney epithelial cells, with potency similar to that of EGF. Induction of HB-EGF mRNA was observed in tubules freshly isolated from rat renal cortex or outer medulla when the tubules were subjected to reoxygenation after incubation in anoxic conditions. The nephrotoxin, mercuric chloride, also caused induction of HB-EGF mRNA both in vivo and in isolated rat cortical tubules. The anoxia/reoxygenation-induced expression of HB-EGF mRNA in isolated tubules was inhibited by the free radical scavengers, di- and tetra-methylthiourea, indicating involvement of reactive oxygen species. These findings indicate that HB-EGF mRNA is inducible in the kidney in vivo by acute tubular injury and suggest that HB-EGF may act as an autocrine/paracrine growth factor involved in proliferation of tubular epithelial cells and repair of the kidney.

Animals↗
PubMed1995

Interim report on the radiosurgical treatment of cerebral arteriovenous malformations. The influence of size, dose, time, and technical factors on obliteration rate.

During the authors' initial 4-year experience with radiosurgery using the Leksell cobalt-60 gamma unit, they treated 121 patients with cerebral arteriovenous malformations (AVMs). The radiosurgical dose to the margin of the nidus was 20 Gy for lesions less than 2.0 cm in diameter (volume < or = 4.2 cm3); 18 Gy for malformations 2.1 to 3.0 cm in diameter (volume 4.2-14.1 cm3); and 16 Gy for malformations greater than 3.0 cm (volume > 14.1 cm3). Fifty-one patients underwent follow-up angiography between 1 and 3 years after treatment, and complete obliteration of the nidus was confirmed in 38 (74.5%) of these patients. Thirty-two (74.4%) of 43 AVMs with volumes of 10 cm3 or less and six (75%) of eight larger AVMs (volume 11-30 cm3) showed complete obliteration. Analysis of the time course of AVM nidus shrinkage and obliteration showed that most of the radiosurgically induced effect had occurred by 36 months after treatment. Retrospective analysis of the dose plans for 10 AVMs that were not obliterated by 36 months after gamma knife radiosurgery at the authors' institution (eight cases) or elsewhere (two cases) revealed that six AVMs had not been covered completely by the prescribed isodose. Six (5%) of the 121 patients developed neurological deficits as a direct result of radiosurgical treatment. The authors infer from these data that malformations up to 30 cm3 in volume (approximately 4.0 cm in average diameter) can be treated effectively with an acceptably low complication rate using a radiosurgical dose of 16 Gy to the margin of the nidus. The obliteration rate for the larger malformations that were treated with a dose of 16 to 18 Gy appears to be similar to that for smaller ones treated with 18 to 20 Gy. As more experience accrues using radiosurgery to treat AVMs, patient selection criteria and the variables associated with successful obliteration of the nidus should become more clearly defined.

Adolescent↗
PubMed1995

Stereotactic radiosurgical treatment of cerebral arteriovenous malformations. Gamma Unit Radiosurgery Study Group.

OBJECTIVE: To assess the role of clinical factors, size of lesion, site of involvement, and radiation dose in patients with cerebral arteriovenous malformations (AVMs) who underwent stereotactic radiosurgical treatment. DESIGN: We reviewed the results in 121 patients with cerebral AVMs treated with the Leksell "Gamma Knife" between January 1990 and December 1993 at the Mayo Clinic in Rochester, Minnesota. MATERIAL AND METHODS: The following strict dose-volume protocol was used: AVMs 2.0 cm or smaller in diameter (volume, 4.2 cm3 or less) received 20 Gy to the margin of the nidus, those between 2.1 and 3.0 cm in diameter (4.3 to 14.1 cm3) received 18 Gy to the margin, and those that exceeded 3.0 cm in diameter (more than 14.1 cm3) received 16 Gy to the margin. Lesions that involved the brain stem received a radiosurgical dose of 18 Gy or less to the margin. Patients participated in regular follow-up clinical and imaging studies for up to 55 months. RESULTS: Follow-up cerebral angiography in 43 patients demonstrated total obliteration of the AVM nidus in 31 (72.1%), including 5 of 7 (71.4%) who had AVMs with a volume larger than 10 cm3. Clinical follow-up revealed that 111 patients (91.7%) had a stable or improved outcome, 3 had a nonfatal AVM hemorrhage, 2 suffered a fatal hemorrhage, and 2 died of causes not directly attributed to the AVM or radiosurgical treatment. Two patients had new or increased, nondisabling neurologic deficits as a result of treatment, and one patient had a temporary partial eyelid ptosis. CONCLUSION: Our findings suggest that previous theories about the relationship between AVM size and rate of obliteration after radiosurgical treatment may need revision. Our experience confirms that radiosurgical treatment for cerebral AVMs is safe and effective, even in cases for which the latency period before obliteration is longer than 2 years.

Adolescent↗
PubMed1995

Transforming growth factor alpha regulation of two zinc finger-containing immediate early response genes in intestine.

The epithelium lining the intestine undergoes rapid and continuous renewal. Growth factors play a role in intestinal epithelial growth regulation in vitro and in vivo. In this study, transforming growth factor alpha (TGF alpha) is shown to act as a mitogen and induce the expression of two zinc finger-containing immediate early genes [Zif268 (zinc finger protein 268) and Nup475 (nuclear protein 475)] in rat intestinal epithelial (RIE-1) cells in culture. These two gene products were initially isolated from serum-treated fibroblasts and represent growth-stimulated transcription factors. In TGF alpha-treated RIE-1 cells, nuclear run-on experiments demonstrate that TGF alpha induction of these two genes is regulated predominantly at the level of gene transcription. Utilizing in situ hybridization techniques, we show that systemic administration of TGF alpha induces expression of these two genes in the rat intestine. The predominant expression of zif268 is observed in the proliferative crypt compartment, whereas nup475 expression is concentrated in the postmitotic luminal compartment. These studies demonstrate that two immediate early genes, Nup475 and Zif268, are induced in intestinal epithelium in vitro and in vivo and thus may play a role in intestinal epithelial growth and/or differentiation.

Animals↗