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Biomedical subjects

S A Newman

Publications and source records attributed to S A Newman.

At least 37 records · Page 2Linked to original sources
PubMed1998

The role of preoperative adjuvant treatment in the management of esthesioneuroblastoma: the University of Virginia experience.

OBJECTIVE: Multidisciplinary management of esthesioneuroblastoma has effected markedly increased survival during the past 20 years. The potential for radical craniofacial surgery for complete en bloc resection, the availability of advanced neuroimaging modalities, and the incorporation of neoadjuvant therapy into treatment strategies for tumor remission have all contributed to this accomplishment. However, a standard protocol for the management of these lesions has not been accepted; preoperative radiation and chemotherapy have been advocated, but neither radiographic nor clinical response has been quantified. METHODS: Thirty-four consecutive patients with biopsy-proven esthesioneuroblastoma treated at one institution from 1976 to 1994 were reviewed to determine the effects of preoperative radiation therapy, with or without chemotherapy, on tumor size and long-term survival. RESULTS: In a multivariate regression analysis, advanced age was predictive of decreased disease-free survival (P=0.008), whereas advanced Kadish stage was associated with a borderline higher rate of disease-related mortality (P=0.056). Two-thirds of the patients showed a significant reduction in tumor burden with adjuvant therapy. Patients with response to neoadjuvant therapy demonstrated a significantly lower rate of disease-related mortality (P=0.050). In this series, the overall 5- and 10-year survival rates were 81.0 and 54.5%, respectively. CONCLUSION: Preoperative neoadjuvant therapy provides a valuable complement to radical craniofacial resection, leading to reduction in tumor burden. Patients experiencing reduction in tumor volume by neoadjuvant therapy demonstrate an improved prognosis.

Adolescent↗
PubMed1997

Interaction of the NH2-terminal domain of fibronectin with heparin. Role of the omega-loops of the type I modules.

Determinants of the interaction of the 29-kDa NH2-terminal domain of fibronectin with heparin were explored by analysis of normal and mutant recombinant NH2-terminal fibronectin fragments produced in an insect cell Baculovirus host vector system. A genomic/cDNA clone was constructed that specified a secretable human fibronectin NH2 fragment. With the use of site-directed mutagenesis a set of 29 kDa fragments was obtained that contained glycine or glutamic acid residues in place of basic residues at various candidate sites for heparin binding in the five type I modules that make up the domain. The recombinant fragment containing the wild type sequence had a nearly normal circular dichroic spectra and a melting profile, as assayed by loss of ellipticity at 228 nm, that was indistinguishable from that of the native fragment obtained by trypsinization of plasma fibronectin. A substantial proportion of the wild type recombinant fragment bound to heparin-Sepharose, where it was eluted at the same NaCl concentration as the native fragment. The wild type fragment was capable of promoting matrix-driven translocation, a morphogenetic effect in artificial extracellular matrices that depends on the interaction of the fibronectin NH2 terminus with heparin-like molecules on the surfaces of particles. Mutant fragments in which arginines predicted to be most exposed in the folded fragment were converted to glycines retained the same affinity for heparin as the wild type fragment. In contrast, a mutant fragment in which the single basic residue (Arg99) in the minor loop ("Omega-loop") of the second type I module was converted to a glycine had an essentially normal melting profile but exhibited no binding to heparin and failed to promote matrix-driven translocation. A mutant fragment in which the single basic residue (Arg52) of the first type I module was converted to a glycine also completely lacked heparin binding activity, but one in which the single basic residue (Arg191) the fourth type I module was converted to a glycine retained the ability to bind heparin. A mutant fragment in which the single basic residue (Lys143) in the Omega-loop of the third type I module was converted to a glutamic acid lacked heparin binding activity but had a CD spectrum similar to the heparin-liganded native protein and was capable of promoting matrix-driven translocation. The results indicate that multiple residues in the Omega-loops of the fibronectin NH2-terminal domain participate in its interactions with heparin. In addition, the conformation of one of the nonbinding mutants may mimic the heparin-induced structural alteration in this fibronectin domain required for certain morphogenetic events.

Amino Acid Sequence↗
PubMed1996

Nuclear localization of type II cAMP-dependent protein kinase during limb cartilage differentiation is associated with a novel developmentally regulated A-kinase anchoring protein.

Differentiation of chicken limb cartilage is accompanied by a rise in intracellular cyclic AMP, an inducer of cartilage-specific gene expression. A basic approximately 35-kDa protein, designated p35, is the major nuclear substrate for cAMP-dependent protein kinase (PKA) during this process. Here we show that whereas both precartilage and cartilage nuclei contain p35, only precartilage nuclei contain PKA. The phosphorylation of p35 in isolated cell fractions was used as an index of changes in the cellular compartmentalization of components of PKA during chondrogenesis. Both the catalytic subunit and type II regulatory subunit (RII) of PKA were present in the precartilage nuclear fraction, but were undetectable or present in only trace amounts in the cartilage nuclear fraction. Furthermore, a novel approximately 150-kDa A-kinase anchoring protein (AKAP), which binds to RII, was detected in the nuclear matrix of precartilage nuclei but, like RII, was virtually absent in the nuclei of fully differentiated cartilage cells. In limb mesenchymal cells undergoing chondrogenesis in culture a corresponding set of changes occurred: cartilage differentiation was accompanied by a marked reduction in the amounts of both nuclear RII and nAKAP150. These observations indicate that type II PKA holoenzyme is imported into the mesenchymal cell nucleus prior to chondrogenesis, an event that appears to depend on the activity of the developmentally regulated nAKAP150.

Affinity Labels↗
PubMed1996

Sticky fingers: Hox genes and cell adhesion in vertebrate limb development.

During vertebrate limb development, various genes of the Hox family, the products of which influence skeletal element identity, are expressed in specific spatiotemporal patterns in the limb bud mesenchyme. At the same time, the cells also exhibit 'self-organizing' behavior--interacting with each other via extracellular matrix and cell-cell adhesive molecules to form the arrays of mesenchymal condensations that lead to the cartilaginous skeletal primordia. A recent study by Yokouchi et al. establishes a connection between these phenomena. They misexpressed the product of the Hoxa-13 gene in chick limb buds and demonstrated both skeletal pattern perturbations and changes in cell-cell adhesivity in mesenchyme aberrantly expressing this protein.

Animals↗
PubMed1996

Prevention and management of complications associated with the hydroxyapatite implant.

The hydroxyapatite orbital implant offers many advantages compared to conventional implants; however, its use is not entirely free of complications. The objectives of this study are to review the complications encountered with the hydroxyapatite orbital implant, suggest mechanisms contributing to the development of these complications, and emphasize aspects of surgical technique that will minimize the risk of the most frequent complication, implant exposure. Preoperative, operative, and postoperative records of 154 patients receiving primary and secondary hydroxyapatite implants were studied retrospectively. Three clinical types of exposure defects were observed; dehiscences along the horizontal suture line, defects over holes in the hydroxyapatite, and a defect adjacent to the site of radiation plaque therapy. Most small exposures healed spontaneously. Medium and large defects were associated with anteriorly malpositioned implants, most often required surgical intervention, and were successfully managed with one or a combination of techniques including flaps, mucous membrane grafts, or repositioning of the implant more posteriorly. Placing the hydroxyapatite implant as far posteriorly as possible and advancing the extraocular muscles 3-5 mm from the apex of the implant will prevent most exposures. Unlike other types of implants, the hydroxyapatite implant does not migrate or extrude, and when exposed, usually does not require removal.

Adolescent↗
PubMed1995

Different roles for fibronectin in the generation of fore and hind limb precartilage condensations.

Fibronectin expression and spatiotemporal distribution were examined in relation to the distinctive patterns of mesenchymal condensation and chondrogenesis seen in high-density serum-free cultures of chicken wing and leg bud precartilage cells. More fibronectin protein was produced on a per cell basis by leg than by wing mesenchyme, both in freshly isolated tissue and during the prechondrogenic condensation period in culture, where the difference was twofold. The quantitative difference in fibronectin expression in freshly isolated wing and leg mesenchyme was also seen at the level of total and poly (A)+ RNA. During the condensation phase, fibronectin was distributed in the wing and leg mesenchymal cultures in a way that prefigured the eventual distribution of cartilage in these cultures: in wing cultures condensations were broad and flat, and rich in diffusely organized fibronectin; in leg cultures, condensations were compact and spheroidal, and contained abundant deposits of fibronectin. In addition, the leg condensations were connected by long fibronectin-rich fibers. Transient treatment with TGF-beta early during the culture period led to increase in fibronectin production and expansion of condensations in both wing and leg cultures. Leg mesenchyme was more responsive to transforming growth factor-beta than wing mesenchyme with respect to fibronectin production, and this was reflected in a greater enhancement of cartilage formation in later cultures. Treatment of cultures with monoclonal antibody 304 directed against the amino-terminal heparin-binding domain of fibronectin inhibited condensation formation and reduced chondrogenesis in wing mesenchyme, but left these two processes unchanged in leg mesenchyme, despite disruption by the antibody of the leg-specific fibronectin fibers. These studies indicate that for both wing and leg mesenchyme the morphology, extent, and spatiotemporal regulation of precartilage condensation and subsequent chondrogenesis closely parallels the deposition of fibronectin. But whereas the interaction between cells and fibronectin in wing bud mesenchyme is mediated in part by the protein's amino-terminal domain, this domain does not appear to be involved in analogous interactions in leg bud mesenchyme.

Animals↗
PubMed1995

A phase 1-2 trial of superselective carboplatin, low-dose infusional 5-fluorouracil and concurrent radiation for high-grade gliomas.

Recent trials have suggested that low-dose infusional 5-FU is more efficacious when given during radiotherapy than is bolus 5-FU. Additionally, intra-arterial cisplatin for brain tumors has been shown to be associated with both high response rates as well as significant toxicity. A dose escalation study was therefore performed using superselective carboplatin, a cisplatin analogue with a favorable CNS toxicity profile in combination with 6 weeks of infusional 5-FU at 225 mg/m2 and concurrent radiotherapy. Eight patients were treated at the starting dose of 200 mg/m2 carboplatin and 11 patients were treated at 300 mg/m2. No toxicity was observed that was attributable to infusional 5-FU. However, two ischemic events related to the superselective delivery of carboplatin were observed, and one patient was noted to have asymptomatic retinal toxicity from the carboplatin. Of 19 patients, 5 had objective responses with 25% or greater reduction in tumor volumes. Continuous infusional 5-FU can be given in combination with partial brain radiotherapy without significant toxicity. Superselective carboplatin delivery is associated with a low incidence of stroke, but no significant retinal toxicity.

Adult↗
PubMed1995

Vascular disease.

This last year has been a particularly busy one in the field of neuro-ophthalmology. The publication of the second, important, randomized multicentered trial in neuro-ophthalmology highlights the power of randomized trials to answer important clinical questions. This and other publications emphasize the pivotal role of vascular pathophysiology in production of neuro-ophthalmic disease. The progress in our understanding of mechanisms of vascular obstruction, risk factors for vascular disease and ocular manifestations, as well as technical advances in our approach to patients with vascular problems have continued the broad-front advancement in neuro-ophthalmology.

Cerebrovascular Disorders↗
PubMed1994

Morphogenetic differences between fore and hind limb precartilage mesenchyme: relation to mechanisms of skeletal pattern formation.

Using a serum-free culture system, we have investigated morphogenetic differences between fore and hind limb precartilage mesenchymal cells derived from stages 21-26 chicken embryos. Across all stages, wing and leg cultures were intrinsically different in the amount and spatial organization of cartilage that they produced. By stage 24, leg cells began to produce a nodular pattern of cartilage while wing cells continued to produce sheets of cartilage. This pattern difference persisted throughout the later stages and was not due to differences in cell survival as judged by DNA content or to the presence of distinctive cell subpopulations in either tissue, as determined by flow cytometry. Chondrogenesis in wing and leg precartilage cell cultures was affected differently by 10% fetal bovine serum, TGF-beta 1 (1 ng/ml for 5 hr on the day after plating), and retinoic acid (5 ng/ml). In wing cultures, the extent of chondrogenesis was significantly enhanced by serum or by a combination of TGF-beta 1 and retinoic acid, but the cartilage pattern was not altered with any treatment. In leg cultures, the extent of chondrogenesis was enhanced by TGF-beta 1 alone, inhibited by retinoic acid alone, and the cartilage pattern was changed from nodular to sheet-like by treatment with TGF-beta 1. Wing and leg cultures also differed from each other in relative cohesivity and in condensation morphology and organization of fibronectin during the early phase of differentiation. Wing cells produced broad, flat condensations containing diffusely organized fibronectin, whereas leg cells elaborated an extensive network of long fibronectin-rich fibrils connecting very compact, fibronectin-rich condensations. These intrinsic and induced differences in fore and hind limb mesenchyme provide insight into the mechanisms that are common to the formation of all limb skeletal elements and those that distinguish skeletal elements from different limb regions and limb types.

Animals↗
PubMed1994

Papaverine-induced mydriasis.

Five cases of ipsilateral pupillary dilatation that developed during local intraarterial infusion of papaverine are reported. All patients were being treated for symptomatic vasospasm secondary to subarachnoid hemorrhage. In each case, the tip of the infusion catheter was positioned in the internal carotid artery in close proximity to the ostium of the ophthalmic artery. Pupillary dilatation in all patients readily resolved after termination of the infusion.

Adult↗
PubMed1993

Is segmentation generic?

When two populations of cells within a tissue mass differ from one another in magnitude or type of intercellular adhesions, a boundary can form within the tissue, across which cells will fail to mix. This phenomenon may occur regardless of the identity of the molecules that mediate cell adhesion. If, in addition, a choice between the two adhesive states is regulated by a molecule the concentration of which is periodic in space, or in time, then alternating bands of non-mixing tissue, or segments, can form. But temporal or spatial periodicities in concentration will tend to arise for any molecule that is positively autoregulatory. It is therefore proposed that segmentation is a 'generic' property of metazoan organisms, and that metamerism would be expected to have emerged numerous times during evolution. A simple model of segmentation, based solely on differential adhesion and periodic regulation of adhesion, can account for segment properties as disparate as those seen in long and short germ band insects, and for diverse experimental results on boundary regeneration in the chick hind brain and the insect cuticle. It is suggested that the complex, multicomponent segment-forming systems found in contemporary organisms (e.g., Drosophila) are the products of evolutionary recruitment of molecular cues such as homeobox gene products, that increase the reliability and stability of metameric patterns originally templated by generic self-organizing properties of tissues.

Animals↗