Search PubMed⌕ Search

Biomedical subjects

A Rosenthal

Publications and source records attributed to A Rosenthal.

At least 163 records · Page 9Linked to original sources
PubMed1994

TGF beta 2 and TGF beta 3 are potent survival factors for midbrain dopaminergic neurons.

The vertebrate ventral midbrain contains 3-4 x 10(4) dopaminergic neurons that influence motor activity, emotional behavior, and cognition. Recently, glial cell line-derived neurotrophic factor (GDNF) was shown to be a potent survival factor for these dopaminergic neurons in culture. However, many midbrain dopaminergic neurons project to targets that do not express GDNF. We report here that transforming growth factors (TGFs) TGF beta 2 and TGF beta 3, which are distantly related to GDNF, also prevent the death of cultured rat embryonic midbrain dopaminergic neurons at picomolar concentrations. Furthermore, we find that TGF beta 2, TGF beta 3, and GDNF are expressed sequentially as local and target-derived trophic factors and that subpopulations of dopaminergic neurons projecting to distinct targets have access to only one of these factors. These findings are consistent with the idea that GDNF, TGF beta 2, and TGF beta 3 are physiological survival factors for developing midbrain dopaminergic neurons and may have applications as therapeutics for Parkinson's disease, a neurodegenerative disorder of dopaminergic neurons.

Animals↗
PubMed1994

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

Aphasia↗
PubMed1994

Improving results with first-stage palliation for hypoplastic left heart syndrome.

Between January 1990 and February 1993, 73 patients underwent first-stage reconstruction for hypoplastic left heart syndrome at the University of Michigan Medical Center. During this period, surgical reconstruction remained essentially constant and consisted of a pulmonary artery-to-aorta anastomosis with allograft augmentation of the ascending, transverse, and proximal descending aorta, restriction of pulmonary blood flow with a polytetrafluoroethylene shunt from the innominate artery to the central pulmonary artery confluence, and atrial septectomy. Hospital survival was 62 of 73 patients, 85% (70% confidence limits: 80% to 89%). These results stand in marked contrast to those obtained during the earlier years of our experience from 1986 to 1989 when only 21 of 50 patients (42%, 70% confidence limits: 35% to 49%) survived (p = 0.001). Among the most recent group of patients, only 2 of 7 patients older than 1 month of age at operation survived, whereas 60 of 66 (91%, 70% confidence limits: 87% to 94%) patients younger than 1 month of age survived (p = 0.0001). Anatomic subtype and ascending aortic diameter were not predictive of survival. Actuarial survivals for those patients younger than 1 month of age at the first-stage operation, including hospital deaths and subsequent operative procedures, were 81%, 74%, and 74% at 6 months, 1 year, and 2 years, respectively. These results indicate that survival for patients after first-stage reconstruction for hypoplastic left heart syndrome has significantly improved in recent years. Older age was a strong risk factor, with a hospital survival of 91% for those patients undergoing first-stage palliation within the first month of life. These data have important implications for the type of operative intervention and its timing.

Actuarial Analysis↗
PubMed1994

Regulation of neurotrophin receptor expression during embryonic and postnatal development.

Members of the NGF family of proteins act as neurotrophic agents for defined populations of peripheral and central neurons during embryonic and postnatal development. We have studied the presence of receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 and -4/5 (NT-3, NT-4/5) by cross-linking radioiodinated neurotrophins to specific cell surface receptors. We have identified neurotrophin receptors representing full-length TrkB and TrkC and their truncated forms (lacking a functional cytoplasmic kinase domain) in neuronal as well as in non-neuronal tissues. During chicken embryonic and early postnatal brain development, expression of full-length TrkB and TrkC proteins preceded the onset of the truncated forms of these receptors. A similar pattern was also observed in mouse embryonic and early postnatal brain. The relative levels of neurotrophin receptors in the basal forebrain and in the hippocampus did not change significantly with age in mice. High levels of receptors for the three neurotrophins were detected in the nigrostriatal system. Full-length TrkB and TrkC receptors were found in chicken and rat embryonic ventral spinal cord, as well as on purified motoneurons. Again, truncated TrkB appeared significantly later than the full-length form on spinal motoneurons. In chicken embryonic retina and optic tectum we detected full-length TrkB and TrkC; however, the optic tectum also expressed large amounts of the truncated form of TrkB. TrkC but not TrkB was detected in chicken embryonic skeletal muscle, suggesting that NT-3 may have a novel function in this tissue. The presence of neurotrophin receptors in a wide variety of embryonic and postnatal tissues underlines the significant role of BDNF, NT-3, and NT-4/5 in embryonic and postnatal development. The regulation of the ratio of full-length versus truncated neurotrophin receptors may play an important role in the development, maturation, and maintenance of various neuronal networks.

Aging↗
PubMed1993

Nonciliated cells of the rat efferent ducts endocytose testicular sulfated glycoprotein-1 (SGP-1) and synthesize SGP-1 derived saposins.

Sertoli cell sulfated glycoprotein-1 (SGP-1) is a heavily glycosylated and sulfated 70 kDa protein that is secreted into the lumen of the seminiferous tubule where it binds to spermatozoa. Recent light and electron microscope immunocytochemistry has suggested that the testicular SGP-1 detaches from the surface of spermatozoa in the lumen of the efferent ducts to be endocytosed within the endocytic apparatus of the epithelial nonciliated cells. The finding of SGP-1 mRNA together with anti-SGP-1 immunogold labeling of the lysosomal compartment suggest that these cells synthesize an efferent duct form of SGP-1. In the present study, a number of different experimental approaches (ligation, tunicamycin treatment and a combination of both) in combination with quantitative electron microscope immunogold labeling and Western blot analysis were performed in order to test this hypothesis. The number of gold particles and the profile area of the early (endosomes, pale multivesicular bodies) and late (dense multivesicular bodies, secondary lysosomes) endocytic apparatus were estimated in each of the experimental groups and expressed as the number of gold particles per micron 2 (labeling densities). The data revealed that ligation produced a significant reduction of anti-SGP-1 immunogold labeling of the early endocytic apparatus but not of the late endocytic apparatus. Tunicamycin treatment on the other hand produced a significant reduction of immunogold labeling of both the early and late endocytic apparatus. The combination of both treatments resulted in a more effective reduction of the labeling densities of these two endocytic compartments. These results thus indicate that the nonciliated cells of the efferent ducts are involved both in the endocytosis of the Sertoli-derived SGP-1 and in the synthesis of an efferent duct form of SGP-1 that is targeted from the Golgi apparatus to secondary lysosomes after its glycosylation. In order to determine the biosynthetic pathway of SGP-1 within the efferent ducts, an I.V. injection of 35S-cysteine followed by immunoprecipitation and SDS-PAGE revealed that SGP-1 was initially biosynthesized as a 55 kDa protein. This protein appears to be post-translationally modified to a 65 kDa form after 1 hour, which preceded the appearance of the 70 kDa form, and smaller peptides of about 15 kDa characteristic of saposins after 3-4 hours. Western blot analysis of ligated efferent ducts showed an increase in the biosynthesis of the 70 kDa form of SGP-1 when compared to untreated controls, however, it has yet to be established if this protein is secreted or retained in an intracellular compartment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Neurotrophin-3 affects proliferation and differentiation of distinct neural crest cells and is present in the early neural tube of avian embryos.

Neurotrophin-3 is mitogenic for cultured quail neural crest cells (Kalcheim et al., 1992, Proc. Natl. Acad. Sci. USA 89:1661-1665). We now report that neurotrophin-3 also influences the survival and/or differentiation of a subset of postmitotic neural crest precursors into neurons, provided these progenitors are grown on a cellular substrate. When cultured for 1 day on monolayers of NT-3-producing, chinese hamster ovary cells, 59% of the neural crest clusters growing on the transfected line revealed the presence of intense neuronal outgrowth, compared to 25% of that in controls. Moreover, dissociated neural crest cells grown for 20 h on top of mesodermal cells in the presence of various concentrations of purified recombinant neurotrophin-3 displayed a dose-dependent increase in neuronal number. Localization experiments using specific polyclonal antibodies, revealed that neurotrophin-3 is confined to neuroepithelial cells of quail neural tubes in situ on E2 and E3, and to E2 neural tubes grown in culture for 24 h. At this stage, neural crest cells and somites were negative. At later stages, staining was likewise apparent in peripheral nerves and dorsal root ganglia. We, therefore, propose that NT-3, a factor that is expressed in the early avian central nervous system, has multiple effects both on the proliferation and differentiation of distinct neural crest cells, which depend on the state of commitment of the responsive progenitors.

Animals↗
PubMed1993

The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells.

Members of the Trk tyrosine kinase family have recently been identified as functional receptors of the NGF family of neurotrophins. Here we show the rat trkC locus to be complex, encoding at least four distinct polypeptides. Three of the encoded polypeptides are full-length receptor tyrosine kinases that differ by novel amino acid insertions in the kinase domain. A fourth protein is a truncated receptor that lacks the catalytic domain. Tyrosine phosphorylation, cross-linking, and ligand binding assays indicate that TrkC receptors interact with NT-3 and not with the related neurotrophins NGF, BDNF, xNT-4, or hNT-5. Furthermore, high and low affinity NT-3-binding sites are associated with the TrkC receptors. Stable and transient expression of TrkC receptors in PC12 cells indicates that the neurite outgrowth response elicited by NT-3 is dramatic in receptors lacking the novel kinase insert (gp150trkC) but absent in receptors containing the 14 amino acid insert in the kinase domain (gp150trkC14). These data suggest that the trkC locus encodes receptors that may be capable of mediating different biological responses within the cell. This could have important implications in understanding the role of neurotrophins in the development of the vertebrate nervous system.

3T3 Cells↗
PubMed1993

A randomized controlled trial of the efficacy, safety and cost of a single-use myocardial bioptome.

A randomized single-blind study was performed comparing a reusable 8 French bioptome with a single-use 7 French bioptome in a consecutive series of 63 myocardial biopsy procedures performed during follow-up of cardiac transplant patients. Safety, efficacy and cost were compared between 30 procedures performed with the single-use bioptome (Group I) and 33 procedures performed with the reusable bioptome (Group II). The two instruments were found equally efficient in obtaining adequate biopsy samples (69% of attempts for both instruments). The average specimen weight was not significantly different (Group I 2.5+/-1.3 mg, Group II 2.7+/-1.1 mg) despite different nominal jaw sizes. There was no significant difference in the incidence of incompletely cut specimens (Group I 13%, Group II 7%) and there were no complications in either group. The cost of the two instruments was, as expected, markedly different with an estimated average per-use cost of $250.00 for the single-use bioptome and $35.89 for the reusable instrument. In this small study, a single-use 7 French myocardial bioptome was found to be an acceptable substitute for the larger, reusable instrument with no decrement in specimen size. The substantial cost differential is noteworthy, although the maintenance required by the reusable instrument can present a formidable challenge.

Biopsy, Needle↗
PubMed1993

Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons.

We have studied the effect of human recombinant neurotrophin-4/5 (NT-4/5) on the survival of developing PNS neurons from embryonic mice and chickens. NT-4/5 transiently supported mouse NGF-dependent trigeminal and jugular neurons at early stages of target field innervation and mouse brain-derived neurotrophic factor (BDNF)-dependent no-dose neurons during the phase of naturally occurring cell death. NT-4/5 was as potent as BDNF in supporting the survival of these neuronal populations. Surprisingly, NT-4/5 was 3 orders of magnitude less potent than BDNF as a survival factor for early chick dorsomedial trigeminal sensory neurons and did not support the survival of chick BDNF-dependent trigeminal mesencephalic or ventrolateral trigeminal sensory neurons at any of the developmental stages tested. Thus, NT-4/5 is a survival factor for certain embryonic mouse cranial sensory neurons. It is the first species-specific neurotrophin to be identified and it can discriminate at high concentrations between different BDNF-responsive chick neurons.

Animals↗
PubMed1993

Results of a policy of primary repair of truncus arteriosus in the neonate.

Although the early mortality for repair of truncus arteriosus has decreased in the modern era, routine correction in the neonate has not been widely adopted. To assess the results of our protocol of early repair, we reviewed 46 neonates and infants undergoing repair of truncus arteriosus at the University of Michigan Medical Center from January 1986 to January 1992. Their ages ranged from 1 day to 7 months (median 13 days) and weights from 1.8 kg to 5.4 kg (mean 3.1 kg). Repair was performed beyond the first month of life in only 8 patients, because of late referral in 7 and severe noncardiac problems in 1. Associated cardiac anomalies were frequently encountered, the most common being interrupted aortic arch (n = 5), nonconfluent pulmonary arteries (n = 4), hypoplastic pulmonary arteries (n = 4), and major coronary artery anomalies (n = 3). Truncal valve replacement was performed in 5 patients with severe regurgitation, 3 of whom also had truncal valve systolic pressure gradients of 30 mm Hg or more. The truncal valve was replaced with a mechanical prosthesis in 2 patients and with a cryopreserved homograft in 3 patients. Right ventricle-pulmonary artery continuity was established with a homograft in 41 patients (range 8 mm to 15 mm), a valved heterograft conduit in 4 (range 12 mm to 14 mm), and a nonvalved polytetrafluoroethylene tube in the remaining patient (8 mm). There were 5 hospital deaths (11%, 70% confidence limits 7% to 17%). Multivariate and univariate analyses failed to demonstrate a relationship between hospital mortality and age, weight, or associated cardiac anomalies. Only 1 death occurred among 9 patients with interrupted aortic arch or nonconfluent pulmonary arteries. Hospital survivors were followed-up from 3 months to 6.3 years (mean 3 +/- 0.4 years). Late noncardiac deaths occurred in 3 patients, all within 4 months after the operation. Actuarial survival was 81% +/- 6% at 90 days and beyond. Despite the prevalence of major associated conditions, early repair has resulted in excellent survival. We continue to recommend repair promptly after presentation, optimally within the first month of life.

Abnormalities, Multiple↗
PubMed1992

Neurotrophin 3 is a mitogen for cultured neural crest cells.

Neurotrophin 3 (NT-3) promotes the survival and induces neurite outgrowth from a subset of neural crest (NC) and placode-derived neurons. We now report that this growth factor regulates the proliferation of cultured NC progenitor cells grown in a serum-free defined medium. In cultures of somites containing NC cells at migratory stages, NT-3 promotes a 2- to 8.4-fold increase in the number of NC cells incorporating [3H]thymidine into nuclei and a 1.8- to 4.8-fold increase in NC cell number compared to controls without added factor. NT-3 also promoted, to a lesser extent, the proliferation of NC cells in homogeneous cultures established from NC clusters. In addition to its effect on NC cells, NT-3 was mitogenic to somite cells in the mixed NC/somite cultures. These data demonstrate that NT-3 can act directly on the NC cells. They also indicate that the response of NC cells to NT-3 may be modulated by the presence of somitic cells. We suggest that NT-3 may be one of the central nervous system-derived factors that mediate NC cell proliferation in vivo.

Animals↗