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Biomedical subjects

T Rosenbaum

Publications and source records attributed to T Rosenbaum.

At least 19 recordsLinked to original sources
PubMed2005

Aplasia cutis congenita of the scalp: how much therapy is necessary in large defects?

AIM: To show that local antibiotic management and a regular inspection of aplasia cutis congenita of the skull can give an excellent result. METHOD: This case reports a girl born with aplasia cutis congenita of the skull presenting with a large aplasia of the epidermis, dermis, subcutaneous tissue and galea, including a bone defect without any additional risk factor, e.g. early eschar formation, cerebrospinal fluid leakage or uncommon dural blood vessels. RESULTS: A primarily conservative treatment with local wet and antibiotic dressings together with a systemic antibiotic treatment for the first 2 wk led to an excellent result and thus prevented untimely operative and peri-operative procedures. CONCLUSIONS: Here we have shown that conservative treatment might be an option, even if the wound diameter is greater than 1 cm(2), to prevent infants from any untimely operative procedure with an elevated operative risk if any additional risk factors are excluded.

Anti-Bacterial Agents↗
PubMed2003

Giant condyloma of Buschke-Loewenstein in association with erythroderma.

The Buschke-Loewenstein tumour is regarded as a type of verrucous carcinoma occurring on anogenital mucosal surfaces. The tumour is locally invasive but displays a benign cytology and rarely metastasizes. It is associated with human papillomavirus types 6 and 11. We describe a case of Buschke-Loewenstein tumour occurring in a 61-year-old man which behaved in a locally aggressive manner and was associated with human papillomavirus type 16 and erythroderma which proved resistant to treatment. The patient refused surgery and therapy with interferon alpha was ineffective. Chemotherapy with systemic cisplatin and 5-fluorouracil produced a partial response before the patient succumbed from gram-negative septicaemia.

Anti-Bacterial Agents↗
PubMed2002

Nerve growth factor increases L-type calcium current in pancreatic beta cells in culture.

We analyzed the effect of culturing adult rat beta cells with NGF2.5 S for 5 to 7 days on macroscopic barium current (I(Ba)), and determined the role of Na and Ca channels on neurite-like process extension induced by NGF and dbcAMP, and by KCI depolarization. After five days in culture with 2.5S NGF, beta cells exhibit a 102% increase in I(Ba) density. This effect is on L-type calcium channels because most of the current is blocked by nifedipine. The application of NGF for 5 minutes to the cells deprived of the trophic factor for 24 hr further increases I(Ba) current by 91%. These results suggest that the trophic factor regulates I(Ba) by two different mechanisms, a) an increase in channel density and b) a rapid modulation of the channels already present in the membrane. Finally, we found that ion-channel activity modifies the growth of neurite-like processes. After 2 weeks in culture with high KCl, almost 14% of beta cells extend neurite-like processes and the most impressive effect is observed in the presence of KCl, NGF, and dbcAMP simultaneously, where nearly 60% of the cells extend neurite-like processes. Tetrodotoxin and nifedipine reduce the morphological changes induced by these agents.

Animals↗
PubMed2001

Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations.

Neurofibromas, benign tumors that originate from the peripheral nerve sheath, are a hallmark of neurofibromatosis type 1 (NF1). Although loss of heterozygosity (LOH) is a common phenomenon in this neoplasia, it only accounts for part of the somatic NF1 mutations found. Somatic point mutations or the presence of "two hits" in the NF1 gene have only been reported for a few neurofibromas. The large size of the NF1 gene together with the multicellular composition of these tumors has greatly hampered their molecular characterization. Here, we present the somatic NF1 mutational analysis of the whole set of neurofibromas studied by our group and consisting in 126 tumors derived from 32 NF1 patients. We report the identification of 45 independent somatic NF1 mutations, 20 of which are reported for the first time. Different types of point mutations together with LOH affecting the NF1 gene and its surrounding region or extending along the 17q arm have been found. Among point mutations, those affecting the correct splicing of the NF1 gene are common, coinciding with results reported on germline NF1 mutations. In most cases, we have been able to confirm that both copies of the NF1 gene are inactivated. We have also found that both somatic and germline mutations can be expressed at the RNA level in the neoplastic cells. Furthermore, we have observed that the study of more than one tumor derived from the same patient is useful for the identification of the germline mutation. Finally, we have noticed that the culture of neurofibromas and their fibroblast clearance facilitates LOH detection in cases in which it is difficult to determine.

Alleles↗
PubMed2001

Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas.

Pure populations of neurofibroma-derived Schwann cells bearing both NF1 mutated alleles (NF1-/-) have been isolated from different neurofibromas showing loss of heterozygosity of nearly the entire 17q chromosome. By comparing molecular and fluorescent in situ hybridization analysis of these cells, we demonstrate mitotic recombination is the mechanism underlying this type of loss of heterozygosity leading to reduction to homozygosity of NF1 germline mutation.

Chromosomes, Human, Pair 17↗
PubMed2001

Nerve growth factor increases insulin secretion and barium current in pancreatic beta-cells.

We analyzed the effect of a brief exposure to nerve growth factor (NGF) on insulin secretion and macroscopic barium currents of single adult rat pancreatic beta-cells. After a 1-h exposure to NGF (50 ng/ml), single beta-cells show a 2.5-fold increase in the insulin secretion index in 5.6 mmol/l glucose and a nearly twofold increase in 15.6 mmol/l glucose compared with control cells. We have recently demonstrated that pancreatic beta-cells synthesize and secrete NGF. We analyzed the effect of endogenous NGF on insulin secretion by incubating islet cells in the presence of an anti-NGF monoclonal antibody for 1 h in different glucose concentrations. Although the basal insulin secretion index (5.6 mmol/l glucose) is not affected, glucose-stimulated insulin secretion (15.6 mmol/l glucose) is decreased by 41% in the presence of the antibody. This effect is mediated by the activation of the NGF receptor TrkA because the specific inhibitor of Trk phosphorylation K252a also blocks NGF-induced increase in insulin secretion, both in the presence and absence of exogenous NGF. Using the whole-cell variation of the patch-clamp technique, we found that cells exposed to NGF for 5 min exhibit a 32% increase in the average barium current density. These results suggest that the effects of NGF on insulin secretion are partially mediated by an increase in calcium current through Ca channels. These results further suggest that NGF plays an important autoregulatory role in pancreatic beta-cell function. Two targets of short-term NGF-modulation are insulin secretion and calcium-channel activity.

Animals↗
PubMed2000

Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations.

Neurofibromas are one of the most characteristic features of neurofibromatosis type 1 (NF1), an inherited autosomal-dominant neurogenetic disorder affecting 1 in 3500 individuals worldwide. These benign tumors mainly consist of Schwann cells (SCs) and fibroblasts. Recent evidence demonstrates that somatic mutations at the NF1 gene are found in neurofibromas, but it has not been demonstrated whether SCs, fibroblasts and/or both cell types bear a somatic loss of NF1. We recently established a cell culture system that allows selective expansion of human SCs from neurofibromas. We cultured pure populations of SCs and fibroblasts derived from 10 neurofibromas with characterized NF1 mutations and found that SCs but not fibroblasts harbored a somatic mutation at the NF1 locus in all studied tumors. Furthermore, by culturing neurofibroma-derived SCs under different in vitro conditions we were able to obtain two genetically distinct SC subpopulations: NF1(-/-) and NF1(+/-). These data strongly support the idea that NF1 mutations in SCs, but not in fibroblasts, correlate to neurofibroma formation and demonstrate that only a portion of SCs in neurofibromas have mutations in both NF1 alleles.

Cell Division↗
PubMed2000

Single cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts.

Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by multiple neurofibromas, peripheral nerve tumors containing mainly Schwann cells and fibroblasts. The NF1 gene encodes neurofibromin, a tumor suppressor postulated to function in part as a Ras GTPase-activating protein. The roles of different cell types and of elevated Ras-GTP in neurofibroma formation are unclear. To determine which neurofibroma cell type has altered Ras-GTP regulation, we developed an immunocytochemical assay for active, GTP-bound Ras. In NIH 3T3 cells, the assay detected overexpressed, constitutively activated K-, N-, and Ha-Ras and insulin-induced endogenous Ras-GTP. In dissociated neurofibroma cells from NF1 patients, Ras-GTP was elevated in Schwann cells but not fibroblasts. Twelve to 62% of tumor Schwann cells showed elevated Ras-GTP, unexpectedly revealing neurofibroma Schwann cell heterogeneity. Increased basal Ras-GTP did not correlate with increased cell proliferation. Normal human Schwann cells, however, did not demonstrate elevated basal Ras activity. Furthermore, compared with cells from wild type littermates, Ras-GTP was elevated in all mouse Nf1(-/-) Schwann cells but never in Nf1(-/-) mouse fibroblasts. Our results indicate that Ras activity is detectably increased in only some neurofibroma Schwann cells and suggest that neurofibromin is not an essential regulator of Ras activity in fibroblasts.

Animals↗
PubMed2000

Long-term culture and characterization of human neurofibroma-derived Schwann cells.

Neurofibromas are benign tumors arising from the peripheral nerve sheath and are a typical finding in neurofibromatosis type 1 (NF1). Schwann cells are the predominant cell type in neurofibromas and thus are supposed to play a major role in the pathogenesis of these tumors. It is not known, however, if NF1 mutations in Schwann cells result in an altered phenotype that subsequently leads to tumor formation. To characterize the biological properties of neurofibroma-derived Schwann cells we developed cell culture techniques that enabled us to isolate Schwann cells from neurofibromas and grow them in vitro for several weeks without significant fibroblast contamination. Neurofibroma-derived Schwann cells were characterized by altered morphology, heterogeneous growth behavior, and increased expression of the P0 antigen while several other features of normal human Schwann cells were retained. We conclude that neurofibroma-derived Schwann cells exhibit a distinct phenotype in vitro but that the observed abnormalities by themselves are insufficient to explain neurofibroma formation. Application of our improved culture conditions makes neurofibroma-derived Schwann cells readily available for further studies to define their role in tumorigenesis in neurofibromatosis type 1.

Adolescent↗
PubMed2000

Distinction among neuronal subtypes of voltage-activated sodium channels by mu-conotoxin PIIIA.

The functional properties of most sodium channels are too similar to permit identification of specific sodium channel types underlying macroscopic current. Such discrimination would be particularly advantageous in the nervous system in which different sodium channel family isoforms are coexpressed in the same cell. To test whether members of the mu-conotoxin family can discriminate among known neuronal sodium channel types, we examined six toxins for their ability to block different types of heterologously expressed sodium channels. PIIIA mu-conotoxin blocked rat brain type II/IIA (rBII/IIA) and skeletal muscle sodium current at concentrations that resulted in only slight inhibition of rat peripheral nerve (rPN1) sodium current. Recordings from variant lines of PC12 cells, which selectively express either rBII/IIA or rPN1 channel subtypes, verified that the differential block by PIIIA also applied to native sodium current. The sensitivity to block by PIIIA toxin was then used to discriminate between rBII/IIA and rPN1 sodium currents in NGF-treated PC12 cells in which both mRNAs are induced. During the first 24 hr of NGF-treatment, PN1 sodium channels accounted for over 90% of the sodium current. However, over the ensuing 48 hr period, a sharp rise in the proportion of rBII/IIA sodium current occurred, confirming the idea, based on previous mRNA measurements, that two distinct sodium channel types appear sequentially during neuronal differentiation of PC12 cells.

Action Potentials↗
PubMed1999

Neurofibromin, the neurofibromatosis type 1 Ras-GAP, is required for appropriate P0 expression and myelination.

The neurofibromatosis type 1 (NF1) gene product, neurofibromin, regulates activation of the Ras intracellular signaling pathway in Schwann cells. Schwann cells purified from mouse embryos with null mutations in the Nf1 gene increase expression of the major myelin glycoprotein P0. v-Ras expression in cultured Schwann cells partially mimics loss of Nf1, suggesting a role for Ras in upregulation of P0 expression in Nf1-deficient cells. We tested whether loss of Nf1 alters the ability of Schwann cells to form myelin. No significant changes in myelin formation resulted when Nf1-deficient or v-Ras-expressing Schwann cells were cultured with normal neurons. Yet, in organotypic cultures of neurons, Schwann cells, and fibroblasts without neurofibromin, myelination was dramatically reduced. We suggest that Nf1-dependent signaling cascades in neurons and/or fibroblasts, as well as Schwann cells, are required for normal myelination.

Animals↗
PubMed1999

MRI abnormalities in neurofibromatosis type 1 (NF1): a study of men and mice.

Hyperintense lesions on T2-weighted MR images of the brain, predominantly located in the basal ganglia, the brainstem and cerebellum, are a frequent finding in patients with neurofibromatosis type 1. Nature and significance of these lesions are still unknown so that the term 'unidentified bright objects' (UBOs) has been introduced to allow an unbiased description. We analyzed brain MRI scans of 31 children with definite diagnosis of neurofibromatosis type 1 according to the NIH criteria. High-intensity lesions on T2-weighted images were present in 86% of the patients. They did not correlate to other MRI findings such as optic pathway gliomas and were not indicative of intellectual impairment. Additionally, brain MR imaging of Nf1 knockout mice was performed to find out if similar abnormalities are present in this animal model. A total of 9 Nf1 knockout mice was examined on a dedicated animal MRI scanner at 4.7 Tesla but no evidence of high-signal intensity lesions on T2-weighted images was found. Therefore, the Nf1 mouse model seems to be unhelpful in providing further insights into the histological basis of hyperintense MRI abnormalities in NF1 patients.

Adolescent↗
PubMed1998

Pancreatic beta cells synthesize and secrete nerve growth factor.

Differentiation and function of pancreatic beta cells are regulated by a variety of hormones and growth factors, including nerve growth factor (NGF). Whether this is an endocrine or autocrine/paracrine role for NGF is not known. We demonstrate that NGF is produced and secreted by adult rat pancreatic beta cells. NGF secretion is increased in response to elevated glucose or potassium, but decreased in response to dibutyryl cAMP. Moreover, steady-state levels of NGF mRNA are down-regulated by dibutyryl cAMP, which is opposite to the effect of cAMP on insulin release. NGF-stimulated changes in morphology and function are mediated by high-affinity Trk A receptors in other mammalian cells. Trk A receptors are present in beta cells and steady-state levels of Trk A mRNA are modulated by NGF and dibutyryl cAMP. Taken together, these findings suggest endocrine and autocrine roles for pancreatic beta-cell NGF, which, in turn, could be related to the pathogenesis of diabetes mellitus where serum NGF levels are diminished.

Animals↗
PubMed1998

Paraneoplastic limbic encephalitis in two teenage girls.

Paraneoplastic neurological disorders represent remote effects of cancer without invasion of tumor cells into the nervous system. Limbic encephalitis is a distinct entity mostly associated with small-cell carcinoma of the lung. We present the cases of two teenage girls who were admitted with clinical symptoms typical for limbic encephalitis. In the course of the disease, they exhibited characteristic evolutionary changes of brain MRI abnormalities. Onset of neurological symptoms and type of underlying neoplasia were different in both patients. In one girl the initial workup led to the diagnosis of nodular sclerosing Hodgkin disease which so far had not caused any symptoms besides the described neurological abnormalities. A diagnostic brain biopsy showed inflammatory changes and excluded invasion of malignant cells into the central nervous system. The other patient had been diagnosed with a small cell carcinoma of the ovary several months before neurological and brain MRI abnormalities were observed. This is the first report in which clinical picture, evolution of MRI abnormalities, and--in one case--characteristic neuropathological changes are suggestive of paraneoplastic limbic encephalitis in two adolescent girls.

Adolescent↗
PubMed1996

Nerve growth factor increases sodium current in pancreatic beta cells.

Nerve growth factor (NGF) induces neuritelike process outgrowth in cultured adult pancreatic beta cells. DbcAMP partially mimics this effect on cell morphology, and both compounds act synergistically to promote neuritelike process outgrowth. To determine if NGF- and dbcAMP-induced differentiation was accompanied by changes in beta cell electrical activity, we studied the macroscopic Na current of adult rat beta cells identified with the reverse hemolytic plaque assay and cultured for one week with these factors. After 5-7 days, beta cells cultured in the presence of 2.5S NGF exhibited a 48% increase on the macroscopic Na current, which was due to an increase on Na current density. We did not observe changes on voltage dependence of current activation, nor on steady-state inactivation. Although dbcAMP also promotes changes on beta cell morphology, it did not affect the Na current density.

Animals↗
PubMed1995

Schwann cells from neurofibromin deficient mice exhibit activation of p21ras, inhibition of cell proliferation and morphological changes.

Schwann cells are thought to be abnormal in type 1 neurofibromatosis (NF1) and to contribute to the formation of benign and malignant tumors in this disease. To test the role of the NF1 gene product neurofibromin as a Ras-GTPase activating protein in Schwann cells, and to study the effect of the loss of neurofibromin on Schwann cell proliferation, we isolated Schwann cells from mice with targeted disruption of NF1. The properties of these neurofibromin deficient cells were strikingly similar to those of v-ras expressing rat Schwann cells with normal levels of neurofibromin. The similarities included: growth inhibition, noted as a decrease in cell division in response to glial growth factor 2 (GGF2) and of neuronal contact; morphological changes such as the appearance of elaborated processes; and elevated levels of Ras-GTP. Furthermore, Ras-GTP levels in the neurofibromin deficient Schwann cells were consistently elevated in response to GGF2 treatment. In contrast to these results, introduction of v-ras into a Schwannoma cell line (RN22) led to cell transformation. We conclude that neurofibromin functions as a major regulator of Ras-GTP in Schwann cells; however, mutation in NF1 by itself is unlikely to explain the hyperplasia observed in Schwann cell tumors in NF1 disease.

Animals↗
PubMed1995

Effect of transforming growth factor-beta 1 and -beta 2 on Schwann cell proliferation on neurites.

Mechanisms regulating Schwann cell proliferation during development are unclear. Schwann cell division is known to be driven by an unidentified mitogen present on the surface of axons, but it is not known whether other molecules play a role in regulating this proliferation. Transforming growth factor-beta (TGF-beta) which is found in the developing peripheral nervous system (PNS) and is mitogenic for neuron-free Schwann cells in vitro could be involved. We have investigated the effects of TGF-beta 1, TGF-beta 2 and antibodies to TGF-beta 1 and TGF-beta 2 on axon driven Schwann cell proliferation. Rat embryonic dorsal root ganglion neurons (DRG) neurons and Schwann cells from the sciatic nerve were isolated, purified and recombined in vitro. Confirming earlier reports by others, we observed that TGF-beta 1 and TGF-beta 2 added to the culture medium stimulated the proliferation of Schwann cells in the absence of neurons. However, when added to neuron-Schwann cell co-cultures, TGF beta caused a variable response ranging from no effect to moderate inhibition of Schwann cell proliferation in different experiments. A stimulation of Schwann cell proliferation by TGF beta was never observed in neuron-Schwann cell co-cultures. Antibodies to TGF-beta 1 and TGF-beta 2 did not influence axon driven Schwann cell proliferation. To further determine the role of TGF-beta in Schwann cell proliferation and myelination, we studied Schwann cell proliferation in cultures from mice in which the TGF-beta 1 gene was delected by homologous recombination. Neuron-Schwann cell cultures from wild-type, heterozygous and homozygous mice were used. No differences were observed in either Schwann cell proliferation or myelination between cultures obtained from homozygous mutants and their heterozygous and wild-type controls. These findings suggest that TGF-beta does not function as a part of the mitogenic mechanism presented by neurons to Schwann cells, but that the presence of active TGF beta in the cellular environment might regulate the degree of proliferation induced by neuronal contact.

Animals↗