Biomedical subjects

E L Feldman

Publications and source records attributed to E L Feldman.

At least 73 records · Page 4Linked to original sources

PubMed1996

Tyrosine phosphorylation and enhanced expression of paxillin during neuronal differentiation in vitro.

Tyrosine phosphorylation has been implicated as a means by which neurite outgrowth is regulated. Because paxillin is a tyrosine-phosphorylated protein that may play a role in regulating cell morphology, we examined its expression in neuronal cells and how its tyrosine phosphorylation is related to neurite outgrowth. Paxillin was identified in several neuronal cell lines with an increased level upon differentiation. In SH-SY5Y cells, paxillin was localized along with actin filaments where processes extended from the cell body and in neuritic growth cones. Furthermore, paxillin was tyrosine-phosphorylated in SH-SY5Y cells upon adhesion to laminin. Paxillin tyrosine phosphorylation paralleled that of focal adhesion kinase and occurred as cell spreading, and neurite formation was initiated. Colchicine blocked neurite outgrowth but had no effect on cell spreading or on paxillin or focal adhesion kinase tyrosine phosphorylation. In contrast, cytochalasin D eliminated neurite outgrowth, cell spreading, and the tyrosine phosphorylation of paxillin and focal adhesion kinase. These results show that paxillin is tyrosine-phosphorylated upon integrin ligand binding in neuronal cells. Our findings suggest that paxillin tyrosine phosphorylation is linked to a remodeling of the actin cytoskeleton that leads to cell spreading and neurite formation and thus a differentiated neuronal phenotype.

Actins↗

PubMed1996

Insulin-like growth factor I rescues SH-SY5Y human neuroblastoma cells from hyperosmotic induced programmed cell death.

Insulin-like growth factor I (IGF-I) and the type I IGF receptor are widely distributed in developing and adult mammalian nervous systems. In vitro, IGF-I is a mitogen for primary neurons and also for cells from the SH-SY5Y human neuroblastoma cell line, a well-characterized model system of neuronal growth. In the current study, we examined the effects of osmotic stress on SH-SY5Y cell viability and the mechanism by which IGF-I serves as a neuronal osmoprotectant. Within 24 hr, exposure of SH-SY5Y cells to hyperosmotic serum-free media decreased (1) the number of viable cells, (2) the rate of 3H-thymidine incorporation, and (3) cell cycle progression. The inclusion of 10 nM IGF-I with hyperosmotic media prevented the loss of cell viability. The osmoprotective effects of IGF-I were inhibited by alpha-IR3, a blocking antibody of the type I IGF receptor. The observed loss of SH-SY5Y cell viability following hyperosmotic shock was due to an induction of programmed cell death as determined by flow cytometry and gel electrophoresis. Our results suggest that IGF-I can protect SH-SY5Y cells from hyperosmotic induced programmed cell death.

Apoptosis↗

PubMed1996

Dysphagia in elderly men with myasthenia gravis.

Eight elderly men whose primary symptoms of myasthenia gravis were decreased speech and swallowing ability were seen for speech pathology evaluations and videofluoroscopic swallow studies. All patients had fatigable flaccid dysarthria and greater than expected pharyngeal phase dysphagia on videofluoroscopy; eight had decreased pharyngeal motility as demonstrated by residual material in the valleculae and pyriform sinuses bilaterally; seven had episodes of laryngeal penetration secondary to overflow of residual material; and five experienced silent aspiration despite gag reflexes and the ability to cough to command. Five patients required feeding tubes because their dysphagia responded poorly to treatment. Videofluoroscopic swallow studies revealed a common swallowing profile with pharyngeal phase dysphagia greater than expected from patient symptoms. Dysphagia did not improve at the same rate as other manifestations of myasthenia gravis.

Aged↗

PubMed1996

Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin-diabetic rat.

Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl-L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose-dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin-induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (MI) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not -insensitive) ATPase activity in a dose-dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC or affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion.

Acetylcarnitine↗

PubMed1996

Characterization of insulin-like growth factor-I and its receptor and binding proteins in transected nerves and cultured Schwann cells.

The insulin-like growth factors (IGFs) are trophic factors whose growth-promoting actions are mediated via the IGF-I receptor and modulated by six IGF binding proteins (IGFBPs). In this study, we observed increased transcripts of both IGF-I and IGF-I receptor after rat sciatic nerve transection. Schwann cells (SCs) were the main source of IGF-I and IGFBP-5 immunoreactivity until 7 days after nerve transection, when invading macrophages in the distal nerve stumps were strongly IGF-I positive. In vitro, IGF-I promoted SC mitogenesis. Northern analysis revealed that SCs expressed IGF-I receptor and IGFBP-5. IGF-I treatment increased the intensity of IGFBP-5 without affecting gene expression. Des(1-3)IGF-I, an IGF-I analogue with low affinity for IGFBP, had no such effect. Incubation of recombinant human IGFBP-5 with SC conditioned media revealed IGF-I protection of IGFBP-5 from proteolysis, implying the presence of an IGFBP-5 protease in SC conditioned media. Collectively, these data support the concept that, in response to nerve injury, invading macrophages produce IGF-I and SC express the IGF-I receptor, to facilitate regeneration. This regenerative process may be augmented further by the ability of SC to secrete IGFBPs, which in turn may increase local IGF-I bioavailability.

Animals↗

PubMed1995

Insulin-like growth factor-II as a paracrine growth factor in human neuroblastoma cells.

The human neuroblastoma line, SK-N-SH, has been subcloned into SH-SY5Y, a neuroblast N cell line, and SH-EP, an epithelial Schwann S cell line. We have previously shown that SH-SY5Y neuroblastoma cells produce insulin-like growth factor II (IGF-II), which acts by an autocrine mechanism to stimulate cell growth. In the current study, we examined the effect of IGF-II on SH-EP neuroblastoma cells. Northern blot and reverse transcriptase-polymerase chain reaction analyses indicate that SH-EP cells do not produce IGF-I or IGF-II but express the type I and type II IGF receptors (IGF-IR and IGF-IIR). Cell surface expression of IGF-IR, assessed by fluorescence-activated sorting, was lower in SH-EP cells than in SH-SY5Y cells. Immunoprecipitation of IGF-IR, followed by anti-phosphotyrosine or anti-IGF-IR immunoblotting, demonstrated functional expression of these receptors in both cell types and confirmed the lower level of IGF-IR expression in SH-EP cells. IGF-II promoted SH-EP cell growth in the presence of low concentrations of calf serum (0.1-0.3%) or 10 ng/ml epidermal growth factor (EGF). IGF-II stimulation of SH-EP growth was eliminated by the IGF-IR blocking antibody (alpha IR-3) but not by an IGF-IIR blocking antibody. Stimulation of cell growth via this receptor was also indicated by the ligand specificity for IGF analogs and insulin (IGF-II approximately IGF-I approximately des(1-3)IGF-I >> insulin). These results indicate that in the presence of a permissive factor such as calf serum or EGF, IGF-II stimulates SH-EP cell growth via the IGF-IR. Collectively, these data suggest that within primary neuroblastomas, IGF-II may act as a paracrine factor to contribute to the promotion of S cell growth.

Base Sequence↗

PubMed1995

Long-term follow-up of patients with chronic inflammatory demyelinating polyradiculoneuropathy, without and with monoclonal gammopathy.

We previously demonstrated differences in presentation and initial clinical course between patients with idiopathic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP-I) and those in whom CIDP was associated with a monoclonal gammopathy of undetermined significance (CIDP-MGUS). We now report the long-term follow-up of 69 patients with CIDP-I and 25 patients with CIDP-MGUS. (i) The clinical course was progressive in most of the CIDP-MGUS patients. CIDP-I patients were more likely to have a monophasic or relapsing course. (ii) Impairment developed more slowly in CIDP-MGUS than CIDP-I patients, with a longer time from onset of deterioration to peak impairment for each episode. (iii) Patients with CIDP-MGUS experienced less severe functional impairment and a lesser degree of measured weakness during their worst episode than did patients with CIDP-I. The primary source of functional impairment in many CIDP-MGUS patients was sensory. In contrast, the deficits in most patients with CIDP-I were primarily motor. (iv) CIDP-MGUS patients experienced a smaller degree of improvement to a poorer functional level after each episode than did patients with CIDP-I. (v) Most patients had a good outcome. However, the strength and functional scores at the time of last follow-up were significantly poorer in CIDP-MGUS than in CIDP-I patients. (vi) The disease was reclassified in seven patients; some patients with CIDP-I developed an MGUS, while some with CIDP-I or CIDP-MGUS developed multiple myeloma or a related malignant lymphoproliferative disease. These findings have implications for patient counselling and long-term prognosis, and underscore the need for long-term clinical and immunological monitoring.

Adolescent↗

PubMed1995

The aetiology of diabetic neuropathy: the combined roles of metabolic and vascular defects.

A combination of metabolic and vascular defects have been implicated in the pathogenesis of diabetic neuropathy. Animal studies have demonstrated that a reduction in nerve blood flow may be an important early defect and that vasodilators can prevent or ameliorate nerve dysfunction. The potential factors contributing to nerve ischaemia include structural defects in the endoneurial microvasculature together with rheological abnormalities, abnormalities in vasoactive agents which regulate nerve blood flow including nitric oxide and the eicosanoids, and alterations in tone of the autonomic innervation of the nerve vasculature. The principle metabolic defects which have been implicated include disruption of the polyol pathway, altered lipid metabolism, advanced glycosylated end-product formation, increased oxidative stress, and diabetes-induced defects in growth factors. The demonstration that activation of the polyol pathway in experimental diabetes may affect nerve blood flow, and conversely that vasoactive agents appear to be important in regulating some aspects of nerve metabolism, has highlighted the interdependence of the metabolic and vascular defects in the pathogenesis of this condition. Thus, selective intervention aimed at a key defect early in this cascade may subsequently correct a number of later abnormalities offering therapeutic hope in this chronic debilitating complication.

Aldehyde Reductase↗

PubMed1995

Insulin-like growth factor II in the pathogenesis of human neuroblastoma.

Insulin-like growth factor II (IGF-II) acts as an autocrine growth factor for many in vitro tumor cell lines including neuroblastoma. To examine the role of IGF-II in tumor biology we have analyzed a total of 56 primary neuroblastoma tumor samples for the presence of IGF-II using a combination of mRNA and protein analysis. A group of 21 samples was examined for the presence of IGF-II mRNA by slot blot and a separate group of 37 samples was examined for IGF-II immunoreactivity. IGF-II was detected in 48% of the total tumor specimens analyzed. IGF-II immunoreactivity was observed in cells resembling developing neuroblasts and was confined to the cytoplasm and proximal neurites. The appearance of IGF-II mRNA and protein did not correlate with tumor prognostic features including stage, histology, or N-myc amplification. These data suggest that the expression of IGF-II is not confined to a specific stage of the disease but may have a broader role in the pathogenesis of neuroblastoma.

Adult↗

PubMed1994

Regulation of insulin-like growth factor binding protein synthesis and secretion in human retinal pigment epithelial cells.

Cultured human retinal pigment epithelial cells (RPE) secrete insulin-like growth factor binding proteins (IGFBPs), a family of polypeptides which modulate the actions of the insulin-like growth factors. RPE cells secrete two IGFBPs with Mr estimates of 34,000 and 46,000, respectively. Treatment of RPE cells with IGF-I markedly stimulated the secretion of the 46,000 Mr form. This stimulation occurred via an IGF-I receptor independent mechanism because both [QAYL]IGF-I (an IGF-I analogue with decreased affinity for the IGFBPs but normal affinity for the IGF-I receptor) and alpha-IR3 (a blocking monoclonal antibody against the IGF-I receptor) had no effect on IGF-I stimulated increases in IGFBPs. Additionally, [QAYL]IGF-I enhanced RPE cell proliferation to the same magnitude as IGF-I. Treatment with IGF-I, [QAYL]IGF-I, or alpha-IR3 had no effect on steady-state levels of the 2.5 kb IGFBP-3 or the 1.3 kb IGFBP-6 mRNA transcripts as measured by Northern blotting and quantitative autoradiography. Forskolin and a group of candidate growth factors, including platelet-derived growth factor, epidermal growth factor, and acidic and basic fibroblast growth factor, modestly increased IGFBP secretion when compared to untreated cells, but these effects were small when compared to IGF-I treatment. Fetal calf serum enhanced the presence of the 2.5 kb IGFBP-3 mRNA transcript in a dose-dependent fashion but had no effect on the 1.3 kb IGFBP-6 mRNA transcript. IGF-I, forskolin, and the candidate growth factors had no effect on either IGFBP-3 or IGFBP-6 mRNA. These data suggest that the production of IGFBPs in human RPE cells is regulated by distinct mechanisms which include (1) an IGF-I receptor independent interaction of IGF-I with secreted IGFBPs and (2) de novo synthesis of IGFBPs by serum-containing factors.

Animals↗

PubMed1994

The natural history of a "benign" rib lesion in a patient with a demyelinating polyneuropathy and an unusual variant of POEMS syndrome.

Patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome exhibit great clinical variability and often have osteosclerotic myeloma. We present a patient with an acquired demyelinating polyneuropathy who was eventually diagnosed as having POEMS syndrome. Her long period of observation permitted documentation of the natural history of a plasmacytoma, including its remarkably slow rate of growth and its transformation from a nonsclerotic to a sclerotic bone lesion. Her clinical and laboratory features emphasize the variability of this syndrome. Biopsy of benign-appearing bone lesions should be considered in patients with acquired demyelinating polyneuropathies who do not respond to standard treatment modalities. Serial x-rays may not distinguish benign lesions from plasmacytomas in this treatable condition.

Bone Diseases↗

PubMed1994

Clinical testing in diabetic peripheral neuropathy.

Diabetic polyneuropathy is a complex disease of progressive nerve fiber loss. Initial screening and diagnosis in clinical practice usually depend on assessment of subjective complaints. A need exists for objective, simple, and reproducible assessment tools that can be readily used in clinical practice. The importance of early diagnosis is highlighted by the recent North American Diabetes Control and Complications Trial where intensive insulin therapy reduced the risk of developing diabetic neuropathy by 61%. At the University of Michigan, we have developed an outpatient neuropathy program. Patients are given a questionnaire and a brief screening examination, designated the Neuropathy Screening Instrument. Diabetic neuropathy is confirmed and staged in patients with a positive Neuropathy Screening Instrument, by a quantitative neurologic examination and nerve conduction studies, designated the Diabetic Neuropathy Score. The Michigan program has been compared with well-established instruments and has been found to be sensitive and reproducible for screening and diagnosis. We believe the program provides a valuable tool for the clinician in the practice setting and should allow diagnosis and intervention earlier in the course of diabetic neuropathy.

Diabetic Neuropathies↗

PubMed1994

The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat.

Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na+,K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolic-ischemic pathogenesis.

Aldehyde Reductase↗

PubMed1994

Immunohistochemical localization of insulin-like growth factor-II (IGF-II) and IGF-binding protein-2 during development in the rat brain.

The insulin-like growth factors (IGF-I and IGF-II) are peptide growth factors with both growth-promoting and insulin-like activities. In the nervous system, the expression of both IGF-I and IGF-II messenger RNAs (mRNAs) is developmentally regulated, with IGF-I expression highest during puberty, and IGF-II levels peaking during the perinatal period. The IGFs interact with and are modulated by a group of six binding proteins, the IGF-binding proteins (IGFBP-1 to IGFBP-6). IGFBP-2 mRNA is most prevalent in the nervous system, where, like IGF-II, its expression correlates with a period of brain growth. In the current study, cells containing IGF-II and IGFBP-2 were identified within the developing nervous system of the rat on embryonic day 12 (E12), E14, E18, and postnatal day 1 and in the adult. IGF-II immunoreactivity was detected within the mesenchymal core of the choroid plexus at all ages examined and was also observed in the developing leptomeninges. IGF-II appeared transiently in the central nervous system in presumptive glia of the hippocampus and medial basal hypothalamus and in a small population of neurons in the brain stem. IGFBP-2 was consistently observed in the epithelium of the choroid plexus as well as in the epithelia of the developing otic and olfactory placodes. While these results confirm the developmental expression of IGF-II and IGFBP-2 mRNA in the central nervous system, discrepancies exist between these data and those using molecular techniques. This may be due in part to differential sites of IGF-II and IGFBP-2 production compared to sites of action.

Animals↗

PubMed1994

A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy.

OBJECTIVE: Early diagnosis of distal symmetric sensorimotor polyneuropathy, a common complication of diabetes, may decrease patient morbidity by allowing for potential therapeutic interventions. We have designed an outpatient program to facilitate diagnosis of diabetic neuropathy. RESEARCH DESIGN AND METHODS: Patients are initially administered a brief questionnaire and screening examination, designated the Michigan Neuropathy Screening Instrument (MNSI). Diabetic neuropathy is confirmed in patients with a positive assessment by a quantitative neurological examination coupled with nerve conduction studies, designated the Michigan Diabetic Neuropathy Score (MDNS). In this study, 56 outpatients with confirmed type I or II diabetes were administered the standardized quantitative components required to diagnose and stage diabetic neuropathy according to the San Antonio Consensus Statement (1) and the Mayo Clinic protocol (2). These same patients were then assessed with the MNSI and the MDNS. RESULTS: Of 29 patients with a clinical MNSI score > 2, 28 had neuropathy. Twenty-eight patients with an MDNS of > or = 7 had neuropathy, while 21 non-neuropathic patients had a score < or = 6. Of 35 patients with diabetic neuropathy, 34 had > or = 2 abnormal nerve conductions. Twenty-one normal patients and one patient with neuropathy had < or = 1 abnormal nerve conduction. CONCLUSIONS: The results indicate that the MNSI is a good screening tool for diabetic neuropathy and that the MDNS coupled with nerve conductions provides a simple means to confirm this diagnosis.

Adult↗

PubMed1993

Low diagnostic yield of sural nerve biopsy in patients with peripheral neuropathy and primary amyloidosis.

Patients with primary amyloidosis may develop peripheral neuropathy as an early feature. Sural nerve biopsy is reported to be a sensitive method for diagnosing amyloidosis in such patients. We identified nine patients, ultimately diagnosed as having amyloidosis, who were referred for peripheral neuropathy of undetermined etiology. In six, a sural nerve biopsy demonstrated no amyloid. Subsequent examination of other tissue or of the contralateral sural nerve eventually resulted in the correct diagnosis. We conclude that sural nerve biopsy may be less sensitive than previously believed for the diagnosis of amyloidosis in patients with peripheral neuropathy secondary to amyloid. When the clinical suspicion of amyloidosis is high, a nondiagnostic sural nerve biopsy should not discourage the performance of further investigative studies.

Aged↗

PubMed1993

Effects of serum and insulin-like growth factors on human neuroblastoma cell growth.

Insulin-like growth factors (IGF-I and IGF-II) are mitogenic polypeptides expressed in both developing and adult tissues. To examine the effects of IGFs on neuronal growth, we used SH-SY5Y neuroblastoma cells as an in vitro model of nervous system development. In the current study, we found that either IGF-I (0.1 to 10 nM), insulin (0.1 to 5 micrograms/ml) or calf serum (0.1 to 3%) increased SH-SY5Y proliferation over a 3 day period in a dose dependent manner. In each case, treatment with anti-IGF-I receptor antibodies blocked cell proliferation. IGF-II mRNA levels correlated with SH-SY5Y cell density; subconfluent cells expressed high levels of IGF-II mRNA while low levels of IGF-II mRNA were present in confluent cells. Similarly, serum deprivation increased IGF-I receptor mRNA by 4-fold. Collectively, these results support the concept that an IGF/IGF-I receptor system at least partially mediates SH-SY5Y cell proliferation and suggests the importance of IGFs in regulating neuronal growth.

Animals↗

PubMed1993

IGF receptor function and regulation in autocrine human neuroblastoma cell growth.

Insulin-like growth factor-II (IGF-II) and its receptors (type I and II IGF receptors) are expressed in the nervous system in a tissue and developmentally specific manner. We have previously shown that SH-SY5Y human neuroblastoma cells synthesize and secrete high levels of IGF-II, and respond to it with increased neuritic outgrowth, DNA synthesis, and cell proliferation. SH-SY5Y cells also produce type I IGF and IGF-II/M6P receptors; however, it is not known whether these receptors mediate the observed growth promoting effects of IGF-II. In this study, we assayed the role of type I IGF receptor and IGF-II/M6P receptor expression in mediating autocrine IGF-II induced growth. Using anti-receptor antibodies, we found that IGF-II stimulates cell proliferation via the type I IGF receptor but not via the IGF-II/M6P receptor. By Northern analysis, we detected increased mRNA expression of both receptors, with more dramatic changes in type I IGF receptor expression. Collectively, our results indicate a role for the type I IGF receptor in mediating IGF-II induced autocrine neuroblastoma cell growth.

Animals↗