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Biomedical subjects

J W Rose

Publications and source records attributed to J W Rose.

At least 37 records · Page 2Linked to original sources
PubMed1994

Usher's syndrome and multiple sclerosis. Review of an individual with Usher's syndrome with a multiple sclerosis-like illness.

We describe an individual with Type I Usher's syndrome and a multiple sclerosis-like illness. MRI scan showed vermian atrophy on T1-weighted images and multiple white matter lesions in the periventricular areas on T2-weighted images. Although MRIs demonstrating increased signal intensity on weighted images are reported in some individuals with Usher's syndrome, the cerebrospinal fluid findings are not described in these cases. In the present case, oligoclonal bands were present in the spinal fluid. The possibility of a linkage between the two diseases is raised.

Adult↗
PubMed1993

Characterization of the integrin specificities of disintegrins isolated from American pit viper venoms.

A new series of homologous disintegrins was isolated from the venoms of new world pit viper genus Bothrops, Crotalus, and Lachesis. The relative activities of each disintegrin in blocking adhesive protein binding activities of GPIIb-IIIa, alpha v beta 3, and alpha 5 beta 1 were determined and correlated with their primary amino acid sequences. Four disintegrins contained the RGDW sequence and were found to be approximately twice as effective in blocking the binding of fibrinogen to GPIIb-IIIa than inhibiting the binding of vitronectin to alpha v beta 3 in solid-phase ligand binding assays (IC50 = 7.3 and 17.2 nM, respectively). A second group of seven disintegrins contained the RGDNP sequence and were found to be more potent inhibitors of vitronectin binding to alpha v beta 3 than fibrinogen binding to GPIIb-IIIa (IC50 = 4.3 and 19 nM, respectively). The RGDNP containing disintegrins were also greater than 10-fold more potent than RGDW containing disintegrins in blocking the adhesion of cells mediated by alpha 5 beta 1. These data illustrate that amino acid sequences immediately adjacent to the RGD site of disintegrins can create an extended RGD locus which coupled with conformational display of the RGD sequence may be involved in determining integrin selectivity and affinity. This information has been used in separate studies to design conformationally constrained integrin antagonists with high affinity for platelet GPIIb-IIIa.

Amino Acid Sequence↗
PubMed1993

Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa.

Members of the snake venon-derived, "disintegrin" peptide family containing the Arg-Gly-Asp (RGD) amino acid sequence are among the most potent inhibitors of the binding of adhesive proteins to platelet glycoprotein (GP) IIb-IIIa. However, GPIIb-IIIa antagonists containing the RGD sequence are not integrin specific and inhibit the adhesive functions of many other RGD-dependent integrins. The single disintegrin peptide, barbourin, containing a conservative amino acid substitution of Lys (K) for Arg (R) in the RGD sequence, is however, highly specific for GPIIb-IIIa. Using this information we have tested the hypothesis that both structural and conformational elements of barbourin are important for its high affinity and selectivity for platelet GPIIb-IIIa by synthesizing a series of conformationally constrained, disulfide-bridged peptides containing the KGD amino acid sequence. Incorporation of the KGD sequence into a cyclic peptide template, followed by systematic optimization of the cyclic ring size, optimization of secondary hydrophobic binding site interactions, and the derivatization of the lysyl side chain functionality of the KGD sequence has resulted in peptide analogs which display inhibitory potency and GPIIb-IIIa selectivity comparable to that of barbourin. This study demonstrates that the specificity and potency of the disintegrin family of antagonists, in particular barbourin, can be mimicked by small, conformationally restrained peptides.

Amino Acid Sequence↗
PubMed1993

Augmentation of adoptively transferred experimental allergic encephalomyelitis by administration of a monoclonal antibody specific for LFA-1 alpha.

We investigated the effect of an anti-leukocyte function antigen 1 (LFA-1 alpha) monoclonal antibody, M17/4.2, on murine relapsing experimental allergic encephalomyelitis (EAE). In vitro investigations demonstrated that M17/4.2 inhibited proliferation with concanavalin A or myelin basic protein. Control mice treated with phosphate buffered saline (PBS) developed a mild to moderate disease at 7-10 days followed by a long-term relapsing clinical course. With administration of M17/4.2, the time of disease onset was unchanged; however, the severity of the disease was greatly augmented, resulting in early mortality. The pathology correlated well with the clinical course. M17/4.2 mice showed more inflammation and demyelination than PBS or anti-CD4 treated mice. Therefore, this anti-LFA-1 specific monoclonal antibody augmented EAE.

Animals↗
PubMed1993

Neuropathology of herpes simplex virus encephalitis in a rat seizure model.

Herpes simplex virus type 1 (HSV-1) is the cause of a serious and often fatal encephalitis. Patients who survive herpes simplex encephalitis (HSE) experience behavioral abnormalities including profound cognitive dysfunctions. We have developed a rat model of acute HSE to investigate the cognitive impairments caused by HSV-1 central nervous system (CNS) infection. Following intranasal inoculation of Lewis rats with a neurovirulent strain of HSV-1, animals shed virus in both ocular and nasal secretions and developed clinical signs of infection, including partial complex motor seizures that eventually generalized. Homogenization assays demonstrated infectious virus in the trigeminal ganglia, olfactory bulbs, and the piriform and entorhinal cortices. Histopathological assessment revealed inflammatory and hemorrhagic lesions in the trigeminal ganglia, olfactory bulbs, amygdala, hippocampus, the piriform and entorhinal cortices, and the spinal trigeminal nuclei. Viral antigens and nucleic acids were also detected within these structures by immunofluorescence microscopy and in situ hybridization, respectively. Viral-induced astrocytic hypertrophy in the CNS was demonstrated by glial fibrillary acidic protein immunoreactivity. Together, these results indicate that HSV-1 has the ability to invade, replicate, and induce site-specific CNS damage in the Lewis rat.

Animals↗
PubMed1992

Establishment and characterization of a human primitive neuroectodermal tumor cell line from the cerebral hemisphere.

The primitive neuroectodermal tumors (PNET) comprise a class of malignant nervous system neoplasms that afflict children. These tumors consist of cells that are morphologically identical to the primitive neuroepithelial cells normally seen in early stages of neural embryogenesis, supporting the notion that PNET result from a disturbance in the process of normal neuronal or glial differentiation. In the central nervous system, PNET occur most commonly in the cerebellum (medulloblastomas), but only occasionally in the cerebral hemispheres. We report here the establishment and characterization of a new human cell line (PFSK) derived from a PNET from the cerebral hemisphere of a child. The growth characteristics of PFSK cells were typical of an immortalized, transformed cell line. Cytogenetic and molecular genetic studies showed that three different sublines were present. In one of these sublines, sequences from chromosome 17 had been lost during establishment in culture. Immunocytochemical studies showed that PFSK cells expressed nestin, an intermediate filament protein normally expressed by neuroepithelial stem cells during neurulation. The PFSK cells did not express antigens typically found in terminally differentiated neurons or glia, indicating that this tumor cell line might represent neuroepithelial stem cells prior to commitment to a neuronal or glial lineage.

Brain Neoplasms↗
PubMed1992

Discordance of the T-cell receptor alpha-chain gene in familial multiple sclerosis.

We studied restriction fragment length polymorphisms of the T-cell receptor alpha-chain (TCR alpha) gene in DNA obtained from 99 individuals of 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Six normal family members had abnormal cranial MRIs. Linkage analysis utilized constructed haplotypes of EcoRV, Sst I, and Taq I polymorphisms. With penetrance values from 0.1 to 0.7, and scoring the normal individuals with abnormal MRIs as either unknown or affected, LOD scores were between -3.16 and -7.95 for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1, the LOD scores ranged from -6.77 to -23.08. These findings do not support a direct role of TCR alpha in the inheritance of MS.

Adult↗
PubMed1992

Atypical herpes simplex encephalitis: clinical, virologic, and neuropathologic evaluation.

An atypical form of herpes simplex encephalitis produced by HSV-1 documented in the present article demonstrates that (1) prominent EEG abnormality may correlate with subtle increase in signal intensity on MRI; (2) the disease may start with prominent involvement of the cingulate gyri; and (3) viral infection of the brainstem may cause early onset of severe neurologic dysfunction and coma.

Brain Stem↗
PubMed1992

Acute VIth cranial nerve dysfunction in multiple sclerosis. Evaluation by magnetic resonance imaging.

VIth nerve palsy is not frequently considered a presenting sign of multiple sclerosis (MS); however, MS has been documented as a fairly common cause of VIth nerve dysfunction. In the present study we have evaluated the clinical features and magnetic resonance imaging (MRI) findings in four MS patients with acute VIth nerve palsy. Diplopia as a result of acute VIth nerve palsy was the prominent symptom leading to the diagnosis of MS in all of the individuals. Other signs specifically localizing to the ipsilateral brainstem were absent in these patients. Cranial MRI revealed multiple white matter lesions with a periventricular predominance in all four patients and pontine white matter lesions in three of the patients. These lesions were either adjacent to the VIth nerve nucleus or involved the fasciculus of the VIth nerve or both.

Abducens Nerve↗
PubMed1991

Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri.

Sixty-two snake venoms were screened to identify those which specifically inhibit the adhesive protein binding function of the glycoprotein (GP) IIb-IIIa complex, the receptor-mediating platelet aggregation. Although 52 of these venoms inhibited GPIIb-IIIa, only one of these, from the southeastern pigmy rattlesnake, Sistrurus m. barbouri, was specific for GPIIb-IIIa versus other integrins. The peptide responsible for this activity, termed barbourin, was sequenced and found to be highly homologous to other peptides of the viper venom GPIIb-IIIa antagonist family but was the first member which did not contain the Arg-Gly-Asp (RGD) amino acid sequence, believed to be required for inhibition of receptor function. Instead, barbourin contains the sequence, Lys-Gly-Asp (KGD). The conservative Lys for Arg substitution appears to be the sole structural feature which imparts integrin specificity to barbourin, since venom peptide analogs with Lys substitutions were also specific for GPIIb-IIIa. Thus, barbourin represents a new structural model useful for designing potent and GPIIb-IIIa-specific compounds that may have therapeutic value as platelet aggregation inhibitors.

Amino Acid Sequence↗
PubMed1991

Discordance of T-cell receptor beta-chain genes in familial multiple sclerosis.

Restriction fragment length polymorphisms of the T-cell receptor beta-chain gene were studied in DNA obtained from 96 individuals from 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Five normal family members had abnormal findings on cranial magnetic resonance imaging (MRI) scans. Linkage analysis was performed using the BglII and the KpnI polymorphisms. With penetrance values from 0.1 to 0.7, and altering the scoring of the normal individuals with abnormal findings on MRI scans from "unknown" to "affected," log of the odds scores between -4.59 to -12.76 were found for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1.0, the LOD scores ranged from -8.20 to -32.98. These findings do not support a direct role of T-cell receptor beta-chain gene in the inheritance of MS.

Alleles↗
PubMed1991

Chimeric cytotoxin IL2-PE40 inhibits relapsing experimental allergic encephalomyelitis.

IL2-PE40 is a chimeric protein composed of human interleukin-2 (IL2) genetically fused to a modified form of Pseudomonas exotoxin lacking the cell recognition domain. IL2-PE40 is cytotoxic for IL2 receptor-bearing lymphocytes in culture and can inhibit activation of T cells in vivo. IL2-PE40 can significantly diminish antigen-stimulated proliferation of lymphocytes sensitized to myelin basic protein. Intraperitoneal administration of IL2-PE40 not only markedly inhibits the clinical manifestations of adoptively transferred relapsing experimental allergic encephalomyelitis but also dramatically reduces both inflammation and demyelination characteristic of the disease.

Animals↗
PubMed1990

MRI in familial multiple sclerosis.

We obtained cranial MRIs of 76 individuals from 13 MS multiplex families. Thirty-one MS patients and 45 normal family members participated in the study. Twenty-eight of the 31 individuals with definite or probable MS had multiple white matter lesions by MRI. Thirty-five normal family members had normal MRIs, and 10 had abnormal studies. Four normal individuals under age 40 had abnormal MRIs. Three had multiple white matter lesions. The 4th had a single small white matter lesion in the left centrum semiovale. Six normal individuals over age 50 had multiple white matter lesions. Although diffuse white matter lesions in individuals over age 50 should be interpreted with caution, these lesions in individuals under age 40 with no history of underlying medical illness are suggestive of demyelination. The results of the present study indicate that subclinical MS may be present in apparently normal members of multiplex families.

Adult↗
PubMed1989

Astrocytic swelling in traumatic-hypoxic brain injury. Beneficial effects of an inhibitor of anion exchange transport and glutamate uptake in glial cells.

Swelling of brain slices is shown to occur in response to elevated potassium levels or glutamate, which is accompanied by astrocytic swelling. Cl-/HCO3- anion exchange inhibitors, such as SITS (4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid) or furosemide, but not the specific cotransport inhibitor bumetanide, inhibit swelling or increased ion uptake in rat brain slices caused by elevated potassium although there were marked species differences in sensitivity. A novel anion exchange inhibitor, L-644,711, inhibits swelling and increased ion uptake caused by glutamate in rat and cat brain slices, as well as inhibiting [3H]glutamate uptake in primary rat astrocyte cultures. Possible mechanisms of action of the inhibitors are discussed. L-644,711 was also found to be effective in promoting recovery from a trauma plus hypoxia head injury model in cats. Marked perivascular astrocytic swelling is associated with this head injury model, and L-644,711 also inhibited such astroglial swelling as determined ultrastructurally. The significance of these findings in relation to possible connections between astrocytic swelling and brain pathology is discussed.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1989

Anticerebellar antibodies in neurologically normal patients with ovarian neoplasms.

Several groups of investigators have confirmed the occurrence of antibodies to Purkinje and other cerebellar neuronal populations in the serum and spinal fluid of patients with paraneoplastic cerebellar degeneration. Although this antibody response suggests that paraneoplastic cerebellar degeneration may have an autoimmune basis, it is not known what role anticerebellar antibodies play in the pathogenesis of this disorder or whether the presence of antibodies invariably results in cerebellar injury. We identified 3 patients with ovarian malignancies in whom high titers of circulating anticerebellar antibodies were present without clinical evidence of cerebellar disease. We followed these patients clinically and serologically until their deaths from their neoplasms. All 3 patients remained neurologically normal. In 2 of the patients, anticerebellar antibodies persisted at high titer. CSF obtained from 1 of these patients postmortem did not contain detectable levels of anticerebellar antibody, but histopathologic examination of her cerebellum revealed patchy loss of Purkinje cells. In the 3rd patient, antibody titers fell with removal of the primary tumor and chemotherapy but did not rise with tumor recurrence. Indirect immunofluorescence did not reveal anticerebellar antibodies in the serum or CSF of other patients with neoplasms, patients with other cerebellar disease, or normal controls. The present study demonstrates that patients with ovarian malignancies may occasionally develop antibodies that react with cerebellar neuronal antigens and can maintain this antibody response for protracted periods of time without clinically evident cerebellar injury. Tumor recurrence may not be accompanied by rise in titers of anticerebellar antibodies.

Aged↗
PubMed1988

Antisomatostatin IgG in major depressive disorder. A preliminary study with implications for an autoimmune mechanism of depression.

IgG reactive with somatostatin 1-14 was identified in human plasma by enzyme linked immunosorbent assay. From a sample of 25 subjects, six (60%) of ten individuals with major depressive disorder demonstrated antibody reactive with somatostatin 1-14, in contrast to one (7%) of 15 controls. Overall, antisomatostatin reactivity was significantly higher in patients with major depressive disorder (0.233 +/- 0.177) than in the normal volunteers (0.084 +/- 0.039; t = 3.18, P less than .01). Antisomatostatin IgG was isolated by affinity chromatography. The recognition site for somatostatin was retained by F(ab)'2 fragments. Although there has been little previous exploration of the existence of antibodies to endogenous neuropeptides, such antibodies could prove of relevance to neuropsychiatric and other human disorders.

Adult↗