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Biomedical subjects

J N Whitaker

Publications and source records attributed to J N Whitaker.

At least 163 records · Page 9Linked to original sources
PubMed1982

Inflammatory myopathy: a review of etiologic and pathogenetic factors.

Human idiopathic inflammatory myopathy is an acquired disorder with an annual incidence of two to five cases per million. A genetic influence on host susceptibility may also play a role. With the marked heterogeneity of the disease one of the major challenges is to identify subsets that might share a more uniform pathogenesis and manifest a less diverse profile of clinical findings, histopathological abnormalities, and natural history. Dermatomyositis can be distinguished by clinical appearance and pathological changes, but the recognition of additional disease subsets remains very inexact. Current evidence suggests that dermatomyositis occurs as a result of a vasculopathy, but immune mechanisms involved in other categories of idiopathic inflammatory myopathy may also involve cell-mediated immunity and possibly multiple mechanisms. Even though viral-induced muscle inflammation occurs in humans, there is no convincing evidence for a viral cause of idiopathic inflammatory myopathy. Experimental allergic myositis may be produced by the injection of animals with skeletal muscle homogenates and complete Freund's adjuvant, but the myositogenic factor is unknown and the parallels between experimental allergic myositis and human idiopathic inflammatory myopathy are limited.

Animals↗
PubMed1982

The appearance of a new antigenic determinant during the degradation of myelin basic protein.

Studies were undertaken to determine of a previously unrecognized or inaccessible antigenic determinant might be exposed during the course of digestion of basic protein by a normal brain enzyme. As studied by double antibody radioimmunoassay, exposure of bovine brain myelin basic protein to bovine brain cathepsin D led to the appearance of an antigenic determinant recognized by an antibody reactive predominantly with the molecular region of BP encompassing residues 79-88. The 5 major microheterogeneous components of basic protein demonstrated this phenomenon. These results indicate that a normally appearing enzyme in brain known to the present in a number of cell types including oligodendrocytes can lead to the appearance of peptides of basic protein whose antigenic determinants may not be revealed in the intact molecule. This finding suggests that a number of basic protein peptides may be released by a similar mechanism so that efforts made to detect and quantitate such peptides must be capable of recognizing their unique antigenic features.

Animals↗
PubMed1982

Neuromyelitis optica (Devic's syndrome) in two sisters.

Neuromyelitis optica (Devic's syndrome) typically occurs in a sporadic pattern. We studied the disorder in two sisters, ages 6 and 10 years, who presented with sudden loss of vision at age 3 years, followed 5 months later by a transverse myelopathy. The older girl had only light perception in either eye, persistent paraparesis and progressive scoliosis; her sister had a visual acuity of 20/200 in both eyes and mild spinal cord dysfunction. Results of electrodiagnostic tests correlated well with the severity of clinical neurologic deficits and provided objective estimates of the extent of tissue damage in both the optic nerves and the spinal cord. The presence of Devic's syndrome in these two sisters could be coincidental; however, the possibility of a shared genetic factor(s) should be considered.

Child↗
PubMed1982

The antigenic reactivity of small fragments derived from human myelin basic protein peptide 43-88.

In an effort to develop immunochemical reagents for detecting small peptides originating from myelin basic protein (BP), the antigenic determinants of fragments from human BP peptide 43-88 were examined. Antisera were produced in nine sheep and forty rabbits immunized with BP, BP peptide 43-88, or a region derived from within or containing a portion of BP peptide 43-88. These included custom synthesized peptides 51-67, 67-80, 74-84, 79-88, and 83-95. Reactivities were assessed by double antibody radioimmunoassay (DA-RIA) using radiolabeled BP or BP peptides. For peptides 74-84, 79-88, and 83-95 it was necessary to synthetically add a terminal tyrosine residue for radioiodination. Antisera to peptides 51-67, 67-80, 74-84, 79-88, and 83-95 showed much greater reactivity with the homologous antigen, with variable, but sometimes no, reactivity against BP or BP peptide 43-88. This was particularly evident in displacement DA-RIA. Of the small peptides, antisera to whole BP reacted best with peptide 83-95, whereas antisera to peptide 43-88 reacted best with peptide 79-88. Placement of the synthetically added tyrosine had a marked influence on the reactivity of BP peptide 79-88: antisera to BP peptide 43-88 reacted much better with radioiodinated tyrosinyl peptide 79-88 than with radioiodinated peptide 79-88-tyrosine. These results indicate that within a region of BP encompassing residues 51 through 95 a number of potential antigenic determinants exist. Some of the determinants on the small peptides represent distinctive conformational determinants or are inaccessible in BP peptide 43-88. The ability to detect small BP peptides by immunoassay necessitates that the identity of the peptide be known and that antibody reagents capable of reacting with the peptide(s) be available.

Amino Acid Sequence↗
PubMed1981

The influence of pH on the degradation of bovine myelin basic protein by bovine brain cathepsin.

The degradation of bovine myelin basic protein by bovine brain cathepsin D (ED 3.4.23.5) was studied over a pH range of 2.75 - 6.0. Throughout this pH range pepstatin, an inhibitor of cathepsin D, prevented the degradation. The degradation at a pH away from the optimum of pH 3.5 was predictably slower, but also resulted in more restricted cleavage. Above pH 4.5 bovine basic protein peptide 1 - 42 was not degraded further to peptide 1 - 36 as occurs at pH 3.5. Additionally, at pH 5.5 another fragment of basic protein, peptide 1 - 91, persisted indicating that under certain basic protein as well as basic protein peptide 43 - 169 may be cleaved in the molecular region of basic protein around the phenylalanyl-phenylalanine residues at position 88 - 89. The small amount of peptides 1 - 91 and 92 - 169 detected at pH 5.5 suggests that the bond between residues 91 and 92 in intact basic protein is a minor cleavage site. The options and variation in cleavage around residues 88 - 92 of basic protein presumably result from pH-dependent changes in conformation in the is region but could also be due to changes in conformation of cathepsin D. These results indicate that local tissue changes such a pH amy affect not only the velocity of the reaction but also the nature of th product formed by the degradation of basic protein by brain cathepsin D

Amino Acid Sequence↗
PubMed1981

Immunocytochemical localization of cathepsin D in rat neural tissue.

The localization of cathepsin D (CD) in normal adult rat neural tissue was determined with an indirect immunoperoxidase technique utilizing rabbit anti rat brain CD followed by a horseradish peroxidase conjugate of the Fab portion of goat antirabbit IgG. The immunoreactive enzyme protein was distributed predominantly in a granular pattern, presumably lysosomal, in neurons and choroid plexus epithelium. Smaller amounts were detected in oligodendrocytes and ependymal cells. The neuronal localization included the perikaryon and its processes, was widely distributed, and displayed a range of staining intensities in different anatomical areas. Immunoreactive CD was heavily concentrated in brain stem and spinal cord motoneurons, large neurons of the caudate nucleus, neurons of several nuclear groups, especially the paraventricular and supraoptic, in the hypothalamus, and neurons of superior cervical and dorsal root ganglia. CD was also readily detected in brain stem sensory neurons, pyramidal cells of the hippocampus, inferior olive and Purkinje cells, but was absent or present in very small quantities in the granule cells of the cerebellar cortex, the more superficial layers of the neocortex, and smaller neurons of the caudate nucleus. This distribution suggests that CD may have a major role in specific chemical events in neural functions and peptidergic pathways and could be involved in the alterations of certain neural structures in disease states.

Animals↗
PubMed1981

The protein antigens of peripheral nerve myelin.

Peripheral nervous system (PNS) tissue contains a variety of proteins, lipids, and carbohydrates that may serve as immunogens in proving immune responses, as antigens participating in immunological reactions, or as both types of agents. Three proteins P0, P1, and P2, account for approximately 70% of PNS myelin proteins. P0 is the major PNS myelin protein and is restricted to the PNS. P1 is similar to, if not identical with, myelin basic protein, the component of central nervous system myelin which induces experimental allergic encephalomyelitis. P2 has neuritogenic properties for inducing experimental allergic neuritis and may be involved in immune-mediated PNS myelin injury in humans. The complete amino acid sequence for P2 has recently been delineated, and its neuritogenic, immunogenic, and antigenic features can now be further characterized.

Amino Acid Sequence↗
PubMed1981

Spinal fluid basic protein immunoreactive material and spinal fluid lymphocyte reactivity to basic protein.

Levels of cerebrospinal fluid (CSF) basic protein (BP) immunoreactive material and CSF lymphocyte in vitro reactivity to BP were determined in patients with demyelinating and other inflammatory diseases of the nervous system. Elevated levels of BP and enhanced in vitro reactivity were observed, but there was no correlation between the magnitude of the in vitro response and the amount of BP-like material in CSF.

Demyelinating Diseases↗
PubMed1980

Molecular features of immunoreactive myelin basic protein in cerebrospinal fluid of persons with multiple slcerosis.

The molecular weight of the myelin basic protein (BP)-like material appearing in cerebrospinal fluid (CSF) of 2 persons with active-phase multiple sclerosis (MS) and 3 with recent cerebral infarctions was determined by gel filtration chromatography under acidic conditions. Column fractions were examined by radioimmunoassay for BP peptide 43-88 antigen as well as for binding activity to BP. Material cross-reactive with BP peptide 43-88 eluted over a wide spectrum of molecular weights. Greater representation of lower molecular weight species occurred in MS. Fractionated CSF from 2 patients with MS and 2 with cerebral infarction contained binding activity, presumably antibody, to BP which was greater than that in unfractionated CSF. Binding to BP was also examined in unfractionated CSF from 70 persons, including 16 with MS and 36 with other neurological diseases. Although CSF from MS patients showed higher binding, the presence of BP binding activity was not specific for MS. Our findings suggest that the antigen cross-reacting with BP and its fragments in CSF appears in a spectrum of molecular weight species, with lower forms predominating in MS. The detection of binding activity to BP as well as its enhancement by treatment at low pH suggest that the BP-like antigen in CSF may exist in free as well as in complexed forms.

Adolescent↗
PubMed1980

Immunoreactive myelin basic protein in the cerebrospinal fluid in neurological disorders.

Cerebrospinal fluid from 582 persons was analyzed by a double-antibody radioimmunoassay for the presence of material cross-reactive with peptide 43-88 of human myelin basic protein (BP). In a group of 104 patients with multiple sclerosis (MS), 23 of 33 individuals clinically judged to have had an exacereation within two weeks prior to the time CSF was obtained had detectable material ranging from 2 to 200 ng/ml. In the remaining 71 MS patients who either were stable or had had an exacerbation more than two weeks before, only 1 patient had a marginally elevated level of immunoreactive material. CSF from 53 persons with cerebrovascular disease was studied, and 13 of 29 with recent infarctions had values of 2 to 540 ng/ml. The degree of elevation in strokes generally paralleled the predicted volume of the lesion, but the amounts detected did not correlate quite so closely temporally with onset as they did with the periods of active disease in MS. Of the remaining 425 patients, 29 had immunoreactive material of 2 to 400 ng/ml in their CSF. Most of these patients with detectable material had acute diseases known to affect the myelin sheath. Eight of 10 persons with acute disseminated encephalomyelitis had no detectable material. The presence in CSF of material cross-reactive with BP peptide 43-88 does not have diagnostic specificity for MS but can be used as a means for determining recent myelin injury. The type of BP peptide formed and mechanisms for clearance of BP and BP peptides may be important in determining the biological consequences following release of this potentially immunogenic material from the central nervous system.

Antigen-Antibody Reactions↗
PubMed1980

Effect of peptides of bovine myelin basic protein on dermal fibroblasts.

Bovine basic protein (BP) was digested with purified bovine brain cathepsin D to produce well defined BP derived peptides 1-42, 43-88, 43-169, and 89-169. BP and these BP peptides were tested for their effects on cultured human dermal fibroblasts using a concentration range of 0.01-1,000 ng/ml. No effect was found on cellular proliferation, and neither total protein nor collagen synthesis was altered in the presence of these substances. Although preparations of brain which contain a fibroblast-growth factor also contain BP peptides, these results indicate that the purified BP peptides studied have no detectable biological effect on the growth of human dermal fibroblasts.

Cells, Cultured↗
PubMed1980

Immunocytochemical localization of calmodulin and a heat-labile calmodulin-binding protein (CaM-BP80) in basal ganglia of mouse brain.

Antisera to calmodulin, a Ca2%-dependent modulator protein, and a heat-labile calmodulin-binding protein have been used to localize these proteins in mouse caudate-putamen. The two proteins appear to be located at identical sites in this brain area. At the light microscopic level, calmodulin and calmodulin-binding protein are found within the cytoplasm and processes of large cells. At the electron microscopic level the proteins are associated with neuronal elements only, primarily at postsynaptic sites within neuronal somata and dendrites. Within the dendrites the immunocytochemical label is associated predominantly with the postsynaptic density and dendritic microtubules. These results are in accord with recent biochemical and immunihistochemical studies of calmodulin in brain and in dividing cells. Thus, calmodulin and the heat-labile calmodulin-binding protein may play a role in the nervous system at the site of neurotransmitter action and at the level of microtubular function.

Animals↗
PubMed1980

Immunocytochemical localization of coated vesicle protein in rodent nervous system.

Immunocytochemistry has been used to study the distribution of the major 180,000-mol wt protein of coated vesicles in rodent cerebellum. An antibody to the coat protein was prepared in rabbits and characterized by immunodiffusion and immunofixation of polyacrylamide gels. At the light microscope level the protein was primarily localized in punctate profiles surrounding Purkinje cells and within the cerebellar glomeruli. At the electron microscope level the punctate distribution was confined to presynaptic terminals of basket and Golgi II neurons as well as mossy fiber terminals of the glomeruli. This label was heaviest on the lattice coat of coated vesicles but, in addition, label was found within the presynaptic axoplasm and along the cytoplasmic surface of the plasmalemma. Coated vesicles in cell somata were labeled as well as the cytosol around groupings of these vesicles. These data suggest that there may be two forms (or more) of coated vesicle protein in neurons, a lattice form associated with coated vesicles and a soluble form associated with the cytoplasmic matrix.

Animals↗
PubMed1980

Metabolism of a peptide of human myelin basic protein in the rabbit.

Material cross-reactive with myelin basic protein (BP) peptide 43-88 has been identified as a major BP-like antigen appearing in human cerebrospinal fluid during acute myelin injury. In an effort to develop a means for detecting this material in the more accessible body fluids of blood and urine, as well as to determine its metabolic fate, the manner in which rabbits handle human BP peptide 43-88 was investigated. Unlabeled peptide was administered intravenously, and its concentration in plasma was monitored by radioimmunoassay. In studies of 10 rabbits, the peptide disappeared from blood in two phases, the first showing a half-life of 6.0 +/- 1.2 minutes and the second a half-life of 51.6 +/- 5.4 minutes. Organ-exclusion experiments indicated a rapid clearance, predominantly by the kidney, for the peptide, with tubular reabsorption and cleavage into smaller peptide fragments a probable catabolic mechanism.

Animals↗