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L D Hudson

Publications and source records attributed to L D Hudson.

At least 91 records · Page 5Linked to original sources
PubMed1992

Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination.

To investigate insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression during experimental demyelination and myelin regeneration, young mice were fed cuprizone (( bis(cyclohexanone) oxaldihydrazone )). This copper-chelating agent produces demyelination in the corpus callosum and superior cerebellar peduncles, and when treatment is stopped, there is rapid remyelination. At intervals during cuprizone treatment and recovery, brain sections were hybridized with specific probes and immunostained with antibodies to determine the localization and relative amounts of IGF-I and IGF-I receptor mRNAs and peptides. In untreated littermates, IGF-I and IGF-I receptor mRNAs and peptides were not detected in white matter. In cuprizone-treated mice, high levels of both IGF-I mRNA and peptide were expressed by astrocytes in areas of myelin breakdown. Astrocyte IGF-I expression decreased rapidly during recovery and oligodendroglial expression of myelin-related genes increased. In severely demyelinated areas, immature oligodendroglia exhibited a transient increase in IGF-I receptor mRNA and peptide immunoreactivity during early recovery. This highly specific pattern of IGF-I induction in astrocytes during demyelination and the expression of the IGF-I receptor in regenerating oligodendrocytes during recovery suggest that IGF-I functions in the regulation of oligodendrocyte and myelin metabolism in vivo.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1992

Expression of the tissue specific splicing protein SmN in neuronal cell lines and in regions of the brain with different splicing capacities.

The SmN protein is closely related to the ubiquitously expressed SmB and B' RNA splicing proteins but is expressed in only a limited range of tissues and cell types. The expression of SmN in a range of neuronal and non-neuronal cell lines correlates with their ability to splice the calcitonin/CGRP transcript to produce the mRNA encoding CGRP rather than that encoding calcitonin. Moreover, the SmN mRNA shows a widespread distribution within the brain and spinal ganglia being present in neuronal cells in all regions which naturally produce CGRP as well as in those areas which do not naturally express the calcitonin/CGRP gene but which can correctly splice the CGRP mRNA in transgenic mice expressing the calcitonin/CGRP gene in all cell types. Interestingly however the mRNA encoding SmN is also found in a few areas of the brain which can only carry out calcitonin-specific splicing in transgenic mice, such as the Purkinje layer of the cerebellum and the inferior colliculus. The possible role of SmN in the regulation of splicing in neuronal cells is discussed in the light of these results.

Animals↗
PubMed1992

Novel member of the zinc finger superfamily: A C2-HC finger that recognizes a glia-specific gene.

A novel member of the zinc finger superfamily was cloned by virtue of its binding to cis-regulatory elements of a glia-specific gene, the myelin proteolipid protein (PLP) gene. Named MyTI (myelin transcription factor I), this gene is most highly transcribed in the developing nervous system, where expression precedes induction of its presumptive target, PLP. Low levels of MyTI transcripts can be detected in nonneural tissues only by polymerase chain reaction analysis. Zinc is a necessary cofactor for DNA binding of MyTI, as the zinc-chelating agent 1,10-orthophenanthroline eliminates binding activity. Zinc may stabilize the DNA-binding domain of MyTI by coordinating three cysteine and one histidine residue in a Cys-X5-Cys-X12-His-X4-Cys (C2-HC) arrangement. The MyTI protein has six fingers of the C2-HC class arranged in two widely separated clusters. These two domains of DNA binding can function independently and recognize the same DNA sequence, suggesting that MyTI may contribute to the higher-order structure of a target promoter by simultaneously binding both proximal and distal sites. The six fingers are highly conserved, suggesting that they arose from successive duplication events, while the linker regions diverge in size and sequence. Both amino acid sequence comparisons and secondary-structure predictions indicate that the C2-HC fingers of MyTI do not resemble the zinc-mediated loops of C2-H2 fingers, C2-C2 fingers, or Cx clusters. MyTI may therefore be the prototype of a new structural family of zinc-stabilized DNA binding proteins.

Amino Acid Sequence↗
PubMed1991

The function of lung and blood neutrophils in patients with the adult respiratory distress syndrome. Implications for the pathogenesis of lung infections.

Pulmonary infections are a frequent cause of morbidity and mortality in patients with the adult respiratory distress syndrome (ARDS), but the reason is uncertain. Because neutrophils are important for lung defense and are found in increased numbers in the bronchoalveolar lavage fluid of patients with ARDS, we compared the functional activities of neutrophils obtained from lavage fluid and pulmonary artery blood of 28 patients shortly after the onset of ARDS. The lavage fluids contained 81.3 +/- 9.9% neutrophils, of which more than 95% were viable by vital dye exclusion, and the total protein concentrations were increased (98.8 +/- 98.5 mg/dl). The production of superoxide anion and hydrogen peroxide by the neutrophils in lavage fluid was significantly impaired compared with simultaneously tested pulmonary artery and normal neutrophils, and the microbicidal activity of the lavage neutrophils for Staphylococcus aureus was significantly impaired. The migration of alveolar neutrophils in response to a variety of stimuli was markedly reduced as compared with both pulmonary artery and normal neutrophils. The alterations in superoxide anion production and chemotaxis could be reproduced by exposure of normal neutrophils to oxidants (glucose:glucose oxidase), but not to other mediators that have been found in ARDS lavage fluids. Although the pulmonary artery neutrophils from the same patients had impaired production of superoxide anion and hydrogen peroxide, their microbicidal activity and chemotactic responses were normal. These findings indicate that the function of alveolar neutrophils is impaired in the lungs of patients with ARDS. This could contribute to the high incidence of pulmonary infections in these patients.

Blood Bactericidal Activity↗
PubMed1991

Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung injury and damage to the alveolar type II cells. This study sought to determine if endogenous surfactant is altered in ARDS. Bronchoalveolar lavage was performed in patients at-risk to develop ARDS (AR, n = 20), with ARDS (A, n = 66) and in normal subjects (N, n = 29). The crude surfactant pellet was analyzed for total phospholipids (PL), individual phospholipids, SP-A, SP-B, and minimum surface tension (STmin). PL was decreased in both AR and A (3.48 +/- 0.61 and 2.47 +/- 0.40 mumol/ml, respectively) compared to N (7.99 +/- 0.60 mumol/ml). Phosphatidylcholine was decreased in A (62.64 +/- 2.20% PL) compared to N (76.27 +/- 2.05% PL). Phosphatidylglycerol was 11.58 +/- 1.21% PL in N and was decreased to 6.48 +/- 1.43% PL in A. SP-A was 123.64 +/- 20.66 micrograms/ml in N and was decreased to 49.28 +/- 21.68 micrograms/ml in AR and to 29.88 +/- 8.49 micrograms/ml in A. SP-B was 1.28 +/- 0.33 micrograms/ml in N and was decreased to 0.57 +/- 0.24 micrograms/ml in A. STmin was increased in AR (15.1 +/- 2.53 dyn/cm) and A (29.04 +/- 2.05 dyn/cm) compared to N (7.44 +/- 1.61 dyn/cm). These data demonstrate that the chemical composition and functional activity of surfactant is altered in ARDS. Several of these alterations also occur in AR, suggesting that these abnormalities occur early in the disease process.

Acute Disease↗
PubMed1991

Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is an X-linked neurologic disorder characterized by dysmyelination in the central nervous system. Proteolipid protein (PLP), a major structural protein of myelin, is coded on the X chromosome. It has been postulated that a defect in the PLP gene is responsible for PMD. Different single-nucleotide substitutions have been found in conserved regions of the PLP gene of four unrelated PMD patients. Novel Southern blot patterns suggested a complex rearrangement in a fifth family. Linkage to PLP has been shown in others. We evaluated the PLP locus in a four-generation family with two living males affected with X-linked PMD. Analysis of DNA from the affected males revealed complete absence of a band, with PLP probes encompassing the promoter region, the entire coding region, and the 3' untranslated region and spanning at least 29 kb of genomic DNA. DNA from unaffected relatives gave the expected band pattern. Two obligate and one probable carrier women were hemizygous for the PLP locus by dosage analysis. Although it is unlikely, the previously described point mutations in PLP could represent polymorphisms. The finding of complete deletion of the PLP gene in our family is a stronger argument that mutations in PLP are responsible for X-linked PMD.

Adult↗
PubMed1990

Rationale and use of corticosteroids in chronic obstructive pulmonary disease.

Several studies of corticosteroid efficacy in patients with COPD performed in the last decade have had stronger study designs and larger patient populations than most of the previously reported investigations. These studies have provided evidence of the objective benefit of corticosteroid therapy on pulmonary function in clinically stable COPD patients. These positive results are due to a relatively marked beneficial effect of corticosteroids in a minority of the subjects studied rather than a modest effect in the majority of subjects. A controlled randomized trial of intravenous corticosteroid administration in patients with COPD and acute respiratory failure admitted to the hospital showed improvement in pulmonary function from 12 hours following initial administration through the remainder of the 3 days of the study in the treatment group as compared to the control group. A greater percentage of patients showed a beneficial response to corticosteroids in this study of patients with acute exacerbations as compared to most of the studies of clinically stable COPD patients with beneficial effects. This suggests the possibility that some patients may show a beneficial response to corticosteroids during an acute exacerbation although they have not shown a response when clinically stable. The response to inhaled corticosteroids in patients with COPD has not been studied as extensively as the response to oral corticosteroids. However, some studies have shown a beneficial response to inhaled corticosteroids, primarily but not exclusively, in individuals who have also shown a positive response to oral agents. Generally, the response in terms of improved pulmonary function has been less striking with the inhaled agent as compared to the oral drug, although higher relative doses of the oral drugs usually were studied. Several limitations of the currently available studies are evident. Most of the studies deal with the effects in clinically stable outpatients with COPD and no studies have dealt with maintenance therapy in patients who have responded to a 1 to 2 week course of 30 mg of prednisone or greater. Data on the efficacy of inhaled corticosteroids in COPD patients are limited. No studies have investigated the role of corticosteroids in acute exacerbations in outpatients with COPD. Recommendations are given regarding use of corticosteroids in patients with COPD. A trial of corticosteroids is recommended at some point during a patient's course, while clinically stable. If a beneficial response is obtained in terms of improvement in airflow obstruction, then clinical judgment must be used regarding whether maintenance therapy is continued and, if so, at what dose and by what route.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1990

A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development.

The differentiation of the oligodendrocyte from its bipotential progenitor culminates in the production of the myelin-specific proteins and the elaboration of membrane processes that ensheath the axon. Mutations in proteolipid protein (PLP) and its alternatively spliced isoform DM-20, the major protein constituents of central nervous system myelin, are characterized by a significant reduction in the number of mature oligodendrocytes, resulting in severe hypomyelination, tremor and early death. The canine shaking pup carries such a mutation, a single base change that substitutes a proline for a histidine near the first transmembrane region of PLP and DM-20. This mutation hinders oligodendrocyte differentiation, as evidence by a splicing pattern at the PLP locus characteristic of immature oligodendrocytes. The spliced transcript expressed earliest in development, DM-20, continues to be overexpressed in shaking pup oligodendrocytes. The disruption of the normal maturation schedule in these X-linked dysmyelinating disorders suggests that PLP or DM-20 plays a fundamental role in oligodendrocyte development. We propose that, while the more abundant PLP is the primary structural component of myelin, DM-20 may be critical to oligodendrocyte maturation.

Amino Acid Sequence↗
PubMed1990

Conservative amino acid substitution in the myelin proteolipid protein of jimpymsd mice.

The capacity for synthesizing and maintaining a compact myelin sheath is destroyed in a number of inborn errors of myelin metabolism. One class of hypomyelinating mutations, which displays an X-linked pattern of inheritance, is distinguished by marked disturbances in oligodendrocyte differentiation. We have defined the molecular defect in one such mutant that lacks mature oligodendrocytes, the X-linked jimpy myelin synthesis deficient (jpmsd) trait in mice. The structure of the gene encoding the most abundant myelin protein, proteolipid protein (PLP), was determined by mapping and partially sequencing genomic clones from jpmsd and wild-type mice. Jpmsd mice have a single base change in PLP, a C----T transition in exon 6 that would substitute a valine for alanine in both PLP and its alternatively spliced isoform, DM20. The mutation was confirmed by polymerase chain reaction-amplifying exon 6 from genomic DNA and then either sequencing the amplified DNA or directly probing exon 6 with oligonucleotides designed to detect a single base mismatch. The conservative amino acid replacement in PLP/DM20 of jpmsd mice results in a pleiotropic phenotype similar to that observed for the allelic mutation jimpy, in which a splicing defect has radically altered the PLP/DM20 protein. The accelerated turnover of oligodendrocytes in both mouse mutants suggests a function for PLP/DM20 in oligodendrocyte differentiation distinct from the role of these proteolipid proteins as structural components of the myelin sheath.

Amino Acid Sequence↗
PubMed1989

Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.

Myelin is a highly specialized membrane unique to the nervous system that ensheaths axons to permit the rapid saltatory conduction of impulses. The elaboration of a compact myelin sheath is disrupted in a diverse spectrum of human disorders, many of which are of unknown etiology. The X chromosome-linked human disorder Pelizaeus-Merzbacher disease is a clinically and pathologically heterogeneous group of disorders that demonstrate a striking failure of oligodendrocyte differentiation. This disease appears pathologically and genetically to be similar to the disorder seen in the dysmyelinating mouse mutant jimpy, which has a point mutation in the gene encoding an abundant myelin protein, proteolipid protein (PLP). We report that the molecular defect in one Pelizaeus-Merzbacher family is likewise a point mutation in the PLP gene. A single T----C transition results in the substitution of a charged amino acid residue, arginine, for tryptophan in one of the four extremely hydrophobic domains of the PLP protein. The identification of a mutation in this Pelizaeus-Merzbacher family should facilitate the molecular classification and diagnosis of these X chromosome-linked human dysmyelinating disorders.

Amino Acid Sequence↗
PubMed1989

The initial events in myelin synthesis: orientation of proteolipid protein in the plasma membrane of cultured oligodendrocytes.

Proteolipid protein (PLP) is the most abundant transmembrane protein in myelin of the central nervous system. Conflicting models of PLP topology have been generated by computer predictions based on its primary sequence and experiments with purified myelin. We have examined the initial events in myelin synthesis, including the insertion and orientation of PLP in the plasma membrane, in rat oligodendrocytes which express PLP and the other myelin-specific proteins when cultured without neurons (Dubois-Dalcq, M., T. Behar, L. Hudson, and R. A. Lazzarini. 1986. J. Cell Biol. 102:384-392). These cells, identified by the presence of surface galactocerebroside, the major myelin glycolipid, were stained with six anti-peptide antibodies directed against hydrophilic or short hydrophobic sequences of PLP. Five of these anti-peptide antibodies specifically stained living oligodendrocytes. Staining was only seen approximately 10 d after PLP was first detected in the cytoplasm of fixed and permeabilized cells, suggesting that PLP is slowly transported from the RER to the cell surface. The presence of PLP domains on the extracellular surface was also confirmed by cleavage of such domains with proteases and by antibody-dependent complement-mediated lysis of living oligodendrocytes. Our results indicate that PLP has only two transmembrane domains and that the great majority of the protein, including its amino and carboxy termini, is located on the extracellular face of the oligodendrocyte plasma membrane. This disposition of the PLP molecule suggests that homophilic interactions between PLP molecules of apposed extracellular faces may mediate compaction of adjacent bilayers in the myelin sheath.

Amino Acid Sequence↗
PubMed1989

First American Board of Internal Medicine critical care examination: process and results.

On November 10, 1987, 2,712 diplomates of the American Board of Internal Medicine (ABIM) took the initial examination recognizing added qualifications in critical care medicine (CCM). The 1-day examination, made up of one-best-answer and multiple true/false questions, covered a broad range of topics from the internal medicine domain of CCM. Diplomates were admitted to the examination through four pathways requiring formal training in CCM and two practice pathways; 89% of the diplomates entered through the practice pathways. The absolute standard for the examination resulted in a total group pass rate of 64% (n = 1,725); the pass rate for diplomates with training in CCM was 84%. Examination performance was positively associated with months of critical care training, earlier ABIM examination scores, certification in pulmonary medicine, program directors' ratings of overall clinical competence, and several factors associated with the critical care work environment.

Certification↗