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Biomedical subjects

P A Singer

Publications and source records attributed to P A Singer.

At least 145 records · Page 8Linked to original sources
PubMed1989

The illusion of futility in clinical practice.

The claim that a treatment is futile is often used to justify a shift in the physician's ethical obligations to patients. In clinical situations in which non-futile treatments are available, the physician has an obligation to discuss therapeutic alternatives with the patient. By contrast, a physician is under no obligation to offer, or even to discuss, futile therapies. This shift is supported by moral reasoning in ancient and modern medical ethics, by public policy, and by case law. Given this shift in ethical obligations, one might expect that physicians would have unambiguous criteria for determining when a therapy is futile. This is not the case. Rather than being a discrete and definable entity, futile therapy is merely the end of the spectrum of therapies with very low efficacy. Ambiguity in determining futility, arising from linguistic errors, from statistical misinterpretations, and from disagreements about the goals of therapy, undermines the force of futility claims. Decisions to withhold therapy that is deemed futile, like all treatment choices, must follow both clinical judgments about the chance of success of a therapy and an explicit consideration of the patient's goals for therapy. Futility claims rarely should be used to justify a radical shift in ethical obligations.

Attitude of Health Personnel↗
PubMed1988

Effect of extracts of injured nerve on initiating the regenerative response in the hypoglossal nucleus in the rat.

The uptake of 2-deoxy-[14C]glucose (2-DG) by motor neurons in adult rat hypoglossal nuclei was studied 3 days after subepineural injection of 'crude' soluble protein extracts from intact and injured peripheral nerves into normal hypoglossal nerves. Injured nerve extracts were obtained from 'proximal' and 'distal' segments of sciatic nerves which were transected between two ligatures 3 days earlier. In one group of animals the hypoglossal nerve (experimental) was injected with a particular nerve extract. In another group of animals (control) the hypoglossal nerve was injected with physiological saline solution. Both proximal and distal nerve extracts caused a significant increase in 2-DG uptake. In turn, no 2-DG was detected after treatment with uncut nerve extracts or saline. These findings support the ideas that a substance(s) produced upon nerve injury is taken up by the axons and transported to the cell bodies where it triggers certain metabolic regenerative changes.

Animals↗
PubMed1988

T-cell receptor alpha-chain variable-region haplotypes of normal and autoimmune laboratory mouse strains.

We used Southern blotting and mRNA analysis to characterize allelic polymorphisms among genes of the T-cell antigen receptor (TCR) alpha-chain variable-region (V alpha) locus in a large panel of normal and autoimmune-susceptible or autoimmune-contributing strains of laboratory mice. Four major V alpha haplotypes were defined on the basis of multiple restriction fragment length polymorphisms for each of nine V alpha subfamily probes used. Southern blotting also revealed haplotype-specific loss of bands within some V alpha subfamilies, consistent with the deletion of particular V alpha genes or sets of genes from haplotype to haplotype. In contrast to the situation in the V beta locus, however, deletion of entire V alpha subfamilies was not observed. The nature of V alpha allelic variability was further explored by using an RNase protection assay to analyze expressed V alpha mRNA sequences in thymocyte RNA. Such analysis revealed both shared and unique patterns of V alpha mRNA expression among the different haplotypes and supported the conclusion that haplotype differences sometimes involve V alpha gene deletions. Interestingly, a disproportionate number of, but not all, autoimmune-susceptible strains, including NZB, SJL, SWR, PL/J, and NOD, share a common V alpha haplotype. The identification of murine TCR V alpha haplotypes should provide a basis for understanding the role of TCR diversity in normal immunoregulatory and immune-response phenomena, as well as autoimmune-disease predisposition.

Alleles↗
PubMed1987

Genomic organization and expression of B and T cell antigen receptor genes in murine lupus.

Studies with genomic DNAs of lupus mice and monoclonal autoantibodies suggest that autoantibody expression does not result from defects in immunoglobulin germline genes nor in mechanisms generating antibody repertoires. Genomic and expression abnormalities of T cell antigen receptor genes have been identified in lupus mice, but their possible contribution to disease manifestations remains to be established.

Animals↗
PubMed1986

Delineation of a defect in T cell receptor beta genes of NZW mice predisposed to autoimmunity.

In an attempt to determine whether genes involved in T cell antigen recognition are structurally abnormal and thereby promote murine systemic lupus, we analyzed the structural integrity of the D, J, and C region elements of the T cell receptor alpha and beta chain genes in all major lupus strains and several normal strains. Within the limits of restriction fragment length polymorphism analysis, all strains had an identical genomic organization, except the NZW mice, in which a deletion of the C beta 1-D beta 2-J beta 2 elements was found. Sequence analysis of NZW genomic elements containing this deletion placed its probable origin within the first exon of C beta 1, and extending to a complementary region within the first exon of C beta 2. The significance of this abnormality in the pathogenesis of systemic autoimmune disease remains to be determined.

Animals↗
PubMed1986

Molecular cloning and characterization of the Endo B cytokeratin expressed in preimplantation mouse embryos.

A cDNA clone of a keratin-related, intermediate filament protein, designated Endo B, was constructed from size-fractionated parietal endodermal mRNA and characterized. The 1466-nucleotide cDNA insert contains an open reading frame of 1272 nucleotides that would result in 5' and 3' noncoding sequences of 54 and 60 nucleotides, respectively. The predicted amino acid composition, molecular weight (47,400), and peptide pattern correlate well with data obtained on the isolated protein. The predicted amino acid sequence fits easily into the general domain structure suggested for all intermediate filament proteins with a unique amino-terminal head domain, a large conserved central domain of predominantly alpha-helical structure, and a relatively unique carboxyl-terminal or tail domain. Over the entire molecule, Endo B is 43% identical with human 52-kDa epidermal type I keratin. However, over two of the three regions contained in the central domain that are predicted to form coiled-coil structures, the Endo B is 54-68% identical with other type I keratin sequences. This homology, along with the presence of the completely conserved sequence DNARLAADDFR-KYE, which is found in all type I keratins, permits the unambiguous identification of Endo B as a type I keratin. Comparison of the Endo B sequence to other intermediate filament proteins reveals 22 residues which are identical in all intermediate filament proteins regardless of whether filament formation requires only one type of protein subunit (vimentin, desmin, glial fibrillar acidic protein, or a neurofilament protein) or two dissimilar types (type I and type II keratins). Endo B mRNA was detectable in RNA isolated from F9 cells treated with retinoic acid for 48 h. Approximately three to five genes homologous to Endo B were detected in the mouse genome.

Amino Acid Sequence↗
PubMed1986

Clonal diversity and T-cell receptor beta-chain variable gene expression in enlarged lymph nodes of MRL-lpr/lpr lupus mice.

The autosomal recessive lpr gene accelerates a systemic lupus erythematosus-like disease in genetically predisposed mice and induces autoantibodies in mice of normal genetic background. The molecular mode(s) of action of the lpr gene and its chromosomal location remain unknown, but it is primarily expressed as a massive T-cell proliferation manifested only in the presence of a thymus. To define the clonal diversity and maturational stage of the abnormally proliferating T cells found in enlarged lymph nodes of MRL-lpr/lpr mice, and their possible role in autoreactive B-cell activation, we analyzed their T-cell receptor beta-chain variable region (V beta) gene sequences. Twenty-five VDJ-containing beta-chain cDNA sequences were examined, each of which was found to derive from a distinct rearrangement in the correct reading frame, yielding translatable beta-chain mRNAs. An additional 10 clones were derived from truncated nonfunctional mRNAs. D beta 1 and D beta 2 elements were used equally in the sequenced clones, and 10 of the possible 12 mouse J beta elements were represented. Remarkably, 60% of the functional beta-chain mRNAs expressed V beta 8.2 or V beta 8.3 genes, whereas the equally homologous V beta 8.1 gene was not represented at all. Other V beta genes were found at lower frequencies in the library, including one previously unidentified V beta gene. The results indicate that the clonal makeup of the abnormally proliferating lymph node T cells in MRL-lpr/lpr mice is heterogeneous, but V beta gene expression is significantly skewed in favor of V beta 8.2/8.3 genes. The preferential representation of V beta 8 genes might be caused by lpr gene-induced modification of T-cell thymic processing and relate to the lpr gene-associated autoimmunity.

Animals↗
PubMed1985

Trismus. An unusual sign in polymyositis.

Neuromuscular disease is an unusual cause of trismus. However, we describe two patients with severe polymyositis who had difficulty opening their mouths during the acute phase of the illness. Electromyography demonstrated involvement of the masseters, and there was no evidence of myasthenia. The mechanism appeared to be decreased elasticity of the masseter because of inflammation, edema, and perhaps contractures.

Adult↗
PubMed1985

Familial postpartum transient hyperthyroidism.

Postpartum painless thyroiditis with transient hyperthyroidism is being recognized with increasing frequency. Evidence tends to support an autoimmune cause. We treated a 33-year-old woman who experienced typical postpartum painless thyroiditis. Her sister had had a similar episode 13 years previously, and their mother had had postpartum hyperthyroidism 42 years earlier. We believe that this familial association provides further support for autoimmunity in postpartum thyroiditis.

Adult↗
PubMed1984

Synthesis of the isoleucyl- and valyl-tRNA synthetases and the isoleucine-valine biosynthetic enzymes in a threonine deaminase regulatory mutant of Escherichia coli K-12.

A mutation in the structural gene for threonine deaminase, ilvA538 , results in lower than normal levels of the isoleucyl, valyl- and leucyl-tRNA synthetases. Moreover, this regulatory mutation decreases the level of expression of the ilv biosynthetic operons and renders their expression non-responsive to limitations of the branched-chain amino acids. In this paper, we present in vitro evidence for the inhibition of isoleucyl- and valyl-tRNA synthetase activity by threonine deaminase and 2-ketobutyrate, the product of the threonine deaminase reaction, through the formation of a high molecular weight complex of the three molecules. Based on these results, we propose a model to explain the regulation of the isoleucyl- and valyt -tRNA synthetases in which transient inhibition of the synthetase enzyme activities by threonine deaminase and 2-ketobutyrate increases the expression of ileS and valS , the structural genes for isoleucyl- and valyt -tRNA synthetase, respectively. Further, the results suggest that the hyperattenuated expression of the ilv biosynthetic operons is due to an increased rate of complex formation of valyl and isoleucyl-tRNA synthetases and the altered form of threonine deaminase of the ilvA538 mutant strain.

Amino Acyl-tRNA Synthetases↗
PubMed1984

Reversion of the effects of a threonine deaminase regulatory mutant by a mutation in ilvH in Escherichia coli K-12.

In a strain carrying an ilvA538 mutation, the ilvGEDA operon expression is decreased (hyperattenuated) and the activity and/or expression of isoleucyl- and valyl- tRNA synthetases is decreased. We have isolated two revertants of ilvA538 owing to mutations in the ilvH gene, whose product is acetohydroxy acid synthase III. The regulatory properties of these revertants are consistent with a dual role for threonine deaminase as an effector of the ilvGEDA operon and the isoleucyl- and valyl- tRNA synthetase structural genes.

Amino Acyl-tRNA Synthetases↗
PubMed1984

Clinical varieties of neuromuscular disease in debrancher deficiency.

Two men and one woman with debrancher deficiency had symptoms and signs of neuromuscular disease. The two men had adult-onset and slowly progressive weakness, distal muscle wasting, "mixed" electromyographic patterns, and slow nerve conduction velocities; the initial diagnosis was Charcot-Marie-Tooth disease in one patient and motor neuron disease in the other. The woman had stunted growth, delayed motor milestones, and lifelong nonprogressive weakness. A muscle biopsy specimen showed severe vacuolar myopathy in all three cases. The glycogen concentration was increased threefold to sixfold and had an abnormal iodine spectrum. Anaerobic glycolysis in vitro showed impaired use of endogenous and exogenous glycogen but normal use of hexose-phosphate glycolytic intermediates. These three cases illustrated the clinical variety of neuromuscular disease in debrancher deficiency. In patients with weakness of adult onset, the diagnosis is impossible to make without performing a muscle biopsy.

Adult↗
PubMed1984

Structure of the murine Ia-associated invariant (Ii) chain as deduced from a cDNA clone.

The invariant (Ii) chain is a membrane-spanning glycoprotein found intracellularly associated with class II major histocompatibility complex (MHC) molecules. Using hybrid-selected translation and the Ii-specific monoclonal antibody In-1, we have isolated a cDNA clone (pIi-5) coding for most of the Ii chain. Sequence analysis of this clone reveals an open reading frame encoding 169 amino acid residues. The protein is rich in methionine and contains two potential N-glycosylation sites. No stretch of uncharged amino acid residues, characteristic for a membrane-spanning segment, is found close to the COOH-terminal end. There is one, however, close to the NH2-terminal end. As it is know that approximately 20 amino acid residues of Ii chain are exposed on the cytoplasmic side, we conclude that the Ii chain spans the membrane exposing the NH2 terminus on the cytoplasmic side and the COOH terminus on the luminal side.

Amino Acid Sequence↗