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Biomedical subjects

S Hodgkinson

Publications and source records attributed to S Hodgkinson.

35 records · Page 2Linked to original sources
PubMed1992

Passive immunization against circulating insulin-like growth factor-I (IGF-I) increases protein catabolism in lambs: evidence for a physiological role for circulating IGF-I.

Primed constant infusions of [14C]urea were used to determine the acute effect of passive immunization against circulating free and protein-bound insulin-like growth factor-I (IGF-I) on the rate of net protein catabolism (NPC) in castrated male lambs fasted for 48 h. Following an intravenous bolus of 50 ml IGF-I antiserum, the rate of NPC increased to a peak 30 min after injection of 1.69 +/- 0.16 g/kg per day from a baseline value of 1.45 +/- 0.22 g/kg per day (P < 0.05, n = 4). In three animals given 50 ml equivalents of the purified immunoglobulin fraction, NPC increased from 1.31 +/- 0.20 to 1.59 +/- 0.16 g/kg per day (P < 0.05). A similar trend was observed in animals given 25 ml antiserum (n = 4). The rate of NPC did not increase following a bolus of non-immune serum in control animals and the rate of NPC in the treated lambs returned to control levels within 60 min of antibody injection. Plasma insulin and glucose concentrations in both the treated and control groups were unchanged throughout the study. These data suggest that circulating IGF-I has a physiological role in regulating whole body protein turnover during starvation and possibly other catabolic states. The effect of immunoneutralization of circulating IGF-I is transient and this suggests that while IGF-I has an endocrine role in the regulation of protein turnover, other regulatory mechanisms are involved.

Animals↗
PubMed1991

A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an experimental demyelinating disease of rodents. In (PL/J x SJL) F1 mice, it is induced by immunization with the myelin basic protein peptide Ac1-11. Ac1-11 [4A], a myelin basic protein peptide analog with a single amino acid substitution, (i) binds to class II major histocompatibility complex molecules and stimulates encephalitogenic T cells in vitro better than Ac1-11, (ii) is nonimmunogenic and nonencephalitogenic in vivo in (PL/J x SJL)F1 mice, (iii) prevents EAE when administered before or at the time of immunization with Ac1-11, and (iv) prevents EAE when administered later, near the time of disease onset. Initial studies suggest that Ac1-11 [4A] does not prevent EAE by competitive inhibition or by activation of regulatory cells. Thus, substitution of a single amino acid in a myelin basic protein peptide confers the capacity to prevent rather than induce EAE, even after peptide-specific encephalitogenic T cells have been activated.

Amino Acid Sequence↗
PubMed1991

Green power.

The NHS has a unique environmental role in the UK and managers need to be eco-conscious. Simon Hodgkinson and Erica Ison provide a checklist for environmental audit.

Environmental Monitoring↗
PubMed1991

Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides.

Chimeric (murine/human) anti-CD4 monoclonal antibody was infused into seven patients with mycosis fungoides. Successive patients received doses of 10, 20, 40, and 80 mg of antibody twice a week for 3 consecutive weeks. All patients had some clinical improvement, but responses were of relatively short duration. Serum levels of chimeric antibody varied as a function of dose. At the 80-mg dose level, antibody was readily observed in biopsied skin lesions. Although there was coating by antibody of most CD4 positive cells in the blood, there was no significant depletion of CD4 positive cells. Low-level antibody responses against the mouse Ig variable region and human Ig allotypic constant region determinants were observed in several patients, but none were of clinical significance. All but two patients made primary antibody and T-cell proliferative responses to a simultaneously administered foreign protein test antigen. However, there was marked suppression of the mixed lymphocyte reaction. We conclude that at the dose levels studied, a chimeric anti-CD4 monoclonal antibody (1) had some clinical efficacy against mycosis fungoides; (2) was well tolerated; (3) had a low level of immunogenicity; (4) had immediate immunosuppressive effects; and (5) did not induce tolerance to a co-injected antigen.

Adult↗
PubMed1991

Stereospecific effect of flupenthixol on neuroreceptor gene expression.

An experimental method to test the hypothesis that antipsychotic (neuroleptic) agents influence gene expression in the mouse brain has been developed using the cis and trans stereoisomers of flupenthixol. The cis form of the drug is known to be clinically effective against some of the psychotic symptoms of schizophrenia as opposed to the trans isomer which is relatively inactive. A 2- to 3-fold increase in the abundance of dopamine 2 receptor mRNA was observed in the cis treated mice after a period of ten weeks. No change was observed in the expression of the dopamine D2 receptor gene upon treatment with the trans isomer. No change in the amount of 5-HT1A, 5-HT1C, alpha 1 adrenergic, beta 1 and beta 2 adrenergic neuroreceptor mRNA was found in the mice treated with active drug. The results show a long-term adaptation to D2 antagonism at the level of gene expression which occurs over a similar time scale to that of the clinical response to neuroleptic treatment of schizophrenia.

Actins↗
PubMed1991

IGF1 and 2 in two models of adrenal growth.

Insulin-like growth factors (IGFs) 1 and 2 were measured in the adrenal glands of rats undergoing either compensatory growth following left unilateral adrenalectomy or adrenal regeneration following bilateral adrenal enucleation. In normal rat adrenal gland, the tissue concentration of IGF2 (7.45 +/- 0.99 pg/micrograms protein) wa higher than IGF1 (1.26 +/- 0.23 pg/micrograms protein), both peptides being more abundant in the inner zones of the adrenal gland compared to the capsule-glomerulosa. During compensatory growth of the right adrenal gland, IGF1 and 2 increased significantly compared with control right adrenal glands at 24 h following left unilateral adrenalectomy (P less than 0.001). At 68 h, the increase remained significant for IGF1 (P = 0.012). The two peptides were measured in the regenerating adrenal gland at 7, 14 and 21 days following bilateral enucleation. Whilst there was a trend towards an increase in the IGF1 and 2 content of regenerating adrenal glands, the increase was significant only for IGF2 in the left adrenal gland at 21 days following enucleation. Plasma IGF1 and 2 did not increase compared to controls during the experiments (110.97 +/- 1.95 and 46.33 ng/ml, respectively), suggesting that the changes in tissue IGF reflect increased local production during rapid growth of the adrenal gland.

Adrenal Glands↗
PubMed1991

A family with multiple instances of definite, probable and possible early-onset Alzheimer's disease.

A family with a multigenerational history of proven or suspected early-onset Alzheimer's disease (AD) consistent with autosomal-dominant inheritance is described. To date, the pedigree comprises five generations in which there are 13 known affected individuals. The mean age of onset of cognitive deficits in those for whom data are available (n = 11) is 47.6 (s.d. 3.0) years and the mean age of death (n = 10) is 58.8 (s.d. 4.0) years. The variability in the extent and quality of available data illustrates the diagnostic difficulties encountered in ascertaining such an extended pedigree, and the need for caution in interpreting the evidence.

Adult↗
PubMed1990

The role of genetic factors in the etiology of the affective disorders.

Recent application of genetic linkage analysis to the affective disorders has suggested that there are at least three genotypic forms. This is an important step toward defining the genetic etiology involved, as it had previously been suggested that the complex nature of the clinical phenotype would preclude any attempt to apply such a technique. However, to date no clinical evidence exists to discriminate these genotypes at the phenotypic level. Molecular geneticists now face a formidable task of identifying the aberrant gene and relating the gene product, a protein, to the observed psychopathology. Current molecular genetic research in the affective disorders is discussed and similar work applied to the study of nonpsychiatric disorders such as cystic fibrosis and Duchenne muscular dystrophy is reviewed. The clinical value of genetic risk analysis for individuals with a family history of the affective disorders is also considered.

Affective Disorders, Psychotic↗
PubMed1989

Prevention of experimental encephalomyelitis with peptides that block interaction of T cells with major histocompatibility complex proteins.

Two synthetic immunodominant and nonencephalitogenic peptides of myelin basic protein, N1-20 and AcN9-20, effectively compete with an encephalitogenic peptide, AcN1-11, in an in vitro T-cell response restricted by class II major histocompatibility complex products (I-Au). These mutant peptide constructs, which do not occur in nature, also compete with the self-antigen for the in vivo induction of T cells primed with the encephalitogen AcN1-11. By using these nonpathogenic competitor peptides, it is possible to prevent the development of a prototypic T-cell-mediated autoimmune disease, experimental allergic encephalomyelitis. These results suggest possibilities for the utilization of competitor peptides for therapy of T-cell-mediated autoimmune diseases linked to specific major histocompatibility complex genes.

Amino Acid Sequence↗
PubMed1988

Molecular genetics and heterogeneity in manic depression.

Recent research has shown that there are X-linked and possibly chromosome 11-linked forms of manic depression as well as at least one other autosomal form. Segregation analyses of large affected families and the finding of genetic linkage between chromosome specific markers and manic depression mutations provide strong evidence that bipolar as well as unipolar forms of manic depression (MD) within the same family are inherited as a dominant gene disorder. This clarification of the etiology of certain types of depression should bring changed attitudes within psychiatry and may serve to stimulate discussion of the role of evolutionary mechanisms. From a clinical point of view, it has now become possible to determine whether clinical (phenotypic) variation reflects the underlying genotypic heterogeneity of linkage. A preliminary analysis of data from four recent studies shows that there is no clear correlation between such clinical features as the ratio of unipolar to bipolar cases and the genotypic form of manic depression. Further recombinant DNA research, proven to be successful in other genetic diseases, can soon be applied to manic depression. The specific problems posed by manic depression for these techniques are discussed.

Bipolar Disorder↗
PubMed1987

Minisatellite mapping in manic depression.

Hypervariable regions of DNA exist at many discrete loci in the human genome. Variations in the length of specific classes of hypervariable DNA termed "minisatellite" sequences may be detected by hybridisation of radioactive probes composed of a common 10-15 base pair repeat or "core" sequence which is shared by each of the minisatellite loci. Such a procedure was used to perform linkage analysis on a kindred in which a disease allele causing manic depression appeared to be segregating as an autosomal dominant. Results indicate no apparent linkage between a manic depression allele and at least 20 hypervariable genetic loci which acted as markers. However, because of the hypervariability of the minisatellite loci these results do not preclude similar analyses of other manic depressive pedigrees being productive because each such family will have distinct observable minisatellite alleles at loci specific to that family. The method could be usefully applied to the genetic analysis of other psychiatric disorders where heterogeneity is suspected and where a single autosomal major gene locus appears to be responsible for causing multiple cases within a single kindred.

Base Sequence↗
PubMed1986

[Neurologic manifestations of ciguatera. 3 cases with a neurophysiologic study and examination of one nerve biopsy].

Ciguatera is the commonest form of poisoning resulting from eating fish in the tropics. It has been recognised since the 15th century. The disease is due to the formation of ciguatoxin by a dinoflagellate, Gambierdiscus toxicus, loosely attached to algae growing on coral reefs. The toxin, which is harmless to the fish, is ingested by small herbivorous fish and passes up the food chain as these are eaten by carnivores. The toxic effects include gastroenteritis, itching of the skin, peripheral neuropathy and central nervous system dysfunction. Though most cases are mild, occasionally the disease is severe and even fatal. There is no effective specific treatment. Three cases, of which one died and which exhibited both peripheral and central nervous system involvement, are described. Histological changes in sural nerve fibers are described. There was striking oedema of the adaxonal Schwann cell cytoplasm. These histological changes are very similar to those seen following the injection of scorpion and spider venoms into the peripheral nerve of experimental animals. Both these venoms and ciguatoxin increase the permeability of the membrane to sodium.

Adult↗
PubMed1985

Stress-induced secretion of adrenocorticotropin in rats is inhibited by administration of antisera to ovine corticotropin-releasing factor and vasopressin.

Intact handled rats were pretreated with the immunoglobulin G fractions from normal rabbit serum or antisera to ovine corticotropin-releasing factor (CRF) and/or vasopressin and subjected to restraint or formalin stress. The formalin-induced rise in plasma ACTH was reduced to 28% in rats pretreated with anti-CRF, to 53% in those pretreated with antivasopressin, and to 16% in rats given both antibodies. Pretreatment of animals with anti-CRF, antivasopressin, or a combination of both antibodies also attenuated the ACTH response to restraint stress to 13%, 37%, and 12%, respectively, of those in normal rabbit serum-treated rats. Antiserum pretreatment did not reduce the restraint- or formalin-induced rise in plasma PRL in the same animals, however. We conclude, therefore, that both vasopressin and an ovine CRF-like peptide are physiologically relevant peptides involved in stress-induced ACTH release.

Adrenocorticotropic Hormone↗
PubMed1984

A glyceraldehyde-3-phosphate dehydrogenase pseudogene on the short arm of the human X chromosomes defines a multigene family.

A human X chromosome-derived gene sequence which recognises an abundant, 1.2-kb mRNA in several cell types was previously isolated during a study to identify expressed sequences from an X chromosome recombinant library. Further characterisation of this clone, acronym OA1, has shown that it maps to the short arm of the X, at Xp21 to Xp22. A 777-bp fragment of the clone which hybridizes to the 1.2-kb mRNA has been sequenced, and the inferred amino acid sequence shows 80% homology with the published protein sequence for human muscle glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The fragment shows even higher homology (87%) with pig muscle GAPDH. The OA1 clone selects an mRNA which translates in vitro into a polypeptide of 36 K, the subunit size of GAPDH. However, the X-sequence is most probably a pseudogene whose structure is consistent with it having arisen by reverse transcription of a GAPDH or GAPDH-related mRNA followed by insertion into the X chromosome. The GAPDH-related portion of OA1 hybridizes to several DNA fragments in human and mouse DNA, and six fibroblast cDNA clones which cross-hybridize to OA1 identify the same genomic fragments as OA1. This series of clones identifies a new, conserved GAPDH-related multigene family.

Amino Acid Sequence↗
PubMed1984

Involvement of rat corticotrophin-releasing factor-41-related peptide and vasopressin in adrenocorticotrophin-releasing activity from superfused rat hypothalami in vitro.

Superfused rat hypothalamic pieces stimulated with a high K+ medium released corticotrophin-releasing factor (CRF) as detected in the rat isolated anterior pituitary cell column bioassay. This activity has components related to ovine CRF-41 (oCRF-41) and vasopressin as assessed by the effects of specific antisera on the ACTH-releasing activity of the hypothalamic column effluent. Release of immunoactive vasopressin paralleled that of CRF bioactivity. Immunoactive oCRF-41 could not be detected, as it is likely to be below the sensitivity of present radioimmunoassays.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Molecular genetic evidence for heterogeneity in manic depression.

Manic depression is a severe cyclic mental illness that can be unipolar or bipolar and has a lifetime risk of approximately 7 per 1,000 in most populations. Families with multiple cases of manic depression have been described that are compatible with both autosomal dominant and X-linked modes of genetic transmission. Psychoactive antidepressant and stimulant drugs that help to ameliorate depression and mania are thought to act by affecting catecholamine neurotransmitter systems such as adrenaline, noradrenaline and dopamine, amongst others. Mutations affecting the tyrosine hydroxylase (TH) gene, which encodes the rate-limiting enzyme for the synthesis of these three neurotransmitters, might therefore be responsible for causing the manic depressive phenotype. We have studied three Icelandic kindreds amongst whom it appears that a single autosomal dominant disease allele is segregating. In these families there were 44 cases amongst 73 individuals at risk. Genetic linkage studies were carried out using clones encoding tyrosine hydroxylase the variable portion of the Harvey-ras-1 (HRAS1) locus and the variable region of the insulin gene (INS). All three markers are closely linked on chromosome 11 and were used to observe the segregation of restriction fragment length polymorphisms (RFLPs) in the three affected kindreds. We found no evidence for linkage to these markers in any of the three families. In contrast, Gerhard et al. found linkage between manic depression and HRAS1 in a single large Amish kindred. We conclude that there is genetic heterogeneity of linkage in manic depression. Therefore mutations at different loci are responsible for the manic depressive phenotype in the Amish and in Iceland.

Bipolar Disorder↗