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Biomedical subjects

J A Corbett

Publications and source records attributed to J A Corbett.

At least 19 recordsLinked to original sources
PubMed1992

Nitric oxide and cyclic GMP formation induced by interleukin 1 beta in islets of Langerhans. Evidence for an effector role of nitric oxide in islet dysfunction.

Treatment of pancreatic islets with interleukin 1 (IL-1) results in a time-dependent inhibition of glucose-stimulated insulin secretion which has recently been demonstrated to be dependent on the metabolism of L-arginine to nitric oxide. In this report IL-1 beta is shown to induce the accumulation of cyclic GMP (cGMP) in a time-dependent fashion that mimics the time-dependent inhibition of insulin secretion by IL-1 beta. The accumulation of cGMP is dependent on nitric oxide synthase activity, since NG-monomethyl-L-arginine (a competitive inhibitor of nitric oxide synthase) prevents IL-1 beta-induced cGMP accumulation. cGMP formation and nitrite production induced by IL-1 beta pretreatment of islets are also blocked by the protein synthesis inhibitor, cycloheximide. The formation of cGMP does not appear to mediate the inhibitory effects of IL-1 beta on insulin secretion since a concentration of cycloheximide (1 microM) that blocks IL-1 beta-induced inhibition of glucose-stimulated insulin secretion and nitric oxide formation does not prevent cGMP accumulation, thus dissociating the two events. By using e.p.r. spectroscopy, IL-1 beta is shown to induce the formation of a g = 2.04 iron-nitrosyl feature in islets which is prevented by cycloheximide, demonstrating the requirement of protein synthesis for IL-1 beta-induced nitric oxide formation. Iron-nitrosyl complex-formation by islets confirms that IL-1 beta induces the generation of nitric oxide by islets, and provides evidence indicating that nitric oxide mediates destruction of iron-sulphur clusters of iron-containing enzymes. Consistent with the destruction of iron-sulphur centres is the finding that pretreatment of islets with IL-1 beta results in an approx. 60% inhibition of mitochondrial oxidation of D-glucose to CO2. Inhibition of islet glucose oxidation appears to be mediated by nitric oxide since both NMMA and cycloheximide prevent IL-1 beta-induced inhibition of glucose oxidation. These results show that IL-1 beta-induced nitric oxide formation parallels the ability of IL-1 beta to inhibit glucose-stimulated insulin secretion by islets, and that protein synthesis is required for IL-1 beta-induced nitric oxide formation. These results also suggest that nitric oxide mediates IL-1 beta-induced inhibitory effects on the pancreatic beta-cell by functioning as an effector molecule responsible for the destruction of iron-sulphur centres of iron-containing proteins, resulting in an impairment of mitochondrial function.

Amino Acid Oxidoreductases↗
PubMed1992

Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide.

Nitric oxide has recently been implicated as the effector molecule that mediates IL-1 beta-induced inhibition of glucose-stimulated insulin secretion and beta-cell specific destruction. The pancreatic islet represents a heterogeneous cell population containing both endocrine cells (beta-[insulin], alpha-]glucagon], gamma[somatostatin], and PP-[polypeptide] secreting cells) and non-endocrine cells (fibroblast, macrophage, endothelial, and dendritic cells). The purpose of this investigation was to determine if the beta-cell, which is selectively destroyed during insulin-dependent diabetes mellitus, is both a source of IL-1 beta-induced nitric oxide production and also a site of action of this free radical. Pretreatment of beta-cells, purified by FACS with IL-1 beta results in a 40% inhibition of glucose-stimulated insulin secretion that is prevented by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (NMMA). IL-1 beta induces the formation of nitric oxide by purified beta-cells as evidenced by the accumulation of cGMP, which is blocked by NMMA. IL-1 beta also induces the accumulation of cGMP by the insulinoma cell line Rin-m5F, and both NMMA as well as the protein synthesis inhibitor cycloheximide prevent this cGMP accumulation. Iron-sulfur proteins appear to be intracellular targets of nitric oxide. IL-1 beta induces the formation of an iron-dinitrosyl complex by Rin-m5F cells indicating that nitric oxide mediates the destruction of iron-sulfur clusters of iron containing enzymes. This is further demonstrated by IL-1 beta-induced inhibition of glucose oxidation by purified beta-cells, mitochondrial aconitase activity of dispersed islet cells, and mitochondrial aconitase activity of Rin-m5F cells, all of which are prevented by NMMA. IL-1 beta does not appear to affect FACS-purified alpha-cell metabolic activity or intracellular cGMP levels, suggesting that IL-1 beta does not exert any effect on alpha-cells. These results demonstrate that the islet beta-cell is a source of IL-1 beta-induced nitric oxide production, and that beta-cell mitochondrial iron-sulfur containing enzymes are one site of action of nitric oxide.

Aconitate Hydratase↗
PubMed1992

Mental impairment in the West Midlands.

The case records of 55 people from the West Midlands (UK) fulfilling the Mental Health Act 1983 criteria for mental impairment or severe mental impairment, were studied. Most were young men with mild mental retardation. 73 per cent were resident in (or on leave from) mental handicap hospitals, and 27 per cent resident in special hospitals. 29 per cent were subject to a Restriction Order. Most had lived in hospital for more than six years. The commonest problem behaviours were aggression, property offences and inappropriate or offending sexual behaviour. 31 per cent were mentally ill or had a past history of mental illness. A diverse range of services appears necessary to meet the needs of this group of people.

Adolescent↗
PubMed1992

Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction.

Increased blood flow and vascular leakage of proteins preferentially affect tissues that are sites of diabetic complications in humans and animals. These vascular changes in diabetic rats are largely prevented by aminoguanidine. Glucose-induced vascular changes in nondiabetic rats are also prevented by aminoguanidine and by NG-monomethyl-L-arginine (NMMA), an established inhibitor of nitric oxide (NO.) formation from L-arginine. Aminoguanidine and NMMA are equipotent inhibitors of interleukin-1 beta-induced 1) nitrite formation (an oxidation product of NO.) and cGMP accumulation by the rat beta-cell insulinoma cell line RINm5F, and 2) inhibition of glucose-stimulated insulin secretion and formation of iron-nitrosyl complexes by islets of Langerhans. In contrast, NMMA is approximately 40 times more potent than aminoquanidine in elevating blood pressure in nondiabetic rats. These results demonstrate that aminoguanidine inhibits NO. production and suggest a role for NO. in the pathogenesis of diabetic vascular complications.

Amino Acid Oxidoreductases↗
PubMed1992

Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM.

Cytokines have been implicated as immunological effector molecules that induce dysfunction and destruction of the pancreatic beta-cell. The mechanisms of cytokine action on the beta-cell are unknown; however, nitric oxide, resulting from cytokine-induced expression of nitric oxide synthase, has been implicated as the cellular effector molecule mediating beta-cell dysfunction. Nitric oxide is a free radical that targets intracellular iron-containing enzymes, which results in the loss of their function. The cytokine IL-1 beta induces the formation of nitric oxide in isolated rat islets and the insulinoma cell line, Rin-m5F. NMMA and NAME, both inhibitors of nitric oxide synthase, completely protect islets from the deleterious effects of IL-1 beta. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. This may preclude their use as therapeutic agents because of increases in blood pressure which result from the inhibition of constitutive nitric oxide synthase activity. Aminoguanidine, an inhibitor of nonenzymatic glycosylation of cellular and extracellular constituents associated with diabetic complications, recently has been reported to inhibit nitric oxide synthase. Aminoguanidine is approximately 40-fold more effective in inhibiting the inducible isoform of nitric oxide synthase, suggesting that aminoguanidine or analogues may serve as potential therapeutic agents to block diseases associated with nitric oxide production by the inducible isoform of nitric oxide synthase. In vivo administration of TNF IL-1 has been shown to induce anti-diabetogenic effects in the NOD mouse. This anti-diabetogenic effect of cytokines appears to conflict with evidence suggesting that cytokines mediate beta-cell dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1991

Interleukin-1 beta-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. Role of nitric oxide in interleukin-1 beta-induced inhibition of insulin secretion.

The molecular mechanism by which interleukin (IL)-1 inhibits insulin secretion and ultimately causes destruction of the pancreatic beta-cell remains unknown. Evidence is presented which suggests that IL-1 beta-induced inhibition of insulin secretion is dependent on the metabolism of L-arginine to nitric oxide. NG-Monomethylarginine, a competitive inhibitor of the L-arginine-dependent enzyme nitric oxide synthase, completely prevents IL-1-induced inhibition of glucose-stimulated insulin secretion as well as nitrite production by islets. It is further shown that IL-1 beta induces nitric oxide formation in islets as evidenced by an electron paramagnetic resonance feature at g = 2.04 which is similar to previously reported iron-nitrosyl complexes formed from the destruction of iron-sulfur centers by nitric oxide. Inhibition of the nitric oxide synthase by NG-monomethylarginine completely prevents the formation of this EPR signal in islets. These results show that IL-1-induced inhibition of insulin secretion is mediated through formation of nitric oxide and suggest that the generation of nitric oxide may represent the cellular mechanism responsible for beta-cell destruction.

Animals↗
PubMed1990

Pharmacokinetics of lithium in patients treated with controlled release lithium formulations.

There has long been discussion as to the relative merits of the lithium formulations available in the UK. Two of these have been shown to exhibit similar pharmacokinetics in normal volunteers and both are now marketed as controlled release formulations. In this study the serum lithium profiles of these formulations were compared in patients at two centres during the first 4 h after the dose, and at 24 h. We were unable to show any significant difference between the formulations in respect of maximum serum lithium concentrations or the concentration at each time point.

Adult↗
PubMed1990

Psychotropic drugs and mental retardation: 1. Disabilities and the prescription of drugs for behaviour and for epilepsy in three residential settings.

The Birmingham Special Needs Register, a computerized database, was used to examine the disabilities of, and the use of psychoactive (psychotropic and antiepileptic) drugs among 1825 people over the age of 20 with mental retardation. People living in three different types of residential setting (hospitals, community residential facilities and family homes) were compared. The prevalence of physical disability, impaired communication and incontinence was highest among people resident in hospital, followed by those living with their families. People resident in community residential facilities were the least disabled group. Psychotropic drugs prescribed to alter behaviour were used most frequently in hospitals (prescribed for 40.2% of people), followed by community residential facilities (19.3%). Use was lowest in family homes (10.1%). Most hospital residents who received medication to alter behaviour did not have a diagnosed psychiatric disorder. The reported prevalence of behaviour disorders among the three populations was not significantly different. Drugs for epilepsy were prescribed for 26.2% of hospital residents, 9.3% of people in community residential facilities and 18.5% of people living with their families.

Activities of Daily Living↗
PubMed1990

Psychotropic drugs and mental retardation: 2. A comparison of psychoactive drug use before and after discharge from hospital to community.

The use of psychoactive medication was examined among 64 people with mental retardation who moved from two hospitals to the community as part of a plan of resettlement. There was no significant difference between the overall use of antipsychotic drugs 2 years before discharge, on the date of discharge and after at least 6 months (mean 25 months) of community living, although changes in drugs and doses prescribed had taken place. About 39% of people were receiving antipsychotics, 32% receiving antiepileptics, 7% receiving antidepressants and 8% receiving benzodiazepines.

Adolescent↗
PubMed1990

Tourette-like disorder in Asperger's syndrome.

An eight-year-old boy with Asperger's syndrome was given haloperidol to control agitation and aggressive outbursts. Withdrawal of the drug after two years was followed by Tourette-like symptoms. Subsequently neither haloperidol nor a second antipsychotic drug altered the core features of Asperger's syndrome, despite suppressing the movement disorder. His first exposure to neuroleptics was in utero.

Adolescent↗
PubMed1990

Aerosol addiction.

A case of dependency on prescribed pressurised aerosols in a patient with asthma and mild mental handicap is reported. The majority of reported cases involve young asthmatics, abuse being reported mainly using salbutamol inhalers although other inhalers have also given cause for concern. The agent of addition is uncertain although it may be the fluorinated hydrocarbons used as propellants, rather than the active substance itself.

Adult↗
PubMed1989

Neuroleptic malignant syndrome with hypomania and mental retardation.

A case of neuroleptic malignant syndrome is described in a 37-year-old man with mental retardation, hypomania and a history of recent hepatitis B infection. The NMS is reviewed and the potential importance of this iatrogenic emergency in mental handicap practice is emphasized.

Adult↗
PubMed1987

Self-injurious behaviour in people with mental handicap: a total population study.

A survey of self-injurious behaviour in people receiving services for mental handicap was carried out in one health region. Six hundred and sixteen adults and children were found to have engaged in self-injurious behaviour sufficient to have caused tissue damage in the previous 4 months and 596 of these were screened. Half were resident in hospital while 28% were in non-hospital residential care and the remainder (21%) were living at home. Nearly one-fifth (19%) showed self-injurious behaviour, of one or more types, at a rate of at least once per hour and a further 13% wore protective or restraining devices for all or part of the day or night. Only 2% were enrolled on formal psychological treatment programmes but nearly half were receiving psychotropic drugs (excluding anticonvulsants).

Adolescent↗