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Biomedical subjects

R Newton

Publications and source records attributed to R Newton.

At least 145 records · Page 8Linked to original sources
PubMed1991

A new detector for fully automatic peptide synthesis.

A new method of monitoring the rate of reactions in solid phase peptide synthesis is described. A conductivity detector in the reaction cell enables the deprotection, washing, and subsequent coupling stages to be examined in detail. The half lives of the reactions can be calculated and hence the optimum reaction times predicted. The aggregation of peptide chains and subsequent collapse of the resin is observed. Difficult sequences are sensed and appropriate action taken completely automatically.

Amino Acid Sequence↗
PubMed1990

Polypeptide growth factors augment interleukin 1-induced release of prostaglandin E2 by rheumatoid arthritis synovial cells in vitro.

When stimulated with increasing amounts of interleukin 1 beta (IL 1 beta) rheumatoid arthritis (RA), as compared with osteoarthritis (OA), synovial cells grown in RPMI plus fetal bovine serum (FBS), released significantly more prostaglandin E2 (PGE2) (p less than 0.05; paired t test, two-tailed). PGE2 release by IL 1 beta-stimulated RA synovial cells grown for 14 days in serum-free RPMI was significantly less than that released by the same cells grown in medium plus 10% FBS (p less than 0.03; two-tailed). Since these data suggest that growth factors present in FBS may augment the effects of IL 1 beta, experiments were conducted to study the influence of four polypeptide growth factors--transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), on IL 1 beta-induced release of PGE2 by cultured RA synovial cells. Both EGF and bFGF significantly enhanced IL 1 beta-induced release of PGE2 (p less than 0.05; paired t test, one-tailed), while PDGF was synergistic with IL 1 beta, significantly increasing release of PGE2 by these cultured cells (p less than 0.02; two-tailed). No such effect was seen when TGF-beta was added to the culture medium. Taken together, these data lend support to the concept that within the synovial micro-environment small quantities of individual growth factors may potentiate the effects of IL 1 beta to amplify intra-articular inflammation.

Arthritis, Rheumatoid↗
PubMed1990

The adrenocorticotropin response to interleukin-1 beta instilled into the rat median eminence depends on the local release of catecholamines.

Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which activates the release of hypothalamic CRF but is unable to cross the blood brain barrier. Recently, it was reported that IL-1 beta, instilled directly into the hypothalamic median eminence (ME), rapidly induced ACTH secretion. Thus, due to the lack of a blood brain barrier the ME appears to be a site whereby iv IL-1 beta can access the brain to stimulate CRF and, consequently, ACTH secretion. To evaluate the role of central catecholamines in this process, 250 g male rats were lesioned with 6-hydroxy-dopamine instilled into the lateral ventricle. Ten days later, rats received recombinant h-IL-1 beta (10 or 30 ng) into the ME and blood was sampled via indwelling jugular cannulae. The ACTH response to IL-1 beta, 30 ng, was reduced by approximately 50% in the lesioned rats (P = 0.05), and it was abolished in those receiving IL-1 beta, 10 ng (P less than 0.05). Moreover, in rats given iv IL-1 beta (1 microgram), 6-hydroxy-dopamine significantly reduced the ACTH response by more than 50% (P less than 0.001). To determine the effect of acute epinephrine depletion, 2,3 dichloro-alpha-methylbenzylamine (DCMB, 60 mg/kg BW) and SKF64139 (SKF) (100 mg/kg BW), inhibitors of the enzyme which converts norepinephrine to epinephrine, were administered ip 4 h before intra-ME IL-1 beta (30 ng). DCMB reduced the ACTH response by 80% and SKF reduced it to its own baseline. LY 10853, which acutely depletes both norepinephrine and epinephrine, also reduced the ACTH response by 80%. Because of the reported capacities of DCMB and SKF to block alpha 2 adrenoreceptors in vitro, yohimbine, an alpha 2 receptor antagonist, was studied. Intra-ME yohimbine failed to inhibit the ACTH response to intra-ME IL-1 beta. In contrast, a significant (P less than 0.01) dose-dependent reduction in the ACTH response to intra-ME IL-1 beta (30 ng) was observed in rats pretreated with either a nonselective alpha or beta adrenoreceptor antagonist (phentolamine, 2-40 micrograms or propranolol, 2-20 micrograms, respectively, into the ME). In contrast, intra-ME phentolamine, 20 micrograms, failed to reduce the ACTH response to iv CRF, 1 microgram/kg BW. Thus, the secretion of ACTH stimulated by the action of IL-1 beta at the ME depends, in part, on the local secretion of norepinephrine and epinephrine interacting with both alpha and beta adrenergic receptors.

Adrenocorticotropic Hormone↗
PubMed1990

X chromosome genes involved in the regulation of facial clefting and spina bifida.

Congenital malformations such as cleft palate and spina bifida may be multifactorial in etiology. They occur as a result of both environmental agents and defective genes. Consequently it is both practically and intellectually difficult to study their effects experimentally. The advent of molecular biology technology has enabled many genes on the human chromosome to be mapped and some to be cloned. Using these techniques and families that display common congenital malformations inherited in a purely genetic manner, the genetic defects can be separated from the environmental components. This report documents our studies of several families that have cleft palate or spina bifida as X-linked disorders. Their phenotype is similar to the more common multifactorial cases but segregates as a single gene in an X-linked fashion. Localization of these genes using different X chromosome DNA probes and linkage analysis is the first step towards our understanding of the genetic contribution to the etiology of congenital malformations.

Anencephaly↗
PubMed1989

Intention to treat febrile convulsions with rectal diazepam, valproate or phenobarbitone.

One hundred and eighty-six consecutive children aged between six and 72 months admitted to the Manchester Children's Hospitals with a febrile convulsion in the first year of life, a complicated febrile convulsion, or more than one febrile convulsion within two years, were allocated randomly to one of three groups who were offered rectal diazepam in the event of a subsequent prolonged febrile convulsion, or prophylactic treatment with sodium valproate or phenobarbitone. Over-all risk of recurrence was 30 per cent and adequate prophylactic treatment did not lessen this risk. Side-effects in 24 per cent of the valproate group and 61 per cent of the phenobarbitone group did not justify the use of prophylactic treatment.

Administration, Rectal↗
PubMed1989

Tumor necrosis factor-alpha is a potent ACTH secretagogue: comparison to interleukin-1 beta.

Tumor necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1) are secreted by activated monocytes and other immune cells. Since IL-1 has been shown to elevate rat plasma ACTH and both of these cytokines induce similar acute-phase responses, the present studies of TNF were undertaken to characterize the ACTH response to this immune cell product. Human rTNF, administered iv at doses (100-1000 ng) which failed to affect blood pressure, food consumption or prolactin levels, resulted in significant peak elevations of rat plasma ACTH within 20 min (mean +/- SE 304 +/- 94 and 958 +/- 128 pg/ml for 100 and 1000 ng, respectively, compared to 53 +/- 16 pg/ml for vehicle). rTNF from two different sources produced similar elevations of ACTH as an equivalent amount of rIL-1. TNF failed to affect cultured anterior pituicytes, and it did not modify the response to CRF. When administered into the upper third cerebroventricle, TNF 20 ng failed to affect ACTH levels whereas IL-1 30 ng raised ACTH to 638 +/- 79 pg/ml compared to 177 +/- 24 pg/ml for vehicle (p less than .001). Furthermore, intraparenchymal injection of IL-1, directly above the median eminence, elevated ACTH to 484 +/- 93 pg/ml; again, TNF was completely ineffective. Thus, TNF-alpha and IL-1 beta are both potent ACTH secretagogues with complementary modes of action; however, the proximate target of TNF action appears to be peripheral to the CNS and pituitary whereas that of IL-1 appears to be the median eminence.

Adrenocorticotropic Hormone↗
PubMed1989

Direct current electrotherapy of internal hemorrhoids: an effective, safe, and painless outpatient approach.

Hemorrhoid disease is one of the most frequently occurring, disabling conditions of man. We report the results of 120 patients with symptomatic internal and mixed hemorrhoid disease treated with direct current (d.c.) via a dual-tipped disposable needle probe (negative electrode). Evaluation and treatment utilized an operative anoscope which visualized one-eighth of the anal canal. Five hundred ninety segments revealed hemorrhoid disease (grade 1 = 114, 2 = 222, 3 = 178, 4 = 76). One or more segments (highest grade) were treated per office visit. Symptoms, frequency, and mean number of treatment applications per patient for complete symptom resolution were: bleeding, 85%, 4.0; protrusion, 58%, 3.9; pain, 52%, 3.6; and pruritus, 49%, 3.9. Ablation of hemorrhoid disease grade was directly correlated with milliampere current and time of application. No major complications occurred. All patients were successfully treated and remained symptom-free at a mean duration of follow-up of 23 months. Direct current electrotherapy is an effective, painless, and safe outpatient treatment approach to all grades of internal and mixed hemorrhoid disease.

Adult↗
PubMed1987

Alpha-melanocyte-stimulating hormone exhibits target cell selectivity in its capacity to affect interleukin 1-inducible responses in vivo and in vitro.

The ability of i.v.-administered recombinant human interleukin 1 (IL 1 beta) to increase core body temperature, stimulate an increased production of serum amyloid P substance, and augment blood levels of circulating neutrophils in mice was inhibited in a dosage-dependent manner by administration of the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH). alpha-MSH administration was also capable of inhibiting the capacity of i.v.-administered IL 1 beta to enhance plasma levels of corticosterone and to depress the generation and/or elicitation of contact hypersensitivity responses to skin-reactive chemicals. An analog of alpha-MSH (Nle4, D-Phe7 alpha-MSH), known to be more potent than native alpha-MSH in a number of melanotropin-sensitive systems, was determined to be more active than alpha-MSH in the modification of these same in vivo responses. Neither alpha-MSH nor its analog were capable of altering the capacity of IL 1 to stimulate increased plasma levels in prostaglandin E2 (PGE2). In vitro, neither alpha-MSH nor its analog were capable of reducing the capacity of IL 1 to stimulate fibroblast production of PGE2 or to augment the proliferation of murine thymocytes exposed to phytohemagglutinin. The apparent selectivity associated with the regulatory influences of alpha-MSH on IL 1-induced responses in vivo suggests that this neuropeptide may function as an endogenous inhibitor of certain immunomodulatory and inflammatory activities of the cytokine IL 1.

Animals↗
PubMed1987

In vivo administration of interleukin 1 to normal mice depresses their capacity to elicit contact hypersensitivity responses: prostaglandins are involved in this modification of immune function.

The administration of pyrogenic doses of interleukin 1 (IL-1) to normal mice before contact sensitization with dinitrofluorobenzene (DNFB) resulted in a significant reduction in the intensity of the elicited contact hypersensitivity (CH) responses. Adoptive transfer experiments established no difference between normal and IL-1-pretreated mice regarding their capacity to generate splenic suppressor-cell activity and lymph node effector-cell activity in response to DNFB. However, a marked reduction in the intensity of elicited responses was observed when primed CH-effector cells, obtained from normal donors, were adoptively transferred to IL-1-pretreated recipients. This finding was paralleled by a consistent reduction in the ability of the adoptively transferred cells to infiltrate the tissue sites of antigen challenge in the IL-1-pretreated animals. Treatment of mice with indomethacin, a potent inhibitor of prostaglandin production, abrogated the capacity of IL-1 to depress CH responses following skin sensitization with DNFB. Similarly, indomethacin was also capable of abrogating the ability of IL-1 to depress CH responses of adoptive recipients of primed CH-effector cells. Our results indicate that the capacity of IL-1 to depress CH responses in normal mice is due to an indomethacin-sensitive process, presumably mediated through the IL-1-induced generation and action of prostaglandins. This was supported by our finding that treatment of mice with arachidonic acid or prostaglandin E2 caused a similar type of inhibition. The mechanism(s) responsible for this effect appears to act at the efferent level of the CH response, as evidenced by the reduced capacity of CH-effector cells to infiltrate the tissue sites of antigen challenge.

Animals↗
PubMed1986

Evidence that interleukin-1 induction of synovial cell plasminogen activator is mediated via prostaglandin E2 and cAMP.

Addition of the cyclooxygenase inhibitor indomethacin to human synovial cells in culture, at concentrations which completely block prostaglandin E2 (PGE2) synthesis, reversibly inhibited the interleukin-1 (IL-1) stimulation of cell-associated and extracellular plasminogen activator (PA) production. Results of mixing experiments suggested that the inhibition by indomethacin was not due to stimulation of production and/or activation of a PA inhibitor, but reflected inhibition of PA synthesis. Simultaneous addition of PGE2 or dibutyryl cAMP prevented the inhibition by indomethacin. Addition of the phosphodiesterase inhibitor, theophylline, the adenylate cyclase stimulator, forskolin, or dibutyryl cAMP caused an enhancement of the IL-1 induction of synovial cell PA. These results suggest that the IL-1 induction of synovial cell PA occurs via generation of endogenous PGE2 and cAMP.

Bucladesine↗
PubMed1986

Interleukin 1 stimulation of synovial cell plasminogen activator production.

Addition of human monocyte interleukin 1 (IL-1) to cultured human synovial cells can cause an increase in both cell associated (30-fold) and extracellular (40-fold) plasminogen activator (PA) activity. This increase was inhibited by antibody directed against IL-1 and phenylglyoxal. PA activity could be detected 3 h after the addition of IL-1, continued to increase for 24 h and was dependent on RNA and protein synthesis. The molecular weight of the PA produced from the IL-1 stimulated synovial cells was 55,000 +/- 1,000. Mononuclear cell conditioned media (MCCM) also stimulated synovial cells to produce PA. This stimulation was partly inhibited by anti-IL-1 thus suggesting the presence of appreciable IL-1 activity in MCCM. These results could provide clues as to how immune events are linked to cartilage destruction associated with rheumatoid arthritis.

Cells, Cultured↗