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Biomedical subjects

R J Warrington

Publications and source records attributed to R J Warrington.

At least 19 recordsLinked to original sources
PubMed2001

Polymer modified electrodes for the reversible oxidation-reduction of NAD+/NADH for use within amperometric biosensors.

Electrochemical enzyme based biosensors continue to attract much attention due to the simplified analyses they promise, in comparison to many more complicated analytical procedures. The largest group of enzymes, are those that rely NAD(P)+/NAD(P)H as cofactors. One of the problems associated with the use NAD(P)+/NAD(P)H redox couples, however, within electrochemical biosensors is their ability to passivate noble metal electrodes. There have been many attempts to overcome this problem, such as the use of carbon paste electrodes [1], although approaches such as these are both cumbersome and typically irreproducible. In recent years conducting polymers such as poly(3-methylthiophene) [2] have also been used to modify noble metal electrode surfaces to lower the overpotentials required, while poly(phenol red) has been incorporated into films to offer selectivity against interferents [3,4]. In this study platinum electrodes have been electrochemically coated with mixed polymer films of poly(phenol red) together with poly(3-methylthiophene), poly(aniline) or poly(o-phenylenediamine) to offer enhanced performance. Cyclic voltammetry has been used to compare the electrochemical behaviour of the NAD+/NADH redox couple over repeated potential cycles, with the most favourable results being seen with the poly(aniline)/poly(phenol red) and poly(o-phenylenediamine)/poly(phenol red) coated electrodes.

Biosensing Techniques↗
PubMed1998

Cell-mediated allergy to a cerebral aneurysm clip: case report.

BACKGROUND AND IMPORTANCE: Titanium aneurysm clips have superior imaging characteristics and have been supplanting their stainless steel counterparts. We report the case of a 36-year-old woman with a histologically demonstrated cell-mediated reaction to a cobalt alloy aneurysm clip. CLINICAL PRESENTATION: The patient underwent a craniotomy and clip placement for a ruptured cerebral aneurysm. Both the aneurysm clip and the wires used to fix the craniotomy were made of stainless steel (cobalt and nickel) alloys. Postoperatively, the patient was plagued by intense pruritus. INTERVENTION: Skin patch testing revealed a severe reaction to nickel and cobalt. Surgical removal of the aneurysm clip and wires resulted in the disappearance of the patient's symptoms. A histological analysis of the tissue adjacent to the clip and wires was consistent with Type IV delayed type hypersensitivity. CONCLUSION: Stainless steel surgical implants in the head can cause diffuse, severe pruritus in susceptible individuals. Although the role of the aneurysm clip, as opposed to the more superficial wires, in the genesis of the patient's symptoms is not certain, this case demonstrates that a cobalt alloy aneurysm clip can activate T cells and cause an immunological reaction in the central nervous system.

Adult↗
PubMed1997

Interleukin-10 response abnormalities in systemic lupus erythematosus.

It has been previously reported that the production of interleukin-6 (IL-6) is often enhanced in systemic lupus erythematosus (SLE). The authors examined the secretion of IL-6, tumour necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor, IL-1 alpha and IL-4 by B cells and monocytes from lupus patients and compared this to the production in normal controls and in rheumatoid arthritis patients. IL-6 production was increased an average of 3.4-fold compared to that in normal subjects and 8.4-fold compared to rheumatoid arthritis patients. In SLE, a strongly positive correlation was found between the levels of IL-6 and TNF-alpha (R = 0.8987, P = 0.002). Since production of both IL-6 and TNF-alpha is regulated by IL-10, the enhancement of the production of these cytokines could reflect a defect in either IL-10 production or responsiveness. However, spontaneous production of IL-10 was enhanced in cultures of B cells and monocytes from lupus patients, compared to normal controls, the levels being increased 3.1- to 6-fold for monocytes and B cells, respectively. The finding of increased secretion of these cytokines implies an abnormality in IL-10-mediated suppression in SLE. To assess this possibility, the authors examined recombinant human IL-10-mediated suppression of IL-6 production by monocytes and B cells from lupus patients, compared to normal controls, and found that whereas IL-10 caused a concentration-dependent suppression of IL-6 production in normal B cells and monocytes, this suppression was deficient in B cells and monocytes from lupus patients. In SLE, it therefore appears that there may be an intrinsic defect in IL-10-induced suppression of cytokine synthesis. This could explain the increased levels of IL-10 and IL-6 found in this condition, and may also be responsible for the characteristic polyclonal B-cell activation that is seen.

Adult↗
PubMed1996

Neuroimmune mechanisms in health and disease: 2. Disease.

In the second part of their article on the emerging field of neuroimmunology, the authors present an overview of the role of neuroimmune mechanisms in defence against infectious diseases and in immune disorders. During acute febrile illness, immune-derived cytokines initiate an acute phase response, which is characterized by fever, inactivity, fatigue, anorexia and catabolism. Profound neuroendocrine and metabolic changes take place: acute phase proteins are produced in the liver, bone marrow function and the metabolic activity of leukocytes are greatly increased, and specific immune reactivity is suppressed. Defects in regulatory processes, which are fundamental to immune disorders and inflammatory diseases, may lie in the immune system, the neuro endocrine system or both. Defects in the hypothalamus-pituitary-adrenal axis have been observed in autoimmune and rheumatic diseases, chronic inflammatory disease, chronic fatigue syndrome and fibromyalgia. Prolactin levels are often elevated in patients with systemic lupus erythematosus and other autoimmune diseases, whereas the bioactivity of prolactin is decreased in patients with rheumatoid arthritis. Levels of sex hormones and thyroid hormone are decreased during severe inflammatory disease. Defective neural regulation of inflammation likely plays a pathogenic role in allergy and asthma, in the symmetrical form of rheumatoid arthritis and in gastrointestinal inflammatory disease. A better understanding of neuroimmunoregulation holds the promise of new approaches to the treatment of immune and inflammatory diseases with the use of hormones, neurotransmitters, neuropeptides and drugs that modulate these newly recognized immune regulators.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Neuroimmune mechanisms in health and disease: 1. Health.

A novel scientific discipline that examines the complex interdependence of the neural, endocrine and immune systems in health and disease has emerged in recent years. In health, the neuroimmunoregulatory network is fundamental to host defence and to the transfer of immunity to offspring; the network also plays important roles in intestinal physiology and in tissue regeneration, healing and reproduction. The proliferation of lymphocytes in primary lymphoid organs (bone marrow, bursa of Fabricius [in birds] and thymus) and in secondary lymphoid organs (spleen, lymph nodes and mucosal lymphoid tissue) depends on prolactin and growth hormone. These hormones allow immune cells to respond to antigen and to soluble mediators, called cytokines. Immune-derived cytokines are capable of inducing fever and of altering neuro-transmitter activity in the brain and hormone secretion by the pituitary gland. The activation of the hypothalamus-pituitary-adrenal axis by cytokines leads to immunosuppression. Lymphoid organs are innervated, and tissue mast cells respond to neurologic stimuli. In general, acetylcholine and substance P exert immunostimulatory and proinflammatory effects, whereas epinephrine and somatostatin are immunosuppressive and anti-inflammatory. In this article, the authors predict that novel approaches to immunomodulation will be possible by altering the level or efficacy of immunoregulatory hormones and neurotransmitters.

Humans↗
PubMed1996

The immune effects of neuropeptides.

Current evidence indicates that the neuroendocrine system is the highest regulator of immune/inflammatory reactions. Prolactin and growth hormone stimulate the production of leukocytes, including lymphocytes, and maintain immunocompetence. The hypothalamus-pituitary-adrenal axis constitutes the most powerful circuit regulating the immune system. The neuropeptides constituting this axis, namely corticotrophin releasing factor, adrenocorticotrophic hormone, alpha-melanocyte stimulating hormone, and beta-endorphin are powerful immunoregulators, which have a direct regulatory effect on lymphoid cells, regulating immune reactions by the stimulation of immunoregulatory hormones (glucocorticoids) and also by acting on the central nervous system which in turn generates immunoregulatory nerve impulses. Peptidergic nerves are major regulators of the inflammatory response. Substance P and calcitonin gene-related peptide are pro-inflammatory mediators and somatostatin is anti-inflammatory. The neuroendocrine regulation of the inflammatory response is of major significance from the point of view of immune homeostasis. Malfunction of this circuit leads to disease and often is life-threatening. The immune system emits signals towards the neuroendocrine system by cytokine mediators which reach significant blood levels (cytokine-hormones) during systemic immune/inflammatory reactions. Interleukin-1, -6, and TNF-alpha are the major cytokine hormones mediating the acute phase response. These cytokines induce profound neuroendocrine and metabolic changes by interacting with the central nervous system and with many other organs and tissues in the body. Corticotrophin releasing factor functions under these conditions as a major co-ordinator of the response and is responsible for activating the ACTH-adrenal axis for regulating fever and for other CNS effects leading to a sympathetic outflow. Increased ACTH secretion leads to glucocorticoid production. alpha-melanocyte stimulating hormone functions under these conditions as a cytokine antagonist and an anti-pyretic hormone. The sympathetic outflow, in conjunction with increased adrenal activity. leads to the elevation of catecholamines in the bloodstream and in tissues. Current evidence suggests that neuroimmune mechanisms are essential in normal physiology, such as tissue turnover, involution, atrophy, intestinal function, and reproduction. Host defence against infection, trauma and shock relies heavily on the neuroimmunoregulatory network. Moreover, abnormalities of neuroimmunoregulation contribute to the aetiology of autoimmune disease, chronic inflammatory disease, immunodeficiency, allergy, and asthma. Finally, neuroimmune mechanisms play an important role in regeneration and healing.

Animals↗
PubMed1995

Normal human cord blood B cells can produce high affinity IgG antibodies to dsDNA that are recognized by cord blood-derived anti-idiotypic antibodies.

It is possible to identify, in Epstein-Barr virus-transformed normal human cord blood B cell populations, cells present at a low frequency that produce IgG antibodies specific for dsDNA. By cloning out these B cells as immortalized monoclonal cell lines, it could be shown that the antibodies were the products of CD5 positive B cells. Two monoclonal anti-dsDNA antibodies were derived from cell lines T52 and A7 and these were further characterized as anionic (pI approximately 6.4) IgG4 kappa antibodies that bound with affinities of 7.18 x 10(9) l/mol and 3.28 x 10(9) l/mol, respectively, to dsDNA but did not bind to ssDNA. These affinities were similar to those of polyclonal IgG anti-dsDNA antibodies from lupus patients, which ranged from 1 x 10(9) -8.9 x 10(10) l/mol. Both T52 and A7 monoclonal anti-dsDNA antibodies were recognized by cord blood-derived IgM antibodies. These IgM antibodies were not rheumatoid factors but bound to the F(ab')2 of A7 and T52 while failing to recognize T50, which is an autologous IgG4 kappa monoclonal antibody without specificity for dsDNA. A cloned B cell line A24 generated from the same cord blood sample as A7 produced an IgM monoclonal antibody that bound to the heavy chains of T52 and A7, but not T50 on Western blot and inhibited the binding of these antibodies to dsDNA. A7 and T52 competitively inhibited each other in their binding to the anti-idiotype A24, and A24 inhibited the binding to dsDNA of some polyclonal IgG anti-dsDNA antibodies purified from sera of lupus patients. The level of inhibition of binding of these antibodies to dsDNA was directly proportional to the levels of expression of the idiotype recognized by A24 on these antibodies. The normal human cord blood, therefore, may contain cells that form an idiotype/anti-idiotype network in which the idiotype is expressed on IgG antibodies with specificity for dsDNA and the anti-idiotype is an IgM antibody that binds to a heavy chain idiotope in such a way as to interfere with its interaction with dsDNA. The presence of a similar idiotype on some polyclonal anti-dsDNA antibodies in lupus that are similarly inhibitable by the cord blood-derived anti-idiotype raises the possibility that this network may persist in later life and perhaps become dysfunctional in systemic lupus erythematosus.

Antibodies, Anti-Idiotypic↗
PubMed1993

The frequency of skin test reactions to side-chain penicillin determinants.

BACKGROUND: Skin testing for immediate hypersensitivity to penicillins is usually carried out with reagents prepared from benzylpenicillin, and it is believed that side-chain-specific reactions to semisynthetic derivatives are rare. Because some experimental and clinical data suggest that antibodies can be induced to immunogenic epitopes on the side chains of penicillins, we looked for side-chain-specific reactions to skin testing in patients with a history of allergy to penicillins or semisynthetic penicillins. METHODS: One hundred twelve patients with a clinical history of allergic reactions to penicillins and other semisynthetic penicillins were skin tested an average of 4.9 +/- 0.7 years after their reactions with the major and minor determinants of benzylpenicillin and minor determinant mixtures of ampicillin, amoxicillin, or cloxacillin. RESULTS: In these patients the most common clinical reactions were urticaria and angioedema (36.6%) and exanthema (48.8%). It was found that 21 cases (18.8%) still exhibited immediate hypersensitivity reactions on skin testing. But of these 21 patients, skin test reactivity was limited in 47.6% to the semisynthetic penicillin reagents derived from ampicillin, amoxicillin, or cloxacillin; that is, skin tests were negative with the benzylpenicillin derivatives. Ampicillin and amoxicillin were the semisynthetic beta-lactams causing most clinical reactions (24.1% and 33.9%, respectively), and ampicillin was the most common penicillin derivative to which skin test reactivity occurred (38.1%), other than the benzylpenicillin derivatives (52.3%). CONCLUSIONS: IgE antibodies appear therefore to discriminate between benzylpenicillin and ampicillin or other semisynthetic penicillins in a significant proportion of patients allergic to penicillin. Although it has not been proved that side-chain-specific skin reactivity implies the presence of clinically significant immediate hypersensitivity to semisynthetic penicillins, it is possible that side-chain-specific reagents may be required to exclude possible immediate hypersensitivity to the penicillins in patients who reacted to these antibiotics clinically.

Adolescent↗
PubMed1993

Hormones in self tolerance and autoimmunity: a role in the pathogenesis of rheumatoid arthritis?

Recent studies indicate that pituitary hormones play an important role in immunoregulation. The evidence that endocrine abnormalities are associated with, and may contribute to the development of autoimmune disease is reviewed and discussed. Patients suffering from rheumatoid arthritis show a number of endocrine abnormalities that indicate altered pituitary function. The decreased bioactivity of prolactin and possible inadequate glucocorticoid response to inflammation found in patients may have an etiological role in rheumatoid arthritis. The further clarification of the possible role of endocrine factors in the etiology of autoimmune disease is needed urgently.

Arthritis, Rheumatoid↗
PubMed1990

Normal mitogen-induced suppression of the interleukin-6 (IL-6) response and its deficiency in systemic lupus erythematosus.

A low-frequency suppressor-cell population in normal peripheral blood inhibits the B-cell CESS response to IL-6, following pokeweed mitogen stimulation. The suppression of IL-6 responsiveness is (i) radiation sensitive, (ii) directed against CESS targets and not mediated by inhibition of IL-6 production, and (iii) associated with nonspecific cytotoxic activity against CESS targets. The generation of these cytolytic cells is also radiation sensitive. A correlation was found between PWM-induced cytotoxicity against CESS and the suppression of IL-6-dependent IgG production. But cytotoxicity toward CESS targets is not responsible for this suppression because (i) IL-2 induces equivalent or greater nonspecific cytotoxicity against CESS in the total absence of suppression of CESS-derived IgG production and (ii) suppression is also induced by mitogen-activated PBL separated from CESS targets by a cell-impermeable membrane. This suppression was not mediated by TNF alpha/beta or IFN-gamma. In systemic lupus erythematosus, suppression of IL-6-dependent IgG production is impaired in patients with active disease (29.2 +/- 13.7%) compared to patients with inactive disease (70 +/- 19.5%) or normal controls (82.8 +/- 9.2%). There is also a defect in mitogen-induced nonspecific cytotoxicity in active SLE (specific lysis 15.1 +/- 3.5%, compared to 34 +/- 4% in normals). Pokeweed mitogen-activated PBL can therefore normally induce suppression of B-cell IL-6 responses and this response is deficient in lupus.

B-Lymphocytes↗
PubMed1989

Low molecular weight B cell growth factor-responsive cloned human B cell lines. I. Phenotypic differences and lack of requirement for CD23 (Fc epsilon RII).

The EBV-transformed B cell line JR-2 proliferates in response to partially purified preparations of low m.w. B cell growth factor (LMW-BCGF). Two clones of JR-2 were generated that retained this LMW-BCGF responsiveness, exhibiting similar dose/response characteristics but differing phenotypically. The B10 clone grows as single, discrete, small round cells, whereas D3 grows in aggregates. The clones also differ in the expression of cell surface Ag, D3 being weakly DR+ and strongly CD23+, whereas B10 lacks these Ag. The CD23 on D3 cells binds IgE. Both clones are T9+, 4F2+, B1-, B2- and CALLA-. D3 expresses surface IgG and differentiates in the presence of LMW-BCGF, to secrete IgG. B10 lacks surface and cytoplasmic Ig and fails to differentiate in response to LMW-BCGF. CD23 cannot be induced on B10 by incubation with either LMW-BCGF or IL-4. B10 does not shed CD23 and shed CD23 is not a growth factor for either cloned line. Expression of CD23 on D3 cells is not affected by preincubation with LMW-BCGF. Neither B10 or D3 cells respond to rIL-1, rIL-2, rIL-4, rIL-6, rTNF-alpha/beta, rIFN-gamma, or to high m.w. BCGF (Namalwa), alone or in combination. Both clones absorb BCGF activity and crossover absorptions indicate that the clones remove growth factors required by each other. D3 and B10 both appear therefore to respond selectively to LMW-BCGF. These data suggest that the loss of CD23 from a cloned derivative of the cell line JR-2, although accompanied by considerable phenotypic change, is not associated with the disappearance of LMW-BCGF responsiveness, indicating that CD23 is not the essential receptor for LMW-BCGF.

Absorption↗
PubMed1989

Severe delayed-onset hypersensitivity reactions to amoxicillin in children.

Amoxicillin, a semisynthetic aminopenicillin, has achieved widespread use in recent years for the treatment of respiratory tract and otic infections. Serious reactions have been relatively infrequent. From July 1986 to June 1987, 11 children aged 6 months to 10 years presented with delayed-onset hypersensitivity reactions. In 10 the symptoms were consistent with a serum-sickness-like illness, including urticaria, angioedema, arthritis and arthralgia. Radioallergosorbent testing for IgE antibodies to penicillin yielded negative results, and lymphocyte transformation testing gave a positive result in only one patient. Because of the negative immunologic test results and the occurrence of reactions only in children, who had received an amoxicillin solution, the reactions may have been caused by the excipient.

Amoxicillin↗
PubMed1989

Interleukin 2 responsive T cell clones from rheumatoid and normal subjects: proliferative responses to connective tissue elements.

In vivo-activated interleukin 2 responsive T cell clones were generated from peripheral blood (PB) and synovial fluid (SF) of rheumatoid arthritis (RA) patients and from normal control PB. The specificity of these clones was assessed by measuring proliferation induced by the connective tissue elements (CTE) collagen types I and II, native and denatured, proteoglycans, and irrelevant control antigens. The cloned T cells from RA patients but not from normal subjects responded in vitro with proliferation to all CTE but not to control antigens purified protein derivative, ovalbumin, or lysozyme. Proliferation occurred in the presence and absence of accessory cells (AC), but the responses were consistently higher in the presence of AC. Antibodies to HLA-DR abrogated the proliferative response to CTE suggesting that DR expression was necessary for the induction of proliferation. These findings demonstrate the existence of clonable T cells responsive to CTE in PB and SF of RA patients. Expression of reactivity to CTE may contribute to the chronicity of the inflammation in RA.

Arthritis, Rheumatoid↗