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Biomedical subjects

M Wilkinson

Publications and source records attributed to M Wilkinson.

At least 19 recordsLinked to original sources
PubMed1992

Antiidiotypic PTH antibodies as a cause of elevated immunoreactive parathyroid hormone in idiopathic hypoparathyroidism, a second case: another manifestation of autoimmune endocrine disease?

A 69-year-old man became hypocalcemic under medical observation. The hypocalcemia occurred in the presence of circulating immunoreactive parathyroid hormone (PTH). Common causes of secondary hyperparathyroidism were excluded, as was PTH resistance using PTH infusions. The immunoreactive PTH was examined in detail. PTH immunoreactivity (1) was not retained on a C18 SPE-column, suggesting unusual molecular or physicochemical properties, unlike bona fide PTH; (2) was precipitated with 15% PEG, indicating a molecular size far in excess of native PTH; (3) had an apparent molecular size similar to immunoglobulins on size exclusion chromatography; (4) was retained on affinity chromatography with both Protein A and anti-hIgG antibodies. These data lead us to conclude that the immunoreactive PTH was due to antiidiotypic PTH autoantibodies. No significant quantities of true PTH were found in the patient's serum suggesting that his hypoparathyroidism was a result of PTH deficiency. Autoimmunity might explain the occurrence of both processes if an arrested antiidiotypic antibody cascade is assumed.

Aged↗
PubMed1992

Characterization of cell-surface beta-adrenergic ([3H]CGP-12177) binding in adult rat ventricular myocytes: lack of regulation by beta-agonists at physiological concentrations.

The major focus of this paper is the characterization and quantification of rat cardiomyocyte, cell-surface beta-adrenergic receptors labelled with the hydrophilic radioligand [3H]CGP-12177. The ventricular cardiomyocytes used in these experiments have previously been extensively studied in our laboratory and confirmed to be functionally compatible with similar cells in vivo. Specific binding of [3H]CGP was stereospecific, saturable and of high affinity. Binding of [3H]CGP was also readily reversible, demonstrated appropriate drug specificity and positively correlated with increasing cell concentrations. The potency of the beta 1-antagonist atenolol was almost 100 times higher than that of the beta 2-antagonist ICI-118.551 in binding to the [3H]CGP binding site. This preparation appears ideal for the investigation of beta-adrenergic receptor regulation in heart cells. Indeed, our initial experiments show clearly that pharmacological concentrations of isoproterenol, and norepinephrine, can reduce (down-regulate) the number of specific [3H]CGP binding sites. This result is in agreement with many other reports on similar experiments in a variety of cell types. However, physiologically relevant concentrations of these two agonists (1-100 nM) do not induce down-regulation of the beta-adrenergic receptors in short-term (2 h) incubations. Nevertheless, the high-affinity receptors that we have described mediate a contractile response to isoproterenol in the nanomolar concentration range (EC50 = 3.6 +/- 0.3 nM). This is approximately 300 times lower than the concentration needed to produce down-regulation. Thus, our data indicate that short-term down-regulation of cardiomyocyte beta-adrenergic receptors can only be observed with high, pharmacological concentrations of isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1992

Ex vivo determination of opiate antagonist binding at mu-opioid ([3H]-DAGO) receptors in hypothalamic micropunches from maturing female rats: comparison between SDZ 210-096 and nalmefene.

We have previously shown that the duration of opioid receptor blockade is critical in determining the degree of opioid antagonist effect following peripheral injection of naloxone and naltrexone. In the present work, we have used this ex vivo technique to compare receptor occupancy of a new opiate antagonist, SDZ 210-096 (SDZ), to that of nalmefene (NLM) in maturing female rats. Two doses (SDZ, 5.6 and 50 mg/kg; NLM, 2.5 and 50 mg/kg) were injected subcutaneously into 3 groups of rats (infantile, juvenile and peripubertal). Micropunches from hypothalamic coronal slices (300 microns) were removed at various times post-injection for quantification of mu-opioid receptors with [3H]-DAGO. Acute administration of the lower dose of SDZ inhibited ligand binding almost completely by 3 h but 50% recovery was observed in all age groups by 12 h. In contrast, SDZ 50 mg/kg provided 80-100% antagonism for at least 24 h. Age-related differences in the ability of SDZ to inhibit [3H]-DAGO binding were observed in that hypothalamic mu-opioid receptors were blocked for longer periods in younger rats. Determination of receptor occupation following NLM injection confirmed that it too has prolonged duration of action but a 24 h blockade is not achieved with either dose of this antagonist. Age-related and dose-related changes in receptor occupancy were minimal compared to SDZ. These studies clarify the interaction of these antagonists at hypothalamic mu-opioid receptors and provide information which allows a clearer interpretation of results in experiments involving opioid blockade.

Age Factors↗
PubMed1992

Age-associated changes in mesenteric arteries.

Vascular disease increases in incidence with age and is the commonest cause of morbidity and mortality among elderly people. Hypertension is associated with hypertrophy of the arterial media. This study was designed to investigate changes in arterial structure that may occur with age independent of blood pressure. Collapsed sections of human mesenteric arteries (external diameter 2-3 mm) were measured using a semi-automatic image analysis system. There was a nonlinear increase in both the wall/lumen area ratio and the relative intimal area with age. There were no significant relationships between blood pressure and either the wall/lumen ratio or the relative intimal area.

Adult↗
PubMed1992

M2 muscarinic ([3H]N-methyl scopolamine) binding in micropunches of rat ventricular myocardium: characterization and modification by progesterone.

A new technique is outlined for the characterization and quantification of M2 muscarinic binding sites (receptors) in micropunches (1 mm diam.), cut from slices (350 microns), of fresh cardiac tissue using the hydrophilic antagonist [3H]N-methyl scopolamine. The use of this water-soluble ligand allows us to label, and quantify, M2 receptors on the cell surface of intact cells contained within the micropunch. We believe that cardiac micropunches offer a simple but powerful approach to the investigation of membrane receptor regulation in tissue that largely retains the in vivo cytoarchitecture. Specific binding is reversible, stereospecific, saturable, of high affinity, and has the drug specificity typical of an M2 muscarinic receptor. In rat left ventricle, Bmax was 151.2 +/- 10.3 fmol/mg protein while KD was 1.0 +/- 0.1 nM. Nonspecific binding of the ligand was very low, varying from 2.8% (at 0.27 nM) to 7.7% (at 3.58 nM). This micropunch assay was used to determine that progesterone can compete with the muscarinic ligand for the M2 receptor in vitro (IC50 = 50 x 10(-6) M). The steroids estradiol and testosterone, as well as ouabain, were without effect. Progesterone inhibited [3H]N-methyl scopolamine binding competitively (KD reduced from 1.9 to 4.3 nM) without affecting the rate of association of the ligand. However, progesterone induced a rapid dissociation of the ligand from its receptor. We conclude that the micropunch assay described here is suitable for the continued study of sex hormone effects on cardiac function.

Animals↗
PubMed1992

Fluid balance, electrolyte profiles and plasma parathyroid hormone concentrations in ewes treated with epidermal growth factor.

The infusion of low doses of epidermal growth factor (EGF) into lactating ewes stimulates water intake and urine volume. The plasma concentrations and daily output of various electrolytes in milk and urine are also affected. We have investigated this further by recording the effects of EGF infusion on fluid balance, electrolyte profiles and plasma concentrations of glucose and parathyroid hormone (PTH) in non-pregnant, non-lactating ewes. Twenty-four animals (n = 8 per group) received infusions of 100 ml saline/day into the jugular vein for 10 days (days 1-10) followed by EGF at a dose rate of either 1 (low dose), 5 (medium dose) or 10 (high dose) micrograms/kg liveweight per day in 100 ml saline for 5 days (days 11-15). All ewes then received an infusion of 100 ml saline/day for 10 days (days 16-25). Most plasma and urine samples had undetectable concentrations of EGF-immunoreactive material during the periods of saline infusion. During EGF infusion, the highest amounts of EGF infusate excreted in urine were 1.6, 5.9 and 5.6% for ewes in low, medium and high dose groups respectively. Water intake increased by 17% (0.5 kg), 88% (2.5 kg) and 89% (2.3 kg) and urine volume increased by 29% (0.5 kg), 108% (2.2 kg) and 134% (2.1 kg) for the three groups respectively. Fluid balance and feed intake were not affected by EGF infusion, but the output of faecal dry matter was reduced in ewes receiving the two higher doses of EGF. All levels of EGF resulted in hypocalcaemia, increased plasma PTH concentrations and hypermagnesaemia. There was no effect of EGF on plasma concentrations of K+ and glucose or on daily urinary excretion of K+ and Mg2+. The only response to the low dose was a reduced plasma concentration of Na+ and an increased daily urinary urate excretion. The two higher doses increased the daily urinary excretion of Na+, PO4(3-) and urate, but had no effect on the respective concentrations in plasma. Urinary Ca2+ excretion was reduced only during infusion of the medium dose of EGF. The responses of most variables were similar during infusion of the medium and high doses of EGF. All three doses of EGF induced polydipsic and diuretic responses in ewes, and infusions of 5-10 micrograms EGF/kg liveweight per day affected renal excretion of Ca2+, Na+ and PO4(3-). We interpret the responses of the kidney and plasma PTH concentrations as a means of maintaining the homeostasis of plasma profiles of electrolytes.

Animals↗
PubMed1992

Prolonged supramaximal stimulation of canine efferent sympathetic neurons induces desensitization of inotropic responses without a change in myocardial beta-adrenergic receptors.

OBJECTIVE: To investigate whether desensitization of inotropic responses elicited during prolonged efferent sympathetic neural stimulation is due to decreased responsiveness of myocardial beta-adrenergic receptors or to alterations in the efferent sympathetic neurons innervating the heart. DESIGN: Increasing doses of noradrenaline and isoproterenol were administered intravenously before and during prolonged (20 mins) stimulation of the intrathoracic efferent sympathetic nervous system of eight dogs. Cardiac augmentor responses were correlated with liberation of catecholamines by the heart. In a second group of experiments (nine dogs), right and left ventricular beta-adrenergic receptor number and affinity were determined before and during such stimulations. MAIN RESULTS: Similar ventricular augmentations were induced when isoproterenol or noradrenaline was administered before and after 20 mins of efferent sympathetic neural stimulation. During the early peak stimulation response, no further augmentations were induced by isoproterenol or noradrenaline. Liberation of noradrenaline by the heart followed a similar course after an initial peak, while noradrenaline values fell to levels which were 6% of those attained during peak response after 20 mins of continuous stimulation. The Bmax and Kd of ventricular beta-adrenergic receptors were similar before and after 20 mins of efferent sympathetic neural stimulation. CONCLUSIONS: Desensitization of ventricular inotropism that occurs during prolonged cardiac efferent sympathetic nervous system stimulation is not primarily due to alteration of myocyte cell surface beta-adrenergic receptors or to a change in myocyte responsiveness to beta-adrenergic agonists, but rather to a reduction in noradrenaline release by sympathetic efferent post ganglionic neurons presumably reflecting a reduction in the activity of these neurons despite continued stimulation.

Animals↗
PubMed1991

Interleukin 1-induced maturation of progenitor thymocytes.

Regulation of thymocyte development was assessed by culturing purified CD4-CD8- thymocytes with cytokines. Sorted CD3-CD4-CD8- adult thymocytes responded to the combination of interleukin (IL) 1 plus IL 2 without additional mitogens or co-mitogens with both cellular proliferation and cell surface expression of the T cell receptor (TcR)/CD3 complex. IL2 alone induced neither proliferation nor cell surface TcR/CD3 expression. IL1 alone was sufficient to induce cell surface TcR/CD3 without proliferation. Prior to stimulation with cytokines, the progenitor CD4-CD8- thymocytes accumulated TcR beta and CD3 gamma, delta, epsilon and zeta mRNA but TcR alpha mRNA was not detectable. Stimulation with IL 1 led to a dramatic induction of TcR alpha mRNA without an increase in the other transcripts. These studies suggest that IL 1 regulates the differentiation status of immature adult thymocytes. Nuclear run-on studies suggested that the increase in TcR alpha mRNA accumulation induced by cytokines might result from post-transcriptional accumulation.

Animals↗
PubMed1991

Clonal diversity of basic protein specific T cells in Lewis rats recovered from experimental autoimmune encephalomyelitis.

T cell lines selected from Lewis rats recovered from experimental autoimmune encephalomyelitis (EAE) respond not only to the immunodominant 72-89 epitope of basic protein (BP), but also to secondary epitopes including the I-A restricted 43-67 region of guinea pig (Gp) BP and the I-E restricted 87-99 sequence of rat (Rt) BP. The current study demonstrates at the clonal level the diversity of T cell responses to Gp- and Rt-BP in EAE-recovered rats. As predicted from the response pattern of BP-selected T cell lines, T cell clones from the lines responded to both the dominant and secondary epitopes of BP. In addition, a new majority clonal type was identified that responded to whole BP but not to epitopes represented on enzymatic cleavage fragments or synthetic peptides spanning the BP molecule. Clones representative of each of the three types of Gp-BP responses were characterized for phenotype, major histocompatibility complex restriction, and biologic activity in vivo. All of the clones were strongly CD4+ and co-expressed CD8 at modest levels as measured by both immunofluorescence and Northern blots. All three T cell specificities were I-A restricted. However, only the 72-89 responsive clone could transfer clinical EAE, due most likely to its unique ability to respond to Rt-BP. In contrast, the Gp-BP 43-67 reactive T cell clone transferred protection against EAE, whereas the whole Gp-BP reactive clone transferred delayed-type hypersensitivity response but was neither encephalitogenic nor protective. Thus, the recovery process from EAE is distinguished by an increased diversity of protective clones as well as innocuous clones that may be spawned as encephalitogenic T cells are regulated.

Animals↗
PubMed1991

The similarities and differences of migraine with aura and migraine without aura: a preliminary study.

A preliminary study was undertaken to provide clinical evidence to support the hypothesis that: "Migraine with aura, migraine without aura and aura alone are the same condition, which differ in degree rather than pathophysiology." At the City of London Migraine Clinic, 50 patients consecutively attending the clinic with a past or present history of migraine with aura were questioned. Of the 50 patients questioned 36 (70%) had a combination of migraine with aura, migraine without aura and/or aura alone; i.e. 70% had had more than one type of migraine attack. The duration, severity and frequency of attacks did not differ between migraine with and migraine without aura. Conclusion--the results support the hypothesis that migraine with and migraine without aura, and aura alone are not separate conditions, because: (1) most patients suffer from more than one type of migraine attack; (2) there are no significant differences in the characteristics of the migraine attacks in the different groups; (3) there are no significant differences in the characteristics of the subjects.

Adolescent↗
PubMed1991

Neurohumoral regulation of excitation-contraction coupling in ventricular myocytes from cardiomyopathic hamsters.

STUDY OBJECTIVE: The aim was to evaluate the regulation of contractility by autonomic stimulation in the necrotic stage of cardiomyopathy in male Syrian hamsters. DESIGN: The electrical and contractile activity of isolated intracellularly stimulated ventricular myocytes has been recorded and dose-response curves to [Ca2+]o, and to beta adrenergic, alpha adrenergic, and muscarinic agonists and antagonists were examined. EXPERIMENTAL MATERIAL: Ventricular cardiomyocytes were isolated by enzymatic dissociation of hearts from 90 to 120 day old cardiomyopathic hamsters CHF 147 and from age matched non-myopathic controls: CHF 148 or golden hamsters. MEASUREMENTS AND MAIN RESULTS: The membrane potential was recorded by suction (patch) electrodes. The contractile activity was recorded by a video system as the shortenings of the myocytes. The contractile response (EC50) to beta adrenergic stimulation (isoprenaline) showed a bimodal distribution: 60% of the myopathic myocytes responded like the controls, while in the remaining 40% the sensitivity was significantly decreased. The electrical activity and beta adrenergic receptor density were not different from the controls. The alpha adrenergic stimulation (by phenylephrine) was enhanced, while response to the muscarinic agonist carbachol (in the presence of isoprenaline) was attenuated in the myopathic cells. Sensitivity to [Ca2+]o was unchanged. CONCLUSIONS: Profound changes occur in the contractile response of myocytes from cardio-myopathic hamster to stimulation by mediators of the autonomic nervous system, which at this necrotic stage are not related to any significant changes in basal contractile response to [Ca2+]o, to the electrical activity, or to the number of beta adrenergic receptors.

Animals↗
PubMed1991

Ciliary beat frequency in newborn infants.

The ciliary beat frequencies of 31 newborns and 14 adults were measured in vitro by a photodiode method at body temperature (37 degrees C). The mean (SD) neonatal ciliary beat frequency (12.7 (0.82) Hz) was faster than that in adults (11.1 (0.84) Hz) (p less than 0.01). Increased ciliary beat frequency may be advantageous during the neonatal period.

Adult↗
PubMed1991

Use of biological response modifiers for management of renal cell carcinoma.

The approach to the treatment of patients with metastatic renal cell carcinoma has changed dramatically during the past 5 years. In the past, efforts to treat metastatic renal cell carcinoma were directed at palliation using chemotherapy, hormonal agents, or radiation therapy to control symptoms. Metastatic renal cell cancer was often resistant to these agents. With the advent of biological response modifiers, an entirely different approach is now available. Both recombinant human interferon-alpha (IFA-alpha) and interleukin-2 (IL-2) have significant activity in advanced renal cell carcinoma. Treatment with IFN-alpha can be given as outpatient therapy and provides effective disease control in a substantial minority of cases. Treatment with IL-2-based therapy, although associated with significant acute toxicity, is capable of inducing durable remissions from this otherwise lethal disease.

Carcinoma, Renal Cell↗
PubMed1991

Occurrence of sexual maturation in chronic opiate-treated female rats.

We have investigated the consequences of chronic morphine or fentanyl exposure on the timing of puberty in female Sprague-Dawley rats. The mu-receptor agonists morphine and fentanyl were either added to the drinking water or, in the case of fentanyl, in osmotic mini-pumps. Morphine and fentanyl treatment, beginning at postnatal day 22, delayed the time of the first ovulation/vaginal opening (VO). For example, morphine included in the drinking water (800 mg/l) delayed VO by 5 days. Fentanyl gave similar results but at lower concentrations (30 mg/l). Surprisingly, these treatments delayed but did not prevent VO; i.e. in the face of continued opiate treatment most rats ovulated normally. In contrast, identical doses of morphine blocked oestrous cyclicity in drug-naive adults rats. However, morphine-dependent rats, which have reached VO (and first ovulation) then became briefly acyclic before beginning regular cycles even though opiate treatment was continued. The effects of fentanyl on immature rats were identical with those of morphine, i.e. VO was delayed but ovulation occurred in spite of continued drug treatment. On the other hand, fentanyl did not prevent cyclicity subsequent to VO. Our observation that immature female rats can reach first ovulation despite chronic opiate treatment suggests that some degree of tolerance to opiates may develop. Such a mechanism could operate in normal drug-free rats, via endogenous opioid peptides, in the timing of puberty.

Animals↗