Showing papers by "St Bartholomew's Hospital published in 1982"

Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin.

Abstract: Initially the hypothalamic factor responsible for the release of corticotropin (CRF), was thought to be a simple peptide. More recent work has led to the conclusion that CRF is a multifactorial complex. In 1979 we proposed that vasopressin, much disputed as a CRF candidate, was a major constituent of the complex, interacting with a potentiating the CRF activity of the other component(s). The recent characterization of a 41 residue ovine hypothalamic peptide capable of releasing adrenocorticotropic hormone (ACTH) in a dose-related manner has allowed us to compare its CRF bioactivity with that of vasopressin and simple extracts of the hypothalamus, and to investigate any interaction it may have with vasopressin and other hypothalamic factors in the release of ACTH. We report here that the new CRF is more potent than vasopressin in releasing ACTH. When given simultaneously with vasopressin a fourfold potentiation of CRF activity with steep dose-response characteristics were observed. It also potentiated vasopressin-free hypothalamic extracts, suggesting that a new CRF does not account for all the nonvasopressin portion of the CRF complex.

The human type-C retrovirus, HTLV, in blacks from the Caribbean region, and relationship to adult T-cell leukemia/lymphoma

Abstract: Type-C RNA tumor viruses have been implicated in the etiology of naturally occurring leukemias and lymphomas of animals. Human T-cell leukemia/lymphoma virus (HTLV) is the first human virus of this class consistently identified in association with a specific type of human leukemia/lymphoma. The isolation of HTLV was made possible by the ability to grow mature T-cells in tissue culture usually with T-cell growth factor (TCGF). We now report a cluster of adult T-cell leukemia/lymphoma among Blacks from the Caribbean in which all eight cases are positive for HTLV virus and/or antibody. These patients have disease that appears indistinguishable from Japanese adult T-cell leukemia/lymphoma which, as we have also reported, is associated with HTLV in over 90% of cases. The finding of HTLV antibodies in some of the normal population in the Caribbean and Japan, and the clustering of a specific form of T-cell leukemia/lymphoma in these virus-endemic areas, suggest that HTLV infection may be associated with the occurrence of a distinctive clinico-pathologic entity.

Calcitonin alters behaviour of isolated osteoclasts.

Abstract: Osteoclasts were incubated on a glass or plastic substrate and the effect of calcitonin (CT) on their behaviour was observed. Before exposure to CT the osteoclasts were actively motile, the cytoplasm advancing behind broad pseudopodial (lamellipodial) processes which showed intense ruflling activity. CT caused cessation of lamellipodial activity within minutes, followed by gradual fragmentation and retraction of lamellipodia. Complete osteoclast quiescence was regularly induced by concentrations of CT above 50 pg/ml, and lesser degrees of quiescence were induced at concentrations down to 10 pg/ml. This quiescent state was reversed on removing CT from the medium, and was abrogated by prior treatement of osteoclasts with trypsin. The quiescent state did not reduce the longevity of the cells in culture. nor did it affect their resistance to removal from glass by trypsin. CT showed no influence on the pseudopodial activity of osteoblasts, peritoneal macrophages or inflammatory giant cells. Osteoclast quiescence seems to be a reversible state induced by the interaction of CT with a trypsin-sensitive CT receptor, present on osteoclasts. The range of concentrations which induce partial osteoclast quiescence are within the physiological range of serum concentrations in man, and this suggests that CT plays a physiological role in the regulation of osteoclast activity. The behavioural change induced by CT in osteoclasts may help to identify the precursor cell of the osteoclast and may assist investigations into the mechanism of control of osteoclasis.

Mitochondrial encephalomyopathies: biochemical studies in two cases revealing defects in the respiratory chain.

Abstract: We describe two patients with mitochondrial myopathies who presented with complex multisystem diseases predominantly affecting the central nervous system. In both cases the disease ran a fluctuating clinical course, eventually leading to profound impairment of intellectual function. In Case 1 dementia was associated with optic atrophy, absent pupillary responses, impaired eye movements and generalized dystonic rigidity without evidence of weakness or loss of muscle bulk. In Case 2 myoclonus preceded the onset of ataxia, generalized weakness and mental confusion by several years. Biochemical studies on isolated muscle mitochondria revealed defects in the mitochondrial respiratory chain which were located at NADH-CoQ reductase in Case 1, and at cytochrome b in Case 2. This study illustrates the potential value of muscle biopsy in the diagnosis of unusual and otherwise unexplained cerebral syndromes in man, even in the absence of muscle weakness.

Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis

Abstract: It has been widely assumed that the activity of ulcerative colitis is related to differences in mucosal appearances seen at sigmoidoscopic examination. We have tested this assumption by making comparisons of the symptoms and clinical signs associated with three reproducible appearances of the rectal mucosa. By cross-tabulating 222 observations of each of 10 symptoms and signs with these sigmoidoscopic appearances it has been shown that the subdivision of hemorrhagic mucosae into those which bleed spontaneously and those which bleed only on light touching or scraping is meaningful clinically. Sigmoidoscopic appearances seemed to correlate better with clinical disease activity than histological assessment, even when quantitative, of mucosal biopsies. On the basis of this study, four variables have been suggested which, in addition to the sigmoidoscopic appearances, could form the basis of regular clinical assessment or scoring.

Stimulation of adrenal mitogenesis by N-terminal proopiocortin peptides.

Abstract: Although it was generally believed that corticotropin (ACTH) maintained both the size of the adrenal gland and its level of steroid production1, there is a growing body of evidence for a specific factor(s) distinct from ACTH which may be responsible for the stimulation of adrenocortical growth and proliferation. While direct neural influences have been proposed to be responsible for the compensatory adrenal growth following unilateral adrenalectomy2, several observations have suggested the involvement of peptides such as angiotensin3 and vasopressin4, which have other hormonal effects, or, for example, fibroblast growth factor5, which has more general mitogenic actions. Moreover ACTH inhibits cell proliferation in vitro6–8, and physiological doses in vivo cannot induce the compensatory growth and hyperplasia seen in the remaining adrenal gland after unilateral adrenalectomy9. These observations coupled with the lack of effect of chronic treatment with an ACTH antiserum on adrenal size10 and the existence of adrenal weight-maintaining activity in the plasma of patients with ACTH-secreting adenomas11, have led to the search for a pituitary factor related to ACTH which is capable of stimulating adrenal growth. We now report that peptides derived from the N-terminal non-γ-melanocyte-stimulating hormone (MSH) portion of the precursor of ACTH, proopiocortin, are potent stimulators of adrenal DNA synthesis in vitro and mitosis in vivo and may thus be involved in the physiological control of adrenal growth.

3H-noradrenaline release potentiated in a clonal nerve cell line by low-intensity pulsed magnetic fields.

Abstract: Recent studies have shown that extremely low-frequency (ELF) electric fields1 and radiofrequency amplitude-modulated electromagnetic fields2,3,25 can influence ion fluxes in neural tissue. Furthermore, the application of low-frequency magnetic (LFM) fields in the successful treatment of non-union fractures and pseudo-arthrosis has been widely reported4–6. Stimulated by these findings and the wide variety of effects reported in other biological systems7–10, we have set out to establish a model system for studying the biological effects of such low-frequencyfields that readily allows analysis of their mechanism of action. Clonal lines in tissue culture are an obvious choice for such a model, first, because the analysis is simplified by the presence of only one cell type and second, because the geometry of the biological sample can be specified to allow precise quantitation of applied field strengths and induced current densities. One such clonal line, designated PC12, is a likely candidate for such an approach as it expresses many properties of differentiated sympathetic neurones11–16, including calcium-dependent release of newotransmitters11,12,14. We report here that 3H-noradrenaline(NA) release from PC12 cells is stimulated by an inductively coupled 500-Hz LFM field with a magnitude comparable with certain cholinergic stimuli in this system.

Gonadal function in Hodgkin's disease: long-term follow-up of chemotherapy.

Abstract: A long-term study of gonadal function was conducted in 46 men and 28 women in prolonged remission of advanced Hodgkin9s disease after cyclical combination chemotherapy with nitrogen mustard, vinblastine, prednisolone, and procarbazine. The mean follow-up was 6.9 years. Azoospermia or profound oligospermia occurred in 36 of the men, but late recovery was occasionally observed. Testosterone secretion was preserved. Amenorrhoea and gonadal hormone deficiency developed in 22 of the women and never recovered. Partial or complete chemical sterilisation and gonadal hormone deficiency is currently a consequence of cure of advanced Hodgkin9s disease in most patients.

Can Future Type I Diabetes Be Predicted? A Study in Families of Affected Children

Abstract: This article examines the risk of type I (insulin-dependent) diabetes in siblings of affected children, in relation to HLA genotypes. The 288 available siblings of 160 diabetic probands were grouped according to the number of HLA haplotypes in common with their probands. HLA-identical siblings (both haplotypes in common) have an approximately 100 times greater risk of developing the disease than that in the general population, and this risk is significantly higher than that in haplo-identical siblings (one haplotype in common) P = 0.008). Thus, in Northern European populations, some 30% of HLA-identical siblings are expected to be diabetic by the age of 30 yr. The risk in nonidentical siblings (neither haplotype in common) is not significantly increased. These findings carry implications for genetic counseling and research.

Treatment of Raynaud's phenomenon by intravenous infusion of prostacyclin (PGI2)

Abstract: SUMMARY Twenty five patients with Raynaud's phenomenon due to systemic sclerosis were infused with prostacyclin (PGI2). In 88% of the patients there was objective improvement, monitored by thermography or radiometry.

Pulsatile gonadotrophin secretion in hyperprolactinaemic amenorrhoea and the response to bromocriptine therapy

Abstract: SUMMARY Serum gonadotrophin concentrations were measured every 15 min for 8 h in six patients before and at weekly intervals during initiation of bromocriptine treatment of hyperprolactinaemic amenorrhoea. Before treatment mean gonadotrophin levels were similar to those found in the normal follicular phase, but LH secretion was characterized by infrequent pulses of large amplitude. In three subjects the patterns of LH pulsatility and serum oestradiol levels returned to normal within 7 days of starting bromocriptine. The other three subjects responded with an increase in the frequency of LH pulses and mean LH levels, but little rise in oestradiol. Thus some hyperprolactinaemic subjects have a defect in the ovarian response to endogenous gonadotrophin stimulation, which may persist for a few weeks after return of prolactin levels to normal. The restoration of a normal rate of LH pulsatility with bromocriptine can occur without any change in serum oestradiol concentration.

Opiate mediation of amenorrhoea in hyperprolactinaemia and in weight-loss related amenorrhoea

Abstract: SUMMARY Endogenous opiates are involved in the control of pituitary gonadotrophin and PRL secretion, and possibly of food intake. Both hyperprolactinaemia and weight loss (especially in anorexia nervosa) are frequently associated with amenorrhoea and an absence of gonadotrophin pulsatility. Since it has been suggested that increased endogenous opiate tone may operate in both conditions, we infused high-doses of naloxone into twelve patients with amenorrhoea of whom five had hyperprolactinaemia and seven had weight-loss related amenorrhoea. Eleven of the twelve patients had low levels of oestradiol (< 50 pmol/l). Naloxone induced a marked rise in both LH and FSH levels in all of the five hyperprolactinaemic patients. In contrast, the patients with weight-loss amenorrhoea responded to naloxone with only a small or no rise in gonadotrophins. There was no consistent change in PRL in either group of patients. It is concluded that in hyperprolactinaemia, but not weight-loss amenorrhoea, there is an important endogenous opiate-mediated tonic inhibition of secretion of hypothalamic gonadotrophin releasing hormone.

Opiates control acth through a noradrenergic mechanism

Abstract: The administration of 16 mg of naloxone to six normal male subjects produced a significant rise in plasma cortisol. Pre‐treatment with the noradrenergic α1‐antagonist, thymoxamine 0.2 mg/kg, blocked this rise. It is suggested that opiate inhibition of the pituitary—adrenal axis is mediated via a noradrenergic pathway.

Opiate modulation of the pituitary‐adrenal axis: effects of stress and circadian rhythm

Abstract: SUMMARY The opiate control of the pituitary-adrenal axis has been investigated in normal subjects. The infusion of 1 mg of the met-enkephalin analogue, DAMME, led to a fall in circulating cortisol in spite of a fall in blood pressure. Conversely, 16 mg of the opiate antagonist, naloxone led to brisk and pronounced elevations in plasma ACTH, lipotrophin (LPH) and cortisol. The rise above basal levels was consistent, irrespective of whether the infusion was given at 09.00, 18.00, or 23.00 h; the peak response obtained was significantly less at 23.00 h than at either 09.00 or 18.00 h. Finally, insulin-induced hypoglycaemia (0.15 u/kg) or naloxone (25 mg) produced a similar rise in plasma cortisol which was no different when the two stimuli were combined. It is suggested that there is a constant tonic inhibition of the pituitary-adrenal axis by endogenous opiates throughout 24 h, and that the circadian rhythm of ACTH/LPH secretion is not due to changes in opiate tone. However, disinhibition of this tone is likely to be responsible, at least in part, for the rise in cortisol in response to hypoglycaemic stress.

Implantable automatic scanning pacemaker for termination of supraventricular tachycardia

Abstract: Thirteen patients suffering from reentrant supraventricular tachycardia have undergone implantation of a scanning extrastimulus pacemaker. This pacemaker is fully implanted and automatic, and it requires no external control device to activate or control it. The pacemaker is activated when tachycardia occurs. After four cycles an extrastimulus is induced with a preset coupling time from a sensed intracardiac potential, and every four cycles thereafter a further extrastimulus occurs, but on each occasion there is a decrement in coupling cycle by 6 ms until 90 ms of the cardiac cycle has been scanned by extrastimuli. When necessary, two extrastimuli can be introduced with a fixed but preset coupling time between them. Every four beats two extrastimuli are induced but the coupling time between the spontaneous cardiac potential and the first stimulus is decreased by 6 ms until 90 ms of the cardiac cycle has been scanned. The coupling time between the two stimuli is fixed throughout the scan. When termination of tachycardia occurs the successful timing variables are retained in the pacemaker memory so that at the onset of the next episode of tachycardia these settings are used first. Pacemaker pulse width, sensitivity, tachycardia trigger rate, coupling intervals for both stimuli and the use of single or double extrastimuli are all programmable transcutaneously. Three patients required single, and seven patients double ventricular premature stimuli; three patients required double atrial premature stimuli for termination of tachycardia. Despite frequent attacks of tachycardia before implantation, only two patients had a sustained attack of tachycardia after pacemaker implantation.

Circulating testosterone, sex hormone binding globulin and prolactin in women with late onset or persistent acne vulgaris.

Abstract: SUMMARY Serum testosterone, sex hormone binding globulin (SHBG) and prolactin were measured in thirty-eight women with acne which persisted or started after the age of 18 years. One or more of these levels were abnormal in 76% of patients. Increased testosterone or low SHBG were present alone or in combination in 60% of patients. This group was presumed to have a raised level of non-protein bound, metabolically-available testosterone. Hyperprolactinaemia, which was present in 45% of patients, may be important in view of the reported association with increased adrenal androgens. The hormonal abnormalities may be causally related to the acne and a greater understanding of them may lead to better treatment.

The ventricular paced QT interval--the effects of rate and exercise

Abstract: Changes in the QT and QTc intervals in 19 patients were studied at a ventricular paced rate difference of 50 beats/min. In all patients the measured QT interval shortened as the pacing rate was increased, from a mean value of 441 ms to 380 ms (p less than 0.001), but when corrected for heart rate the QTc lengthened from a mean value of 518 ms to 575 ms. In 11 patients the QT interval was measured at rest and immediately following exercise sufficient to increase the atrial rate by approximately 50 beats/min at identical ventricular paced rates. In all patients exercise-induced QT interval shortening from a mean value of 433 ms to 399 ms (p less than 0.001). These results show first that Bazett's formula is unsuitable for correction of QT interval induced by ventricular pacing, and second that heart rate and changes in sympathetic tone independently influence the duration of the QT interval. It is suggested that these results are relevant to the design of physiological pacemakers in which the duration of the QT interval influences the discharge frequency of the pacemaker and to the consideration of ventricular pacing for the treatment of abnormal repolarization syndromes.

Long-term switching to low-tar low-nicotine cigarettes.

Abstract: Summary Puffing patterns and blood measures of smoke intake were studied in 12 subjects before and after switching to low-tar (10.9 mg) low-nicotine (0.7 mg) cigarettes for 12 weeks. Puff rate, puff volume, total volume puffed per cigarette and the number of cigarettes smoked were not changed significantly after switching lo the lower yield cigarettes. The reduction in mouth-level nicotine intake (calculated from butt content) was identical to the 47 per cent reduction in the machine-smoked nicotine yields. This is in keeping with the measures of puffing in showing the absence of any tendency to compensate for the reduced yields by increasing the intensity of puffing. In contrast, plasma nicotine and cotinine levels were reduced proportionally less than the nominal yields indicating that the subjects compensated to some extent by increasing inhalation. The average reductions in plasma nicotine and cotinine were identical (30per cent). Plasma thiocyanate and COHb levels were not significantly different after switching to the lower yield cigarettes but the estimated tar intake to the lungs was reduced by about 15per cent. Although the low-yield cigarettes were rated as slightly too weak, there was no significant loss of satisfaction. The fact that subjects tolerated a 30 per cent reduction in plasma nicotine without loss of satisfaction and without puffing more intensively suggests that the increase in inhalation was not determined by a need to maintain nicotine intake. This and the, discrepancies between natural and experimental switching studies are discussed.

The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high-dose therapy.

Abstract: Subcutaneous bolus administration of cytosine arabinoside (Ara-C) has been used as an alternative to continuous intravenous infusion. However, the pharmacokinetics of subcutaneous bolus Ara-C have not been satisfactorily documented in man. The plasma concentrations of Ara-C were therefore compared following intravenous bolus injection, subcutaneous bolus injection, and intravenous infusion in five patients with acute myelogenous leukemia. A triphasic decline in plasma Ara-C levels was seen after intravenous bolus administration. Subcutaneous bolus Ara-C was rapidly absorbed (mean absorption half-life 3.4 ± minutes) and then declined biexponentially with initial and terminal half-lives similar to intravenous bolus injection. Ara-C concentrations were above the steadystate infusion levels for only 40 minutes following the intravenous bolus and for 100 minutes following subcutaneous bolus administration. The decline in plasma Ara-C concentrations continued rapidly following both these routes of administration and after five hours were approximately 10% of the steady-state infusion levels. This study demonstrates that it is not possible to achieve comparable steadystate levels of Ara-C with the same total dose given by twice or thrice daily subcutaneous bolus injection as by continuous intravenous infusion. High-dose Ara-C has been used to treat patients with relapsed acute leukemia resistant to Ara-C in conventional doses and may provide a means of overcoming such resistance. Significant concentrations of Ara-C are achieved in the cerebrospinal fluid (CSF) during conventional-dose intravenous infusions, and it seemed likely that much greater levels would be reached during these high-dose infusions. The pharmacokinetics of Ara-C in the plasma and CSF during high-dose intravenous infusions (1 g/m2) has therefore been investigated. Five patients were treated with a three-hour infusion preceded by a loading dose, and five patients received a one-hour infusion with no loading dose. The CSF Ara-C concentrations were similar during both infusions, and the concentrations in the CSF at the end of the infusions were higher than the plasma Ara-C levels obtained with intravenous infusion at conventional doses. In addition CSF Ara-C levels were measured in a patient with an Ommaya reservoir during intravenous infusion of 100 mg/m2 and 1 g/m2. It was demonstrated that Ara-C equilibrated rapidly betweenthe plasma and CSF and crossed the blood brain barrier as effectively at 1 g/m2 as at 100 mg/m2. Extrapolation of these data suggests that during therapy with high-dose Ara-C at a dose of 3 g/m2 12 hourly, Ara-C levels in the CSF in excess of 100 ng/ml (410 nmol/liter are likely to be maintained almost continuously, and should therefore be effective therapy for CNS leukemia.

TWO ACTIONS OF γ-AMINOBUTYRIC ACID ON THE RESPONSES OF THE ISOLATED BASILAR ARTERY FROM THE RABBIT

Abstract: 1 In the isolated basilar artery of the rabbit, gamma-aminobutyrate acid (GABA) (ED50 +/- s.e. mean, 2.4 +/- 1.1 x 10(-5) M) produced a relaxation, if the tone had been increased with 5-hydroxytryptamine (5-HT). 2 3-Aminoproprane sulphonic acid (3-APS) produced a similar, but smaller relaxation, while baclofen had no effect. The relaxation produced by GABA was inhibited by bicuculline. 3 Transmural electrical stimulation produced a reproducible contraction of the isolated basilar artery. In 9 out 14 preparations GABA (ED50 +/- s.e. mean, 5.6 +/- 2.1 x 10(-7) M) caused a reduction of the response, with a maximum of 49.2 +/- 4.3%. Bicuculline did not inhibit these responses to GABA. 4 Baclofen (ED50 +/- s.e. mean, 6.8 +/- 1.4 x 10(-7) M) produced a similar inhibition (47.4 +/- 3.2% maximum) but 3-APS had no effect. 5 GABA (10(-4) M) had no effect on the tone of isolated mesenteric or internal carotid arteries from the rabbit, whether or not the tone was increased with 5-HT. Similarly, GABA (10(-4) M) did not produce any change in the responses to transmural stimulation in isolated mesenteric or internal carotid arteries. 6 These findings are consistent with the presence of two types of GABA receptor on the rabbit basilar artery.

Specific IgM class antibody production following infection with cytomegalovirus.

Abstract: Specific IgM class antibody production was studied in different groups of patients with characterized cytomegalovirus (CMV) infections using a radioimmunoassay (RIA). In pregnant women, IgM antibodies were detected only following primary infection and generally persisted less than 4 months. The demonstration of CMV-specific IgM during pregnancy is therefore diagnostic of recent primary CMV infection. In patients with symptomatic CMV infections, the appearance of IgM antibody was shown to be closely related to the onset of symptoms and coincided with production of complement fixing (CF) antibody. IgM antibodies were at maximum levels 3-4 weeks after presentation but generally declined to low or undetectable levels by 3-4 months. The significance of the results of testing for CMV-specific IgM in relation to clinical and other serological findings in these patients is discussed. IgM antibody production was also demonstrated in renal transplant patients with primary infections and in 6 of 21 recipients with secondary infections. In both groups the antibodies became detectable 3-6 weeks after transplantation but the titres were much higher following primary infection. IgM antibodies persisted throughout follow-up periods of up to 2 years after transplantation in some cases.