Biomedical subjects
C Chapman
Publications and source records attributed to C Chapman.
Activation of kappa-opioid receptors inhibits depolarisation-evoked exocytosis but not the rise in intracellular Ca2+ in secretory nerve terminals of the neurohypophysis.
Nerve endings of the magnocellular neurohypophysial neurones possess kappa-opioid receptors. Using a preparation of isolated terminals from the neurohypophysis we studied kappa-opioid effects on secretion of oxytocin and vasopressin and on intracellular Ca2+ concentration ([Ca2+]i) measured fluorimetrically or using digital video imaging with Fura-2. The dihydropyridine Ca(2+)-channel antagonist nicardipine reduced [Ca2+]i responses to K(+)-depolarisation (30-40 mM K+) by 55-75% and inhibited evoked secretion of oxytocin and vasopressin to a similar extent. The selective kappa-receptor agonist D-Pro10 Dynorphin A 1-11 (DPDYN) substantially inhibited K+ evoked secretion of oxytocin by 40-90% and secretion of arginine vasopressin (AVP) by 20-50%. DPDYN caused only a 10% reduction in the average total population [Ca2+]i response to K+ depolarisation. No sub-population of inhibitory responses was observed when samples of individual terminal [Ca2+]i responses were examined with imaging. Although kappa-receptors are coupled to Ca(2+)-channels at neuronal somata our data suggest that alternative effector mechanisms operate in these secretory nerve endings.
Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. The Medical Research Council Working Party for Leukaemia in Adults.
Both melphalan and cyclophosphamide increase life expectancy in patients with myelomatosis, but few large randomised studies have compared combination chemotherapy regimens with these single agents. In the Vth MRC myelomatosis trial, the survival of 314 patients randomised to receive ABCM (adriamycin, BCNU, cyclophosphamide, and melphalan) as first-line treatment was significantly longer than that of 316 patients given intermittent melphalan (M7) (p = 0.0003). The 75%, median, and 25% survivals were 7, 24, and 42 months, respectively, with M7 and 10, 32, and 56 months, respectively, with ABCM. Stable disease with few symptoms (plateau) was achieved by 61% of patients given ABCM and 49% of those given M7 (p = 0.004). Myelotoxicity was comparable between regimens. Cross-trial analysis suggests that M7 is comparable to melphalan and prednisone or melphalan, prednisone, and vincristine; that the efficacy of ABCM in the Vth trial and VIth MRC trials is comparable; and that ABCM gave better survival than intermittent melphalan regimens in the prognostic groups analysed. The results indicate that ABCM is an acceptable regimen that is more effective than melphalan, with or without prednisone, for first-line treatment of myelomatosis.
Naloxone prevents interruption of parturition and increases plasma oxytocin following environmental disturbance in parturient sows.
Experiments in rodents have suggested that environmental disturbance can disrupt parturition through an opioid-mediated inhibition of oxytocin secretion. To test this hypothesis in a large animal model, 14 primiparous female pigs were allowed to commence parturition in a strawed pen. Five of these gilts were allowed to continue parturition undisturbed in this pen, while the remainder were moved to a farrowing crate immediately after the birth of the first piglet. At this time, pigs were injected subcutaneously with either the opioid antagonist naloxone (n = 4; dose 1 mg/kg body weight) or saline (n = 5). Whereas the undisturbed pigs all gave birth to a second piglet within 53 min, in three of the five disturbed and saline-treated pigs no further births occurred for 2 h, at which time oxytocin was administered subcutaneously to restart parturition. By contrast, all of the naloxone-treated pigs gave birth spontaneously within 2 h, although mean interbirth intervals were still prolonged compared to undisturbed pigs. In a second experiment, nine primiparous female pigs with chronic catheters preplaced in the external jugular vein were similarly moved after the birth of their first piglet and either injected with naloxone (n = 5) or saline (n = 4). Again, parturition was interrupted in three out of four saline-treated animals for at least 2.5 h, but resumed promptly when exogenous oxytocin was administered. Plasma concentrations of oxytocin in these pigs were significantly lower than in naloxone-treated pigs, five out of six of which gave birth spontaneously to one or more piglets within 2.5 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of age, sex and the oral contraceptive on the platelet membrane fibrinogen binding site (glycoprotein IIb/IIIa).
1. We have studied the effects of age, sex and the oral contraceptive pill on platelet fibrinogen 'receptor' density (Bmax) and affinity (Kd). 2. [125I]-fibrinogen binding to gel-filtered platelets was assessed after stimulation with adenosine 5-diphosphate (ADP) and thrombin in 60 normal subjects; 37 females and 23 males. 3. For both agonists there was no significant difference in Bmax or Kd between the sexes. A trend towards increasing affinity (reduced Kd) with age was noted in the female group following ADP stimulation. This was not considered to be physiologically relevant. In the group as a whole no significant relationship of Bmax and Kd with age was demonstrated. 4. A further group of eight women taking low dose oestrogen combined oral contraceptive pill were studied on days 7, 14, 21 and 28 of the treatment cycle and compared with eight women with regular ovulatory cycles. No significant variations in Bmax or Kd were detected within or between cycles in these two groups.
Reduced erythropoietin response to anaemia in elderly patients with normocytic anaemia.
We studied the effect of age on the relationship between haemoglobin and serum erythropoietin (EPO) levels in anaemic patients. 568 patients over 70 years of age were compared with 137 patients under 70 and a reference group of 144 patients of all ages with proven iron deficiency. EPO was measured using a radioimmunoassay. We found that elderly patients with a normocytic anaemia (N = 375) had a statistically lower EPO response than younger patients with normocytic anaemia (N = 61) (p < 0.05) or patients of all ages with iron-deficiency anaemia (p < 0.05). There was no difference between the sexes. Elderly patients with microcytic or macrocytic anaemia had a normal EPO response as compared to the "gold standard" of iron deficiency. These findings suggest that a proportion of elderly patients with normocytic anaemia has an impaired EPO response.
Splenic rupture following splenic vein thrombosis in a man with protein S deficiency.
We present a case of spontaneous splenic rupture in a man with splenic vein thrombosis. The splenic vein thrombosis appears to have been caused by protein S deficiency. We are not aware of this having been described before.
Glomerular and tubular proteinuria in type 1 (insulin-dependent) diabetic patients with and without retinopathy.
We compared the urinary excretion of albumin, transferrin, N-acetyl-beta-D-glucosaminidase and alpha-1-microglobulin in 78 Type 1 (insulin-dependent) diabetic patients: 39 with retinopathy and 39 without. The two groups were matched for age, sex and duration of diabetes. The patients with retinopathy had increased excretion (median and range) of albumin [1.7(0.3-399.1) versus 1.0(0.3-116.6) mg/mmol creatinine, P less than 0.05], transferrin [114.2 (4.1-37126.2) versus 33.4 (1.0-4176.7) micrograms/mmol creatinine, P less than 0.01] and N-acetyl-beta-D-glucosaminidase [23.8 (1.1-119.1) versus 15.0 (0.1-65.1) mumol/h/mmol creatinine, P less than 0.05] but not alpha-1-microglobulin. Transferrin excretion correlated with albumin excretion. The prevalence of increased transferrin excretion (transferrinuria) was greater than that of microalbuminuria in patients both with and without retinopathy (P less than 0.01 in both cases). Urinary transferrin seems likely to be predominantly of glomerular origin and merits prospective longitudinal evaluation as a potential index of the microangiopathic process.
The role of alpha interferon in the pathogenesis of GVHD.
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125I-fibrinogen binding to platelets in myeloproliferative disease.
Recent reports have suggested a variation in the density and affinity of fibrinogen binding sites in platelets from patients with myeloproliferative disorders (MPD) which may reflect platelet functional abnormalities in these subjects. We have investigated the binding of 125I-fibrinogen (125I-Fb) to gel-filtered platelets from a large relatively homogeneous group of patients with MPD compared to normal age matched controls. Twenty-two of the patients investigated had polycythaemia vera and four essential thrombocythaemia. The maximal density and affinity (Kd) of 125I-Fb binding was assessed by saturation analysis in gel-filtered platelets (GFP) stimulated with either 10 microM ADP or 150 mU thrombin. In addition the functional significance of the binding sites was studied by evaluating the response of GFP from the two experimental groups by assessing the effects of increasing concentrations of added fibrinogen on the response to 10 microM ADP using standard light transmission aggregometry. In both groups the density of fibrinogen binding sites expressed in response to thrombin stimulation was significantly higher (approximately 2-3 fold) than that found in response to ADP. However, fewer binding sites were detected in the MPD group as compared with the control group in response to both ADP and thrombin. The Kd for 125I-Fb was similar for both agonists in normal controls and was significantly lower than that found in the MPD subjects. Although the 125I-Fb binding study results indicate a significant reduction in both the number and affinity of fibrinogen binding sites in patients with myeloproliferative disorders, the clinical and functional significance of these findings remain uncertain.
Monozygotic twins with seizures. Shared characteristics.
Eleven sets of monozygotic twins with idiopathic seizure disorders seen at Children's Hospital, Boston, Mass, were reviewed Nine twin pairs were concordant for seizures. A marked correlation in the precise timing of onset of seizures was found; three sets of twins had their first clinical seizures within a 24-hour period of one another. The clinical features of the seizures and the electroencephalographic patterns, including the location of focal discharges, were strikingly similar in the twin pairs. The significance of these findings in suggesting aberrant processes that may contribute to epileptic syndromes is discussed.
Role of medial preoptic GABA neurones in regulating luteinising hormone secretion in the ovariectomised rat.
The role of GABA neurones in the medial preoptic area (MPOA) in regulating the activity of the luteinising hormone-releasing hormone (LHRH) neurones projecting to the median eminence was investigated in the conscious ovariectomised rat. Plasma luteinising hormone (LH) concentrations were measured while (1) endogenous GABA release from the MPOA was monitored with the technique of microdialysis, or (2) activity at the GABA receptor was modulated by local infusions into the MPOA. Microdialysis studies revealed a fluctuating level of GABA release in the MPOA which did not correlate with pulsatile LH secretion. Infusion of 10 microM GABA (n = 8) or bicuculline methiodide (BMI, n = 6) into the MPOA, at a rate of 1 microliter/30 min, significantly inhibited mean LH concentrations (P less than 0.05-0.001) and LH pulse frequency (P less than 0.05-0.001) compared with controls (n = 8). LH pulse amplitude was not significantly altered by infusion of GABA (P greater than 0.05) while too few pulses were found after BMI treatment to enable statistical analysis. Infusions of GABA into the ventral half of the MPOA had a more significant inhibitory effect upon LH secretion compared with dorsal infusions (P = 0.012). A similar relationship did not exist for BMI infusions. These results show that acute changes in preoptic GABA receptor occupancy result in disruption of pulsatile LH secretion in the ovariectomised rat. This suggests that GABA neurones provide a tonic input important for the functional integrity of the neural network controlling LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
A technique for managing terminally ill ovarian carcinoma patients.
A patient with terminal ovarian carcinoma was admitted with malnutrition, abdominopelvic pain, and an inoperable complete small bowel obstruction after failing standard therapy and several experimental regimens for her disease. Despite this serious situation, she had an overall high performance status. Instead of administering intravenous narcotics, providing nasogastric suction, and giving other supportive care to make her apparently imminent death as comfortable as possible, her malnutrition was treated with total parenteral nutrition administered through an indwelling central venous catheter during the night hours only. The pain was successfully treated with an indwelling epidural catheter with the continuous infusion of morphine through a portable pump carried by a shoulder strap. The intestinal obstruction was relieved by a percutaneous endogastric tube which drained spontaneously into a leg bag. This regimen allowed the patient complete daytime mobility. She remained active, largely at home, with slowly progressing tumor until her death 9 months after the institution of this supportive care.
Storage and preparation of samples for erythropoietin radioimmunoassay.
The evaluation of a radioimmunoassay for erythropoietin developed using recombinant material as immunogen and radiotracer is presented. A series of serum samples prepared and stored under varying conditions showed that immunoreactive erythropoietin levels were stable at room temperature for at least 10 days and at -20 degrees C for 5 months. The optimum time for separating sera from samples was between 6 and 24 h after venepuncture. Serum EPO values were significantly higher than those measured in heparin or potassium EDTA plasma.
Changes in serum erythropoietin levels during allogeneic bone marrow transplantation.
Serial serum erythropoietin levels were measured in 10 consecutive patients undergoing allogeneic bone marrow transplantation. Observed erythropoietin levels are compared with those predicted from a large control population of anaemic patients not receiving chemotherapy. There was an initial acute rise in serum erythropoietin, peaking between days 1 and 4 after marrow transfusion, which was unrelated to changes in haemoglobin concentration. Patients maintained serum erythropoietin concentrations at around twice the predicted level for the first 2 weeks following transplantation, with a gradual fall into the expected range by wk 3. Erythropoietin levels did not change with episodes of bacterial infection or acute graft-versus-host disease. A patient with severe aplastic anaemia had initial successful engraftment with normalisation of erythropoietin levels, but showed a marked and amplified rise in erythropoietin 2 wk before falling peripheral blood counts indicated failure of the bone marrow graft.
Progressive renal toxicity due to ifosfamide.
A prospective and follow up study of renal tubular and glomerular function in 11 children receiving ifosfamide treatment was conducted. Each child received between four and 14 courses of ifosfamide, given as a continuous infusion of 3 g/m2 over 24 hours for two or three days. Evidence of renal toxicity was seen in all patients. There was a treatment related rise in urinary tubular markers (N-acetyl-glucosaminidase and alpha 1 microglobulin). Recovery was limited, so that by the fourth course of treatment all values remained abnormal. There was an associated treatment related reduction in plasma phosphate concentration. Urinary albumin also showed a treatment related rise, but with fewer abnormal values. Electrophoresis was used to confirm tubular or glomerular patterns. Glomerular toxicity was less severe and occurred in fewer patients. The follow up study showed persistence of tubular damage in all seven patients examined, and there was evidence of glomerular damage in five of the seven children. Children receiving ifosfamide need to be carefully monitored for renal toxicity both during treatment and at follow up.
Three cases of 16q duplication.
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Field methods for capture and measurement of three monkey species in Costa Rica.
A total of 54 free-ranging monkeys were captured and marked in Santa Rosa National Park, Costa Rica, during May 1985, and an additional 17 were captured during March 1986. The animals were darted using a blowpipe or a CO2 gun. The drugs used were Ketaset, Sernylan and Telazol. Ketaset was effective for Cebus capucinus but unsuccessful for Alouatta palliata and Ateles geoffroyi. Sernylan was successful for A. geoffroyi and A. palliata but is no longer commercially available. Telazol proved to be an excellent alternative capture drug for both A. palliata and A. geoffroyi.