Cyclosporine A alleviates severe anaemia associated with refractory large granular lymphocytic leukaemia and chronic natural killer cell lymphocytosis

Large granular lymphocytic (LGL) leukaemia and chronic natural killer cell lymphocytosis (CNKL) are chronic indolent disorders often associated with neutropenia and constitutional symptoms. Severe anaemia occurs in about 20% of patients and is currently treated with corticosteroids followed by oral cyclophosphamide in non-responders. 30% of patients fail initial measures, and salvage therapy is inadequate. We describe three transfusion-dependent patients (two with T-LGL leukaemia, one with CNKL) refractory to corticosteroids, cyclophosphamide, and in one case fludarabine. Cyclosporine A (CSA) initiation resulted in prompt transfusion-independence and was well tolerated in all patients, making it an attractive alternative therapy for this disorder.     

Features of pediatric head injury in Hong Kong

Head injury in children causes special concern in most communities. From 1989 to 1994, 2,785 children younger than 16 years old were admitted to our neurosurgical service because of head injury. Fall from a height was the major cause of head injury leading to admission in infants and children in preschool age groups, whereas traffic-related or bicycle-related accidents were more likely to be the cause of head injury for those aged 11–15 years. In all age groups there was a male preponderance. The overall mortality was 0.6%. Traffic-ralated accidents caused more severe injury and accounted for 67% of all fatalities. For patients under 6 years old, about 40% of head injuries occurred at home. Preventive measures for pediatric head injury in Hong Kong are suggested.     

Memory following cholinergic (NBM) and noradrenergic (DNAB) lesions made singly or in combination: potentiation of disruption by scopolamine

Groups of rats were trained on either delayed matching or nonmatching to position tasks, then divided into four subgroups and given the following bilateral lesions: (a) SHAM [vehicle injection into the nucleus basalis magnocellularis (NBM) and dorsal noradrenergic bundle (DNAB)], (b) DNAB (6-hydroxydopamine lesion of the DNAB, vehicle into the NBM), (c) NBM (quisqualic acid lesion of the NBM, vehicle into the DNAB) and (d) DUAL (neurotoxin lesions of both DNAB and NBM). Following postoperative recovery, the DUAL lesion subjects were slightly impaired, but by the seventh day of testing all groups were performing at similar levels. This strongly suggests that quisqualate lesions of the NBM are not sufficient to produce severe and lasting mnemonic disorders resembling those seen in Alzheimer's disease (AD). These data also indicate that the noradrenergic system may not be of critical importance with respect to cognition. It was reasoned that an additional anticholinergic treatment might exacerbate an underlying deficiency. All groups were injected, peripherally, with the cholinergic antagonist scopolamine (0-0.5 mg/kg). This drug dose-dependently disrupted performance in all groups. Moreover, the highest dose had a marked effect in the DUAL group, impairing performance even when no mnemonic burden was present (at zero delay). The results suggest that cholinergic NBM and noradrenergic DNAB lesions produce only transient mnemonic deficiencies. A combination of the two can be disruptive, but longer term task (or reference) memory is the primary process affected, and only under certain conditions. The implication of these findings to research concerning animal models relating to Alzheimer's disease is discussed.     

Effect of glycated albumin on phenytoin binding in elderly patients with type II diabetes mellitus

We evaluated the effect of glycated albumin on phenytoin protein binding in 36 elderly (age range 63-94 yrs) patients with type II diabetes mellitus (DM) under diet management. Serum was spiked with 15 mg/L phenytoin and incubated. A serum ultrafiltrate was obtained from each sample for determining total and free phenytoin concentrations. Glycated hemoglobin was determined by boronate-affinity chromatography, and glycated albumin was separated from nonglycated fractions with boronate-agarose gel. Glycated hemoglobin in the study group ranged from 4.3-14.6% (mean 7.8 +/- SD 2.1%) and glycated albumin ranged from 3.7-12.5% (7.4 +/- SD 2.6%). We observed no correlation between glycated albumin and the percentage of free phenytoin (r2 = -0.14; p = 0.419). The concentration of nonglycated albumin ranged from 0.66-4.28 g/dl (mean 3.45 +/- 0.67 g/dl) and was calculated from measured total and glycated albumin concentrations. A correlation between the free fraction of phenytoin and nonglycated albumin was not demonstrated (r2 = 0.22, p = 0.22). In addition, a correlation was not observed between total glycated albumin and the free fraction of phenytoin (r2 = -0.095; p = 0.58). We conclude that elderly patients with type II DM under diet control do not have significant alterations in phenytoin protein binding. The use of total serum phenytoin levels therefore appears appropriate for determining phenytoin dosages in elderly patients with well controlled type II DM.     

Calcium Concentration-dependent Mechanisms through which Ketamine Relaxes Canine Airway Smooth Muscle

Background: Ketamine is a potent bronchodilator that, in clinically used concentrations, relaxes airway smooth muscle in part by a direct effect. This study explored the role of calcium concentration (Ca2+) in this relaxation.

Methods: Canine trachea smooth muscle strips were loaded with the fluorescent probe fura-2 and mounted in a spectrophotometric system to measure force and intracellular calcium concentration ([Ca2+]i) simultaneously. Calcium influx was estimated using a manganese quenching technique. Cyclic nucleotides in the airway smooth muscle strips were measured by radioimmunoassay.

Results: In smooth muscle strips stimulated with submaximal (0.1 micro Meter) and maximal (10 micro Meter) concentrations of acetylcholine, ketamine caused a concentration-dependent decrease in force and [Ca2+]i. The sensitivity of the force response to ketamine significantly decreased as the intensity of muscarinic receptor stimulation increased; the median effective concentration for relaxation induced by ketamine was 59 micro Meter and 850 micro Meter for tissue contracted by 0.1 micro Meter or 10 micro Meter acetylcholine, respectively (P < 0.05). In contrast, the sensitivity of the [Ca2+] sub i response did not depend on the intensity of muscarinic receptor stimulation. Ketamine at 1 mM significantly inhibited calcium influx. Ketamine did not significantly increase cyclic nucleotide concentrations.     

Regional haemodynamic effects of human and rat adrenomedullin in conscious rats.

1. Male, Long Evans rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters to permit assessment of the regional haemodynamic responses to human and rat adrenomedullin, to compare the responses to human adrenomedullin to those of human alpha-CGRP in the absence and presence of the CGRP1-receptor antagonist, human alpha-CGRP [8-37], and to determine the involvement of nitric oxide (NO)-mediated mechanisms in the responses to human adrenomedullin, relative to human alpha-CGRP. 2. Human and rat adrenomedullin (0.3, 1, and 3 nmol kg-1, i.v.) caused dose-dependent hypotension and tachycardia, accompanied by increases in renal, mesenteric and hindquarters flows and vascular conductances. At the lowest dose only, the hypotensive and mesenteric vasodilator effects of rat adrenomedullin were significantly greater than those of human adrenomedullin. 3. Human alpha-CGRP at a dose of 1 nmol kg-1 caused hypotension, tachycardia and increases in hindquarters flow and vascular conductance, but reduction in renal and mesenteric flows, and only transient vasodilatations in these vascular beds. These effects were substantially inhibited by human alpha-CGRP [8-37] (100 nmol kg-1 min-1), but those of human adrenomedullin (1 nmol kg-1) were not; indeed, the mesenteric haemodynamic effects of the latter peptide were enhanced by the CGRP1-receptor antagonist. 4. In the presence of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 183 nmol kg-1 min-1), there was only a slight, but significant, inhibition of the hindquarters hyperaemic vasodilator effect of human adrenomedullin, but not that of human alpha-CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Infusion clearance of subcutaneous iothalamate versus standard renal clearance

 Accurate, timed urine collections for the measurement of glomerular filtration rate (GFR) may be impractical in infants or in patients with urological abnormalities. GFR may be measured without urine collection using a constant subcutaneous infusion of iothalamate. We compare the infusion clearance with conventional renal clearance in 14 children and young adults. The mean clearance ratio (infusion clearance/renal clearance ± 1 SD) was 0.99±0.1 and the mean discrepancy between the two methods was 8.5%±4.7%. The 95% limits of agreement for the ratio of the two methods are 0.83–1.23. These data indicate that subcutaneous infusion of iothalamate is a practical method for measuring GFR in children without a urine collection. Received March 18, 1996; received in revised form February 12, 1997; accepted March 26, 1997