Maintenance of growth in cystic fibrosis despite reduction in pancreatic enzyme supplementation

Twenty one children with cystic fibrosis were advised to decrease their pancreatic enzyme supplement (PES) dose to less than 10,000 units lipase/kg/day. Mean PES dosage was significantly decreased in 15 patients from 18,380 to 8647 units lipase/kg/day. There were no significant changes in energy or fat intake, but there were significant increases in weight SD score, height SD score, and weight/height ratio.     

Visual detection of transport-P in peptidergic neurones

1. Hypothalamic peptidergic neurones possess an uptake process for amines (transport-P), for which prazosin is a substrate. It is characterized by a paradoxical increase in the accumulation of [³H]-prazosin when the concentration of unlabelled prazosin is increased above 10⁻⁷ M. This increase is due to activation of a proton-dependent, vacuolar-type ATPase-linked pump that is blocked by tricyclic antidepressants. This study utilized a fluorescence method to detect amine uptake in individual cells.
2. Prazosin is fluorescent but most of its emission spectrum is in the ultraviolet range. We therefore used an analogue of prazosin in which the furan ring had been substituted with a fluorescent group, BODIPY FL. This compound''s emission maximum is in the green part of the visible spectrum.
3. BODIPY FL prazosin accumulated in immortalised peptidergic neurones and the characteristic emission spectrum of the compound was evident in these cells. Accumulation of BODIPY FL prazosin was saturable and was inhibited by the tricyclic antidepressant desipramine and by unlabelled prazosin. As previously described for prazosin, uptake of BODIPY FL prazosin was blocked by cold temperature and by the organic base chloroquine. Thus, prazosin and BODIPY FL prazosin were accumulated by the same uptake process.
4. BODIPY FL prazosin accumulated in a granular distribution, which is compatible with storage in intracellular vesicles.
5. Hypothalamic cells from foetal rats in primary culture also accumulated BODIPY FL prazosin by a desipramine-sensitive process. Uptake was predominantly in neurones and glial cells did not accumulate the amine.
6. Fluorescent detection provides visual evidence for amine uptake in peptidergic neurones and should enable detailed study of the distribution of this process in the brain.

     

Catecholamine metabolism during clonidine withdrawal

Abrupt cessation of clonidine treatment in hypertensive patients may precipitate a withdrawal syndrome. Since this drug is likely to be more widely prescribed to normotensive patients with neuropsychiatric diseases, we studied neurochemical, cardiovascular, and behavioral changes upon placebo substitution in seven patients receiving clonidine (6 g/kg/day for 3 weeks) for treatment of alcohol amnestic disorder. Urinary excretion of all major catecholamine metabolites returned to pretreatment levels 3–5 days after discontinuing clonidine, without significant overshoot. The percentage increase during clonidine withdrawal of the norepinephrine metabolite normetanephrine was greater than were those of vanillylmandelic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the epinephrine metabolite metanephrine. Excretion of the dopamine metabolites homovanillic acid and 3-methoxytyramine did not change. Total plasma MHPG, heart rate, and mean arterial pressure were significantly elevated above pretreatment values 72 h after the last dose of clonidine. There was an enhancement of episodic memory compared to predrug values but no other behavioral changes were noted during clonidine withdrawal. These findings are consistent with augmented catecholamine release and central noradrenergic activation which may produce psychopathology in some psychiatric patients during clonidine withdrawal.     

Pharmacological and kinetic properties of uptake of [H]-norepinephrine by superior cervical ganglia of rats in organ culture

The increase in uptake of [³H]-norepinephrine ([³H]-NE) by superior cervical ganglia grown in organ culture was used as an index of the uptake of norepinephrine (NE) by axonal sprouts formed during organ culture. The kinetic and pharmacologie properties of NE uptake by such axonal sprouts were examined. The K_m (1.9 × 10⁻⁶M) for [³H]-dl-NE uptake by axonal sprouts was similar to that found in sympathetic nerve endings; the K_m in fresh ganglia was 8.0 × 10⁻⁶M. The intensity of inhibition by cocaine, metaraminol and phenoxybenzamine of the [³H]-NE uptake into axonal sprouts also resembled that found for nerve endings and was significantly different from that of fresh ganglion. Our observations indicate that the uptake mechanism for NE into axonal sprouts is pharmacologically and kinetically similar to the uptake mechanism in sympathetic nerve endings.     

Effect of imipramine on norepinephrine and blood pressure in enuretic boys.

The effect of imipramine, desmethylimipramine, and methscopolamine on blood pressure (BP) and plasma norepinephrine (NE) was measured in enuretic boys in a double-blind, placebo-controlled study. Measurements were obtained on the thirteenth day of medication (75 mg at bedtime). The tricyclic drugs induced a rise in diastolic BP as well as an increase in plasma NE but there was no significant relationshhip between the increments in plasma NE and BP. The plasma concentration of drug correlated with the drug-induced BP rise. This is the fifth study to demonstrate a hypertensive effect of tricyclic drugs in children in contrast to the systolic hypotension usually seen in adult patients. It is not clear from our data whether children have different cardiovascular compensatory reflexes or whether they experience a greater stimulant effect from the drug.     

Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.     

Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL- 1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.     

Central GABAergic innervation of neurointermediate pituitary lobe: biochemical and immunocytochemical study in the rat.

Activity of glutamic acid decarboxylase GluDCase, the biosynthetic enzyme of gamma-aminobutyric acid (GABA) was measured in low-speed homogenate supernatant of the neural and intermediate (neurointermediate) lobe (28--30 pmol of CO2 per microgram of protein per hr) and of the anterior lobe (2--4 pmol of CO2 per microgram of protein per hr). In the neurointermediate lobe, stalk transection reduced the GluDCase activity by more than 95%. By using an antiserum to rat brain GluDCase and the unlabeled antibody--peroxidase method of Sternberger, GluDCase immunoreactivity was localized in many terminals within the neurointermediate lobe of the hypophysis. In pars intermedia, immunoreactive terminals occurred in apposition to secretory cells and to glial cells and were near nonimmunoreactive axonal profiles; in pars neuralis they were apposed to pituicytes and to unlabeled axons including the neurosecretory terminals and were along fenestrated portal capillaries. GluDCase immunoreactive axons terminals exhibited diverse morphological features and would not have been identified as a distinct population without the GluDCase antiserum. No GluDCase-immunoreactivity was found in the anterior pituitary lobe. Stalk transection abolished GluDCase immunoreactivity in the neurointermediate lobe. These data provide biochemical and morphological evidence for a central GABAergic innervation of neural and intermediate lobes of the hypophysis.