Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

Beta-adrenergic receptor changes during coronary artery bypass grafting

To evaluate whether the function of beta-adrenergic receptors, essential to the biologic activity of catecholamines, is altered during coronary artery bypass grafting, we measured, in 16 patients undergoing myocardial revascularization, the density and the affinity of lymphocyte beta-adrenergic receptors before anesthesia induction (control) and at the end of cardiopulmonary bypass. Variations in the density and affinity of beta-adrenergic receptors were determined in vitro. Repeated determinations of plasma epinephrine and norepinephrine concentrations were also performed. Overall, no significant modification was observed in mean density and affinity of beta-adrenergic receptors at the end of cardiopulmonary bypass when compared with control values. However, a significant decrease (p less than 0.05) in affinity for isoproterenol was found in the six patients who had high catecholamine levels during cardiopulmonary bypass. In contrast, no significant modification of beta-adrenoreceptor affinity for isoproterenol was observed in the 10 patients who did not have this degree of adrenergic activation. In addition, beta-adrenoreceptor affinity for isoproterenol was decreased in the three patients in whom intraaortic balloon pumping was mandatory after discontinuation of cardiopulmonary bypass. We suggest that this decreased affinity of lymphocyte beta-adrenergic receptors could be related, at least in part, to a sustained adrenergic activation occurring in some patients during cardiopulmonary bypass.     

Opposite effects of angiotensin-II and corticotropin on bovine adrenocortical cell steroidogenic responsiveness.

The long-term effects of angiotensin-II (A-II) and corticotropin (ACTH) on bovine adrenal fasciculata cells (BAC) were studied. Cells were pretreated for 3 days with either A-II or ACTH followed by an examination of the acute steroidogenic response to both hormones as well as the ability to convert several steroid precursors to cortisol and corticosterone. ACTH pretreatment caused a marked increase in cortisol output associated with a decrease in corticosterone secretion in response to both hormones leading to a 50-fold decrease in the corticosterone/cortisol ratio compared to control cells. After incubation with saturating concentrations (5 X 10(-5) M) of 22 R-hydroxycholesterol, pregnenolone or progesterone, ACTH-pretreated cells produced more cortisol than corticosterone whereas the contrary was observed in control cells. However, the conversion of 17 alpha-hydroxyprogesterone and 11-deoxycortisol to cortisol by ACTH-pretreated cells was lower than by control cells. Thus, the main effects of ACTH were a marked increase of 17 alpha-hydroxylase and a small but significant decrease of 21-hydroxylase and 11 beta-hydroxylase activities. A-II pretreatment produced, in a concentration-dependent manner, a down-regulation of its own receptors and homologous and heterologous steroidogenic desensitization. At maximal concentrations (10(-6) M) A-II reduced by 70% its own receptors while the steroidogenic response to A-II and ACTH was reduced by 95% and 75%, respectively. However, the coupling of A-II receptors to phosphoinositide pathway and to Ca2+ influx, as well as its potentiation effect on ACTH-induced cAMP production were similar in control and A-II pretreated cells. Moreover, the conversion of several steroid precursors to corticosterone was similar in control cells and A-II-pretreated cells, whereas the conversion to cortisol was reduced by approximately 30% due mainly to a decrease of 17 alpha-hydroxylase activity. Thus, the marked steroidogenic desensitization induced by A-II is most likely related to some alteration located beyond the activation of the two branches of the phosphoinositide pathway and before the first steps of steroidogenesis.     

Biodosimetry for a radiation worker using multiple assays.

Four state-of-the-art biodosimeters--GPA mutations, chromosome translocations, micronuclei, and dicentrics--were used to evaluate a radiation worker who believed that the official dosimetry records substantially underestimated his actual dose. Dosimetry records indicated that the worker received 0.56 Sv during a 36-y employment history, always within the dose limits. In contrast, the worker believed that his dose equivalent may have been more than 2.5 Sv because much of the exposure was received during the early days of health physics when dosimetry capabilities and practices were not as good as they are today. Because there are no biodosimetric assays that have been fully validated for the long-term low-level exposures received by the worker, we did not expect to obtain particularly useful point-estimates of dose. However, because the discrepancy between the dosimetry records and the worker's belief was so large, we believed that biodosimetry using multiple assays together with probabilistic assessment of the uncertainties would provide useful insight. Results showed that the frequencies of chromosome translocations and GPA mutations (stable biodosimeters) were significantly elevated when compared with those for unexposed controls. Our analysis suggests that dose-equivalent estimates in the approximately 0.4 to approximately 2 Sv range (which include the value in the dosimetry records) cannot be confidently excluded at this time based on biodosimetry; however, a value greater than 2.5 Sv appears unlikely. Important new information on the temporal stability of chromosome translocations is also presented.     

Midazolam: kinetics and effects on memory, sensorium, and haemodynamics.

This study aimed not only to compare the pharmacokinetics of oral and intravenous doses of the new water-soluble benzodiazepine, midazolam, but also to study the effects on haemodynamics, sensorium, and memory performance. Eight normal human volunteers each received a single 15 mg dose of midazolam base orally and intravenously in randomized sequence 2 weeks apart. Serial venous samples were obtained for 12 h after dosing. Vital signs, sensorium testing and memory testing using word lists were also performed. Computerized non-linear least squares curve-fitting of the two-compartment open model to the oral and intravenous data simultaneously yielded the following estimates: V1, 0.33 1 kg-1, VdSS, 1.08 1 kg-1, t1/2,lambda, 0.10 h, t1/2,Z, 1.89 h, ka 1.17 h-1 and bioavailability, 49%. The intravenous dose decreased the systolic pressure 22 mm Hg during the first half-hour and the oral dose had 50% less effect. Most subjects became drowsy halfway through the infusion and were only rousable to voice by its end. The sensorium was clear by 2-3 h. After oral dosing the peak sensorium effects of ataxia-dysarthria were seen at 30 min and had cleared by 2 h. Memory testing showed that memory acquisition was markedly impaired for at least 90 min after the intravenous dose and slight recovery was apparent at this time after the oral dose. Memory performance was proportionately more impaired than the sensorium score. We conclude that: midazolam kinetics are characterized by rapid absorption, but incomplete bioavailability and rapid elimination, midazolam intravenously may lower blood pressure significantly, and the level of consciousness correlates poorly with the degree of memory impairment.     

Kinetic and biologic properties of recombinant ChIFN-gamma expressed via CELO-virus vector.

In this study, a replicative fowl adenovirus serotype 1 (CELO) recombinant expressing chicken interferon-gamma (ChIFN-gamma) was constructed. In the engineered recombinant, the ChIFN-gamma gene was placed under the control of cytomegalovirus (CMV) promoter. The ChIFN-gamma expression cassette was inserted in the right end of the CELO genome (D fragment), which was able to carry the largest insertion of foreign DNA without affecting the replication functions of the vector. The recombinant ChIFN-gamma (rChIFN-gamma) produced in the CELO-virus expression system was characterized by comparing its biologic activities with that of rChIFN-gamma produced via the baculovirus expression system (Bac-ChIFN-gamma). CELO-ChIFN-gamma inhibited the replication of cytolytic virus in chicken embryo fibroblasts (CEFs) and activated macrophages in a better manner than did Bac-ChIFN-gamma . Moreover, the in vitro and in vivo stability of the CELO-derived rChIFN-gamma was considerably higher than that of the Bac-ChIFN-gamma. The CELO-ChIFN-gamma recombinant vector was able to replicate in vitro in the loghorn male hepatoma (LMH) hepatocyte cell line and to produce detectable levels of recombinant cytokine in supernatant as early as 90 min post-infection. Therefore, the CELO-virus expression system is an appropriate system for high-level expression of biologically active and stable ChIFN-gamma.