The sequential administration of growth hormone-releasing hormone followed 120 minutes later by hexarelin, as an effective test to assess the pituitary GH reserve in man

OBJECTIVE GH deficiency, either in children or in adults, is a clinically relevant problem. The diagnosis is based on dynamic tests of GH secretion, which are clear cut on a group basis but highly problematic for individual diagnosis. The controversy surrounding the diagnosis of GH deficiency reflects the absence of a gold standard dynamic test. The synthetic hexapeptide hexarelin and GHRH stimulate GH secretion using different mechanisms. A sequential test has been devised using the administration of GHRH as first stimulus followed 120 minutes later by hexarelin. The two aims of the study were (a) to evaluate the interaction of GHRH and hexarelin, and (b) to devise a sequential test of GH reserve. DESIGN The GH stimuli used were GHRH (1 μg/kg i.v.) as a pituitary stimulus, and hexarelin (1 μg/kg i.v.) as a GH stimulus whose main action is hypothalamic. Each subject was tested twice in order to serve as his own control. Three different studies, each with two duplicate tests, were performed on separate groups of individuals: (a) GHRH followed 120 minutes later by hexarelin and on the second day hexarelin followed 120 minutes later by GHRH; (b) GHRH followed 120 minutes later by GHRH and on the other day hexarelin followed 120 minutes later by hexarelin; (c) GH 0.5 IU i.v. followed 120 minutes later by GHRH and on the other day, the same dose of GH followed 120 minutes later by hexarelin. PATIENTS Eighteen normal volunteers (12 women, 6 men) after giving informed consent. MEASUREMENTS Plasma GH levels were measured by time-resolved fluoroimmunoassay; each value shown is the mean ± SEM of n = 6. RESULTS GHRH followed 120 minutes later by hexarelin induced two episodes of GH secretion (expressed as mean GH peak, mU/l). The GHRH-mediated GH release showed a mean GH peak of 38.2 ± 13.6 mU/l and after hexarelin 120 minutes later of 56.7 ± 18.0 mU/l. The contrary sequence blocked the second stimulus, i.e. the hexarelin-stimulated GH mean peak was 54.7 ± 18.4, and the GH release 120 minutes later after GHRH was 4.8 ± 1.9 (P < 0.05 vs GHRH used as first stimulus). In the two sequential tests using the same stimulus, the second GH peak was reduced. In fact, GHRH induced a GH mean peak of 63.8 ± 21.1 mU/l as first stimulus, greater (P < 0.05) than when GHRH was administered again 120 minutes later (22.0 ± 5.9 mU/l). Similar results were obtained with hexarelin, with a first mean peak of 70.6 ± 10.3 mU/l, and a second one 120 minutes later of 13.4 ± 4.6 mU/l (P < 0.05). The blockade of the second stimulus was not due to the feed-back action of the GH released by the first stimulus. In fact, the i.v. administration of exogenous GH induced a mean GH peak of 168.0 ± 89.7 and reduced the action of GHRH administered 120 minutes later (26.1 ± 8.1). The previous administration of GH (mean peak 115.5 ± 42.0) did not alter the action of hexarelin injected 120 minutes later, showing a mean peak of 71.9 ± 11.2. The large variability in the stimulatory action of GHRH contrasted vividly with the reproducibility of hexarelin. Furthermore, individually analysed, only one of the 12 subjects tested first with hexarelin, compared to 4 out of 12 tested with GHRH as first stimulus, presented a blunted response (<13 mU/l). After the sequential stimulus there were no false negatives. CONCLUSION The sequential administration of GHRH in normal subjects and of hexarelin 120 minutes later provides separate information regarding pituitary GH reserve, of both secretagogues without mutual interference. There were not false negative results to the combined test. This sequentially delayed test may be of some value in the clinical setting for assessing pituitary GH reserve.     

A Perfluorochemical Oxygen Carrier (Fluosol-43) in a Synthetic Medium Used for Perfusion of Isolated Rat Liver

An emulsion of perfluorotributylamine (Fluosol-43) was used as substitute for the gas-carrying function of erythrocytes in a synthetic medium for perfusion of isolated rat liver. The efficiency and effect of this synthetic gas-carrier were evaluated from measurements of the concentrations of rat albumin, the unsaturated vitamin B.,-binding capacity of small-molecular-size vitamin B₁₂-binding proteins (UBBC of SBP), urea nitrogen, glucose, sodium, potassium, alanine amino transferase (ALAT) in the medium, and the incorporation of ¹⁴C-lysine into the circulating proteins. Secretion of bile, portal pressure, PO₂, PCO₂ and pH in the affluent and the effluent mediums were also measured. The results demonstrate that the oxygen-carrying capacity of the medium and the metabolic functions of the liver were higher, and the liver damage less, when the medium included Fluosol-43 than without it. The albumin synthesis and the secretion of bile were as high as has been reported for perfusions with erythrocytes. This indicates that the oxygen carried by the Fluosol-43 was utilised by the liver, and that the metabolic functions were not adversely affected during 4 h of perfusion by the medium containing Fluosol-43.     

The inhibitory power of 2-isopropoxyphenyl-N-methylcarbamate against serum cholinesterase of various individuals

Summary The inhibition of serum cholinesterase by 2-isopropoxyphenyl-N-methylcarbamate in the sera of 10 subjects was measuredin vitro at a pH of 7.4 and at 25 C. Using two different methods, spectrophotometric and titrimetric, the same rate constantk _i=0.95·10³ M^–1 min^–1 for the inhibition of cholinesterase was obtained. No individual variations in the rate constantk _i were observed.     

Hypophysenstieldurchtrennung und Geschlechtsreifung

Ohne ZusammenfassungMit 12 TextabbildungenMit Unterstützung der Akademie der Wissenschaften und der Literatur in Mainz.     

Utilizing Nottingham Prognostic Index in microarray gene expression profiling of breast carcinomas.

We report a novel approach to gene expression profiling using the Nottingham Prognostic Index (NPI) to stratify 26 patients with invasive breast carcinoma. As an aggregate index of parameters reflecting metastatic potential, growth rate, and genetic instability the NPI has distinct advantages over other clinicopathologic features used to segregate breast cancer patients. As a continuous variable it offers a responsive and sensitive means of modeling a continuum of clinical aggressiveness. Using RNA extracted from 26 tumors and cDNA microarrays with 23 343 unique genetic elements, 84 genes and expressed sequence tags were identified whose expression patterns correlated with NPI. Differential expression by immunohistochemistry (IHC) was also observed for two of three genes evaluated by this method. Correlation was determined by the Spearman rank correlation method with null distribution analysis. Among the 84 genetic elements were seven previously implicated in neoplastic progression (including the two demonstrating differential expression by IHC), 11 without specific cancer association but localized to chromosomal sites whose loss or gain has been identified in cytogenetic studies of breast carcinoma, and 73 not previously associated with breast carcinoma. Collectively, the expression patterns of these 84 elements have potential to distinguish high and low NPI patient samples. These data add support to the assertion that prognostic groups of breast carcinoma are reflected in distinguishable expression profiles of a limited set of genes.     

Midline facial defects with hypertelorism and low-grade astrocytoma: a previously undescribed association.

We report on a child with midline facial defects with hypertelorism (MFDH), median cleft lip, sphenoidal ventriculocele, partial agenesis of the corpus callosum, and low-grade astrocytoma in the cervicomedullary junction. This combination of findings has not been reported previously. Although this association might be casual, it demonstrates a relationship between disorders of frontonasal process and posterior fossae. It also suggests that individuals with MFDH might require a prospective follow-up with central nervous system magnetic resonance imaging.     

Number of potential reversals (turns) and amplitude of the pattern of electrical activity of the abductor pollicis brevis muscle in patients with neurogenic diseases

We have quantified the pattern of electrical muscle activity at a force of 0.3 kg, 30% of maximum force, and maximum force in the abductor pollicis brevis muscle of 21 patients with neurogenic disorders (10 with carpal tunnel syndrome, 9 with polyneuropathy and 2 with motor neurone disease) and of 15 normal subjects. In normal subjects, the number of turns, the mean amplitude and the ratio between them were independent of maximum force, age and sex of the subjects. In 21 patients with neurogenic disorders, the cumulative diagnostic yield of the analysis of the pattern of electrical activity was 86% compared to the diagnostic yield of the mean duration and mean amplitude of individual motor unit potentials of 90%. These diagnostic yields in a small distal muscle were of the same order as those of the brachial biceps muscle in previous studies.