[A Contribution to the Current Debate on Public and Global Health in Germany]. / Public und Global Health in Deutschland - Eine Stellungnahme zur aktuellen Debatte.

In June 2015 the German Academies of Science and Technology published a report on the structures, developments and challenges in the field of public and global health in Germany. Its call for a strengthening of public and global health in Germany was well received among researchers and practitioners in the field. At the same time criticism arose. Key controversies relate to the future institutional set-up of public and global health research in Germany, the consideration of the social determinants of health versus biomedical and technological approaches, the need for further research versus the need for political implementation of what is already known, and the consideration of the political context, such as intellectual property rights. This contribution provides an overview on the debate and lays down the perspective of the German Medical Students' Association (bvmd) and the Globalisation and Health Initiative (GandHI), putting forward demands regarding the role of public and global health in medical education in Germany.

Simple isotope dilution assay for propionic acid and isovaleric acid.

A gas chromatographic-mass spectrometric method is described for the assay of propionic acid and of isovaleric acid in physiological fluids by isotope dilution. The acids are derivatized to the pentafluorobenzyl esters to decrease volatility to render them suitable for GC-MS analysis. The following reference values were found. Propionic acid: plasma 0.54 +/- 0.38 mumol/l (n = 13, range 0.03-1.38 mumol/l), urine 1.7 +/- 1.6 mumol/mmol creatinine (n = 9, range 0.1-4.9 mumol/mmol creatinine). Isovaleric acid: plasma 0.89 +/- 0.93 mumol/l (n = 10, range 0.01-3.03 mumol/l), urine 0.38 +/- 0.51 mumol/mmol creatinine (n = 10, range 0.01-1.70 mumol/mmol creatinine).

Rocuronium- and mivacurium-induced neuromuscular block and intubating conditions: a comparison with vecuronium.

The time-course of action after an initial 2 x ED90 dose and after maintenance doses of 0.5 x ED90, and intubating conditions at 90 s after a 2 x ED90 dose following rocuronium, vecuronium and mivacurium were evaluated in anaesthetized adult patients. Neuromuscular measurements were performed with mechanomyography. Rocuronium produced a significantly deeper neuromuscular block at 90 s (mean and (standard deviation)) (91 (11%), compared to vecuronium (61 (22%)%) and mivacurium (58 (23)%). The onset time following rocuronium (172 (71)s) was significantly shorter than that following mivacurium (229 (60)s). At 90 s, intubating conditions were significantly better in the rocuronium group than in the vecuronium or mivacurium group. Mivacurium offered a significantly faster recovery of neuromuscular block following the 2 x ED90 dose and following an average of 45 min of clinical muscle relaxation (single twitch response < or = 25%) compared to rocuronium and vecuronium: clinical duration 13 (4), 28 (9) and 33 (9) min, respectively, and recovery time from 25 to 75% recovery of the single twitch response: 6 (2), 11 (4) and 14 (7) min, respectively.

Time course of action and intubating conditions following vecuronium, rocuronium and mivacurium.

The purpose of this study was to compare the time course of action and tracheal intubating conditions of vecuronium, rocuronium and mivacurium in anaesthetised patients. Anaesthesia consisted of thiopentone, fentanyl, N2O/O2 and isoflurane. After a 2 x ED90 dose the first attempt at tracheal intubation was made at 90 s. If required, maintenance doses of 0.5 x ED90 were administered. The intubating conditions after rocuronium were significantly better than those after vecuronium and mivacurium. The average onset times of rocuronium (172 s) and vecuronium (192 s) were significantly shorter than that of mivacurium (229 s). The clinical duration and recovery time were significantly shorter after mivacurium (13 and 6 min, respectively) than with vecuronium (33 and 14 min, respectively) and rocuronium (28 and 11 min, respectively). We conclude that rocuronium might be of advantage whenever the interval between the administration of the muscle relaxant and tracheal intubation must be short, whereas mivacurium may be of benefit if fast spontaneous recovery is required.

Loss of neurotransmitter receptors by hyperphenylalaninemia in the HPH-5 mouse brain.

The binding of the muscarinic acetylcholine antagonist quinuclinidylbensilate to its specific receptors was measured by quantitative autoradiography in the brain of the HPH-5 mouse, a phenylalanine hydroxylase-deficient mouse mutant, as a model for human PKU. Three types of response to a hyperphenylalaninemic condition were observed: no effect as in the putamen; a gradual decrease over time such as in several areas of the cerebral cortex and the hippocampus; a transient increase, followed by a decrease, such as in the frontal area of the cerebral cortex. Of particular significance is the effect on the CA1 and CA3 layer of the hippocampus, since this structure has been implicated in the acquisition and storage of long-term memory. Hyperphenylalaninemia leads to a decrease in neurotransmitter receptor density and, therefore, to a decrease in connectivity, which may form the basis for the mental retardation in this condition.

Quality control for selective screening of inborn errors of metabolism.

A comprehensive program for proficiency testing of biochemical genetics laboratories is described. Inborn errors of metabolism of amino acids, organic acids, glycosaminoglycans and oligosaccharides are covered, as well as the assay of galactose-1-phosphate. Participants are not only required to report the analytical results but to give an interpretation of the results as well. Sixteen rounds of testing have been completed. A slow, but definite improvement in performance can be observed.

Pharmacokinetics and pharmacokinetic/dynamic relationship of rocuronium bromide in humans.

The existing human pharmacokinetic studies have been reviewed and compared with data derived from animals. The earliest study confirms the similarity of rocuronium to vecuronium with respect to the variables derived from the plasma concentration decay curves and the proportion excreted renally. Other studies led to the conclusion that concurrent administration of volatile anaesthetics did not significantly influence rocuronium pharmacokinetics and that the potentiation must be due to an increased sensitivity of the neuromuscular junction. These studies do not provide an explanation for the clinical observation of a more rapid onset of action. One possible explanation was the finding of a more rapid onset of block in the laryngeal muscles than in the adductor pollicis. However, no pharmacokinetic explanation for this observation has emerged. Alternative concepts need to be modelled. There is a need for comparative pharmacokinetic studies which focus on the period immediately following administration of rocuronium and vecuronium.

Clinical pharmacology of ORG 7617, a short-acting non-depolarizing neuromuscular blocking agent.

The dose-response relationship and the time course of action of Org 7617, a short acting non-depolarizing neuromuscular blocking agent, were evaluated during thiopentone, fentanyl, halothane and N2O anaesthesia. Neuromuscular transmission was monitored mechanomyographically. The ED50 and ED90 were calculated after single bolus doses of the drug. Twelve, seven and three patients received 2.5, 3.75 or 5.0 mg.kg-1 Org 7617, respectively. Neuromuscular block was characterized by a short lag time (average 30 s) and rapid development of neuromuscular block (69-84 s). Maximum block approximated to 66%, 91% and 95%, and the duration until clinically adequate recovery (TOF ratio of 0.7) to 7.4, 12.1 and 12.2 min after 2.5, 3.75, 5 mg.kg-1 of Org 7617, respectively. The calculated ED50 and ED90 were 1.8 and 3.4 mg.kg-1. Adverse effects, including a moderate fall in systolic and diastolic arterial blood pressure and a concomitant increase in heart rate appeared to be dose-dependent. Some patients showed flushing. One patient given 5 mg/kg Org 7617 had serious adverse effects suggestive of histamine release, i.e. flushing, urticaria, tachycardia, hypotension and bronchospasm. Therefore further clinical investigations were terminated. Although its low potency and the adverse effects observed will prevent further clinical development of ORG 7617, the results do support the contention that it is feasible to develop short-acting non-depolarizing neuromuscular blocking agents from the steroidal series.

Inborn errors of fructose metabolism.

A review is presented of genetic defects affecting fructose metabolism in humans. Presently, six conditions have been recognized: fructose malabsorption, fructokinase deficiency, aldolase A and aldolase B deficiency, fructose-1,6-diphosphatase deficiency and D-glyceric aciduria. Clinical presentations of these conditions, enzymatic and/or molecular defects, pathophysiological consequences, and modes of treatments are discussed.

The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH-5 mouse brain.

Previous studies on the effect of hyperphenylalaninaemia on the development of the muscarinic acetylcholine receptor in the cerebrum of the rat, using alpha-methylphenylalanine-induced hyperphenylalaninaemia, have shown a gradual and steady decrease in the number of binding sites for this neurotransmitter. The HPH-5 mouse, a phenylalanine hydroxylase mutant, can be hyperphenylalaninaemic without the use of a hydroxylase inhibitor. By employing quantitative autoradiography using [3H]quinuclinidylbenzilate to label muscarinic acetylcholine receptors, a refined analysis of this decrease in neurotransmitter binding sites can be made. The decrease was confirmed and is therefore due to the hyperphenylalaninaemia per se and not to the use of the inhibitor. Various areas of the brain reacted differently to hyperphenylalaninaemia, from no change (putamen) to a gradual decrease (external layer of the olfactory bulb, parietal, occipital and cingulate areas of the cerebral cortex, CA1 and CA3 layer of the hippocampus) to a decrease preceded by a transient increase (frontal area of the cerebral cortex, caudate nucleus). The extent of these changes depends on the duration of exposure to hyperphenylalaninaemia as well as on the degree of brain maturation, but can even be observed in the brain of the adult mouse on a hyperphenylalaninaemic regimen for 11 days. Since the hippocampus has been shown to be involved in the long-term storage of information, damage to this structure by hyperphenylalaninaemia may provide a clue to the global mental retardation observed in untreated PKU.

Intubating conditions and onset of neuromuscular block of rocuronium (Org 9426); a comparison with suxamethonium.

The intubating conditions and neuromuscular blocking profile following 600 micrograms.kg-1 rocuronium (Org 9426) have been investigated in patients under various experimental conditions. They were compared with conditions following 1.5 mg.kg-1 suxamethonium, preceded by a precurarising dose (10 mg) of gallamine, and with those in a control group in the absence of a muscle relaxant. Rocuronium produced good to excellent intubating conditions at 60 as well as at 90 s after administration, even though there was only a partial blockade of the adductor pollicis muscle. Intubating conditions following suxamethonium were comparable with those after rocuronium. Half of the control patients could be intubated. The clinical duration and the recovery time of 600 micrograms.kg-1 of rocuronium were 24(4) and 9(3) min (mean(s.d.)), respectively. Rocuronium may have a major advantage over existing non-depolarising muscle relaxants due to the early presence of excellent intubating conditions. The results indicate that rocuronium may replace suxamethonium in procedures in which rapid sequence induction is required.

An infant with multiple congenital abnormalities and biochemical findings suggesting a variant of galactosialidosis.

A female newborn probably with a variant form of galactosialidosis is described. The patient, in addition to the common findings seen in early infantile forms of classical galactosialidosis, displayed an unusual combination of congenital malformations including complex cyanotic congenital heart disease with dextrocardia and situs inversus.

Myelin turnover in hyperphenylalaninaemia. A re-evaluation with the HPH-5 mouse.

Myelin turnover has been studied in the 25-day-old HPH-5 mouse, a phenylalanine hydroxylase-deficient mouse mutant. The half-life of the fast component of myelin decreased from 15 days in control mice to 4.5 days at blood phenylalanine levels of 2.5 mmol/L. The slow component of myelin seems also to be affected by the high phenylalanine level. These observations confirm similar observations obtained with chemically induced models of hyperphenylalaninaemia and are therefore due to the hyperphenylalaninaemia per se, independently of the inhibitors of phenylalanine hydroxylase. An intermediate blood level of phenylalanine (0.7 mmol/L) likewise seems to interfere with myelin metabolism, although to a lesser degree.

High-performance liquid chromatography of urinary oligosaccharides in the diagnosis of glycoprotein degradation disorders.

Urinary oligosaccharides can be separated by high-performance anion-exchange chromatography using a Dionex CarboPac PA1 column, elution with aqueous sodium hydroxide and sodium acetate solutions and detection by pulsed amperometry. Each of the urines of patients with glycoprotein degradation disorders yielded a pattern of oligosaccharide excretion unique for that disorder, facilitating an unambiguous diagnosis. The method is sensitive (10 microliters of urine required) and fast (40 min).

N-acetylglutamate synthetase deficiency: clinical and laboratory observations.

Two male siblings presented in the first 6 weeks of life with emesis, diarrhoea, metabolic acidosis and lethargy. A male sibling had previously died at 14 months of age from liver failure of unknown aetiology. Both of the current cases had mild hyperammonaemia with normal orotic acid, organic acid and argininosuccinic acid levels. Citrulline and arginine levels were normal or mildly decreased. One of the brothers was biopsied and had no detectable N-acetylglutamate synthetase activity and normal values for other enzymes of the urea cycle in liver. Treatment with a low-protein diet and sodium benzoate/sodium phenylacetate resulted in near normal blood ammonia levels, except during viral illness. Subsequent neurological development has been normal to mildly delayed. These patients differ from those previously described with N-acetylglutamate synthetase deficiency in that their presentation and subsequent course were relatively benign.

The control of 5-hydroxytryptamine and dopamine synthesis in the brain: a theoretical approach.

The transport of the eight amino acids (phenylalanine, tyrosine, tryptophan, valine, leucine, isoleucine, histidine and methionine) using the large neutral amino acid transporter of the blood-brain barrier (BBB) has been calculated using published kinetic data. The fate of the amino acids has been followed from blood to interstitial space, to cell and through metabolism which included, for tyrosine and tryptophan, the hydroxylases. The system was analysed in terms of flux control coefficients. Since the summation theorem did not hold, the system clearly behaved as a non-homogeneous system. At physiological levels of these eight amino acids, the largest contribution to the control of the flux of tyrosine is given by the hydroxylase step, followed by the diffusional component of the transport across the BBB. For tryptophan it is the hydroxylase step, followed by the carrier-mediated transport across the BBB. For the other amino acids it is the metabolism, followed by the diffusional component of the BBB transport. These parameters for tyrosine and tryptophan were determined at increased levels of blood phenylalanine, tyrosine or histidine. The flux through tryptophan hydroxylase can be affected by high blood levels of tyrosine and histidine to values also observed in hyperphenylalaninaemia. Since hypertyrosinaemia (type II) and hyperhistidinaemia are not associated with mental retardation, it is concluded that interference with transport across the BBB of tyrosine and tryptophan, as well as the flux through tryptophan hydroxylase leading to the synthesis of 5-hydroxytryptamine, do not contribute to the cause of permanent brain dysfunction in hyperphenylalaninaemia. It can be calculated that addition of tyrosine to the diet to raise the blood tyrosine level in phenylketonuria patients may have a beneficial effect for the synthesis of neurotransmitters derived from tyrosine.