Showing papers by "University of Copenhagen published in 1976"

Receptor-binding region of insulin

Abstract: X-ray analysis, circular dichroism, receptor binding and biological potencies of chemically modified insulins suggest that the conformation of the insulin molecule is critical to the formation of both the zinc insulin hexamer and the insulin–receptor complex. Results are consistent with an insulin receptor-binding region including many of the hydrophobic residues important to dimerisation in addition to more polar surface residues. There is a further possibility of formation of an antiparallel sheet structure between the insulin and receptor molecules in the complex similar to that between monomers in the insulin dimer.

Rational diagnosis and treatment

Abstract: Clinical decisionmaking includes reasoning from prescientific or scientific theories, reasoning from uncontrolled or controlled experience, and reasoning based on empathic understanding and moral beliefs. The development of contemporary clinical thinking is discussed, and it is found that successive generations of medical practitioners have had different views of the rationality and relative importance of these modes of reasoning: that which is considered rational by one generation of doctors is sometimes denounced by the next. The author's book, Rational Diagnosis and Treatment, which is an example of clinical thinking in the 1960s and early 70s, is used to illustrate one particular view of clinical decisionmaking.

The primary inhibitor of plasmin in human plasma.

Abstract: A complex between plasmin and an inhibitor was isolated by affinity chromatography from urokinase-activated human plasma. The complex did not react with antibodies against any of the known proteinase inhibitors in plasma. A rabbit antiserum against the complex was produced. It contained antibodies agianst plasminogen+plasmin and an α2 protein. By crossed immunoelectrophoresis the α2 protein was shown to form a complex with plasmin, when generated by urokinase in plasma, and with purified plasmin. The α2 protein was eluted by Sephadex G-200 gel filtration with KD approx. 0.35, different from the other inhibitors of plasmin in plasma, and corresponding to an apparent relative molecular mass (Mr) of about 75000. By sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, the Mr of the complex was found to be approx. 130000. After reduction of the complex two main bands of protein were observed, with Mr, about 72000 and 66000, probably representing an acyl-enzyme complex of plasmin-light chain and inhibitor-heavy chain, and a plasmin-heavy chain. A weak band with Mr 9000 was possibly an inhibitor-light chain. The inhibitor was partially purified and used to titrate purified plasmin of known active-site concentration. The inhibitor bound plasmin rapidly and strongly. Assuming an equimolar combining ratio, the concentration of active inhibitor in normal human plasma was estimated to be 1.1 μmol/1. A fraction about 0.3 of the antigenic inhibitor protein appeared to be functionally inactive. In plasma, plasmin is primarily bound to the inhibitor. Only after its saturation does lysis of fibrinogen and fibrin occur and a complex between plasmin and α2 macroglobulin appear.

VV and VT rate coefficients in N2 by a quantum-classical model

Abstract: Vibration—vibration (V—V) and vibration—translation/rotation (VT/R) rate coefficients for H 2 H 2 collisions are calculated by a semi-classical 3-dimensional model. The model used treats the translational and rotational motion classically while treating the vibrational motion quantum mechanically. The effects of both the long range and short range interaction potential is included in the model. The results obtained for the VT/R processes are in good agreement with available experimental data over the temperature range of 200–800 K and predicts considerably faster scaling with increasing vibrational level than expected from harmonic oscillator models. Non-resonant and multi-quantum VV rate coefficients show substantial disagreement with earlier collinear collision models both in magnitude and scaling with increasing vibrational level.

Quantitative Measures of Enzyme Activities in Type I and Type II Muscle Fibres of Man after Training

Abstract: The effect of 7 to 8 weeks of physical training on oxidative and glycolytic enzyme activities in the 2 major fibre types of human quadriceps femoris muscle has been investigated. 2 groups of 4 and 5 subjects respectively were trained at the same total work-load on a bicycle ergometer 3 days per week using interval exercise with maximal intensity (I.T.) or continuous exercise with submaximal intensity (C.T.). Succcinate dehydrogenase (SDH) and phosphofructokinase (PFK) activities were determined on crude homogenates of muscle biopsy samples and on pools of type I and type II fibres dissected from freeze-dried samples taken before and after training. Crude homogenate SDH activity increased to the same extent in both groups, average increases were 27.5% (I.T.) and 22% (C.T.) respectively. Only type I-SDH increased in the C.T. group (p less than 0.01), the average increase being 32%. On the other hand only type II-SDH increased in the I.T. group (p less than 0.01), with an average increase of 49%. No changes in PFK activity could be detected. The results of the present study emphasize the great adaptability in oxidative potential of both the two major human skeletal muscle fibre types and further that this adaptation seems to be related to the pattern of fibre recruitment during exercise.

Absence of axonemal arms in nasal mucosa cilia in Kartagener's syndrome

Abstract: A TOTAL lack of axonemal arms in the spermatozoa of infertile men has been described1–3 and those results included those from four men, three of whom had situs inversus of the thoracic organs while the fourth was a brother to one of the others. The total absence of axonemal arms (dynein arms) was deemed to be responsible for the complete immobility of their sperm tails. Kartagener's syndrome4 exhibits the following symptoms: chronic sinusitis, bronchiectasis and situs inversus. Sperm flagella and cilia have similar ultrastructure in principle, so it was thought possible that the respiratory tract symptoms in patients with Kartagener's syndrome might be caused by a lack of dynein arms in the cilia. We have thus investigated the cilia of Kartagener patients at the substructural level.

The morphology of regeneration of skeletal muscles in the rat.

Abstract: Muscle regeneration was studied by light and electron microscopy in soleus muscles of rat. After segmental crushing, the number of fibres increased in some muscles within 30 days, indicating that numerical hyperplasia can take place. Locally applied Ringer solution of 60–70 °C caused necrosis of myofibres but left satellite cells and blood supply largely intact. Following phagocytosis, four mechanisms of regeneration were seen. (1) Lost fibres were replaced by clusters of myotubes formed by satellite cells within persisting basal lamina tubes. These clusters displaced the surrounding endomysium and looked like longitudinally ‘split’ fibres. (2) Viable fibre fragments fused with satellite cells. (3) Satellite cells of surviving fibres proliferated and fused to myotubes localized beneath the basal lamina. (4) Thin new fibres occurred in the interstitium. Their origin remained unknown. After 6 months the mean size of the new myofibres was normal, but the scatter of diameters was increased, central nuclei, fibre ‘splitting’ and branching, and fibrosis were prominent. Staining for acetylcholinesterase revealed that many fibres were short and not innervated. The similarity with dystrophic muscles in man suggested, that the most prominent histological changes in myopathie muscles may be due to attempts of regeneration.

Lack of correlation between tight junction morphology and permeability properties in developing choroid plexus.

Abstract: ELECTRON microscopical investigations of tight junctions (zonulae occludentes) using marker substances, have indicated that in some tissues these junctions may represent an extracellular pathway for transepithelial movement of certain small solutes1 and also restrict the movement of larger solutes2. The electrical resistance across some epithelial tissues has been used as a measure of the degree of permeability of the tight junctions to ions3, and it was suggested that junctions that are “leaky” to ions are also leaky to small non-electrolytes. Examination of tight junctions with the freeze-fracture technique has revealed the presence of a network of intramembranous fibrils4 or strands5,6. Some evidence suggests that these strands constitute the sealing component of the junction7, and Claude and Goodenough6 correlated the transepithelial permeability of a given epithelium with the number of strands in the tight junction network. Artificial methods of altering transepithelial permeability (hypertonic solutions applied to the mucosal side of the epithelium) have been used to investigate changes in transepithelial electrical resistance8, and freeze-fracture morphology9 or both10. Results from these studies do not consistently support the above correlation. An alternative approach is described here, in which the freeze-fracture technique has been used to study tight junctions of the sheep choroid plexus during foetal development. The results obtained suggest that there is no change in the ultra-structural features of tight junctions which have previously been suggested to correlate with transepithelial permeability, in spite of considerable changes in permeability during the developmental period studied11–13.

Clinical Pharmacokinetics of Anticonvulsants

Abstract: Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half-life of phenobarbitone is only half of that in adults. An optimum therapeutic plasma range has been established and monitoring is recommended. Primidone may have an anticonvulsant activity in itself, but its main metabolite is phenobarbitone. The relatively rapid elimination of primidone is offset by the long half-life of phenobarbitone. An optimum therapeutic range has been suggested, but plasma level monitoring must include determination of phenobarbitone. Ethosuximide. The clinical pharmacokinetics of this important petit mal anticonvulsant is not well known. It has a relatively long half-life (in adults 2 to 3 days; in children shorter). An optimum therapeutic range has been suggested, and routine monitoring of plasma levels may be recommended. Diazepam exerts a repid anticonvulsant activity when the plasma concentration exceeds approximately 500ng/ml after intravenous injection. The kinetic pattern is complex in man. Clonazepam. The clinical pharmacokinetics are still not fully investigated but a therapeutic range has been suggested...

Self-inhibiting action of nortriptylin's antidepressive effect at high plasma levels: a randomized double-blind study controlled by plasma concentrations in patients with endogenous depression.

Abstract: Below the toxic plasma level of nortriptyline (NT) an upper therapeutic limit has been postulated in patients with endogenous depression. If so the clinical significance is obvious and a double-blind, randomized study was performed in order to solve this problem. Two groups of patients were controlled at different plasma levels ( 180 ng/ml). The degree of depression was rated weekly. Only about one third (n=24) of the patients originally included, were carried through the full protocol, the most prominent reason for drop out beeing spontaneous remission during an initial placebo period. After 4 weeks of NT treatment the majority in the high level group was still depressed, but the difference barely significant (P=5.5%). However, a randomized reduction of the plasma level among the patients at the high level resulted in a significant correlation to remission. Evaluation of the total material after 6 weeks of NT treatment demonstrated a strong correlation of high plasma level to poor antidepressive effect of NT. No correlation could be obtained between side-effects, which were few, and plasma level. The non-proteinbound fraction in plasma was found to 7% (SD 1.83) by simultaneous determinations of NT in plasma and CSF in 13 patients. The variation in the proteinbinding was not likely to invalidate the over all results based on total NT determination. A therapeutic plasma range of 50–150 ng/ml is recommended.

The number of satellite cells in normal human muscle.

Abstract: The satellite cell population in skeletal muscles of ten normal subjects aged 7 to 73 years was quantitated by electron microscopy. In all 1,414 nuclei were assessed. Satellite cell nuclei comprised 4% (standard deviation 2%) of all nuclei within the fibre basal lamina. The lowest incidence (0.6%) was found in a 73-year-old man. The study confirms, that satellite cells are regularly present in human skeletal muscle.

Plasma levels and antidepressive effect of imipramine.

Abstract: The relationship between the antidepressive effect of imipramine and the plasma concentrations of imipramine and the active metabolite desipramine was studied in 24 patients suffering from endogenous depression. After a placebo period of 7 days, the patients received imipramine, 75 mg 3 times a day. The dose was reduced in patients with pronounced side effects. Blood samples for drug assay were drawn in the morning, 15 hr after the last drug intake. Imipramine and desipramine in plasma were assayed by quantitative in situ thin-layer chromatography. Individual variations in plasma concentration were 20- to 30-fold in both imipramine and desipramine. Severity of depression was assessed on the Hamilton Rating Scale (HRS). Eleven of 12 patients who responded satisfactorily to the treatment (HRS post-treatment score less than 8) had plasma concentration of imipramine greater than or equal to 45 mug/L, and desipramine greater than 75 mug/L, whereas the 12 patients not responding satisfactorily (post-treatment score on HRS greater than or equal to 8) all had concentrations of imipramine or desipramine or both below these limits.

The biology of Myxosoma cerebralis: the causative organism of whirling disease of salmonids.

Abstract: The literature describing the biology and control of Myxosoma cerebralis (whirling disease) is reviewed. New data on the world distribution of the parasite are presented. It is concluded that the presence of M. cerebralis is not an important limiting factor in salmonid fanning per se but only limits methods of production.

Quasi-free “second quantization”

Abstract: Araki and Wyss considered in 1964 a mapA→Q(A) of one-particle trace-class observables on a complex Hilbert-space ℋ into the fermionC*-algebraU(ℋ) over ℋ. In particular they considered this mapping in a quasi-free representation.

Analytical and Preparative Polyacrylamide Gel Electrophoresis

Abstract: Biochemistry may be viewed as the attempt to fragment living matter to its component molecular species, and to elucidate the chemical reactions of these species first in two-component systems, then in ever more complex systems and finally to reconstitute life as the sum of its component chemical reactions. The first task, i.e., the isolation of nature’s building-block molecules, remains a formidable task. This chapter is concerned with the instrumentation and procedures available for isolation of any given charged species according to a generally applicable fractionation strategy.

The role of amino acids and taurine in isosmotic intracellular regulation in Ehrlich ascites mouse tumour cells

Abstract: 1 Ehrlich ascites tumour cells swollen in hypotonic medium reduce their volumes towards that found in isotonic medium 2 This regulation of cell volume implies an adjustment of the intracellular amount of osmotically active substances, ie a type of “isosmotic intracellular regulation” 3 Non-protein ninhydrin-positive substances were lost from the cells during this volume regulation 4 Amino acid analyses show that the non-essential amino acids play a significant role in this process 5 The relative decrease in concentration was larger for taurine than for any other measured inorganic and organic substance The absolute change in intracellular taurine concentration is third only to changes in chloride and potassium The role of taurine in osmoregulation is similar to that observed in many aquatic invertebrates 6 The steady state distribution of amino acids varies with the magnitude of the Na+ and K+ concentration gradients between the cells and their environment The ion gradient hypothesis fits our data only if we introduce a leakage pathway for the amino acids which is independent of the amino acid pump and which varies with the cell volume