Showing papers by "University of Copenhagen published in 1985"

Plasminogen activators, tissue degradation, and cancer.

Abstract: Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

The effect of proteinuria on relative mortality in Type 1 (insulin-dependent) diabetes mellitus

Abstract: We followed 1, 134 patients with Type 1 (insulin-dependent) diabetes, diagnosed between 1933 and 1952, until 1982 or death or until their emigration. Their age at onset of diabetes was under 31 years. Information concerning the development of persistent proteinuria was sought in every case. In 104 cases, the data were either questionable or the patient could not be traced. Twenty-nine patients developed non-diabetic proteinuria. Among the remaining 1,001 patients, 406 developed persistent proteinuria (350 died) and 595 did not (166 died). The incidence of persistent proteinuria was highest among men; it decreased with increasing year of diabetes onset from 1933 to 1952, and decreased with increasing age at onset. The relative mortality was extremely high among patients with persistent proteinuria, increasing to a maximum of about 100 at age 35 years. Patients not developing proteinuria had a relatively constant low relative mortality of about 2. The decreasing incidence of persistent proteinuria and the decreasing mortality with increasing calender year of diabetes onset resulted in a 50% increase in life-expectancy among patients diagnosed in 1950 compared with patients diagnosed in 1935. In patients who developed persistent proteinuria, relative mortality was higher in women than men at all ages. In patients who did not develop proteinuria, relative mortality was similar in men and women after the age of 35. Uraemia was the main cause of death in patients with persistent proteinuria, although cardiovascular deaths were more frequent than in patients without proteinuria. Thus, proteinuria is associated not only with death from uraemia but also from cardiovascular disease. It is concluded that the development of persistent proteinuria is a major life-threatening complication in patients with early-onset Type 1 diabetes. Patients who do not develop proteinuria have almost a normal life expectancy.

Cellular origin of ischemia-induced glutamate release from brain tissue in vivo and in vitro

Abstract: The uptake and release of d-[3H]aspartate (used as a tracer for endogenous glutamate and aspartate) were studied in cultured glutamatergic neurons (cere-bellar granule cells) and astrocytes at normal (5 mM) or high (55 mM) potassium and under conditions of hypo-glycemia, anoxia or “ischemia” (combined hypoglycemia and anoxia). In glutamatergic neurons it was found that “ischemic” conditions led to a 2.4-fold increase in the potassium-induced release of d-[3H]aspartate as compared to normal conditions. Hypoglycemia or anoxia alone affected the release only marginally. The ischemia-induced increase in the evoked d-[3H]aspartate release was shown to be calcium-dependent. In astrocytes no difference was found in the potassium-induced release between the four conditions and the K+-induced release was not calcium-dependent. The uptake of d-[3H]-aspartate was found to be stimulated at high potassium in both glutamatergic neurons (98%) and in astrocytes (70%). This stimulation of d-aspartate uptake, however, was significantly reduced under conditions of anoxia or “ischemia” in both cell types. In glutamatergic neurons (but not in astrocytes) hypoglycemia also decreased the potassium stimulation of d-aspartate uptake. In a previous report it was shown, using the microdialysis technique, that during transient cerebral ischemia in vivo the extracellular glutamate content in hippocampus was increased eightfold. In the present paper it is shown that essentially no increase in extracellular glutamate is seen under ischemia when the perfusion is performed using calcium-free, cobalt-containing perfusion media. The results from the in vitro and in vivo experiments indicate that the glutamate accumulated extracellularly under ischemia in vivo originates from transmitter pools in glutamatergic neurons. Moreover, the released glutamate cannot be efficiently disposed of due to a lack of activation by potassium of the high-affinity glutamate uptake system in neurons and astrocytes under ischemic conditions.

Prognosis of luxated permanent teeth — the development of pulp necrosis

Abstract: A population of 400 patients, comprising 637 luxated permanent teeth was studied prospectively with respect to the development of pulp necrosis after luxation injuries. The patients were treated for traumatic dental injuries over a period of 10 years. While initial treatment was provided according to established treatment guidelines by the attending oral surgeon at the emergency room, follow-up examination and treatment was provided by one oral surgeon. It appeared that pulp necrosis occurred soon after injury, within 3 months after concussion, within the 1st yr after subluxation and extrusion, and might be diagnosed up to 2 yr after lateral- and intrusive luxation. While many factors, when considered one at a time, were found to have a significant or nearly significant died on the development of pulp necrosis (i.e. type of injury, age of patient, stage of root development, degree of dislocation, reduction/repositioning procedure, type of fixation, restorations in place at the lime of injury), a multivariate regression analysis revealed that when the type of injury (diagnosis) and stage of root development were taken into account, the effect of other factors was no longer significant. The risk of pulp necrosis increased with the extent of injury, i.e. concussion and subluxation represented the least risk, followed in ascending order by extrusive-, lateral-, and intrusive luxation. Moreover, teeth with completed root formal ion demonstrated a greater risk of pulp necrosis than teeth with incomplete root formation. No treatment effect could be demonstrated. However, as treatment was performed according to established guidelines, which might introduce bias, it would appear justified to conduct randomized clinical studies in order to determine the value of different forms of treatment (e.g. reduction and fixation of luxated teeth) to improve the prognosis with respect to the development of pulp necrosis after injury. In conclusion, the major factors influencing development of pulp necrosis after luxation injuries appear to be the extent of the initial injury to the pulp and periodontium, as reflected by the type of luxation, and the repair potential of the injured tooth, as reflected by the stage of root development.

Hemodynamic adaptations to exercise

Abstract: It is not currently known whether central hemodynamic or peripheral (vascular or metabolic) factors limit maximal oxygen uptake. By measuring the blood flow and oxygen uptake of exercising muscles when only a small fraction of the total muscle mass is engaged in exercise, it has been demonstrated that the skeletal muscle of man could accommodate a blood flow of at least 200 ml/100 g min, and consume 300 ml O2/100 g min at exhaustive exercise. Thus, in whole body exercise the limiting factor is the capacity of the heart to deliver oxygen, not the muscle. It has also been observed that at high perfusion of the muscle the arteriovenous O2 difference is small (14 to 15 vol %), and that the low extraction of oxygen is related to the mean transit time (MTT) of red blood cells passing through the capillaries. It has been concluded that the primary importance of enlargement of the capillary bed with endurance training is not to accommodate flow but to maintain or elongate MTT. It has also been concluded that, in whole body exercise, the capacity of the muscles to receive a flow exceeds by a factor of 2 to 3 the capacity of the heart to supply the flow. Thus, vasoconstrictor tone must also be present in the arteries that "feed" exercising muscles.

Development of epiphytic communities on eelgrass (Zostera marina) along a nutrient gradient in a Danish estuary

Abstract: The effect of nutrient enrichment on epiphyte development was examined by following the seasonal development of epiphyte biomass on eelgrass (Zostera marina L.) at four localities along a nutrient gradient in Roskilde Fjord, Denmark between March and December 1982. In the most nutrient-poor area, epiphyte biomass followed a distinct bimodal seasonal pattern with maxima in spring and early fall. Low nutrient availability and a high rate of eelgrass leaf renewal kept epiphyte biomass at a low level throughout the summer period. Unlike phytoplankton, the epiphytic community was not stimulated by nutrient enrichment during spring, however, from May through August, the biomass of both components increased exponentially with increasing concentrations of total N in the water. Along the nutrient gradient, phytoplankton biomass increased 5- to 10-fold, while epiphyte biomass increased 50- to 100-fold. Thus differences in nutrient conditions among study sites were more clearly reflected by epiphytes than phytoplankton.

Simultaneous demonstration of multiple antigens by indirect immunofluorescence or immunogold staining. Novel light and electron microscopical double and triple staining method employing primary antibodies from the same species.

Abstract: Available techniques for light and electron microscopical double immunocytochemical staining are all associated with certain problems. We have developed a novel multiple staining procedure, which allows use of antibodies of differing specificities, raised in the same species (e.g. rabbit). Its essential features include 1) saturation of antigenic epitopes on the first layer primary antiserum by second (fluorophor- or gold-) labelled anti-IgG antibodies and 2) denaturation of free anti-IgG binding sites by formaldehyde vapour treatment. Various combinations of gastrin, somatostatin, glucagon, ACTH, growth hormone and enkephalin/endorphin antibodies have been tested at the light and electron microscopical level and have been found to give highly reproducible double- and triple-staining results. The technique has also been evaluated by use of cytochemical paper models. The method is simple and very useful for multiple staining of a wide variety of antigens.

Electron microscopy of the initial stages of placentation in the pig.

Abstract: To elucidate the morphology of the initial stages of epitheliochorial placentation in the pig, material from 10 sows of the Danish Landrace and from one Gottinger minipig gilt from day 13 to day 26 of gestation was processed for scanning and transmission electron microscopy. The observed foetomaternal interaction from day 19 1/2 minipig placenta corresponded well to the observations on the Danish Landrace placenta. From the results and the discussion it was concluded that the following structures were implicated in the initial phases of placentation in the pig: (1) Protruding epithelial proliferations of the uterine epithelium enclosed by chorionic caps serving to immobilize the blastocyst (days 13 and 14). (2) A thick glycocalyx on the maternal and a thin one on the foetal epithelium before contact. (3) Close apposition between the apical plasma membranes from trophoblastic and uterine epithelium (day 14). (4) Development of interdigitating microvilli (days 15–16). (5) Formation of apical domes on the uterine epithelium closely related to the trophoblast provided with long cytoplasmic extensions into a luminal space between the apical domes, apparently representing a transition from histiotropic to haemotrophic nutrition (days 15–20). (6) Placentation, development of interdigitating microvilli between foetal and maternal epithelium, was extended but not terminated in the peripheral zone at day 26.

Autoregulation of the dnaA gene of Escherichia coli K12.

Abstract: Regulation of the dnaA gene, which codes for an essential factor for the initiation of replication from the chromosomal origin, was studied in vivo using transcriptional and translational gene fusions. We found that the dnaA gene was autoregulated over a 30-fold range by the activity of dnaA protein. Expression from the dnaA promoter region of a dnaA"lacZ fusion was inhibited up to sevenfold by surplus dnaA protein and was stimulated up to fivefold upon thermoinactivation of the mutant protein in five different dnaA(Ts) strains. The autoregulation was found to be exerted at transcription from the major dnaA promoter and was eliminated by deletion of sequences around position -65 of this promoter where a 9-bp sequence, which is also found four times in the chromosomal origin, is located.

Stratigraphic Noise in Time Series Derived from Ice Cores

Abstract: Because of snow drifting, two time series of any variable derived from two adjacent ice cores will differ considerably. The size and statistical nature of this noise element is discussed for two kinds of measured substance. A theory is developed and compared to data from Greenland and Canadian Arctic ice cores. In case 1, the measured substance can diffuse and the seasonal cycle degrade with time and depth, e.g. δ(18O). In case 2, the measured substance cannot diffuse, e.g. microparticles. The case 2 time series contain drift noise proportional to that in the accumulation series. For accumulation series, the spectral power is concentrated at the high frequencies, i.e. is “blue”. Such noise can be easily reduced by taking relatively short time averages. The noise in the case 1 time series, however, starts out “blue” but quickly diffuses to have a “red” character with significant power at longer wavelengths, and many decades of such series must be averaged to reduce the noise level. Because the seasonal amplitude of any given variable is an important input to the drift noise and because the seasonal amplitudes of some variable types are latitude-dependent, some sites have inherently less drift noise than others.

Glial cells express N-CAM/D2-CAM-like polypeptides in vitro.

Abstract: The joining together of neurites to form fascicles and the growth of axons along glial surfaces during early development suggest that neurone-neurone and neurone-glial adhesion interactions are of considerable importance for defining nerve tracts. In vitro studies have indicated that adhesion between neurones involves a glycoprotein that has been independently studied under the names of N-CAM (for neural cell adhesion molecule), D2-CAM and BSP-2 (refs 10, 11). As N-CAM/D2-CAM appears to be a homophilic ligand that binds to N-CAM/D2-CAM polypeptide on adjacent cells, this glycoprotein is potentially important in adhesion interactions between any two N-CAM/D2-CAM-expressing cells. While it has been suggested that neurone-glial adhesion involves molecules other than N-CAM/D2-CAM, it is known that N-CAM/D2-CAM antigenic determinants are expressed by glial cells in vivo and that injection of anti-N-CAM antibodies into the eye-cup of chick embryos disrupts normal patterns of neuritic apposition to glial endfeet in the developing optic stalk. Do the molecules expressed by glia share restricted antigenic determinants, or binding domains, with N-CAM/D2-CAM, or are N-CAM/D2-CAM polypeptides expressed by glia? Here we present immunocytochemical evidence which suggests that all classes of macroglia express N-CAM/D2-CAM antigenic determinants on their surfaces and immunochemical analyses which indicate that the molecules expressed by purified astrocytes are closely similar, or identical, to at least some forms of N-CAM/D2-CAM obtained from whole brain or purified neurones. However, our results also suggest that different N-CAM/D2-CAM polypeptides may be separately expressed by neurones and astrocytes.

A fast procedure for model search in multidimensional contingency tables

Abstract: SUMMARY A procedure to select the simplest acceptable models for a multidimensional contingency table is proposed. It is based on two rules: first, that if a model is accepted, then all models that include it are considered to be accepted, and secondly, that if a model is rejected, then all its submodels are considered to be rejected. Two versions are described, one for the class of graphical models, and the other for the class of hierarchical log linear models. Application of both versions to a six-dimensional table is illustrated. The procedure can be regarded as an alternative to fitting all possible models, made computationally feasible by application of the two rules. It is a generalization of the procedure proposed by Havr'anek (1984), but is in many cases considerably faster.

Comparative Regional Analysis of 2-Fluorodeoxyglucose and Methylglucose Uptake in Brain of Four Stroke Patients. With Special Reference to the Regional Estimation of the Lumped Constant

Abstract: The glucose metabolic rate of the human brain can be measured with labeled deoxyglucose, using positron emission tomography, provided certain conditions are fulfilled. The original method assumed irreversible trapping of deoxyglucose metabolites in brain during the experimental period, and it further requires that a conversion factor between deoxyglucose and glucose, the “lumped constant,” be known for the brain regions of interest. We examined the assumption of irreversible trapping of fluorodeoxyglucose metabolites in brain of four patients in 365 normal and 4 recently infarcted regions. The average net, steady-state rate of fluorodeoxyglucose (KD) accumulation in normal regions of the four patients was 0.025 ml g−1 min−1. We also examined the variability of the lumped constant. We first confirmed that methylglucose is not phosphorylated in the human brain. We then estimated the lumped constant from the regional distribution of labeled methylglucose in brain. The average (virtual) volume of distribution...

Comparison of single- and dual-photon absorptiometry in postmenopausal bone mineral loss

Abstract: The authors describe a single photon absorptiometric (SPA) technique, which enables differential estimation of the rates of loss from trabecular and cortical bone. Ten scans are obtained in the forearm: six in an area with about 7% trabecular bone and four scans in the adjacent distal area with a trabecular bone content of 25%. By comparing bone masses of these two sites in 19 postmenopausal and 53 premenopausal women, the postmenopausal trabecular bone loss was estimated to be approximately seven times greater than cortical loss within the first years of cessation of regular vaginal bleeding. On a group basis the bone loss at the distal forearm scan site (by SPA) corresponded closely to the spinal bone loss (by dual-photon absorptiometry). The reproducibility of the two scan sites in the forearm was 1-1.5% (CV%), which makes the method suitable for longitudinal studies. Corrections for variations in fatty tissue covering can be made without deterioration of the reproducibility.

Neuronal cholecystokinin: one or multiple transmitters?

Abstract: The discovery of large amounts of regulatory peptides in the brain over the last decade is an important milestone in neurobiology. Neuropeptides are no longer considered a small group of hypothalamic substances regulating the secretion of pituitary hormones. Neuropeptides are potent transmitters in all parts of the central and peripheral nervous systems. Sometimes the peptides coexist and operate synergistically with the so-called classic transmitters (monoamines, acetylcholine, and amino acids) in acute synaptic transmissions. Possibly, neuropeptides are involved also in functions such as control of neuronal growth and metabolism (for recent general reviews, see Krieger, 1983; Krieger et al., 1984). Among the neuropeptide systems known today perhaps the largest group are hormones synthesized also in endocrine cells of the gastrointestinal tract and the pancreas. Thus, when they were found in the brain, methods for analysis were already at hand for some of these peptides-a fact that has advanced the study of the brain-gut peptides considerably. Although most of gut peptides occur only in discrete brain areas and/or in limited amounts (for instance, secretin, gastrin, insulin, glucagon, and motilin) others are distributed to most regions of the central and peripheral nervous systems [e.g., cholecystokinin (CCK), somatostatin, and vasoactive intestinal polypeptide (VIP)]. The CCK peptides, however, hold a unique position among brain peptides-including those originally isolated from brain tissue (substance P and other tachykinins, neurotensin, enkephalins, and others). First, the total amount of CCK in the mammalian CNS is higher than that of any other known regulatory peptide; and second, the distribution is unique, with the highest CCK concentrations in the cerebral cortex (Rehfeld, 197th; Larsson and Rehfeld, 1979a: Lamers et al., 1980; Beinfeld et al., 1981; Marley et al., 1984). The amounts and concentrations in the brain are significantly above also those of the recently discovered neuropeptide Y (Tatemot0 et al., 1982; Tatemoto, 1982), which by some has been claimed to be the most abundant peptide in mammalian brain (Allen et al., 1983; Adrian et al., 1983). In addition, CCK has aroused specific interest in schizophrenia research, because of its coexistence with 3,4-dihydroxyphenylethylarnine (dopamine) in the crucial mesolimbic neurons (Hokfelt et al., 1980a, 6) . The great interest in neuronal CCK has been emphasized by two recent international symposia devoted exclusively to brain CCK. Interested readers are referred to the proceedings from these meetings (de Belleroche and Dockray, 1984; Crawley and Vanderhaeghen, 1985). In spite of the substantial interest, fundamental questions about neuronal CCK are still unanswered, as reflected in the often confusing literature on CCK. The problem is not least attributable to ignorance of the extensive molecular heterogeneity of CCK. Therefore this review addresses the heterogeneity in terms of structure and biosynthesis of the different CCK molecules in the nervous system. In other words, is neuronal CCK a system comprising different neurotransmitters rather than one‘? As a starting point for neurochemists unfamiliar with gut endocrinology, a summary of the long history of intestinal CCK may give some perspective.

An experiment in partial evaluation - the generation of a compiler generator

Abstract: The present paper is an extended abstract of (Jones 1985), in which a running , non-trivial partial evaluator is described . As far as we know, this partia l evaluator is the first which has been used in practice to transform interpreters into corresponding stand-alone compilers, or to generate a compile r generator by transforming itself . A partial evaluator is a program (call it mix) written in a programmin g language L, which takes as input a program p and a known value d l of p' s first input argument . It produces as output a so-called residual program :

Potential importance of fish predation and zooplankton grazing on natural populations of freshwater bacteria

Abstract: The rates of ingestion of natural bacterial assemblages by natural populations of zooplankton (>50 mum in size) were measured during a 19-day period in eutrophic Frederiksborg Slotsso, Denmark, as well as in experimental enclosures (containing 5.3 m of lake water). The fish and nutrients of the enclosures were manipulated. In enclosures without fish, large increases in ingestion by zooplankton >140 mum in size were found (up to 3 mug of C liter h), compared with values less than 0.3 mug of C liter h in the enclosures with fish and in the open lake. Daphnia cucullata and D. galeata dominated the community of zooplankton of >140 mum. Ingestion rates for zooplankton between 50 and 140 mum decreased after a period of about 8 days, in all enclosures and in the lake, to values below 0.1 mug of C liter h. On the last 2 sampling days, somewhat higher values were observed in the enclosures with fish present. The >50-mum zooplankton ingested 48 to 51% of the bacterial net secondary production in enclosures without fish, compared to 4% in the enclosures with added fish. Considering the sum of bacterial secondary production plus biomass change, 35 to 41% of the available bacteria were ingested by zooplankton of >50 mum in the enclosures without fish, compared with 4 to 6% in the enclosures with added fish and 21% in the open lake. Fish predation reduced the occurrence of zookplankton sized >50 mum and thus left a large proportion of the available bacteria to zooplankton sized <50 mum. In fact, there were 4.6 x 10 to 5.0 x 10 flagellates (4 to 8 mum in size) ml in the enclosures with fish added as well as in the lake, compared with 0.5 x 10 to 2.3 x 10 ml in the enclosures without fish. This link in the food chain was reduced when fish predation on zooplankton was eliminated and a direct route of dissolved organic matter, via the bacteria to the zooplankton, was established.

Development of polyneuropathy during thalidomide therapy.

Abstract: SUMMARY Seven patients with prurigo nodularis and one with aphthous stomatitis were given 40–115 g of thalidomide for 1 to 6 years. They all developed a predominantly sensory peripheral neuropathy mainly involving the lower limbs. Five patients had an unpleasant tight feeling around the feet. Nerve conduction studies showed small sensory action potentials from the lower limbs with normal or only mild slowing of sensory conduction velocity indicating an axonal neuropathy. The dermatological disorder improved dramatically in all, but treatment had to be discontinued because of the severe side-effects. Thalidomide, if used, should be given only over a short period because of its neurotoxic effect.