Showing papers by "Karolinska Institutet published in 1986"

Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy

Abstract: Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.

Quantitative Analysis of D2 Dopamine Receptor Binding in the Living Human Brain by PET

Abstract: D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2 dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85 to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.

Distribution of galaninlike immunoreactivity in the rat central nervous system

Abstract: The localization of galanin (GAL) immunoreactive (IR) neuronal structures in the rat central nervous system has been investigated by using the indirect immunofluorescence technique. GAL-IR structures were seen in high concentrations in the hypothalamus, medulla oblongata, and spinal cord. Less extensive systems were detected in the telencephalon, thalamus, mesencephalon, and pons, while virtually no GAL-positive structures were seen in the olfactory bulb and cerebellum. Major populations of cell bodies staining for GAL-like material were seen in many areas. In the telencephalon somata were revealed in the bed nucleus of stria terminalis, in the nucleus of the diagonal band, medial septum, and in the medial aspects of the central amygdaloid nucleus, and in small numbers in cortical areas. The anterodorsal and periventricular nuclei of the thalamus contained positive cell bodies. In the hypothalamus GAL-IR somata were seen in the medial and lateral preoptic nuclei, arcuate nucleus, periventricular nucleus, in the dorsomedial nucleus, in the medial forebrain bundle area, in the tubular, caudal, accessory, supraoptic, and paraventricular magnocellular nuclei and lateral to the mammillary recess. The dorsal raphe nucleus hosted a large number of GAL-positive somata. Locus coeruleus of the pons contained a large number of GAL-IR perikarya. In the medulla oblongata positive somata were found in the caudal spinal trigeminal nucleus, the nucleus of the solitary tract, and in the ventral lateral area just rostral to area postrema. Small cell bodies were detected in the superficial layers of the dorsal horn of the spinal cord at all levels and in lamina X at lumbar levels. Analysis of GAL-positive fibers in the telencephalon revealed highly or medium-dense networks in the lateral septal nucleus, in the bed nucleus of stria terminalis, and in the central and medial amygdaloid nuclei. Positive fibers were found in the thalamus in and around the periventricular nucleus as well as to the lateral habenular nucleus and extending in a lateral, caudal direction from the third ventricle and fasciculus retroflexus to the lateral tip of the medial lemniscus. In the hypothalamus the external layer of the median eminence contained a very dense fiber network. Dense or medium-dense GAL-IR networks were detected in the periventricular nucleus, throughout the medial and lateral preoptic areas, in the medial forebrain bundle area, in the dorsomedial nucleus, and lateral to the mammillary recess. In the pons GAL-IR fibers were seen in the parabrachial nuclei, dorsal to the superior olive, and in the periaqueductal central gray. The external layers of the caudal spinal trigeminal nucleus, the nucleus of the solitary tract, and the ventral portions of the medulla oblongata contained extensive positive fiber networks. In the spinal cord GAL-IR fibers were noted in high numbers in the superficial layers (lamina I and II) of the dorsal horn and at lumbar and sacral levels in lamina X.

Applied Physiology of Soccer

Abstract: Soccer is characterised as a high intensity, intermittent non-continuous exercise. Players cover approximately 10 km of ground per game, of which 8 to 18% is at the highest individual speed. In higher levels of competition there is a greater number of tackles and headings plus a greater percentage of the game is performed at maximum speed. The average aerobic energy yield during a national level game is around 80% of the individual maximum. Blood lactate concentration during a game averages 7 to 8 mmol/L. Because of a high energy yield most players have empty muscle glycogen stores at the end of the game, were hypohydrated and also have an increased body temperature. Soccer players of national and international standard have a maximal aerobic power of around 60 to 65 ml/kg/min, an above average anaerobic alactacid power, and a greater buffer capacity and muscle strength compared with untrained controls, yet seem to be less flexible.

Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion

Abstract: In mammalian tissues the C-terminal amide structure has been found to occur only in neuroactive or hormonally-active peptides. About half known neuropeptide and peptide hormones have this unique chemical feature. Using a chemical detection method, a search for previously unknown peptides that possess the C-terminal amide structure in extracts of brain and intestine was carried out and a number of novel neuropeptides and hormonal peptides, designated neuropeptide Y, PHI, peptide YY, galanin and neuropeptide K were isolated. We recently performed a similar search in porcine pancreas and found a high concentration of a peptide having a glycine amide at its C-terminus. Here we report the isolation, primary structure and biological activity of this novel peptide. The 49-residue peptide strongly inhibits glucose-induced insulin release from the isolated perfused pancreas and was therefore named pancreastatin. It may be important in the regulation of insulin secretion and in the pathogenesis and treatment of diabetes mellitus.

Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter.

Abstract: Complementary DNA encoding the IgG1 induction factor, the first lymphokine directed to B lymphocytes, from a murine T-cell line has been cloned using a new strategy. The putative primary amino-acid sequence was deduced from the nucleotide sequence determined. The lymphokine synthesized by the direction of this cloned cDNA has many other functions, such as production of B-cell growth factor-1 and induction of Ia on B cells.

Pressure-pain threshold in human temporal region. Evaluation of a new pressure algometer

Abstract: A hand-held pressure algometer with a pressure sensitive strain gauge at the tip was used to measure the pressure-pain threshold (PPT) in the temporal region of healthy volunteers. Various sizes of circular tips and various application rates were tested before selecting an area of 0.5 cm2 and a constant application rate of 0.68 N X sec-1 for future use. A highly significant correlation was found between PPT values obtained from the two sides (of the head) (P less than 0.001) and between PPT values obtained with a 3-week interval (P less than 0.001). In a series of 50 immediate consecutive measurements in the same individual, the mean PPT was 171 kPa (N = 6, 2 S.D. 24%). The mean relative change in PPT after a 3-week interval was 0 +/- 51% (N = 11, 2 S.D.). In the course of 5 repeated determinations at weekly intervals there was a significant increase in PPT (ANOVA, P less than 0.05). Subcutaneous lignocaine significantly elevated PPT compared to placebo. Due to the high inter-individual variation, determinations of PPT for group comparisons should include rather large population samples, whereas in paired studies, the intra-individual variation allows the investigation of much smaller groups (10-20 subjects). It is our experience that the pressure algometer is easy to operate in the hands of a skilled laboratory assistant.

Nicotinic effects on the firing pattern of midbrain dopamine neurons

Abstract: The effects of systemic administration of nicotine or the nicotinic antagonist mecamylamine on the midbrain dopamine (DA) systems of the rat were studied with single cell recording techniques. Dopamine cells of the zona compacta, substantia nigra (ZC-SN) and the ventral tegmental area (VTA) were identified by their characteristic action potentials, antidromic stimulation methodology and conventional histological procedures. Firing rates as well as firing patterns were determined from computer-generated interspike interval histograms describing burst-firing in relation to single-spike firing. A larger proportion of burst-firing DA cells was found in the VTA when compared with the ZC-SN area. (-)-Nicotine bitartrate (0.5 mg kg-1 i.p.) not only increased the firing rate of ZC-SN neurons but also the amount of burst firing of the ZC-SN neurons and VTA neurons, respectively. Mecamylamine HCl (4.0 mg kg-1 i.p.) decreased the firing rate of VTA cells which, in principle, indicates a tonic nicotinic input in this area. The increase in firing rate of central DA neurons following nicotine administration was found to be associated with increased bursting of the burst firing cells whereas, in contrast, the non-bursting neurons did not respond with burst-firing. Generally, the correlation between nicotine induced changes in firing rate and in burst-firing activity, respectively, was found to be low for midbrain DA neurons. These observations, in conjunction with the previous demonstration of nicotinic receptors in these areas, indicate the existence of a nicotinic input, specifically regulating the firing pattern of these central DA cells. This neuromodulatory effect of nicotine may be significant for its behavioural stimulant action.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequence determinants of cytosolic N-terminal protein processing

Abstract: N-terminal methionine removal has been analyzed statistically in a large sample of prokaryotic and eukaryotic cytosolic proteins in an attempt to uncover common sequence determinants. We find that the residue next to the initiator Met is the most important determinant of N-terminal processing: Lys, Arg, Leu and (in prokaryotes) Phe and Ile protect the initiator Met from being removed when next to it in the sequence; Ala, Gly, Pro, Ser, Thr and (in eukaryotes) Val in this position cause its removal. Subsequent acetylation is confirmed to be strongly biased towards Ala, Met and Ser residues; when Met is acetylated, Asp is the predominant penultimate residue in eukaryotes. Also, we find major differences in the relative abundance of the various residues next to the initiator Met between prokaryotes and eukaryotes: prokaryotic proteins are much more biased towards Lys as the Met-protecting residue, and towards Ala when met is to be removed, than eukaryotic ones. Finally, we show that our results can explain a part of the mRNA 'consensus sequence' found around eukaryotic initiator AUG codons.

Mechanisms of movement in outer hair cells and a possible structural basis.

Abstract: Isolated outer hair cells were found to slowly shorten when subjected to a solution that would induce contraction in a muscle fibre. Two possible mechanisms underlying this behaviour emerge from ultrastructural and immunocytochemical investigations. Antibody labelling at the electron microscopic level demonstrates that actin is present not only in the stereocilia and in the cuticular plate but also along the wall of outer hair cells, between the plasma membrane and the subsurface fenestrated cisternae. The latter are interconnected by regularly spaced pillars, resembling those seen between the T-tubules and sarcoplasmic reticulum in muscle fibres. Contraction also results from the application of positively charged macromolecules to the bathing solution. This implies sensitivity of the membrane-associated complex (the cortex system) to an electrical current. A second contractile system may reside in the cytoplasm, where calmodulin is present in contracted hair cells. This protein is a calcium-binding control protein for contraction-like events in smooth muscle and non-muscle cells. The unique presence of the cortex system in outer hair cells, and its absence in inner hair cells, indicates a functional significance that relates to a motor function of outer hair cells in hearing.

Microdialysis in the study of extracellular levels of amino acids in the rat brain.

Abstract: Microdialysis has been used for in vivo studies of extracellular amino acids in rat brain. We describe a method where a probe was designed to be implanted vertically. This probe is suitable for regional stereotaxic studies of the rat brain. The dialysis probe was perfused with Ringer's solution and the perfusates were analysed for their amino acid content with a high performance liquid chromatography (HPLC) technique. An orthophthaldialdehyde derivative of the amino acids was formed before the sample was injected onto the column. In vitro studies of the dialysis probe show that the relative recovery of substances outside the membrane is dependent on perfusion speed and length of dialysing membrane but not on the concentration outside. We were also able to show that the probe was within the blood-brain barrier (BBB) when implanted into the brain since after intravenous injection of Na99mTcO4, a substance that cannot pass through the intact BBB, it was not possible to recover any isotope from the perfusate. We conclude that microdialysis is a unique method of studying regional neurochemical events within the BBB, for example, changes in putative amino acid neurotransmitters and their metabolites.

Chapter 16 Multiple co-existence of peptides and classical transmitters in peripheral autonomic and sensory neurons—functional and pharmacological implications

Abstract: Publisher Summary This chapter focuses on some recent advances in studies on the co-existence of peptides with acetylcholine (Ach) and noradrenaline (NA) in certain autonomic nerves, as well as on the occurrence of multiple peptides in sensory nerves Noradrenaline has for long been known to be the primary transmitter of peripheral sympathetic neurons with minor exceptions—for example, the sympathetic innervation of sweat glands, which is cholinergic Immunohistochemical evidence has suggested that a member of the pancreatic polypeptide family—avian pancreatic polypeptide (APP)—has a widespread neuronal localization in mammals Only a proportion of sympathetic NA nerves seems to contain the NPY-like peptide and these neurons innervate target organs such as blood vessels, the muscle of the heart, spleen, and vas deferens Other populations of sympathetic neurons projecting to, for instance, exocrine elements in certain salivary glands or brown fat cells do not contain NPY, suggesting a chemical heterogeneity and a morphological basis for a functional differentiation of the sympathetic nerves Sympathetic nerve stimulation is accompanied not only by release of NA but also of NPY-LI Thus, by using the blood-perfused cat or pig spleen as an experimental model, it has been demonstrated by earlier studies that nerve stimulation causes a co-release of NA and NPY-LI Intermittent stimulation with bursts of impulses at a high frequency enhances selectively the release of NPY-LI compared to NA

Liver Investigation in 149 Asymptomatic Patients with Moderately Elevated Activities of Serum: Aminotransferases

Abstract: The accidental finding of raised levels of serum aminotransferase levels may lead to extensive investigations of the liver in apparently healthy people. To identify diagnostic groups and their need for investigations, we have evaluated the results of all investigative procedures carried out in 149 asymptomatic patients with persistently raised serum levels of aminotransferases. Fatty liver was found in 64%. These patients often had a high body weight. A high alcohol intake and diabetes mellitus were also noted. Chronic active or persistent hepatitis was found in 20% of the patients. Six per cent had cirrhosis, 4% had alpha 1-antitrypsin deficiency, and 3.5% had hemochromatosis. Apart from ferritin, alpha 1-antitrypsin, and markers for hepatitis B, blood tests were of little value for distinguishing among different diagnostic groups. This was the case also for the imaging procedures, and neither liver scintigraphy nor ultrasonography was a reliable source of diagnostic information. The results of our study indicate that diagnosis in this group of patients cannot be made without liver biopsy.

Brain Stem Mechanisms for Generation and Control of Breathing Pattern

Abstract: The sections in this article are: 1 Homeostatic and Behavioral Regulation of Breathing—Aims and Compromises 2 Some General Features of Rhythm-Generating Mechanisms for Automatic Breathing 2.1 Is There More Than One CPG for Automatic Breathing? 2.2 Spinal Pattern Generator 2.3 Bilaterally Symmetric CPG 3 Localization of Basic Rhythm Generator for Automatic Breathing 3.1 Brain Stem Transections 3.2 Localization by Electrical Stimulation 3.3 Localization by Recording RR Neural Activity 4 Distribution of RR Neurons and Their Functional Properties 4.1 General Outline of Medullary RR Neurons 4.2 Ventral Respiratory Group 4.3 Dorsal Respiratory Group 4.4 Problem of Reciprocal Interaction Between Inspiratory and Expiratory Bulbospinal Neurons 4.5 Why Are There Two Separate Pools of Inspiratory Premotor Neurons? 4.6 Summary 5 Functional Organization of Respiratory CPG—Systems Behavior 5.1 Methods 5.2 General Organizational Features of CPG and Its Main Afferent Feedback Systems 5.3 Mechanisms Controlling Inspiratory Parameters 5.4 Control of Expiratory Parameters 5.5 Concept of Breathing Pattern for Ergometric Minimization 6 Conclusions

Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update

Abstract: Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression.

A correlation analysis of the regional distribution of central enkephalin and beta-endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission.

Abstract: By means of semiquantitative immunocytochemistry and quantitative receptor autoradiography a correlation analysis has been performed on the pre- and post-synaptic features of enkephalin andβ-endorphin immunoreactive neuron systems of the 3- and 24-month-old male rat. A parallel disappearance of enkephalin- andβ-endorphin-like immunoreactivity and of the density of mu and delta opiate receptors is shown during ageing. Furthermore, the lack of an overall correlation between the amount of pre- and post-synaptic components of the enkephalin andβ-endorphin synapses give evidence for the existence of a volume type of transmission in such systems in the telencephalic, diencephalic and mesencephalic areas analysed.

Maternal smoking influences cord serum IgE and IgD levels and increases the risk for subsequent infant allergy

Abstract: The effects of parental smoking on IgE and IgD levels in cord serum and subsequent infant allergy were investigated in an unselected series of 186 European newborn infants. Maternal smoking caused a significant rise in both IgE ( p p p p = 0.005, respectively). Furthermore, newborn infants of nonallergic parents had a more than threefold ( p p = 0.005) higher risk of developing definite or probable atopic disease before 18 months of age if the mother smoked than if she did not. Paternal smoking did not influence, in whatever the subgroup, cord IgE or subsequent infant allergy but increased cord IgD ( p p

Muscle metabolism during intense, heavy-resistance exercise.

Abstract: The objective of this study was to examine the muscle metabolic changes occurring during intense and prolonged, heavy-resistance exercise Muscle biopsies were obtained from the vastus lateralis of 9 strength trained athletes before and 30 s after an exercise regimen comprising 5 sets each of front squats, back squats, leg presses and knee extensions using barbell or variable resistance machines Each set was executed until muscle failure, which occurred within 6-12 muscle contractions The exercise: rest ratio was approximately 1:2 and the total performance time was 30 min Concentrations of adenosine triphosphate (ATP), creatine phosphate (CP), creatine, glycogen, glucose, glucose-6-phosphate (G-6-P), alpha-glycerophosphate (alpha-G-P) and lactate were determined on freeze-dried tissue samples using fluorometric assays Blood samples were analyzed for lactate and glucose The exercise produced significant reductions in ATP (p less than 001) and CP (p less than 0001), while alpha-G-P more than doubled (p less than 005), glucose increased tenfold (p less than 0001) and G-6-P fourfold (p less than 0001) Muscle lactate concentration at cessation of exercise averaged 173 mmol X kg-1 w w Glycogen concentration decreased (p less than 0001) from 160 to 118 mmol X kg-1 w w It is concluded that high intensity, heavy resistance exercise is associated with a high rate of energy utilization through phosphagen breakdown and activation of glycogenolysis

Short-Chain Fatty Acids in Germfree Mice and Rats

Abstract: The short-chain fatty acids (SCFAs) have been analyzed in small intestinal and cecal content of 10 germfree and six conventional mice from a Norwegian laboratory, in cecal content and serum of five germfree rats and two germfree mice from a Swedish laboratory and in Norwegian and Swedish autoclaved, nonpurified rodor diets. The mean total SCFA concentration was 1020 mumol/kg in cecum and 1010 mumol/kg in small intestine of Norwegian germfree mice; 124,600 mumol/kg in cecum and 6,250 mumol/kg in small intestine of conventional mice; 490 mumol/kg in cecum and 370 mumol/L in serum of Swedish rats; 360 mumol/kg in cecum and 290 mumol/L in serum of Swedish mice; 31.4 mmol/kg in Norwegian and 19.5 mmol/kg in Swedish nonpurified diets. Acetic acid accounted for more than 90% of the total concentration in all samples from germfree animals and diet, but detectable concentrations of propionic, isobutyric, n-butyric, isovaleric and n-valeric acid were also present. Thus, germfree animals have low, but measurable, concentrations of SCFAs in intestinal content compared to conventional animals. Most probably these acids originate mainly from the diet.

Coexistence of neuronal messengers--an overview.

Abstract: Publisher Summary This chapter discusses results demonstrating that neurons often contain more than one chemical compound. The different types of coexistence situations are described, including (1) a classical transmitter and one or more peptides, (2) more than one classical transmitter, and (3) a classical transmitter, a peptide, and adenosine triphosphate (ATP). The functional significance of these histochemical findings is at present difficult to evaluate, but in studies on the peripheral nervous system evidence has been obtained that classical transmitter and peptide are coreleased and interact in a cooperative way on effector cells. In addition to enhancement, there is evidence that other types of interactions may occur—for example, the peptide may inhibit the release of the classical transmitter. Also in the central nervous system (CNS), indirect evidence is present for similar mechanisms—that is, to strengthen transmission at synaptic (or non-synaptic) sites and for the peptide inhibition of release of a classical transmitter. Multiple messengers may provide the means for increasing the capacity for information transfer in the nervous system.