Showing papers by "Karolinska Institutet published in 1983"
TL;DR: Leukotrienes C4, D4, and E4, which are released from the lung tissue of asthmatic subjects exposed to specific allergens, seem to play a pathophysiological role in immediate hypersensitivity reactions.
Abstract: Arachidonic acid plays a central role in a biological control system where such oxygenated derivatives as prostaglandins, thromboxanes, and leukotrienes are mediators. The leukotrienes are formed by transformation of arachidonic acid into an unstable epoxide intermediate, leukotriene A4, which can be converted enzymatically by hydration to leukotriene B4, and by addition of glutathione to leukotriene C4. This last compound is metabolized to leukotrienes D4 and E4 by successive elimination of a gamma-glutamyl residue and glycine. Slow-reacting substance of anaphylaxis consists of leukotrienes C4, D4, and E4. The cysteinyl-containing leukotrienes are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. Leukotriene B4 causes adhesion and chemotactic movement of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils. Leukotrienes C4, D4, and E4, which are released from the lung tissue of asthmatic subjects exposed to specific allergens, seem to play a pathophysiological role in immediate hypersensitivity reactions. These leukotrienes, as well as leukotriene B4, have pro-inflammatory effects.
2,676 citations
TL;DR: It was found that galanin consists of 29 amino acids and the complete amino acid sequence is: contract smooth muscle preparations from the rat and to cause a mild and sustained hyperglycemia in dog.
1,482 citations
TL;DR: Column chromatography of brain extracts and double immunostaining experiments indicate that neuropeptide Y is the endogenous brain peptide responsible for Immunostaining of pancreatic polypeptides-like immunoreactivity in the mammalian brain.
Abstract: A massive neuronal system was detected by immunocytochemistry and radioimmunoassay with antibodies to neuropeptide Y, the recently isolated peptide of the pancreatic polypeptide family. Immunoreactive cell bodies and fibers were most prevalent in cortical, limbic, and hypothalamic regions. Neuropeptide Y was extracted in concentrations higher than those of any other peptide hitherto discovered in the mammalian brain. Column chromatography of brain extracts and double immunostaining experiments indicate that neuropeptide Y is the endogenous brain peptide responsible for immunostaining of pancreatic polypeptide-like immunoreactivity in the mammalian brain.
1,110 citations
TL;DR: The fusion genes were expressed in all tissues examined, but the ratio of human growth hormone messenger RNA to endogenous metallothionein-I messenger RNA varied among different tissues and different animals, suggesting that expression of the foreign genes is influenced by site of integration and tissue environment.
Abstract: The promoter or regulatory region of the mouse gene for metallothionein-I was fused to the structural gene coding for human growth hormone. These fusion genes were introduced into mice by microinjection of fertilized eggs. Twenty-three (70 percent) of the mice that stably incorporated the fusion genes showed high concentrations of human growth hormone in their serum and grew significantly larger than control mice. Synthesis of human growth hormone was induced further by cadmium or zinc, which normally induce metallothionein gene expression. Transgenic mice that expressed human growth hormone also showed increased concentrations of insulin-like growth factor I in their serum. Histology of their pituitaries suggests dysfunction of the cells that normally synthesize growth hormone. The fusion genes were expressed in all tissues examined, but the ratio of human growth hormone messenger RNA to endogenous metallothionein-I messenger RNA varied among different tissues and different animals, suggesting that expression of the foreign genes is influenced by site of integration and tissue environment.
744 citations
TL;DR: Chloroquine treatment of rodent cells during the first hours of polyoma DNA transfection increase the fraction of cells expressing viral functions, and the effect was even more pronounced in transfections with linear forms of polyomas DNA, suggesting that chloroquine inhibits degradation of DNA absorbed by the cells.
Abstract: Chloroquine treatment of rodent cells during the first hours of polyoma DNA transfection increase the fraction of cells expressing viral functions. The effect has been observed after DNA absorption using both the DEAE-dextran and calcium phosphate coprecipitation methods. Exposure to chloroquine increased the proportion of transfected mouse cells to approximately 40%. From a culture of one million such cells, microgram quantities of newly synthesized viral DNA could be isolated. Similarly, the transformation frequency of rat cells following polyoma DNA transfection was approximately 6-fold increased by chloroquine treatment. The effect of the compound was even more pronounced in transfections with linear forms of polyoma DNA, suggesting that chloroquine inhibits degradation of DNA absorbed by the cells.
630 citations
TL;DR: By using a new technique, intracerebral dialysis, in combination with high performance liquid chromatography and electrochemical detection, it was possible to recover and measure endogenous extracellular dopamine, together with its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) from the striatum and nucleus accumbens of anaesthetized or freely moving rats.
Abstract: By using a new technique, intracerebral dialysis, in combination with high performance liquid chromatography and electrochemical detection, it was possible to recover and measure endogenous extracellular dopamine, together with its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) from the striatum and nucleus accumbens of anaesthetized or freely moving rats. In addition, measurements of extracellular 5-hydroxyindoleacetic acid, ascorbic acid, and uric acid were made. Basal extracellular concentrations of dopamine and DOPAC in the striatum were estimated to be 5 X 10(-8) M and 5 X 10(-6) M, respectively. d-Amphetamine (2 mg/kg s.c.) increased dopamine levels in the striatum perfusates by 14-fold, whereas levels of DOPAC and HVA decreased by 77% and 66%, respectively.
620 citations
TL;DR: NPY seems to be a major peptide in the sympathetic nervous system, supporting its proposed role in sympathetic neurotransmission, and is also observed in the adrenal medulla of guinea-pig and cat.
611 citations
TL;DR: Five regions of MTV DNA that are bound specifically by purified receptor are mapped and compared, suggesting that receptor affinity for upstream and internal regions may differ by less than one order of magnitude.
605 citations
TL;DR: It is shown that some neurons contain more than one classical transmitter, e.g. 5-HT plus GABA, further underlining the view that transfer of information across synapses may be more compex than perhaps hitherto assumed.
556 citations
TL;DR: It is reported here that cigarette smoke as well as light mechanical or local chemical irritation and vagal nerve stimulation induced a subepithelial oedema in the rat trachea and bronchial tree, as indicated by extravasation of Evans blue.
Abstract: The mucosa of the trachea and bronchi is very sensitive to various types of stimuli. Thus, cigarette smoke as well as mechanical or chemical irritation induce local mucosal reactions and bronchial smooth muscle spasm via sensory reflexes1–4. However, only the chemical transmitters involved in these local or vago-vagal reflexes acting to produce bronchoconstriction are known, while the mediator of the vasodilation remains to be established2. Unmyelinated sensory neurones of the C-fibre group have been associated with ‘neurogenic inflammation’, that is, increased vascular permeability and antidromic vasodilation in the skin5. These responses are abolished after pretreatment with capsaicin, the pungent agent of red peppers5,6. Simultaneously, there is a loss of substance P-immunoreactive nerves7, which may explain the long-term effect of capsaicin, as substance P normally increases vascular permeability and blood flow6. Capsaicin-sensitive, substance P-immunoreactive neurones of vagal sensory origin have also recently been found in the lower respiratory tract8. Furthermore, preliminary observations suggest that an increase in vascular permeability occurs in the tracheal mucosa on vagal nerve stimulation8–10. The capsaicin-sensitive afferents of vagal origin are probably also involved in local regulation of bronchial smooth muscle tone8,11. We report here that cigarette smoke as well as light mechanical or local chemical (ether, formalin, histamine, bradykinin or capsaicin) irritation and vagal nerve stimulation induced a subepithelial oedema in the rat trachea and bronchial tree, as indicated by extravasation of Evans blue. The increase in vascular permeability induced was markedly reduced or abolished in capsaicin-pretreated animals, where substance P-containing C-fibre afferents in the respiratory tract had degenerated. Substance P had a potent direct stimulatory effect on vascular permeability in the airways. Irritation of the respiratory tract mucosa seems to activate capsaicin-sensitive neurones, which via local axon reflexes induce an interstitial oedema probably by releasing substance P. Capsaicin pretreatment induces a long-lasting desensitization of the airways to various exogenous and anaphylactic irritants. These findings may give new aspects of the pathophysiology and treatment of hyperreactive airways in man.
486 citations
01 Jan 1983
TL;DR: The blood contact properties as studied in vitro revealed that the surface was highly thromboresistant in terms of reduced platelet adhesion, surface catalyzed adsorption and inhibition of thrombin and capacity to prevent clotting of nonanticoagulated blood.
Abstract: A new method for the covalent binding of heparin to artificial surfaces has been developed. The heparinized surface releases insignificant amounts of heparin and can be regarded as stable. The blood contact properties as studied in vitro revealed that the surface was highly thromboresistant in terms of reduced platelet adhesion, surface catalyzed adsorption and inhibition of thrombin and capacity to prevent clotting of nonanticoagulated blood.
TL;DR: It is concluded that removal of carbohydrate chains from IgG molecules may have a profound and highly select impact on the biological activity to these antibodies.
Abstract: We have prepared monoclonal hapten-specific mouse IgG2b antibodies depleted of asparagine-linked carbohydrate chains by treating the hybridoma cells with tunicamycin. The carbohydrate-deficient antibodies behaved in an identical manner to the normal antibodies with regard to fine antigen-binding reactivity (a Fab fragment feature) and protein A binding capacity [a feature requiring integrity at the CH2 and CH3 domain-interaction regions in the constant region of the heavy chain (CH)]. However, they lost the ability to activate complement, to bind to Fc receptors on macrophages, and to induce antibody-dependent cellular cytotoxicity. Furthermore, antigen-antibody complexes produced from such carbohydrate-deficient antibodies failed to be eliminated rapidly from the circulation. We conclude that removal of carbohydrate chains from IgG molecules may have a profound and highly select impact on the biological activity to these antibodies.
TL;DR: Certain neurons in the brain are specifically and intensely stained by a histochemical method which demonstrates nicotinamide adenine dinucleo‐tide phosphate NADPH‐diaphorase activity, finding that within the striatum all of the neurons that were selectively stained by this technique also contained both somatostatin‐ and APP‐like immunoreactivities.
Abstract: Certain neurons in the brain are specifically and intensely stained by a histochemical method which demonstrates nicotinamide adenine dinucleo-tide phosphate NADPH-diaphorase activity. The cell types containing this enzyme in certain areas of the rat forebrain were examined by combining NADPH-diaphorase histochemistry with the indirect immunofluorescence technique. Neurons containing somatostatin- or avian pancreatic polypep-tide (APP)-like immunoreactivities were found throughout the forebrain including the striatum and neocortex. These two neuropeptides were also found to coexist in many telencephalic neurons. After photography, the sections processed for immunohistochemistry were stained for NADPH-diaphorase activity by a histochemical method. It was found that within the striatum all of the neurons that were selectively stained by this technique also contained both somatostatin- and APP-like immunoreactivities. Also in the neocortex NADPH-diaphorase was found only in those neurons displaying somatostatin- or APP-like immunoreactivity. In other brain regions such as the nucleus laterodorsalis tegmenti, NADPH-diaphorase-containing cells did not contain these neuropeptides.
The results indicate that NADPH-diaphorase histochemistry provides a simple, reliable, histochemical method to demonstrate those striatal neurons in which somatostatin- and APP-like immunoreactivities coexist. The selective occurrence of this enzyme within these neurons may provide a useful target for pharmacological studies of these neuropeptide-containing cells.
TL;DR: It is suggested that Evans blue fluorescence can be applied for quantification ofprotein leakage with high sensitivity which opens the possibility of measuring this reaction in very small regions with high accuracy, as well as for tissue localization of protein leakage at the microscopic level.
TL;DR: Several substances including anaphylaxis induce protein leakage in many tissues with differing selective distribution patterns as well as SP, a likely mediator of neurogenic protein leaking in many organs.
Abstract: Plasma extravasation was induced in rats or guinea-pigs by intravenous injections of (1) substance P (SP), (2) the C-terminal SP-hexapeptide SP(6--11), (3) serotonin (5-HT), (4) histamine, (5) bradykinin, (6) capsaicin and (7) by antigen challenge. Plasma extravasation induced by SP, SP(6--11), by 5-HT and by capsaicin was, with few exceptions, observed in the same tissues. The effect of SP was not blocked by H1 and H2 histamine receptor antagonists. The effect of i.v. capsaicin was absent in capsaicin desensitized animals. Plasma extravasation upon i.v. SP, SP(6--11), 5-HT and capsaicin was seen in the skin and in all organs containing mucous membranes except the intestinal mucosa. Plasma extravasation by histamine, bradykinin, and antigen challenge of sensitized guinea-pig was, in addition, also observed in the stomach and intestine. Plasma extravasation and bronchoconstriction by antigen challenge with 20 micrograms/kg ovalbumin was completely blocked by combined H1 and H2 histamine receptor blockade. Both responses were reduced to about the half capsaicin desensitized guinea-pigs, although the reduction of the permeability response was statistically not significant in all organs. In conclusion, several substances including anaphylaxis induce protein leakage in many tissues with differing selective distribution patterns. Anaphylactic histamine release leads to protein leakage partly via activation of sensory neurons. SP is a likely mediator of neurogenic protein leakage in many organs.
TL;DR: Brain P and PS levels did not seem to depend on steroidogenic gland secretion: no meaningful difference occurred in brain 15 days after adrenalectomy plus orchiectomy, compared with sham-operated controls and it is proposed that P andPS formation or accumulation in the rat brain depend on in situ mechanisms unrelated to the peripheral endocrine gland system.
TL;DR: The relationship between maximum voluntary concentric strength, muscle fibre type distribution and muscle cross-sectional areas were examined and Maximal tension developed per unit of muscleCross-sectional area did not correlate significantly with per cent type I fibre area and did not differ between the female and male students or bodybuilders.
Abstract: The relationship between maximum voluntary concentric strength, muscle fibre type distribution and muscle cross-sectional areas were examined in 23 subjects (7 female and 11 male phys. ed. students as well as 5 male bodybuilders). Maximal knee and elbow extension as well as elbow flexion torque at the angular velocities 30, 90 and 180 degrees per second was measured. Muscle biopsies were taken from vastus lateralis and m. triceps brachii. The muscle cross-sectional area of the thigh and upper arm was measured with computed tomography scanning. The maximal torque correlated strongly to the muscle cross-sectional area times an approximative measure on the lever arm (body height). Maximal tension developed per unit of muscle cross-sectional area did not correlate significantly with per cent type I fibre area and did not differ between the female and male students or bodybuilders. Neither did the relative decrease in torque with increasing contraction velocity show any significant relationship to the per cent type I fibre area. The total number of muscle fibres was estimated by dividing the muscle cross-sectional area with the mean fibre area of m. triceps brachii. The number of fibres did not seem to differ between the sexes.
TL;DR: Evidence is presented that the structurally related peptide, neuropeptide Y (NPY), is likely to be the biologically active material in these nerves, as demonstrated by immunocytochemistry and pharmacological evidence.
TL;DR: The motor pattern could be entrained by applying sinusoidal hip movements, even when a very extensive denervation of the leg had been performed leaving only some of the muscles around the hip and the hip joint innervated.
Abstract: Acute low spinal and curarized cats injected with noradrenergic agonists i.v. can elicit an efferent burst pattern which can be recorded in muscle nerve filaments and can be referred to as “fictive locomotion”. This study investigates the effect that feedback, arising from movements in the hip joint, can exert on the central network generating fictive locomotion. The central network is uncoupled from generating any active movements by curarization. The motor pattern could be entrained by applying sinusoidal hip movements, even when a very extensive denervation of the leg had been performed leaving only some of the muscles around the hip and the hip joint innervated. During flexion movements, efferents to different flexor muscles became active and during movements in the reverse direction (extension), efferents to extensors were active. With an increasing movement frequency the onsets of both flexor and extensor bursts were delayed in the movement cycle. The duration of the extensor bursts varied markedly with the movement cycle, whereas pure flexors changed less in burst duration. The frequency range within which the efferent burst activity was entrained in a strict 1:1 relation to the movement varied between 5 to 70% above and below the resting burst period. In preparations with a narrow 1:1 range, a “relative coordination” was encountered outside this range. The flexor burst duration was in these cases dependent on where in the hip movement cycle the bursts appeared.
TL;DR: The present data indicate that all SP nerves in the trachea and lung are afferent and capsaicin-sensitive, and the SP innervation of the lung seems to have a dual origin.
Abstract: The origin of substance P (SP)-immunoreactive neurons in the lower respiratory tract, esophagus and heart of guinea-pigs was demonstrated by surgical denervation or capsaicin pretreatment with subsequent determination of the tissue levels of SP by radioimmunoassay. In other experiments the effect of vagal nerve stimulation on the SP levels in these tissues was studied. The effects of capsaicin-sensitive afferents in the respiratory tract mucosa and bronchial smooth muscle was also studied by analysis of vascular permeability to Evans blue and insufflation-pressure changes. Our present data indicate that all SP nerves in the trachea and lung are afferent and capsaicin-sensitive. The trachea and stem bronchi receive SP afferents mainly from the right vagus nerve with cell bodies located in both the nodose and jugular ganglia. The SP innervation of the lung seems to have a dual origin: 1. Afferents from both vagal nerves with a crossed type of innervation pattern. 2. A non-vagal source which consists of about 40% of the SP nerves in the lung. These nerves probably originate from thoracic spinal ganglia. The effects of ether and capsaicin on insufflation pressure and increase in vascular permeability were dependent on the integrity of capsaicin-sensitive afferents of both vagal and non-vagal origin. In the guinea pig, systemic capsaicin pretreatment to adult animals seemed to result in irreversible changes in the respiratory tract, while in the rat a successive recovery of the functional response of capsaicin-sensitive afferents occurred. Different regimes of systemic capsaicin pretreatment induced different effects on the cholinergic (atropine-sensitive) insufflation-pressure response. Capsaicin pretreatment, using multiple injections over two days, depressed the cholinergic insufflation-pressure increase, while the cholinergic vagal component was unaffected in animals which received a single dose of capsaicin or local pretreatment with capsaicin on the vagal nerves. The local treatment was more effective with regard to SP depletion in target areas when using alcohol as solvent than when capsaicin was dissolved in paraffin oil, while the functional deficits were similar. The SP nerves in the esophagus were mainly of vagal afferent origin, while the heart atrium seemed to have a dual innervation by both vagal and non-vagal SP nerves.
TL;DR: Results indicate that the Striatal somatostatin/APP/NADPH‐diaphorase neurons occur throughout the striatum and have long, aspiny dendrites, oval, invaginated nuclei with prominent nucleoli, and receive few axosomatic contacts.
Abstract: Striatal neurons containing both somatostatin- and avian pancreatic polypeptide (APP)-like immunoreactivities have been shown to be selectively stained by the histochemical method for nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity. In the present study, we have utilized this histochemical technique to examine the morphology of these striatal neurons at the light and electron microscopic levels. Our results indicate that the striatal somatostatin/APP/NADPH-diaphorase neurons occur throughout the striatum and have long, aspiny dendrites, oval, invaginated nuclei with prominent nucleoli, and receive few axosomatic contacts. These cells appear to correspond to a population of medium-sized aspiny interneurons reported previously in Golgi and electron microscopic studies of the striatum.
TL;DR: In the largest series of patients with glibenclamide-associated hypoglycaemia reported so far, 51 cases reported to the Swedish Adverse Drug Reactions Advisory Committee and six additional cases are reviewed and related to sales and prescription data of glibanclamide.
Abstract: In the largest series of patients with glibenclamide-associated hypoglycaemia reported so far, 51 cases reported to the Swedish Adverse Drug Reactions Advisory Committee and six additional cases are reviewed and related to sales and prescription data of glibenclamide. Median age of the patients with hypoglycaemia was 75 years and 21% were 85 years or above. For comparison, the median age of a random sample (1 in 288 of all patients prescribed glibenclamide) was 70 years and only 5% were 85 years or older. In eight out of 40 cases where duration of glibenclamide treatment was recorded, the hypoglycaemic event occurred during the first month of treatment. The median daily dose of glibenclamide prescribed was 10 mg both in the hypoglycaemic cases and in the prescription sample. Coma or disturbed consciousness was the most common clinical presentation in this series and the minimum blood glucose value was 1.3 mmol/l (median). Twenty-two patients responded immediately to treatment, 24 had protracted hypoglycaemia of 12-72 h duration and 10 died. Fatal outcome was observed even with small doses of glibenclamide (2.5-5 mg/day). Previous strokes and cardiac disorders were isolated as two independent determinants of a serious course of the hypoglycaemia. Other contributing factors included impaired renal function, low food intake, diarrhoea, alcohol intake and interaction with other drugs. Thus, it is not uncommon for glibenclamide, like the first-generation sulphonylureas, to cause serious, protracted and even fatal hypoglycaemic events.
TL;DR: It was found that the degree of alveolar bone loss and the number of teeth lost were greater in twins with a high life- time smoking exposure than in their twin partners with a low life-time exposure.
Abstract: The study was based on 164 twin pairs from the older cohort of the Swedish twin registry. The main purpose of the study was to analyze previously recorded data concerning gingival bleeding in members of twin pairs with differing smoking exposure. Other periodontal disease factors analyzed were plaque index, alveolar bone index and tooth loss. It was found that I he degree of alveolar bone loss and the number of teeth lost were greater in twins with a high life-time smoking exposure than in I heir twin partners with a low life-time exposure. Contrary to expectation, it was found that gingival bleeding propensity was less prevalent in the high exposure group. It is concluded that the validity of gingival bleeding as a sign and a symptom of inflammatory periodontal disease may be reduced as a consequence of smoking.
TL;DR: 73As-arsenobetaine was the only labelled arsenic compound detected in urine and soluble extract of tissues, indicating that no biotransformation occurred.
TL;DR: It is introduced that following ganglioside treatment some lesioned DA nerve cells do not degenerate, but elongate their dendrites to give increased trophic support to DA cell bodies with intact DA axons, and may possibly represent a new type of drug in the treatment of Parkinson's disease and aging processes in DA systems.
Abstract: The effects of chronic ganglioside treatment GM-1 (10 mg/kg, i. p., once daily for 56 days) have been evaluated on the degenerative and regenerative features of nigrostriatal dopamine (DA) neurons following a partial lesion by tyrosine hydroxylase immunocytochemistry in combination with morphometrical analysis and by quantitative DA receptor autoradiography. Chronic GM-1 treatment resulted in the maintenance in the number of DA cell bodies, terminals and striatal area on the lesioned side and also increased dendrite length of the DA nerve cells in the zona reticulata on that side. The lesion induced DA receptor supersensitivity was counteracted by chronic treatment with GM-1 and the apomorphine induced rotational behaviour was significantly reduced. The hypothesis is introduced that following ganglioside treatment some lesioned DA nerve cells do not degenerate, but elongate their dendrites to give increased trophic support to DA cell bodies with intact DA axons. These increased dendro-dendritic interactions may enable the unlesioned DA cells to increase the density of their striatal nerve terminal networks via collateral sprouting leading to recovery of dopaminergic synaptic function as evidenced in the receptor autoradiographical and behavioural analysis. Gangliosides may therefore possibly represent a new type of drug in the treatment of Parkinson's disease and aging processes in DA systems.
TL;DR: In vitro incubation of [74As]arsenite, -arsenate or -dimethylarsinic acid with liver, lung and kidney homogenate of mice and rabbits showed that arsenite is the main form of arsenic bound to tissues, and the similar binding pattern after exposure to arsenite and arsenate indicates further that one and the sameform of arsenic, arsenite, is retained independent of the form of exposure to inorganic arsenic.
TL;DR: A newly discovered bioactive peptide, neuropeptide tyrosine (NPY), has been found in the human cardiac nervous system, and analysis of the peptide by high-performance liquid chromatography demonstrated that it was present in a single molecular form, closely similar or identical to that of the isolated bio active peptide.
TL;DR: A UNEP/WHO project on the assessment of human exposure to lead and cadmium through analysis of blood and kidneys, with considerable variation in metal exposure between areas, found that males had higher blood levels than females and smokers higher than nonsmokers.