European Association of Poison Centres and Clinical Toxicologists.
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Biomedical subjects
Publications and source records attributed to H Persson.
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Renal transplant biopsies were obtained from 16 patients with systemic lupus erythematosus 6 months to 11 years post-transplant. Eight biopsies were taken on clinical grounds while eight were elective. Histopathological findings suggesting recurrent lupus nephritis were found in seven biopsies, five of which were taken on clinical indication. By light-microscopy, five graft biopsies showed proliferative glomerulopathy and two glomerulosclerosis. Immunofluorescence was positive for IgM and C3 in a finely granular pattern in all biopsies, for C1q in three, but for IgG in only two. Electron-dense deposits were found in all seven biopsies with predominantly subendothelial location. All but one patient had clinical signs of renal involvement, but only three had extrarenal symptoms and three had serological signs of active SLE. Upon increased immunosuppressive therapy, renal and serological signs improved but one graft was later lost due to recurrent SLE nephritis.
The distributions of mRNAs for the protooncogene trk and the low-affinity NGF receptor (LNGFR) were studied by hybridization with oligonucleotide probes on sections of adult rat primary sensory and sympathetic ganglia. For comparison with high-affinity binding sites, adjacent sections were processed for NGF receptor radioautography. Among neurons in lumbar dorsal root ganglia and trigeminal ganglia, trk mRNA and NGF-binding sites were closely colocalized; this finding together with previous direct evidence in other cell types is taken to indicate that trk protein is an essential component of the high-affinity NGF receptor in adult sensory neurons. In lumbar dorsal root ganglia and trigeminal ganglia, abundant LNGFR mRNA was found in all neurons with strong 125I-NGF labeling and on additional neurons lacking high-affinity NGF-binding sites. The presence of abundant LNGFR in neurons with high-affinity receptors could be the cause and/or consequence of their ability to respond to NGF. Neurons with abundant LNGFR mRNA but few high-affinity NGF-binding sites may have receptors for other members of the neurotrophin family. In nodose ganglia, neurons with high concentrations of LNGFR mRNA greatly outnumbered the small percentage with abundant trk mRNA. Following intrathecal infusion of NGF to otherwise normal dorsal root ganglia, the concentrations of LNGFR mRNA but not those of trk mRNA and NGF-binding sites were increased in NGF-responsive neurons. The usual single normal pattern of frequency histograms of LNGFR labeling indices became bimodal in response to NGF. Concentrations of NGF-binding sites, LNGFR mRNA, and trk mRNA were all decreased by peripheral nerve transection and restored by exogenous NGF, the restoration being complete for LNGFR mRNA and partial for trk mRNA and NGF-binding sites. The data indicate that NGF can regulate both LNGFR and trk mRNAs but do not clarify the possible contribution of the LNGFR protein to high-affinity binding sites.
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Sixty patients treated for gynecological malignancies with radiation therapy and operated upon because of late intestinal complications of the treatment were studied. Among patients irradiated for cervical carcinoma an incidence of 3.2% of operated intestinal lesions was encountered. Fifty-nine per cent of the women had a history of previous pelvic inflammatory disease on pelvic surgery. The most common symptoms leading to surgery were mechanical subileus/ileus, pain and fistulas. The majority of patients (53%) were operated upon within 2 years after irradiation, but an interval up to 20 years was recorded. 50% were operated upon within 2 years after irradiation, but an interval up to 20 years was recorded. 50% were reoperated during follow-up. Intestinal resections (38%) and by-passes (15%) were the most frequent surgical procedures at first operation. 57% of the patients were operated upon due to acute conditions and 31% were due to chronic problems, 12% due to tumour suspicion. An operation mortality rate of 5% was found. No obvious correlation could be seen between accumulated irradiation dose and severity of complications. The results of surgical intervention and complications are analysed and different strategies in handling these patients discussed.
Neurotrophin-4 (NT-4), a recently discovered novel member of the family of neurotrophic factors structurally related to nerve growth factor (NGF), is abundantly expressed in the Xenopus laevis ovary. In this study we have localized NT-4 mRNA expressing cells in the Xenopus ovary by in situ hybridization and have used this technique together with Northern blot analyses to quantify NT-4 mRNA expression during oogenesis in Xenopus. In situ hybridization of sections through the Xenopus ovary using an alpha-[35S]-dATP labeled Xenopus NT-4 mRNA specific probe showed an intense labeling over the cytoplasm of oocytes with a diameter of 50-200 microns corresponding to stage I according to Dumont (1972). Labeling was also seen over the cytoplasm of stages II to IV although with a lower intensity than over stage I oocytes. No labeling was seen over more mature oocytes of stages V and VI. NT-4 mRNA could not be detected in the early embryo from the onset of cleavage division to the neurula stage suggesting that the NT-4 gene is not expressed during Xenopus early embryogenesis. The confinement of NT-4 mRNA in the Xenopus ovary to immature oocytes suggests that NT-4 mRNA expression is strictly regulated during oogenesis and that the NT-4 protein could play a role as a maturation factor for immature oocytes.
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The expression of nerve growth factor (NGF) receptor mRNA was examined in the rat brain during postnatal development using in situ hybridization. Cells expressing NGF receptor mRNA were detected in the basal forebrain at all ages examined, with a peak in expression at 2 weeks of age. NGF receptor mRNA was further demonstrated to be expressed transiently in several brainstem nuclei. Expression of NGF receptor mRNA was high at postnatal day (P) 1 and 1 week of age in the facial and abducens nuclei, but was undetectable in the facial nucleus by 2 weeks of age. In the abducens nucleus, a few labeled cells were still present at 2 weeks of age, but absent by 3 weeks. In the cerebellum, a strong signal was present at P1 and 1 week of age which clearly diminished by 2 weeks and disappeared by 3 weeks of age. The labeled cells in the cerebellum had the size and morphology of developing Purkinje cells. These data suggest that the population of NGF-responsive cells in the brain is more widespread during development than in the adult, and that the trophic requirements of specific brain regions are altered with maturity.
The effect of intracerebroventricular injection of the mitosis inhibitor colchicine on expression of mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 was studied in the rat brain with in situ hybridization. Colchicine up-regulates mRNA for NGF and BDNF in many of the neuronal systems normally expressing these factors. In addition, after colchicine treatment NGF and BDNF mRNAs were localized in several brain areas where they normally cannot be detected. Thus, NGF mRNA was present, for example, in many motor nuclei and in the basal forebrain, and BDNF mRNA was seen in many nuclei in the brain stem and in catecholamine neurons, including dopamine neurons in the substantia nigra. The latter neurons have recently been shown to be sensitive to BDNF, and the present results show that these neurons can produce this factor themselves. A decrease in mRNA for BDNF and neurotrophin 3 was seen only in the granular-cell layer of the hippocampal formation. A strong hybridization signal for BDNF and neurotrophin 3 mRNA was also observed over several myelinated tracts in treated rats, supporting the hypothesis that glial cells as well as neurons can produce these trophic factors.
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Marchi-positive bodies are structures present paranodally in large myelinated nerve fibers. They have morphological and biochemical characteristics closely resembling the partially degraded myelin fragments formed during the early phases of Wallerian degeneration. Levels of calcium-activated neutral proteases (calpains) and their endogenous specific inhibitor calpastatin were measured in highly purified rabbit myelin and a spinal cord subcellular light ('floating') fraction heavily enriched in Marchi-positive bodies. Calpain levels were found to be significantly higher in the floating fraction as compared to myelin. No calpastatin was detectable in either fraction.
In vivo microdialysis and in situ hybridization were combined to study dopaminergic regulation of gamma-amino butyric acid (GABA) neurons in rat caudate-putamen (CPu). Potassium-stimulated GABA release in CPu was elevated following a dopamine deafferentation. Local perfusion with exogenous dopamine (50 microM) for 3 h via the microdialysis probe attenuated the potassium-stimulated increase in extracellular GABA in CPu. Expression of glutamic acid decarboxylase (GAD) mRNA was also increased in the dopamine deafferented CPu. However, local perfusion with dopamine had no significant attenuating effect on the increased GAD mRNA expression. These findings indicate that dopaminergic regulation of GABA neurons in the dopamine deafferented CPu includes both a short-term effect at the level of GABA release independent of changes in GAD mRNA expression and a long-term modulation at the level of GAD gene expression.
The gene encoding choline acetyltransferase (ChAT; EC 2.3.1.6), the key enzyme in the synthesis of the neurotransmitter acetylcholine (ACh), is shown to be expressed in rat and human testes. High levels of two ChAT transcripts of 3.5 and 1.3 kilobases were detected by Northern blot analysis of adult rat testis RNA. A single ChAT mRNA species of 3.2 kilobases was detected in human testis. Cells responsible for the synthesis of ChAT mRNA in rat testis were localized by in situ hybridization in the middle part of the seminiferous epithelium, where the labeling was mostly found over spermatocytes and spermatids. Studies on the ontogeny of ChAT mRNA expression showed low levels in prepubertal rats with increasing levels as sexual maturation is reached. A peak of expression was seen at postnatal day 32, correlating with the onset of postmeiotic spermatogenesis. Results from surgical and pharmacological treatments suggest that androgens, as well as pituitary factors, could influence the relative levels of the two ChAT mRNAs detected in rat testis. Evidence for translation of the mRNA detected in the testis was obtained from the demonstration of ChAT-like immunoreactivity in ejaculated human spermatozoa. The staining was restricted to the postacrosomal region of the head, where the membrane of the sperm first fuses with that of the egg during fertilization, and to the annulus, a ring of dense material in the caudal end of the midpiece. Combined, these findings support the hypothesis that the neurotransmitter ACh is involved in reproductive function.
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two members of a family of neurotrophic factors which show both overlapping and distinct neurotrophic activities. Using site-directed mutagenesis, chimeric molecules were constructed where different combinations of sequences from BDNF replaced the corresponding sequences in NGF. The resulting molecules were transiently expressed in COS cells and conditioned media containing the chimeric proteins were assayed for biological activity in explanted chick sympathetic, spinal and nodose ganglia. Our results show that the biological specificities of the two proteins are obtained by specific combinations of a set of sequences that differ between the two molecules. Some of these combinations allowed us to engineer molecules which display multiple neurotrophic activities recruited from both the NGF and BDNF proteins.