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- Björklund, Anders
(författare)
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Hypoglycaemia in pregnancy : hypoglycaemic clamp studies during and after pregnancy in women with IDDM
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Problem: In pregnant women with IDDM a strict insulin regimen is generally instituted, which permits the possibility of a normal fetal outcome. This, however, increases the risk of hypoglycaemia, and a high prevalence of severe hypoglycaemia has been reported during pregnancy in these women. Depletion of glucose, the most important source of energy in intrauterine life, most certainly places the fetus at risk. There are also reports that symptoms of hypoglycaemia diminish in pregnant IDDM patients. Such decreased symptomatology, possibly in combination with cognitive impairments, would increase the risk of more severe hypoglycaemia. An impairment in the important hormone response counterregulating hypoglycaemia could be a contributory cause of hypoglycaemia. The placenta secretes several hormones that have a blood glucose-raising effect, and these might further counteract hypoglycaemia. Alterations in insulin metabolism during pregnancy might also affect the risks in connection with hypoglycaemic events. Thus the aims of the studies were to elucidate: first, whether fetal heart rate, blood flow velocity waveforms in the umbilical artery and placentary hormones are affected by maternal hypoglycaemia; secondly, whether hormonal counterregulation of hypoglycaemia, along with symptoms and cognitive function during hypoglycaemia, are modified during pregnancy, and thirdly whether the clearance of insulin during hypoglycaemia is altered during pregnancy. Methods: Ten women with IDDM in the third trimester of pregnancy were studied with hyperinsulinaemic, hypoglycaemic clamp methodology, repeated six months to one year after delivery. During the 150-min procedure fetal heart rate was monitored continuously and blood samples were collected for the analysis of insulin and of counterregulatory and placentary hormones. Subjective symptoms of hypoglycaemia were recorded on a visual analogue scale. Before start, in normoglycaemia, Doppler examination of the umbilical artery blood flow velocity waveforms and a computerised cognitive function test were performed, both repeated when the final hypoglycaemic arterial blood glucose level of about 2.2 mmol/l had been reached. To further study the effects observed in cognitive function during pregnancy, the same cognitive test was applied to a group of 15 healthy women during and after pregnancy. Results: There were no signs of fetal distress during hypoglycaemia, since the fetal heart rate recording disclosed both increased number and increased amplitude of heart rate accelerations, and since blood flow velocity waveform analysis revealed a slightly decreased pulsatility index in the umbilical artery. Further, there were no signs of diminished counterregulatory hormone response to hypoglycaemia, with the exception of pituitary GH. Instead, the serum levels of placental GH increased. This finding of an acute hormonal response by the placenta may represent a new concept in placental physiology. The metabolic clearance rate of insulin was decreased during pregnancy, as were some subjective symptoms of hypoglycaemia; and in addition pregnancy seemed to alter, and in some aspects impair, performance in cognitive function tests. The three latter phenomena could increase the risk of severe hypoglycaemia. For this reason during pregnancy caution is of utmost importance when identifying impending hypoglycaemia.
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- Björklund, Anders, et al.
(författare)
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Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease
- 1997
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 4:3-4, s. 186-200
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Forskningsöversikt (refereegranskat)abstract
- Intrastriatal 6-hydroxydopamine injections in rats induce partial lesions of the nigrostriatal dopamine (DA) system which are accompanied by a delayed and protracted degeneration of DA neurons within the substantia nigra. By careful selection of the dose and placement of the toxin it is possible to obtain reproducible and regionally defined partial lesions which are well correlated with stable functional deficits, not only in drug-induced behaviors but also in spontaneous motoric and sensorimotoric function, which are analogous to the symptoms seen in patients during early stages of Parkinson's disease. The intrastriatal partial lesion model has proved to be particularly useful for studies on the mechanisms of action of neurotrophic factors since it offers opportunities to investigate both protection of degenerating DA neurons during the acute phases after the lesion and stimulation of regeneration and functional recovery during the chronic phase of the postlesion period when a subset of the spared nigral DA neurons persist in an atrophic and dysfunctional state. In the in vivo experiments performed in this model glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neurotrophic effects both at the level of the cell bodies in the substantia nigra and at the level of the axon terminals in the striatum. Intrastriatal administration of GDNF appears to be a particularly effective site for induction of axonal sprouting and regeneration accompanied by recovery of spontaneous sensorimotor behaviors in the chronically lesioned nigrostriatal dopamine system.
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- Hagell, Peter, et al.
(författare)
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Sequential bilateral transplantation in Parkinson's disease: effects of the second graft
- 1999
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156. ; 122:6, s. 1121-1132
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Tidskriftsartikel (refereegranskat)abstract
- Five parkinsonian patients who had received implants of human embryonic mesencephalic tissue unilaterally in the striatum 10-56 months earlier were grafted with tissue from four to eight donors into the putamen (four patients) or the putamen plus the caudate nucleus (one patient) on the other side, and were followed for 18-24 months. After 12-18 months, PET showed a mean 85% increase in 6-L-[18F]fluorodopa uptake in the putamen with the second graft, whereas there was no significant further change in the previously transplanted putamen. Two patients exhibited marked additional improvements after their second graft: 'on-off' fluctuations virtually disappeared, movement speed increased, and L-dopa could be withdrawn in one patient and reduced by 70% in the other. The improvement in one patient was moderate. Two patients with atypical features, who responded poorly to the first graft, worsened following the second transplantation. These findings indicate that sequential transplantation in patients does not compromise the survival and function of either the first or the second graft. Moreover, putamen grafts that restore fluorodopa uptake to normal levels can give improvements of major therapeutic value.
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- Horger, B A, et al.
(författare)
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Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons
- 1998
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 18:13, s. 4929-4937
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Tidskriftsartikel (refereegranskat)abstract
- Glial cell line-derived neurotrophic factor (GDNF) exhibits potent effects on survival and function of midbrain dopaminergic (DA) neurons in a variety of models. Although other growth factors expressed in the vicinity of developing DA neurons have been reported to support survival of DA neurons in vitro, to date none of these factors duplicate the potent and selective actions of GDNF in vivo. We report here that neurturin (NTN), a homolog of GDNF, is expressed in the nigrostriatal system, and that NTN exerts potent effects on survival and function of midbrain DA neurons. Our findings indicate that NTN mRNA is sequentially expressed in the ventral midbrain and striatum during development and that NTN exhibits survival-promoting actions on both developing and mature DA neurons. In vitro, NTN supports survival of embryonic DA neurons, and in vivo, direct injection of NTN into the substantia nigra protects mature DA neurons from cell death induced by 6-OHDA. Furthermore, administration of NTN into the striatum of intact adult animals induces behavioral and biochemical changes associated with functional upregulation of nigral DA neurons. The similarity in potency and efficacy of NTN and GDNF on DA neurons in several paradigms stands in contrast to the differential distribution of the receptor components GDNF Family Receptor alpha1 (GFRalpha1) and GFRalpha2 within the ventral mesencephalon. These results suggest that NTN is an endogenous trophic factor for midbrain DA neurons and point to the possibility that GDNF and NTN may exert redundant trophic influences on nigral DA neurons acting via a receptor complex that includes GFRalpha1.
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- Kirik, Deniz, et al.
(författare)
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Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat
- 1998
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 152:2, s. 259-277
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Tidskriftsartikel (refereegranskat)abstract
- Partial lesions of the nigrostriatal dopamine system have been investigated with respect to their ability to induce consistent long-lasting deficits in movement initiation and skilled forelimb use. In eight different lesion groups 6-hydroxydopamine (6-OHDA) was injected at one, two, three, or four sites into the lateral sector of the right striatum, in a total dose of 20-30 microgram. Impairments in movement initiation in a forelimb stepping test, and in skilled paw use in a paw-reaching test, was seen only in animals where the severity of the lesion exceeded a critical threshold, which was different for the different tests used: single (1 x 20 microgram) or two-site (2 x 10 microgram) injections into the striatum had only small affects on forelimb stepping, no effect on skilled paw use. More pronounced deficits were obtained in animals where the same total dose of 6-OHDA was distributed over three or four sites along the rostro-caudal extent of the lateral striatum or where the injections were made close to the junction of the globus pallidus. The results show that a 60-70% reduction in tyrosine hydroxylase (TH)-positive fiber density in the lateral striatum, accompanied by a 50-60% reduction in TH-positive cells in substantia nigra (SN), is sufficient for the induction of significant impairment in initiation of stepping. Impaired skilled paw-use, on the other hand, was obtained only with a four-site (4 x 7 microgram) lesion, which induced 80-95% reduction in TH fiber density throughout the rostrocaudal extent of the lateral striatum and a 75% loss of TH-positive neurons in SN. Drug-induced rotation, by contrast, was observed also in animals with more restricted presymptomatic lesions. The results indicate that the four-site intrastriatal 6-OHDA lesion may be a relevant model of the neuropathology seen in parkinsonian patients in a manifest symptomatic stage of the disease and may be particularly useful experimentally since it leaves a significant portion of the nigrostriatal projection intact which can serve as a substrate for regeneration and functional recovery in response to growth promoting and neuroprotective agents.
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