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- Sandström, Göran, et al.
(författare)
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Järnbrist och idrott
- 2008
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Ingår i: Svensk Idrottsforskning : Organ för Centrum för Idrottsforskning. - 1103-4629.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Iosif, Robert
(författare)
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Factors Regulating Neurogenesis in Intact and Pathological Brain: Role of TNF-alpha
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During the last decade it has been clearly demonstrated that the adult brain contains neural stem cells (NSCs) localized mainly in two regions: the subgranular zone in the dentate gyrus and the subventricular zone (SVZ) lining the lateral ventricles. In the intact brain, these NSCs give rise to new dentate granule cells and olfactory bulb neurons, respectively. Following a brain damage such as stroke and an epileptic seizure, the generation of new neurons (neurogenesis) in the hippocampus and the SVZ in adult rats, mice and probably humans is increased. The molecular mechanisms regulating the different steps of insult-induced neurogenesis (cell proliferation, survival, migration, and differentiation) are poorly understood. To learn more about the molecular mechanisms regulating neurogenesis we examined which factors in the epileptic and stroke generated environment that affects the newly formed neurons. In this thesis we explored the role of a prostaglandin and a cytokine in the hippocampus and subventricular zone, both during physiological conditions and after an insult. In the first paper we induced status epilepticus (SE) in rats by electrical stimulation in the hippocampus. We then compared the two different seizure grades, partial status epilepticus (pSE) and generalized status epilepticus (gSE), in order to identify factors in the microenvironment which are differentially regulated by SE severity and may underlie differences in neurogenesis. We particularly addressed the question whether SE severity differentially affects the expression of prostaglandin E2 (PGE2), cyclooxygenase (COX-2), the enzyme catalyzing the first committed step in PGE2 synthesis, and the brain-derived neurotrophic factor (BDNF). In conclusion, the results from paper I showed clear differences between pSE and gSE rats in hippocampal PGE2 and BDNF levels 7 days after SE. We found no evidence that the high levels of PGE2 and BDNF, in rats exhibiting pSE, during the first days after SE are of major importance for the survival of new neurons during the first days after formation. In the second study, we developed a new SE model for mice based on continuous electrical stimulation in the hippocampus, as done previously in rats. We then investigated whether the cytokine, tumor necrosis factor alpha (TNF-α), could influence neurogenesis. TNF-α is a well-known proinflammatory factor and we speculated that the detrimental action of inflammation on insult-induced neurogenesis might be caused by TNF-α. It had also been shown that NSCs themselves express TNF-α, which raised the possibility of an autocrine action involved in neurogenesis. We used transgenic mice with various genetic manipulations of TNF-α signaling to determine the influences on neurogenesis under physiological conditions and following a brain insult. Taken together, the results from paper II demonstrate the involvement of TNF-R1 and TNF-R2 signaling in the regulation of adult hippocampal neurogenesis, and that signaling through the two different receptors have differential actions on neurogenesis. Our data indicate that TNF-α can modulate the formation of new neurons both under physiological and pathological conditions by acting on these two receptors with differential effects on proliferation and survival, with TNF-R1 as the key mediator of TNF-α signaling. In the final study we examined whether signaling through TNF-R1 could influence progenitor proliferation in another neurogenic area during physiological conditions and following a pathological condition such as stroke and SE. We used the same transgenic mice to study TNF-α and its effects on the formation of new neurons in the SVZ. We found that mice lacking TNF-R1 function responded to stroke with enhanced SVZ cell proliferation and thereby that TNF-R1 signaling mediates a suppressant effect on the proliferation of progenitor cells. Following stroke TNF-R1 acts as a negative regulator on the progenitor proliferation. In contrast, deletion of TNF-R1 did not influence basal cell proliferation in SVZ. Further, loss of TNF-R1 function had differential effects on SVZ cell proliferation following the two pathological conditions SE and stroke and we did not find any differences in cell proliferation after SE. Although both insults gave rise to increased cell proliferation in the SVZ, the dampening action of TNF-R1 on proliferation was revealed only after stroke. Taken together, the results from paper II and III suggest that suppression of TNF-R1 signaling might be a strategy to promote the proliferative response in the SGZ after SE and in the SVZ after stroke, to stimulate neurogenesis in the adult brain. However, it will be important to establish how such an approach will affect other steps of neurogenesis and the functional outcome after both SE and stroke. There could be a positive therapeutic potential of neurogenesis from endogenous stem cells after brain insults. However, we need to know much more about the regulation of neurogenesis in order to make this response more effective. The current thesis work aims at elucidating some of the mechanisms of neuronal self-repair, which could have implications for the development of stem cell-based approaches for the treatment of brain disorders.
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- Cunha Goncalves, Doris
(författare)
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Levosimendan in early experimental sepsis: effects on the heart and hepatosplanchnic circulation
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sepsis-related cardiovascular dysfunction associated with fluid-unresponsive tissue hypoperfusion might require inotropic treatment. This cardiovascular dysfunction seems to involve calcium desensitization and adrenergic unresponsiveness. We investigated the effects of clinically relevant plasma concentrations of the calcium sensitizer levosimendan during the first 6 h of endotoxemia in a model of experimental sepsis in pigs (21.8-44.0 kg). Levosimendan given to endotoxemic pigs receiving moderate volume resuscitation elicited tachycardia, hypotension and myocardial ischemia, as evidenced by a negative myocardial lactate flux (study I). Likewise, compared to non-treated controls, levosimendan did not improve systemic or hepatosplanchnic perfusion during endotoxin shock: the animals developed signs of tissue hypoperfusion with elevated blood lactate and low oxygen venous saturations (study II). Aggressive volume resuscitation before levosimendan treatment induced a hyperdynamic state that was sustained by levosimendan and norepinephrine treatment, whereas control animals gradually developed shock. Nevertheless, splanchnic blood flow was redistributed and the superior mesenteric artery, the hepatic artery and the portal vein blood flows (PVF) decreased. Similarly to study II, there were signs of systemic and hepatosplanchnic tissue hypoperfusion. In contrast, administration of dobutamine and norepinephrine, increased cardiac output (CO) and oxygen delivery, maintained PVF and improved tissue perfusion (study III). Load independent measurements of cardiac function showed that systolic function was actually enhanced during the first 2 h of sepsis, whereas diastolic function was depressed in both ventricles. The initial decrease seen in CO was a result of volume depletion, and recovered with aggressive volume resuscitation. Although endotoxin-induced lung injury caused early right ventriculovascular uncoupling and increased right ventricular (RV) myocardial oxygen demand, right coronary artery blood flow improved markedly with resuscitation, maintaining adequate myocardial perfusion (study IV). In resuscitated septic pigs, levosimendan supported RV function by increasing RV contractility at a low energy cost. CO and left ventricular ejection fraction increased, and right ventriculovascular coupling and mechanical efficiency tended to improve (study V). In conclusion, early treatment with levosimendan during resuscitated sepsis can increase CO and improves RV contractility at a low energy cost, but it does not improve hepatosplanchnic perfusion significantly, which is better achieved with dobutamine-norepinephrine. In addition, because levosimendan is an inodilator, its use in sepsis should be restricted to thoroughly fluid-resuscitated subjects.
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Internmedicin
- 2006
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Internmedicin är en heltäckande lärobok i ämnet och beskriver organrelaterade sjukdomar, allergier, förgiftningar och drogskador. Boken innehåller även ett kapitel i symtomlära. Sjukdomarna beskrivs grundligt med uppgifter om bland annat symtom, förekomst, etiologi, anamnes och utredning samt handläggning
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Allmänmedicin
- 2007
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- I Norge har den redan blivit en klassiker i två upplagor, 1997 och 2003. Nu kommer den på svenska. Den svenska redaktionen, hämtad från samtliga allmänmedicinska avdelningar inom de medicinska fakulteterna, har under ledning av Birgitta Hovelius bearbetat de inte mindre än 74 författarnas insatser. Resultatet är ett uppslagsverk som saknar motstycke. De 883 sidorna ger bredd, omfattning och en unik överblick av allmänmedicinen i teori och praktik. Encyklopediskt, men också med utrymme för egna reflektioner och slutsatser. Allmänmedicin täcker in primärvårdens hela sjukdomspanorama i sex delar och hela 54 kapitel.
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