1,354,727 research outputs found
Long-term effect of inhibition of ced 3-like caspases on the survival of axotomized retinal ganglion cells in vivo
No full textThere is growing evidence that caspase inhibition exerts neuroprotective effects in various models of neuronal injury in vivo. However, whether caspase inhibition provides long-term neuroprotection is not known yet. In the present study, we therefore investigated the effects of prolonged caspase inhibition on the survival of adult rat retinal ganglion cells (RGCs) following optic nerve (ON) transection. Four weeks following ON transection the number of surviving RGCs in untreated animals declined to 11% of controls. Treatment for the initial 2 weeks with z-DEVD-cmk, an irreversible inhibitor of ced 3-Like caspases, increased the number of surviving RGCs 4 weeks postlesion to 24%. Z-DEVD-cmk treatment over the entire experimental period of 4 weeks had no additional effect. Thus, we still found a neuroprotective effect of caspase inhibition on axotomized RGCs after extended survival time. However, in comparison to our recent observations 2 weeks after optic nerve transection, in which z-DEVD-cmk rescued 46% of RGCs (P. Kermer, N. Klocker, M. Labes, and M. Bahr, 1998, J. Neurosci. 18(12), 4656-4662) the positive effect clearly decreased. In conclusion, our results indicate that the therapeutical approach presented here results in a significant delay of secondary death rather than providing a permanent and complete rescue of axotomized RGCs. (C) 1999 Academic Press
Klocker Headstone at Cemetery, Mitchell SD, Davison County
No full text35 mm slide, headstone with the name "Klocker" and images of a deer and ducks by a pondDrawer info: Custer- Fall River; Mitchell SurveyKodachrome Slide Klocker Tombstone Mitchell 3 Sep 83C
Both the neuronal and inducible isoforms contribute to upregulation of retinal nitric oxide synthase activity by brain-derived neurotrophic factor
No full textAlthough neurotrophins are best known for their trophic functions, growing evidence suggests that neurotrophins can also be neurotoxic, for instance by enhancing excitotoxic insults. We have shown recently that brain-derived neurotrophic factor (BDNF) limits its neuroprotective action on axotomized rat retinal ganglion cells (RGCs) by upregulating nitric oxide synthase (NOS) activity (Klocker et al., 1998). The aim of the present study was to investigate this interaction of BDNF and NOS in the lesioned adult rat retina in more detail. We used NOS immunohistochemistry and NADPH-diaphorase (NADPH-d) reaction to characterize morphologically retinal NOS expression and activity. Using reverse transcription-PCR and Western blot analysis, we were able to identify the NOS isoforms being regulated. Six days after optic nerve lesion, we observed an increase in neuronal NOS (NOS-I) mRNA and protein expression in the inner retina. This did not lead to a marked increase in overall retinal NOS activity. Only RGC axons displayed strong de novo NADPH-d reactivity. In contrast, intraocular injection of BDNF resulted in a marked upregulation of NOS activity in NOS-I-immunoreactive structures, leaving the level of NOS-I expression unchanged. In addition, an induction of inducible NOS (NOS-II) was found after BDNF treatment. We identified microglial cells increasing in number and being activated by BDNF, which could serve as the cellular source of NOS-II. In summary, our data suggest that BDNF upregulates retinal NOS activity by both a post-translational regulation of NOS-I activity and an induction of NOS-II. These findings might be useful for developing pharmacological strategies to improve BDNF-mediated neuroprotection
Free radical scavenging and inhibition of nitric oxide synthase potentiates the neurotrophic effects of brain-derived neurotrophic factor on axotomized retinal ganglion cells in vivo
No full textBrain-derived neurotrophic factor (BDNF) partially promotes the survival of axotomized retinal ganglion cells (RGCs). In analogy with in vitro experiments (Koh et al., 1995; Samdami et al., 1996), we tested whether neuroprotection by BDNF is limited by adverse effects as a consequence of excessive free radical formation. First, we investigated whether BDNF and the free radical scavenger N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN) cooperate in protecting RGCs from axotomy-induced death. Although systemic S-PBN treatment alone did not influence RGC survival after axotomy, it potentiated the neuroprotective effects of BDNF significantly. Single BDNF treatment rescued 27% of the RGCs, which otherwise would have died 14 d after optic nerve transection, whereas a combined treatment of BDNF and S-PBN improved this rescue rate up to 68%. We then investigated whether the adverse effects of BDNF could be ascribed to activation of nitric oxide synthase (NOS). We found colocalization of NOS and the BDNF receptor TrkB in the retina. NADPH-diaphorase reactivity, a reliable marker for NOS in the rat retina, increased after chronic BDNF treatment in vivo. Systemic application of the NOS-inhibitor N-omega-nitro-L-arginine-methylester (L-NAME) potentiated the neuroprotective action of BDNF (55% rescue rate). We conclude that activation of NOS is a pathological consequence of BDNF application, which reduces its neuroprotective potential. The observation that this adverse effect can be antagonized by systemic application of free radical scavengers could be of relevance for clinical applications of neurotrophins in human neurodegenerative diseases
Effect of heat exposure on viability and contractility of cultured prostatic stromal cells
No full textObjectives: Different thermotherapeutic modalities such as transurethral microwave therapy or transurethral needle ablation have been developed to provide effective alternatives to surgical management of benign prostate hyperplasia (BPH). The mechanisms of thermotherapy, however, are not completely understood. We developed a model to investigate the effects of heat application on stromal cell viability and contractility. Methods: Cells isolated from prostatectomy and cystoprostatectomy specimens were cultured in a selective medium. Temperatures ranging from 37 to 50 degrees C were applied for 1 h. Cell contraction was visualized by means of a cell culture microscope equipped with a time-lapse video system. For quantitative analysis, the percentage of contracting cells was evaluated; 10 mu M of phenylepherine were applied for adrenergic stimulation of the eel Is. Results: On immunohistochemistry and phase-contrast microscopy, these cells were identified as prostatic myofibroblasts. Incubation at 50 degrees C for 1 h in vitro induced immediate death of all cells, whereas at 45 degrees C a II cells survived. At 37 degrees C 55% of the cells were seen to contract after addition of phenylephrine. Immediately after incubation at 45 degrees C contraction rate decreased to 29%, but returned to 46% 1 day later. Conclusions: With this model, it is possible to study the mechanisms of thermotherapy in vitro. The results suggest that the effects of thermotherapy are due to the induction of cell death rather than to reduced stromal cell contractility. Furthermore, the data show that treatment is probably only successful if temperatures in excess of 50 degrees C are maintained. Copyright (C) 2000 S. Karger AG, Basel
BDNF increases the number of axotomized rat retinal ganglion cells expressing GAP-43, L1, and TAG-1 mRNA--a supportive role for nitric oxide?
No full textThe death of neurons and the limited ability to activate growth-associated genes prevent the restoration of lesioned fiber tracts in the adult mammalian CNS. Here, we characterized the effects of the survival-promoting neurotrophin brain-derived neurotrophic factor (BDNF) on mRNA expression of GAP-43, L1, TAG-1, and SC-1 in axotomized and regenerating rat retinal ganglion cells (RGCs). BDNF led to de novo upregulation of TAG-1 mRNA in axotomized RGCs and to a threefold increase in the number of GAP-43 and L1 mRNA-expressing RGCs. SC-1 expression remained unchanged. However, BDNF did not improve long-distance axon regeneration into a peripheral nerve graft. Surprisingly, potentiating BDNF-mediated neuroprotection by simultaneous administration of a spin trap or a NOS inhibitor counteracted the BDNF-induced growth-associated gene expression. This led us to hypothesize that the BDNF effects on GAP-43, L1, and TAG-1 mRNA expression are mediated by a NO-dependent mechanism. In summary, our data support the idea that survival and axon regeneration of lesioned CNS neurons can be regulated independently.publishe
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Neuronal death after brain injury - Models, mechanisms, and therapeutic strategies in vivo
No full textNeuronal damage in the central nervous system leads to primary cell death, induced directly by the trauma, and delayed secondary death of neurons, the latter depending on environmental changes, lack of metabolic and trophic supply, and altered gene transcription. While primary death of neurons occurring within a short time after trauma is not a realistic target for therapy, secondary cell death might be prevented by new neuroprotective strategies. Although there are increasing data concerning cell rescue after ischemic and traumatic brain injury through the last decade, the mechanisms that underlie secondary death of neurons following lesion are still incompletely understood and are now the subject of a more detailed investigation. In this review, we want to give an overview on what is known about the molecular mechanisms of delayed ischemic and traumatic neuronal death in vivo and about promising neuroprotective treatment strategies that might be of future clinical relevance or have already entered clinical trials
Axotomy-induced early down-regulation of POU-IV class transcription factors Brn-3a and Brn-3b in retinal ganglion cells
No full textIt has been proposed that neurons being exposed to proapoptotic stimuli undergo dedifferentiation, a process that can either allow for regeneration and axon regrowth or, if remaining incomplete, can force the cell to activate apoptotic pathways. A pivotal step in the differentiation program from neuronal precursor cells to differentiated, postmitotic neurons is their exit from the cell cycle. The POU domain transcription factors Brn-3b and Brn-3a, which are expressed in retinal ganglion cells (RGCs) directly after the exit of RGC precursors from the cell cycle, can be employed as RGC-specific differentiation markers to study potential dedifferentiation of RGCs after axotomy. Here, we examined mRNA and protein expression of Brn-3a and -3b in rat RGCs following axonal lesion. We observed a rapid down-regulation of Brn-3a and -3b protein expression in axotomized RGCs, clearly preceding apoptosis of RGCs. Using real-time PCR, we show that regulation of Brn-3 expression occurred at the transcriptional level. The small subset of RGCs regenerating into a peripheral nerve graft did not (re-)express Brn-3a or -b. In conclusion, we found further evidence supporting the hypothesis of a dedifferentiation process in severed mature neurons. As Brn-3b expression has been shown to be a prerequisite for developmental survival of most RGCs and Brn-3a activates transcription of anti-apoptotic genes, down-regulation of Brn-3 transcription factors might be causally involved in the secondary death of adult RGCs following axotomy
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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