| 1. |
- Bivalacqua, Trinity J., et al.
(författare)
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Dysregulation of cGMP-dependent protein kinase 1 (PKG-1) impairs erectile function in diabetic rats: influence of in vivo gene therapy of PKG1 alpha
- 2007
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 99:6, s. 1488-1494
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the expression of cGMP-dependent protein kinase 1 (PKG1)alpha and PKG1 beta in the corpus cavernosum, and to evaluate the effect of adenoviral gene transfer of PKG1 alpha to the erectile compartment on erectile function in a rat model of diabetes. Diabetic (DM; induced by streptozotocin) male Sprague Dawley rats were transfected with adenoviruses (AdCMV beta gal or AdCMVPKG1 alpha, in 10 rats each) 2 months after the induction of DM. Intracavernosal pressure (ICP) during stimulation of the cavernosal nerve (CN) was assessed, and compared with mean arterial pressure (MAP). Erectile tissue was harvested for Western blot analysis, immunohistochemistry and total PKG activity. Ten age-matched rats without DM served as the control. Compared to controls, AdCMV beta gal-transfected DM rats had significantly lower peak ICP responses, ICP/MAP ratios, and filling rates during CN stimulation. In DM rats transfected with AdCMVPKG1 alpha, peak ICP, ICP/MAP ratios and filling rates were significantly better than in DM rats transfected with the reporter gene. As assessed by Western blot and immunohistochemistry, expression of PKG1 alpha and PKG1 beta was lower in corporal tissue from DM AdCMV beta gal-transfected rats than in controls. PKG1 alpha expression was improved after AdCMVPKG1 alpha gene therapy. Total PKG activity was lower in DM rat corporal tissue than in controls, and PKG1 alpha gene transfer significantly improved DM corporal PKG activity to a value greater than in the control. PKG1 alpha and PKG1 beta activities are reduced in the erectile tissue of the diabetic rat, and gene transfer of PKG1 alpha to the penis restored PKG activity and erectile function in vivo in diabetic rats. Gene therapy procedures targeting PKG1 alpha might be an interesting future therapeutic approach to overcome diabetic erectile dysfunction resistant to oral pharmacotherapy.
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| 2. |
- Björck, Matts, et al.
(författare)
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Segregation and interdiffusion in (Fe,Co)/Pt superlattices
- 2009
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 79:8, s. 085428-
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Tidskriftsartikel (refereegranskat)abstract
- We report on the chemical structure of (Fe,Co)/Pt superlattices, which recently have shown high uniaxial magnetocrystalline anisotropy combined with high saturation magnetic moments. In particular, the homogeneity of the (Fe,Co) alloy is studied with a combination of x-ray and neutron reflectometry-the latter in a configuration where magnetic scattering is negligible. It is deduced, with support from off-specular x-ray reflectivity patterns and corresponding simulations, that the lower (Fe,Co)-on-Pt interface contains more Co than the upper Pt-on-(Fe,Co) interface. This can occur as Co interdiffuses into Pt more easily than Fe, as shown by density-functional calculations. The effect of this interdiffusion and segregation on the uniaxial anisotropy is discussed, and it is found that the previously observed discrepancy between experimental and theoretical anisotropy values can be quantitatively accounted for.
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| 4. |
- Gratzke, Christian, et al.
(författare)
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Distribution and Function of Cannabinoid Receptors 1 and 2 in the Rat, Monkey and Human Bladder
- 2009
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Ingår i: JOURNAL OF UROLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 181:4, s. 1939-1948
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We investigated the distribution of cannabinoid receptor subtypes 1 and 2 in the detrusor of different species and studied the effects of cannabinoid receptor 1 and 2 agonists on bladder function. Materials and Methods: Cannabinoid receptor 1 and 2 expression was studied with Western blot and immunohistochemistry in rat, monkey and human detrusors. Co-staining was done for markers of sensory nerves using calcitonin gene-related peptide (Euro-Diagnostica, Malmo, Sweden) and transient receptor potential vanilloid 1, and for cholinergic nerves using VAChT (Santa Cruz Biotechnology, Santa Cruz, California). Actions of the endogenous cannabinoid receptor-1 and 2 agonist anandamide (Sigma (R)), and the cannabinoid receptor 1 and 2 agonist CP55,940 (Sigma) on isolated detrusor and during cystometry in conscious rats were recorded. Results: Higher expression of cannabinoid receptor 2 but not cannabinoid receptor 1 was noted in the mucosa than in the detrusor. Compared to the detrusor larger amounts of cannabinoid receptor 2 containing nerves that also expressed transient receptor potential vanilloid 1 or calcitonin gene-related peptide were observed in the suburothelium. Nerve fibers containing cannabinoid receptor 2 and VAChT were located in the detrusor. Neither anandamide nor CP55,940 affected isolated detrusor carbachol (Sigma) contractions. Nerve contractions were enhanced by 10 mu M anandamide and decreased by 10 AM CP55,940 (P<0.05). In vivo CP55,940 increased the micturition interval by 46% and threshold pressure by 124% (p <0.05). Anandamide increased threshold pressure by 26% and decreased the micturition interval by 19% (p <0.05 and <0.01, respectively). Conclusions: The distribution of cannabinoid receptor 2 on sensory nerves and in the urothelium, and effects by CP55940 on the micturition interval and threshold pressure suggest a role for cannabinoid receptor 2 in bladder afferent signals. Co-expression of VAChT and cannabinoid receptor 2, and effects by CP55940 on nerve contractions suggest a cannabinoid receptor 2 mediated modulatory effect on cholinergic nerve activity. Anandamide may not be a good tool for cannabinoid receptor studies due to its activity at other receptors.
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| 9. |
- Johansen, Kari, et al.
(författare)
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Norovirus strains belonging to the GII.4 genotype dominate as a cause of nosocomial outbreaks of viral gastroenteritis in Sweden 1997-2005 - Arrival of new variants is associated with large nation-wide epidemics
- 2008
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Ingår i: Journal of Clinical Virology. - : Elsevier BV. - 1386-6532 .- 1873-5967. ; 42:2, s. 129-134
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Tidskriftsartikel (refereegranskat)abstract
- Background: In recent years an increase of the incidence of nosocomial outbreaks caused by noroviruses has been observed throughout Sweden, with high peaks noted in the winter seasons 2002/2003 and 2004/2005, respectively. Objectives: To phylogenetically characterize norovirus strains causing nosocomial outbreaks from 1997 to 2005 and estimate the impact of norovirus-like disease on the Swedish health care system during the peak season 2002/2003 when a new variant of norovirus occurred. Study design: Stool samples from 115 randomly selected nosocomial outbreaks occurring during 1997-2005 throughout Sweden were studied by RT-PCR and sequencing. In addition, to investigate the impact on the health-care system, a questionnaire was distributed to infection control units (n = 90) serving all Swedish hospitals, nursing homes and other health-care institutions during the largest epidemic of nosocomial outbreaks. Results: Sequencing of 279 nucleotides of the norovirus RNA polymerase gene in stools containing norovirus RNA showed that strains belonging to the GII.4 genotype dominated. Each of the two large epidemics was due to a new variant within this cluster. The questionnaire revealed that 30,000-35,000 episodes of nosocomial norovirus-like infections occurred in 80 of 82 major Swedish hospitals affected in 2002/2003. Conclusion: New norovirus variants within the cluster GGII.4 may have a major impact on the health-care system. (c) 2008 Elsevier B.V. All rights reserved.
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| 10. |
- Johansson, Erik M. J., et al.
(författare)
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Photovoltaic and Interfacial Properties of Heterojunctions Containing Dye-sensitized Dense TiO2 and Triarylamine derivatives
- 2007
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Ingår i: Chemistry of Materials. - : American Chemical Society (ACS). - 0897-4756 .- 1520-5002. ; 19:8, s. 2071-2078
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Tidskriftsartikel (refereegranskat)abstract
- A series of solid-state heterojunctions comprising a dense TiO2 film electrode as an electron conductor, a ruthenium polypyridine complex (Ru(dcbpy)2(NCS)2) as a light-absorbing dye, and different triarylamine derivatives as hole conductors were prepared, and their photovoltaic properties as well as the molecular and electronic interfacial structures were investigated. The photovoltaic properties were compared to systems containing the hole conductors dissolved in an organic solvent as well as to a system containing a liquid electrolyte containing the iodide/tri-iodide redox couple. Two of the solid-state heterojunctions showed conversion efficiencies close to those of the system containing the iodide/tri-iodide redox couple, while one system was clearly less efficient. To explain the differences in photovoltaic properties the electronic and molecular interfacial structures of the solid-state heterojunctions were investigated by photoelectron spectroscopy (PES). By valence level PES the electronic energy levels highest in energy for the dye and the hole conductors were mapped, and the differences in energy matching partly explain the trends in photovoltaic properties. Differences in the molecular surface structure of the heterojunctions were also observed from the N Is core level measurements. Specifically it was found that the smaller hole conductor, showing low photocurrent yield, is inserted into the dye layer.
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| 14. |
- Ueckert, Stefan, et al.
(författare)
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Update on phosphodiesterase (PDE) isoenzymes as pharmacologic targets in urology: Present and future
- 2006
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 50:6, s. 1194-1207
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Forskningsöversikt (refereegranskat)abstract
- Objectives & Methods: Diseases of the human urinary tract represent common morbidities characterized by a high prevalence in the population of most westernized countries. The existeince of a significant number of affected patients and the recent increase in scientific attention has resulted in various experimental and clinical efforts in order to evaluate the mechanisms controlling the function of urinary tract organs. This review attempts to describe the physiology and pharmacology of phosphodiesterase (PDE) isoenzymes with special regard to their (potential) use in disorders of the human urogenital tract. Results: The promising clinical data for the orally active phosphodiesterase (PDE) inhibitors sildenafil, vardenafil and tadalafil, used in the treatment of male erectile dysfunction (MED), has boosted research activities on the significance of the cyclic GMP- and cyclic AMP pathway in other genitourinary tract tissues, such as the bladder, prostate, ureter, urethra, as well as female genital tissues. Based on the more extensive understanding of the pathways controlling the function of the male and female urogenital tract, orally administered phosphodiesterase inhibitors are considered a logical and straightforward approach for treating urological diseases. Due to the unending charge to conceive advanced first-line treatments, new therapeutic options taking into consideration the cyclic nucleotide signaling have been introduced or might be launched in the near future. Upcoming strategies will not only focus on the nitric oxide (No)/cGMP cascade but also on compounds modulating signal transduction mediated by cyclic adenosine monophosphate, as well as combined agents in order to affect multiple peripheral intracellular targets. Conclusions: The article highlights cGMP- and cAMP-pathways, PDE subtypes and their present or putative future clinical significance in urological practice. (c) 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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| 15. |
- Waldkirch, E, et al.
(författare)
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Cyclic AMP-specific and cyclic GMP-specific phosphodiesterase isoenzymes in human cavernous arteries - immunohistochemical distribution and functional significance
- 2005
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Ingår i: World Journal of Urology. - : Springer Science and Business Media LLC. - 1433-8726 .- 0724-4983. ; 23:6, s. 405-410
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: It has been well established that male erectile dysfunction is frequently associated with vascular diseases. The normal function of cavernous arteries is considered a prerequisite to maintain sufficient blood flow to the trabecular spaces in order to enable penile erection. Contractility of cavernous arteries is regulated by the peripheral autonomic nervous system and endogenous factors released from the endothelial cell layer. A significant increase of blood flow in the central cavernous arteries is the initial event leading to penile tumescence and rigidity. Besides the significance of the nitric oxide/cyclic guanosine monophosphate (cGMP)-mediated mechanisms, the cyclic AMP (cAMP) signalling pathway is also involved in the regulation of tone of the erectile tissue, and interactions between cGMP- and cAMP-mediated mechanisms have been demonstrated. The aim of the present study was to investigate by means of immunohistochemistry the presence of the phosphodiesterase (PDE) isoenzymes 3, 4 (cAMP-specific PDEs) and 5 (cGMP-specific PDE) in thin sections of human central cavernous arteries (HCA) and their functional significance in the mechanism of vessel tone regulation. Methods: Functional experiments were performed using circular segments of HCA and strip preparations of the human corpus cavernosum (HCC). Relaxant effects induced by the cumulative addition of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram (PDE4 inhibitor) and sildenafil (PDE5 inhibitor; 0.01, 0.1, 1 and 10 M) were studied in preparations of HCA and HCC challenged by 1 M norepinephrine (NE). Moreover, immunohistochemistry was carried out in order to evaluate the expression of PDE3, PDE4 and PDE5 in thin sections of HCA. Results: Milrinone, rolipram and sildenafil dose-dependently reversed the NE-induced tension of the isolated vascular segments and HCC strips with sildenafil being the most effective drug. Neither rolipram nor milrinone reached an EC50 value. Abundant immunoreactivities specific for PDE3, PDE4 and PDE5 were observed in the entire smooth musculature of the wall of HCA and resistance arteries. In addition, immunoreactivity for PDE4 was also detected in the cytoplasm of endothelial cells lining the cavernous arteries. Conclusions: The cGMP-dependent relaxation of cavernous arteries is not only dependent on the normal function of the peripheral autonomic nervous system but also on the functional integrity of the vascular endothelium. The expression of the cGMP-specific PDE5 and the ability of the PDE5 inhibitor sildenafil to reverse the adrenergic tension of isolated segments of HCA underline the important role of the NO/cGMP pathway in the control of smooth muscle tone of human trabecular smooth musculature and penile cavernous arteries. Our results also suggest a significance of the cAMP-dependent signaling mechanisms in the regulation of tension of central HCAs. The present findings are also in support of the hypothesis of interactions between the cGMP- and cAMP-mediated signaling pathways in HCAs. Further investigations are indicated in order to outline potential differences between central HCAs and helicine resistance arteries. This may help to understand better the relations between structural and functional changes in the penile erectile tissue in patients with cardiovascular diseases and endothelial dysfunction.
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| 17. |
- Waldkirch, Eginhard, et al.
(författare)
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Non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue
- 2008
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Ingår i: BJU International. - : Blackwell Publishing Ltd. - 1464-4096 .- 1464-410X. ; 101:1, s. 71-74
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES To evaluate non-genomic effects of testosterone and dihydrotestosterone (DHT) on isolated human cavernosal arteries (HCA) and corpus cavernosum (HCC) using organ-bath studies and radio-immunoassays (RIA), as non-genomic effects of androgens are reported for vascular smooth musculature and there is evidence that the relaxant response involves a modulation of cyclic nucleotide tissue levels. MATERIALS AND METHODS The relaxation induced by the cumulative addition of testosterone and DHT (0.01-10 mu M) was studied using circular segments of HCA and strip preparations of HCC. To evaluate the effects of testosterone and DHT on tissue levels of cAMP and cGMP, specimens were exposed to increasing concentrations of the hormones. Forskolin and sodium nitroprusside (SNP) served as reference compounds. RESULTS Testosterone and DHT dose-dependently reversed the noradrenaline-induced tension of vascular segments and HCC strips. At the maximum concentration, testosterone and DHT reduced the mean (SD) tension to 79.8 (4.43)% and 83.9 (10.94)%, respectively. SNP and forskolin significantly stimulated the production of cGMP and cAMP. No effects of testosterone and DHT on cGMP and cAMP levels were detected. CONCLUSION Rapid androgen-induced relaxation of HCA and HCC occurs via non-genomic mechanisms. In penile erectile tissue, non-genomic relaxant effects of testosterone and DHT are not mediated via modulation of cyclic nucleotide tissue levels. Additional studies are required to establish if non-genomic relaxant effects are important in ensuring a basal level of perfusion to maintain overall penile function.
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| 18. |
- Waldkirch, Eginhard S, et al.
(författare)
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Immunohistochemical Distribution of Cyclic GMP-Dependent Protein Kinase-1 in Human Prostate Tissue.
- 2007
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 52:2, s. 495-502
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Phosphodiesterase 5 (PDE5) inhibitors improve smooth muscle relaxation and therefore are considered for pharmacotherapy of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Cyclic guanosine monophosphate (cGMP) -dependent protein kinase-1 (cGKI) has been identified as one of the downstream targets for cGMP. The aim of the present study was to evaluate, by means of immunohistochemistry and Western blot analysis, the expression and localization of cGKI isoforms in relation to smooth muscle alpha-actin and cGMP in the human prostate. Methods: Cryostat sections of tissue segments excised from the transition zone of human prostates from 11 patients (aged 54-68 yr) were incubated with primary antibodies directed against smooth muscle alpha-actin, cGMP, cGKI, c:GKI alpha, and cGKI beta. Visualization of double-labelled immunofluorescent staining was achieved by laser microscopy. Western blot analysis was performed to confirm the expression of cGKI isoforms. Results: Immunoreactivities specific for cGKI, cGKI alpha, and cGKI beta were observed in the smooth musculature of the transition zone. Double-staining revealed the colocalization of smooth muscle alpha-actin, cGMP, and cGKI isoforms in smooth muscle cells of the fibromuscular stroma. The expression of cGKI isoforms was confirmed by Western blot analysis. Conclusions: Our results confirm the presence of cGKI isoforms a and P in the transition zone of human prostate tissue. in addition, the colocalization of alpha-actin, cGMP, and cGKI isoforms provides further evidence for a significant role of the nitric oxide/cGMP pathway in the regulation of smooth muscle contractility in human prostate tissue and therefore could provide additional targets for pharmacotherapy of BPH and LUTS. (C) 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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