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- Geli Rolfhamre, Patricia, 1979-
(author)
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From Penicillin Binding Proteins to Community Interventions : Mathematical and Statistical Models Related to Antibiotic Resistance
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Antibiotic resistance has become a major public health concern and mathematical models are important analytical tools for the understanding, evaluation and prediction of the resistance problem and related control strategies.The risk of emerging antibiotic resistance and selection has rarely been a concern in the design of antibiotic drug dosing regimens. In the first paper, a selection of antibiotic resistant subpopulations for different antibiotic dosing regimens was studied in vitro. The demonstrated complex relationship was influenced by both the rise of new mutants and a postantibiotic effect (PAE) (continued inhibition of bacterial growth after removal of the antibiotic drug). By constructing a mathematical model that incorporated biologically relevant parameters, we were able to assess the risks of resistance development under different dosing strategies.In the second paper, the model for PAEs is further developed to determine the implications for different dosing regimens. The result challenges the conventional notion that long PAEs promote extended drug dosing intervals and it allows new hypotheses to be tested experimentally based on the findings from the theoretical framework.Since PAE experiments often are time-consuming and laborious, very few studies have been reporting variation for this phenomenon. In the third paper, an extension to capture the stochastic behavior of bacterial population growth under drug exposure is made. The stochastic nature of the model is also an important complement to the existing deterministic models on drug dose drug effect relationships.The last paper describes a controlled clinical intervention study aiming at determining whether the frequency of trimethoprim resistance in E. coli can be decreased by a sudden and drastic reduction in trimethoprim use. In addition to evaluating the intervention effect, the model, given estimated parameters, is also used for predicting other interesting outcomes.
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| 2. |
- Gomez-Pinilla, Pedro J., et al.
(author)
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Effect of melatonin on age associated changes in guinea pig bladder function
- 2007
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In: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 177:4, s. 1558-1561
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Journal article (peer-reviewed)abstract
- Purpose: The incidence of urinary incontinence increases with age but the cause and effect relationship between aging and altered bladder function is poorly understood. It was suggested that melatonin can ameliorate negative effects induced by aging by its free radical scavenging activity and its ability to decrease oxidative stress. We investigated the changes in bladder function evoked by aging and the possible benefits of melatonin treatment on age related bladder disturbances. Materials and Methods: Bladder function was assessed using cystometry in conscious, freely moving female guinea pigs. Animals were grouped according to age as young adults (4 months old) and senescents (18 to 20 months old). A group of senescent animals were treated with 2.5 mg kg(-1) day(-1) melatonin for 21 days. Results: Aging led to increased detrusor activity, as demonstrated by short micturition intervals, decreased bladder capacity and spontaneous contractions during the filling phase. During the voiding phase aged animals showed lower micturition pressures than young adults. Melatonin counteracted the cystometric changes in senescent animals and restored micturition parameters to those of young adults. Conclusions: These results show that in guinea pigs aging induces detrusor overactivity. Melatonin treatment improved age induced changes in bladder function. If similar effects can be demonstrated in humans, melatonin treatment may be a new approach to decrease the impact of age related bladder disorders.
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| 3. |
- Gomez-Pinilla, Pedro J, et al.
(author)
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Melatonin restores impaired contractility in aged guinea pig urinary bladder
- 2008
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In: Journal of Pineal Research. - : Blackwell Publishing Ltd. - 1600-079X .- 0742-3098. ; 44:4, s. 416-425
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Journal article (peer-reviewed)abstract
- Urinary bladder disturbances are frequent in the elderly population but the responsible mechanisms are poorly understood. This study evaluates the effects of aging on detrusor myogenic contractile responses and the impact of melatonin treatment. The contractility of bladder strips from adult, aged and melatonin-treated guinea pigs was evaluated by isometric tension recordings. Cytoplasmatic calcium concentration ([Ca2+](i)) was estimated by epifluorescence microscopy of fura-2-loaded isolated detrusor smooth muscle cells, and the levels of protein expression and phosphorylation were quantitated by Western blotting. Aging impairs the contractile response of detrusor strips to cholinergic and purinergic agonists and to membrane depolarization. The impaired contractility correlates with increased [Ca2+](i) in response to the stimuli, suggesting a reduced Ca(2+)sensitivity. Indeed, the agonist-induced contractions in adult strips were sensitive to blockade with Y27362, an inhibitor of Rho kinase (ROCK) and GF109203X, an inhibitor of protein kinase C (PKC), but these inhibitors had negligible effects in aged strips. The reduced Ca2+ sensitivity in aged tissues correlated with lower levels of RhoA, ROCK, PKC and the two effectors CPI-17 and MYPT1, and with the absence of CPI-17 and MYPT1 phosphorylation in response to agonists. Interestingly, melatonin treatment restored impaired contractility via normalization of Ca2+ handling and Ca2+ sensitizations pathways. Moreover, the indoleamine restored age-induced changes in oxidative stress and mitochondrial polarity. These results suggest that melatonin might be a novel therapeutic tool to palliate aging-related urinary bladder contractile impairment.
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| 4. |
- Nilsson, Karl-Fredrik, et al.
(author)
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A probabilistic methodology to determine failure probabilities and acceptance criteria for the KBS-3 inserts under ice-age load conditions
- 2008
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In: Nuclear Technology. - 0029-5450 .- 1943-7471. ; 163:1, s. 3-14
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Journal article (peer-reviewed)abstract
- The Swedish KBS-3 copper-cast iron canister for geological disposal of spent nuclear fuel is in an advanced stage. This paper deals with the cast iron insert that provides the mechanical strength of the canister and outlines an approach to assess the failure probabilities for manufactured canisters at large isostatic pressure (44 MPa) that could occur during future glaciations and first steps to derive acceptance criteria to ensure that failure probabilities are extremely small. The work includes a statistical test program using three inserts to determine the tensile, compression, and fracture properties. Specimens used for material characterization were also investigated by microstructural analysis to determine the microstructure and to classify and size defects. It was found that the material scatter and low ductility were caused by many defect types, but slag defects in the form of oxidation films were the most important ones. These data were then used to compute defect distributions for the probabilistic failure analysis of the KBS-3 canisters. A large number of finite element-analyses of canisters were performed at the maximum design load (44 MPa) covering distributions of material parameters and geometrical features of the canisters. The computed probabilities for fracture and plastic collapse were very low even for material data with low ductility. Two large-scale isostatic compression tests of KBS-3 mock-ups to verify safety margins are also described. The failure occurred at loads above 130 MPa in both cases, indicating a safety margin of at least a factor 3 against the maximum design load. As a result of the project, new acceptance criteria are being proposed for insert geometry and material properties, and the manufacturing process for inserts has been modified to ensure that these criteria are always fulfilled.
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| 5. |
- Streng, T., et al.
(author)
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Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder
- 2008
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In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 53:2, s. 391-400
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Journal article (peer-reviewed)abstract
- Objectives: To investigate the distribution of the transient receptor potential (TRP) A1 ion channel in the rat urinary bladder, and to study the effects of hydrogen sulfide (H2S) and known TRPA1 activators on micturition in conscious rats and on heterologously expressed ion channels. Methods: The expression of TRPA1 in urinary bladder was studied with fluorescence immunohistochemistry and real-time PCR in female Sprague-Dawley rats. Cystometric investigations were performed in conscious animals subjected to intravesical administration of sodium hydrogen sulfide (NaHS, donor of H2S), allyl isothiocyanate (AI), and cinnamaldehyde (CA). Fluorometric calcium imaging was used to study the effect of NaHS on human and mouse TRPA1 expressed in CHO cells. Results: TRPA1 immunoreactivity was found on unmyelinated nerve fibres within the urothelium, suburothelial space, and muscle layer as well as around blood vessels throughout the bladder. All TRPA1 immunoreactive nerves fibres also expressed TRPV1 immunoreactivity and vice versa. TRPA1 was also detected in urothelial cells at both transcriptional and protein levels. AI increased micturition frequency and reduced voiding volume. CA and NaHS produced similar changes in urodynamic parameters after disruption of the urothelial barrier with protamine sulfate. NaHS also induced calcium responses in TRPA1-expressing CHO cells, but not in untransfected cells. Conclusions: The expression of TRPA1 on C-fibre bladder afferents and urothelial cells together with the finding that intravesical TRPA1 activators initiate detrusor overactivity indicate that TRPA1 may have a role in sensory transduction in this organ. The study also highlights H2S as a TRPA1 activator potentially involved in inflammatory bladder disease. © 2007.
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| 7. |
- Abrams, P, et al.
(author)
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Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder
- 2006
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 148:5, s. 565-578
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Research review (peer-reviewed)abstract
- 1 The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2 Muscarinic M-3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M-2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3 Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4 This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M-3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.
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| 8. |
- Albrecht, Knut, et al.
(author)
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Immunohistochemical distribution of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human vagina: : A potential forensic value?
- 2007
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In: Journal of forensic and legal medicine. - : Elsevier BV. - 1752-928X. ; 14:5, s. 270-274
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Journal article (peer-reviewed)abstract
- Objectives Phosphodiesterase (PDE) isoenzymes are key proteins involved in the maintenance of the normal function of various tissues of the human body including those of the male and female urogenital tract. More recently, PDEs and their main substrates, cyclic GMP and cyclic AMP, have also been assumed to play a crucial role in the control of the human vagina. In order to elucidate the potential significance of phosphodiesterases as marker proteins in female genital organs, it was the aim of the present study to evaluate by means of immunohistochemistry the distribution of cGMP- and cAMP-PDE isoenzymes in specimens of the human vagina. Methods Conventional immunohistochemical techniques (double antibody technique, laser fluorescence microscopy) were applied to sections of the human vaginal wall in order to evaluate the presence of the PDE isoenzymes 1, 2, 3, 4, 5 and 10. Results Immunoreactivities (IR) specific for PDE1 (cAMP/cGMP-PDE, Ca2+/Calmodulin-dependent), PDE2 (cAMP-PDE, cGMP-dependent) and PDE5 (cGMP-PDE) were exclusively registered in the smooth musculature of vaginal arterial vessels, whereas no signals were detected in non-vascular tissue. IR indicating the expression of the cAMP-degrading PDE4 was mainly observed in the vaginal epithelium. Vaginal epithelial cells also presented immunosignals specific for PDE3 (cAMP-PDE, inhibited by cGMP) and PDE10 (dual substrate PDE), nevertheless, these stainings were less abundant than those related to the PDE4. IR for PDE10 was also registered in inflammatory cells located in the subepithelial region of the vaginal wall. Conclusion Our study revealed the presence of IR specific for PDE1, PDE2, PDE4, PDE5 and PDE10 in sections of the human vagina and demonstrated that these enzymes are not evenly distributed in the tissue. Especially, the prominent expression of the cyclic AMP-PDE4A in the vaginal epithelium may give hint to a potential significance of this isoenzyme as a forensic marker protein. The findings give a rationale to investigate further as to whether the immunohistochemical detection of PDE4 may represent a new forensic tool in order to identify human vaginal epithelial cells.
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| 10. |
- Andersson, B. L., et al.
(author)
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Assessment of sound propagation modelling from a wind turbine site at sea
- 2009
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In: 16th International Congress on Sound and Vibration 2009, ICSV 2009. - 9781615677368 ; , s. 896-903
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Conference paper (peer-reviewed)abstract
- We present results from numerical modelling of sound propagation from Utgrunden lighthouse in Kalmarsund to a receiver at Hammarby on the island Ö land east of Sweden in the Baltic. The propagation distances from source to shore and from shore to receiver are ca 9 km and 0.7 km, respectively. Our purpose is to assess prediction of atmospheric sound propagation by methods that use detailed knowledge of the local geometry and meteorology, by comparing model predictions of the transmission loss with experimental data. The experimental data, collected several times daily during a one-week campaign in June 2005, consist of (i) data on the transmission loss of narrow band signals from controlled sources with frequencies 80 Hz, 200 Hz and 400 Hz, (ii) atmospheric parameters as function of height from radio-soundings and balloon-tracking at the receiver location and (iii) atmospheric parameters from sensors mounted on a meteorological mast at the source location. Model-predicted soundfields were computed once per hour during the one-week period, with a windfield composed of a laminar field determined from data at the receiver, superimposed by a turbulent field determined by data from the meteorological mast. Comparisons of the experimentally observed transmission loss with predictions by the Green's Function Parabolic Equation (GFPE) method by Gilbert and Di are presented. A reasonably good fit of the model predicted transmission loss as function of time to experimental data at all frequencies is observed.
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