| 51. |
- Liu, Yuanhua, 1971, et al.
(författare)
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Usability Tests as a Benchmarking Tool - A Case Study on Complex Medical Ventilators
- 2009
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Ingår i: Contemporary Ergonomics 2009. - 9780415804332 ; , s. 182-188
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Konferensbidrag (refereegranskat)abstract
- Medical ergonomics has become an important topic in the field of ergonomics due to the increasing deficiencies in medical device design. The aim of the present study was to use usability testing as a benchmarking tool of modern and complex ventilator machines in a real hospital setting to propose future redesign ideas for a target machine – SERVO-i. A usability study was carried out at the neonatal intensive care unit (ICU) with 6 expert nurses. During the tests, an artificial lung was used to simulate the real treatment context on a neonatal patient. A number of potential usability problems were detected on SERVO-i. Using Babylog and Stephanie as two reference machines, the strengths and weaknesses of SERVO-i were identified as well. Some valuable lessons were learnt from the study, which could be used as guidance for the choice of test subjects and control of tests in real life human-machine working environments.
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| 52. |
- Nilsson, Maria E
(författare)
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Interactions between Streptococcus pyogenes and the human immune defence
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Streptococcus pyogenes is an important human pathogen frequently colonizing the throat and skin of humans. To facilitate colonization and spread and to avoid the host immune defence, streptococci are endowed with a variety of virulence factors, two of which are investigated in this thesis namely streptolysin O (SLO) and M protein. SLO is a secreted cytolysin that forms pores in eukaryotic membranes by binding to cholesterol. This thesis shows that SLO, via calcium and p38 MAPK, stimulates polymorphonuclear neutrophilic granulocytes (PMNs) to release the pro-inflammatory mediators heparin binding protein (HBP), LL-37, ?-defensin, and elastase. This will lead to an exaggerated immune response that may be beneficial to streptococci and could explain some of the symptoms of severe streptococcal infections. M proteins form a family of membrane anchored surface proteins that project from the streptococcal surface and have been linked to the characteristic feature of S. pyogenes to escape phagocytosis. The exact mechanisms underlying this phagocytosis resistance remain unknown. In one of the papers included in this thesis, we investigated the contribution of the binding of complement regulatory proteins factor H (FH) and factor H like protein-1 (FHL-1) to M5 protein. Surprisingly, FH/FHL-1 binding affects neither complement deposition nor phagocytosis resistance. In another paper, we investigated the binding between M and M-like proteins of the M1 serotype and ?2-glycoprotein I (?2-GPI). Fragments of ?2-GPI were shown to be antibacterial, and we found that the interaction of M1 protein and protein H with full-length ?2-GPI inhibited the cleavage into potentially harmful fragments of the plasma protein. In addition, M1 protein and protein H were able to neutralize the effect of the ?2-GPI antibacterial fragments in vitro. In immune donors, streptococci are opsonized by specific antibodies and subsequently killed. Our results show that these neutralizing antibodies are directed to the N-terminal of the M protein and that they mediated killing by complement activation. We also found that surface deposited C3b binds to complement receptor 3 (CR3) on PMNs which leads to activation of Cdc 42 and Rac 2 that starts the phagocytosis process and triggers the induction of oxidative burst.
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| 53. |
- Asimus, Sara, 1976, et al.
(författare)
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Artemisinin--a possible CYP2B6 probe substrate?
- 2009
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Ingår i: Biopharmaceutics & drug disposition. - : Wiley. - 1099-081X .- 0142-2782. ; 30:5, s. 265-75
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To compare in vitro metabolism rates for artemisinin and the CYP2B6 substrates, bupropion, propofol and efavirenz in human liver microsomes. METHODS: Rate constants of artemisinin, bupropion, propofol and efavirenz metabolism by human liver microsomes from a panel of 12 donors, with different levels of CYP2B6 activity, were estimated in WinNonlin. Correlations between the metabolic rate constant for artemisinin and the other CYP2B6 substrates were examined. RESULTS: Artemisinin and propofol depletion data in human liver microsomes were described by first order kinetic models. For bupropion and efavirenz, metabolite formation data were incorporated in the model. Rate constants varied considerably for all substrates. There was a high degree of correlation of rate constants between substrates (r> or =0.87, p<0.001). CONCLUSIONS: The rate of in vitro metabolism of artemisinin was correlated significantly to that of bupropion, propofol and efavirenz, suggesting artemisinin to be a potential alternative marker to assess CYP2B6 activity. Further studies characterizing the metabolic fate of artemisinin are needed in order to evaluate its utility as an in vitro and in vivo CYP2B6 probe substrate, since CYP2B6 might not be the only CYP isoform involved in the depletion of artemisinin.
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| 54. |
- Birnir, Bryndis, et al.
(författare)
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Conductance of recombinant GABA(A) channels is increased in cells co-expressing GABA(A) receptor-associated protein
- 2004
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Ingår i: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 279:21, s. 21701-21706
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Tidskriftsartikel (refereegranskat)abstract
- High conductance gamma- aminobutyric acid type A ( GABA(A)) channels (> 40 picosiemens ( pS)) have been reported in some studies on GABA(A) channels in situ but not in others, whereas recombinant GABA(A) channels do not appear to display conductances above 40 pS. Furthermore, the conductance of some native GABA(A) channels can be increased by diazepam or pentobarbital, which are effects not reported for expressed GABA(A) channels. GABARAP, a protein associated with native GABA(A) channels, has been reported to cause clustering of GABA(A) receptors and changes in channel kinetics. We have recorded single channel currents activated by GABA in L929 cells expressing alpha(1), beta(1), and gamma(2S) subunits of human GABA(A) receptors. Channel conductance was never higher than 40 pS and was not significantly increased by diazepam or pentobarbital, although open probability was increased. In contrast, in cells expressing the same three subunits together with GABARAP, channel conductance could be significantly higher than 40 pS, and channel conductance was increased by diazepam and pentobarbital. GABARAP caused clustering of receptors in L929 cells, and we suggest that there may be interactions between subunits of clustered GABA(A) receptors that make them open co- operatively to give high conductance " channels." Recombinant channels may require the influence of GABARAP and perhaps other intracellular proteins to adopt a fuller repertoire of properties of native channels.
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| 55. |
- Friberg Hietala, Sofia, 1973, et al.
(författare)
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Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria
- 2007
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Ingår i: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 12, s. 222-222
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Tidskriftsartikel (refereegranskat)abstract
- The study aimed to characterize the population pharmacokinetics of amodiaquine (AQ) and its major metabolite N-desethylamodiaquine (N-DEAQ), and to assess the correlation between exposure to N-DEAQ and treatment outcome. Blood samples from children in two studies in Zanzibar and one in Papua New Guinea were included in the pharmacokinetic analysis (n = 86). The children had been treated with AQ in combination with artesunate or sulphadoxine-pyrimethamine. The population pharmacokinetics of AQ and N-DEAQ were modeled using the non-linear mixed effects approach as implemented in NONMEM. Bayesian post-hoc estimates of individual pharmacokinetic parameters were used to generate individual profiles of N-DEAQ exposure. The correlation between N-DEAQ exposure and effect was studied in 212 patients and modeled with logistic regression in NONMEM. The pharmacokinetics of AQ and N-DEAQ were best described by two parallel two-compartment models with a central and a peripheral compartment for each compound. The systemic exposure to AQ was low in comparison to N-DEAQ. The t (1/2lambda) of N-DEAQ ranged from 3 days to 12 days. There was a statistically significant, yet weak, association between N-DEAQ concentration on day 7 and treatment outcome. The age-based dosing schedule currently recommended in Zanzibar appeared to result in inadequate exposure to N-DEAQ in many patients.
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| 56. |
- Graffner-Nordberg, Malin, et al.
(författare)
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Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues
- 2000
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 43:21, s. 3852-3861
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Tidskriftsartikel (refereegranskat)abstract
- The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibit the highest binding affinity to human dihydrofolate reductase, and a reference ester (more structurally related to methotrexate) were synthesized. As deduced from the measured IC(50) values, the calculated ranking of the ligands was correct although a greater difference in affinity was indicated by the experimental measurements. Among the new antifolates the most potent inhibitor exhibited a similar pharmacokinetic profile to methotrexate but lacked activity in a complex antiarthritic model in rat in vivo.
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| 57. |
- Lindquist, Catarina
(författare)
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Physiology and Pharmacology of GABAA receptors: The Brakes in the Brain
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inhibitory neurotransmission in the brain is mostly mediated by gamma-aminobutyric acid type A (GABAA) receptors. These receptors are involved in both phasic inhibition (point-to-point inhibition, synaptic transmission) and tonic inhibition (diffuse form of inhibition, brain homeostasis). In this thesis the functional and pharmacological properties of GABAA receptors expressed in brain slices or in Sf 9 cells were studied. GABAA receptors expressed extrasynaptically are believed to be involved in tonic inhibition. In hippocampal dentate gyrus granule cells we identified and characterized three types of extrasynaptic receptor types (GABARex) that varied in their affinity for GABA, maximal single-channel conductance and sensitivity to drugs. For the first time we showed how the GABA concentration determines the conductance of GABAA receptors in brain tissue. There is thus a direct link between the extracellular GABA concentration and the level of the tonic inhibition, providing dynamic control. It is only within the last ten years or so that the tonic inhibition was discovered and only recently has it gained widespread interest. One reason is that it has become quite clear that the first site of action and probably often the most important site of action of drugs are the extrasynaptic receptors. We found that a drug now in clinical trials (THIP) at the clinically relevant concentration activates these extrasynaptic receptors. It has been assumed that spontaneous openings of the receptors are only functionally significant in receptor complexes containing the epsilon-subunit or mutations. We show that alpha/beta and alpha/beta/gamma?receptors can open spontaneously and be modified by drugs. The capacity to open spontaneously may be vital for fast responses such as at synapses. This suggests that the functional properties of receptors located at synapses and outside of synapses (extrasynaptic receptors: GABARex) differ. Those at synapses open rapidly (ms) whereas those at extrasynaptic sites open after a delay of ten to hundreds of seconds. This functional difference is very important in terms of brain function as it ensures fast flow of information (synaptic transmission) but in a controlled way that is set by the gain and the time window for synaptic transmission integration via the tonic inhibition. By using the compound SR95531, we constructed a model that accounts for activation and inhibition of both phasic- and tonic-like currents in an expression system. This model can be used to calculate what concentrations of the inhibitor to use to specifically block certain GABARex receptors in brain tissue to study how a particular population of GABARex contributes to the tonic inhibition and how it affects both excitatory and inhibitory synaptic transmission.
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| 58. |
- Lindström, L, et al.
(författare)
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Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia.
- 2005
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Ingår i: Schizophrenia research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 80:2-3, s. 315-22
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n=49) and male patients with schizophrenia (n=90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM+/-0.10 vs. 1.06 nM+/-0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM+/-0.19, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM+/-0.17, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM+/-0.10, n=19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.
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| 59. |
- Weinberg, AJ, et al.
(författare)
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Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study
- 2004
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Ingår i: Am J Nephrol. ; 24:3, s. 340-345
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The progression of renal disease is ameliorated by drugs that inhibit the renin-angiotensin system (RAS). The doses used to slow the progression of renal disease may not completely suppress the RAS for 24 h and may explain why some patients do not obtain optimal renoprotective benefits from therapy. This pilot study was initiated to determine the safety and tolerability of using higher doses, than currently approved by the Food and Drug Administration, for the angiotensin-receptor blocker (ARB) candesartan cilexetil in patients with chronic kidney disease. We hypothesized that higher doses will be safe and well tolerated. Consequently, this should be a viable strategy for larger clinical trials evaluating the preservation of renal function. METHODS: Twelve patients (10 males; age = 57 +/- 14 years) with a history of diabetic or non-diabetic chronic kidney disease were enrolled in an 8-week open-label trial. Patients received candesartan titrated to a targeted dosage of 160 mg/day (5 times above the currently approved maximum dose) and remained at that dosage for the subsequent 4 weeks. The safety and tolerability of the higher doses were determined by measures of blood pressure, serum creatinine and potassium. RESULTS: Candesartan was well tolerated with no serious drug-related adverse events reported. Serum creatinine concentrations throughout the study were not different (p > 0.05) from baseline levels (2.0 +/- 0.5 mg/dl). Plasma potassium concentrations at 160 mg/day candesartan (4.9 +/- 0.7 mEq/l) were similar (p > 0.05) to those at baseline (4.8 +/- 0.5 mEq/l). CONCLUSIONS: The results of this pilot study suggest that supramaximal doses of ARBs are safe and well tolerated in patients with chronic kidney disease, while reducing both blood pressure and proteinuria. This study demonstrates the need to further investigate the optimal dosing strategy for ARBs in reducing the progression of renal disease.
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| 60. |
- Wettermark, Bjoern, et al.
(författare)
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Secondary prevention in a large stroke population - A study of patients' purchase of recommended drugs
- 2008
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Ingår i: Stroke. - New York : American Heart Association. - 0039-2499 .- 1524-4628. ; 39:10, s. 2880-2885
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose - In this study, linked, anonymous data from The National Hospital Discharge Register and the Swedish Prescribed Drug Register were used for studying to what extent recommended drugs for secondary prevention after stroke and TIA were purchased by patients in the region of Stockholm, Sweden (2 million inhabitants). Methods - Data on purchased drugs for secondary stroke prevention during July 2005 to June 2006 by 17 902 patients > 18 years discharged after stroke or TIA during the period 1997 to June 2005 were analyzed by age, gender, and year of discharge. Results - Antiplatelets and warfarin were purchased by 87% of all stroke and 83% of all TIA patients, antihypertensives by 74% and 70%, and lipid lowering drugs by 41% and 39%, respectively. Conclusion - Time after discharge had only a minor influence on the proportion of patients purchasing the medicines.
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