| 1. |
- Hellgren, Mikko, 1972-, et al.
(author)
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Hypertension management in primary health care : a survey in eight regions of Sweden
- 2023
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In: Scandinavian Journal of Primary Health Care. - : Taylor & Francis. - 0281-3432 .- 1502-7724. ; 41:3, s. 343-350
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Journal article (peer-reviewed)abstract
- Purpose: To explore hypertension management in primary healthcare (PHC).Design: Structured interviews of randomly selected PHC centres (PHCCs) from December 2019 to January 2021.Setting: Seventy-six PHCCs in eight regions of Sweden.Main outcome measures: Staffing and organization of hypertension care. Methods of measuring blood pressure (BP), laboratory tests, registration of co-morbidities and lifestyle advice at diagnosis and follow-up.Results: The management of hypertension varied among PHCCs. At diagnosis, most PHCCs (75%) used the sitting position at measurements, and only 13% routinely measured standing BP. One in three (33%) PHCCs never used home BP measurements and 25% only used manual measurements. The frequencies of laboratory analyses at diagnosis were similar in the PHCCs. At follow-up, fewer analyses were performed and the tests of lipids and microalbuminuria decreased from 95% to 45% (p < 0.001) and 61% to 43% (p = 0.001), respectively. Only one out of 76 PHCCs did not measure kidney function at routine follow-ups. Lifestyle, physical activity, food habits, smoking and alcohol use were assessed in & GE;96% of patients at diagnosis. At follow-up, however, there were fewer assessments. Half of the PHCCs reported dedicated teams for hypertension, 82% of which were managed by nurses. There was a great inequality in the number of patients per tenured GP in the PHCCs (median 2500; range 1300-11300) patients.Conclusions: The management of hypertension varies in many respects between PHCCs in Sweden. This might lead to inequity in the care of patients with hypertension.
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| 2. |
- Backman, Christian, et al.
(author)
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Knowledge in and support for standardised cancer care pathways among general practitioners and other physicians in Sweden
- 2021
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In: Scandinavian Journal of Primary Health Care. - : Taylor & Francis. - 0281-3432 .- 1502-7724. ; 39:1, s. 17-22
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the expertise in and support of the implemented new method of cancer patient pathways (CPPs) among general practitioners (GPs) and other working physicians in Sweden.DESIGN: A survey in the form of 10 knowledge-based multiple-choice questions (MCQs) and two general questions about CPPs.SETTING: Physicians from two different regions in Sweden answered the survey between December 2018 and January 2019.SUBJECTS: GPs in primary care compared to other physicians. 155 participants completed the survey and the response rate was 65%.MAIN OUTCOME MEASURES: Physicians' self-estimated knowledge of CPPs in general and opinion of CPPs effect on mortality and morbidity. Their scores on 10 different MCQs. Scores were analysed in subgroups related to the physicians medical specialty and experience.RESULTS: A majority of all physicians (63%) felt that they had insufficient knowledge regarding the procedure of CPPs, and the average score from the MCQs was 3.8 out of 10 correct answers. The results showed that GPs performed significantly better than specialists from other disciplines.CONCLUSIONS: The low percentage of correctly answered MCQs shows that the information about the entry part of CPPs needs to be improved. The study demonstrates a support for the system with CPPs because the physicians believed in its' positive effects on morbidity and mortality, however, it also reveals a lack of self-estimated knowledge about the system with CPPs.Key pointsCancer patient pathways (CPPs) is a newly implemented method in Sweden that aims to equalize cancer care and reduce the time to diagnosis and treatment.The proficiency of when to initiate an investigation according to a specific CPP seems low. General practitioners (GPs) performed significantly better on knowledge-based questions than other specialists did.Physicians rated their knowledge as insufficient regarding the procedure of CPPs.A clear majority of physicians believed that CPPs promotes a lower mortality and morbidity in cancer.
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| 3. |
- Brandt, Erik G., et al.
(author)
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Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site
- 2009
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In: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 11:6, s. 975-983
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Journal article (peer-reviewed)abstract
- The binding of zinc (Zn) ions to proteins is important for many cellular events. The theoretical and computational description of this binding (as well as that of other transition metals) is a challenging task. In this paper the binding of the Zn ion to four cysteine residues in the structural site of horse liver alcohol dehydrogenase (HLADH) is studied using a synthetic peptide mimic of this site. The study includes experimental measurements of binding constants, classical free energy calculations from molecular dynamics (MD) simulations and quantum mechanical (QM) electron structure calculations. The classical MD results account for interactions at the molecular level and reproduce the absolute binding energy and the hydration free energy of the Zn ion with an accuracy of about 10%. This is insufficient to obtain correct free energy differences. QM correction terms were calculated from density functional theory (DFT) on small clusters of atoms to include electronic polarisation of the closest waters and covalent contributions to the Zn-S coordination bond. This results in reasonably good agreement with the experimentally measured binding constants and Zn ion hydration free energies in agreement with published experimental values. The study also includes the replacement of one cysteine residue to an alanine. Simulations as well as experiments showed only a small effect of this upon the binding free energy. A detailed analysis indicate that the sulfur is replaced by three water molecules, thereby changing the coordination number of Zn from four (as in the original peptide) to six (as in water).
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| 4. |
- Brandt, Erik G., et al.
(author)
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Molecular Dynamics Study of Zinc Binding to Cysteines in a Peptide Mimic of the Alcohol Dehydrogenase Structural Zinc Site
- 2009
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In: Electronic Supplementary Material for PCCP. - : Royal Society of Chemistry. ; 11, s. 975-983
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Journal article (other academic/artistic)abstract
- This document contains additional information regarding the details of the three methods for free energy calculations employed in the study. All three methods are based on molecular dynamics. For methods I and II the binding free energy is obtained by numerical integrationas: ∆Fbind = Fbound − Ffree =∫ 10⟨ dHdλ⟩N V T ; λdλ . (1)The ensemble average is calculated as a time average from a molecular dynamics simulations in the canonical (NVT) ensemble. The coupling parameter, λ, is chosen such that the Hamiltonian is changed from describing the bound state to describing the free state of theZn ion. If the transformation process is reversible, the free energy change is independent of the reaction path and only depends on the initial and final states. Therefore we are free to choose the path of integration in Eq. (1) as long as the reversibility condition is met. Determining differences between two large numbers, as is the case in Eq. (1), can be problematic since the statistical errors involved are large as well. If λ is constructed wisely, large energy differences and their errors can be made to cancel in the final result. In general 2 it is non-trivial to find ways which allow for such cancellations. In our case we are comparing two states where the long-range electrostatics are very similar and therefore minimises the otherwise serious issues linked to changing charges in free energy calculations.
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| 5. |
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| 6. |
- Hellgren, Mikko, 1972-, et al.
(author)
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A comparison between two prokaryotic potassium channels (KirBac1.1 and KcsA) in a molecular dynamics (MD) simulation study
- 2006
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In: Biophysical Chemistry. - : Elsevier BV. - 0301-4622 .- 1873-4200. ; 120:1, s. 1-9
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Journal article (peer-reviewed)abstract
- The two potassium ion channels KirBac1.1 and KcsA are compared in a Molecular Dynamics (MD) simulation study. The location and motion of the potassium ions observed in the simulations are compared to those in the X-ray structures and previous simulations. In our simulations several of the crystallography resolved ion sites in KirBac1.1 are occupied by ions. In addition to this, two in KirBac1.1 unresolved sites where occupied by ions at sites that are in close correspondence to sites found in KcsA. There is every reason to believe that the conserved alignment of the selectivity filter in the potassium ion channel family corresponds to a very similar mechanism for ion transport across the filter. The gate residues, Phe146 in KirBac1.1 and Ala111 in KcsA acted in the simulations as effective barriers which never were passed by ions nor water molecules.
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| 7. |
- Hellgren, Mikko, 1972-, et al.
(author)
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A hydrogen-bonding network in mammalian sorbitol dehydrogenase stabilizes the tetrameric state and is essential for the catalytic power
- 2007
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 64:23, s. 3129-3138
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Journal article (peer-reviewed)abstract
- Subunit interaction in sorbitol dehydrogenase (SDH) has been studied with in vitro and in silico methods identifying a vital hydrogen-bonding network, which is strictly conserved among mammalian SDH proteins. Mutation of one of the residues in the hydrogen-bonding network, Tyr110Phe, abolished the enzymatic activity and destabilized the protein into tetramers, dimers and monomers as judged from gel filtration experiments at different temperatures compared to only tetramers for the wild-type protein below 307 K. The determined equilibrium constants revealed a large difference in Gibbs energy (8 kJ/mol) for the tetramer stability between wild-type SDH and the mutated form Tyr110Phe SDH. The results focus on a network of coupled hydrogen bonds in wild-type SDH that uphold the protein interface, which is specific and favorable to electrostatic, van der Waals and hydrogen-bond interactions between subunits, interactions that are crucial for the catalytic power of SDH.
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| 8. |
- Hellgren, Mikko, 1972-, et al.
(author)
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Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism
- 2007
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 64:4, s. 498-505
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Journal article (peer-reviewed)abstract
- The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2 (ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined K(m) values ranged from 0.05 to 0.3 microM and k(cat) values from 2.3 to 17.6 min(-1), while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup. This mutation increased the retinoid activity up to 100-fold. The K(m) values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic retinol oxidation at physiological concentrations.
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| 9. |
- Hellgren, Mikko, 1972-, et al.
(author)
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Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3
- 2010
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In: CELLULAR AND MOLECULAR LIFE SCIENCES. - : Springer Science Business Media. - 1420-682X .- 1420-9071. ; 67:17, s. 3005-3015
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Journal article (peer-reviewed)abstract
- Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated binding scoring energies correlated well with the logarithm of the k (cat)/K (m) values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids.
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| 10. |
- Hellgren, Mikko, 1972-
(author)
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Enzymatic studies of alcohol dehydrogenase by a combination of in vitro and in silico methods
- 2009
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Doctoral thesis (other academic/artistic)abstract
- The family of alcohol dehydrogenases (ADHs) catalyzes conversions of alcohols, ketons and aldehydes. The early discovery and isolation of ADH (1937) was followed by numerous investigations. It was also the first dimeric enzyme for which the threedimensional structure was determined (1974). Recent findings have revealed new physiological functions for the ADH enzymes. One type is a key enzyme in hepatic retinol metabolism, another is a main formaldehyde scavenger and a regulator of Snitrosothiols levels. ADH genes have been shown to be connected to diseases and syndromes, such as alcoholism and asthma. Hence, investigations of structure-function relationships of the ADH enzymes are of both physiological and medical interest. The aim of this thesis was to study structure-function relationships and to investigate and identify ligands for ADH, with in vitro and in silico methods. The catalytic activities of human, mouse and rat ADH2 for retinoids, were determined. The Km values for human ADH2 are the lowest among all known human dehydrogenases, which supports a key role for human ADH2 in the hepatic retinoid metabolism. ADH3 is an enzyme with a proposed role as an NO scavenger. Two new lines of ligands, bile acids and fatty acids, were investigated for their potential effects on NO homeostasis. The bronco dilatatory effect of NO suggests that ADH3 inhibition could potentially work as treatment of obstructive lung disorders. The stability of the quaternary structure of sorbitol dehydrogenase (SDH) was determined by in vitro experiments and in silico energy calculations. A hydrogen-bonding network crucial for the tetrameric stability in SDH was identified. This network is located at a region enclosing the structural zinc site in mammalian ADHs. The structural zinc site was studied in detail by a combination of molecular dynamics and quantum mechanics simulations. The simulations revealed that the interaction between the cysteine residues and the zinc atom is of an electrostatic and covalent nature. With in silico and in vitro simulations, interactions between ligands and the active site were determined, revealing site specific interactions within both ADH2 and ADH3. Furthermore, studies of subunit interactions and the structural zinc site revealed properties of the quaternary stability.
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| 11. |
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| 12. |
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| 13. |
- Hellgren, Mikko, 1972-, et al.
(author)
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Multi-level modelling of the parallell metabolism of ethanol and retinol, with implications for foetal alcohol syndrome
- 2008
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In: The 9th International Conference on Systems Biology (ICSB-2008) in Gothenburg (Sweden). - 9781615673322
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Conference paper (peer-reviewed)abstract
- Objective: Models of the human metabolism are important for understanding diseases and could serve as a powerful tool in the drug discovery process. The complexity of even a unicellular organism is tremendous and most researchers have therefore limited their modelling efforts to bacteria, or single intracellular pathways. We studied the parallel metabolism of ethanol and retinol in humans, because of its suggested physiological importance for the development of foetal alcohol syndrome. Large ethanol intake will inhibit the conversion of retinol into retinoic acid, which is a crucial transcription factor during embryonic development. In this study the objective was to construct a quantitative model that connects phenotype observations at a population, organic and intracellular level with differences in genotype and ethanol metabolism, for further prediction of the influence on the foetus. Results: We constructed a multiple compartments model, which included a detailed desccription of the ethanol and retinol metabolism in hepatic cells for different genotypes. The model has been validated using published time-series measurements of ethanol, acetaldehyde and acetate concentrations in the blood. This model correctly accounts for differences in geno- and phenotype observed within the human population. Furthermore, the model shows that the retinol metabolism is decreased by ethanol ingestion, both via a reduced intracellular NAD+ concentration, and by an inhibition of alcohol and aldehyde dehydrogenases. Conclusions: We considered the problem of multi-level modelling with a human model for the ethanol and retinol metabolism in different compartments. This links intracellular mechanisms to macroscopic observations. The model explained the connection between geno- and phenotype differences observed at a population level. This model also shows a plausible relationship between ethanol and retinol metabolism for e.g. foetal alcohol syndrome.
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| 14. |
- Staab, Claudia A., et al.
(author)
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Medium- and short-chain dehydrogenase/reductase gene and protein families : Dual functions of alcohol dehydrogenase 3: implications with focus on formaldehyde dehydrogenese and S-nitrosoglutathione reductase activities
- 2008
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 65:24, s. 3950-3960
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Research review (peer-reviewed)abstract
- Alcohol dehydrogenase 3 (ADH3) has emerged as an important regulator of protein S-nitrosation in its function as S-nitrosoglutathione (GSNO) reductase. GSNO depletion is associated with various disease conditions, emphasizing the potential value of a specific ADH3 inhibitor. The present study investigated inhibition of ADH3-mediated GSNO reduction by various substrate analogues, including medium-chain fatty acids and glutathione derivatives. The observed inhibition type was non-competitive. Similar to the Michaelis constants for the corresponding ω-hydroxy fatty acids, the inhibition constants for fatty acids were in the micromolar range and showed a clear dependency on chain length with optimal inhibitory capacity for eleven and twelve carbons. The most efficient inhibitors found were undecanoic acid, dodecanoic acid and dodecanedioic acid, with no significant difference in inhibition constant. All glutathione-derived inhibitors displayed inhibition constants in the millimolar range, at least three orders of magnitudes higher than the Michaelis constants of the high-affinity substrates GSNO and S-hydroxymethylglutathione. The experimental results as well as docking simulations with GSNO and S-methylglutathione suggest that for ADH3 ligands with a glutathione scaffold, in contrast to fatty acids, a zinc-binding moiety is imperative for correct orientation and stabilization of the hydrophilic glutathione scaffold within a predominantly hydrophobic active site.
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| 15. |
- Staab, Claudia A., et al.
(author)
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Medium-chain fatty acids and glutathione derivatives as inhibitors of S-nitrosoglutathione reduction mediated by alcohol dehydrogenase 3
- 2009
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In: Chemico-Biological Interactions. - : Elsevier. - 0009-2797 .- 1872-7786. ; 180:1, s. 113-118
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Journal article (peer-reviewed)abstract
- Alcohol dehydrogenase 3 (ADH3) has emerged as an important regulator of protein S-nitrosation in its function as S-nitrosoglutathione (GSNO) reductase. GSNO depletion is associated with various disease conditions, emphasizing the potential value of a specific ADH3 inhibitor. The present study investigated inhibition of ADH3-mediated GSNO reduction by various substrate analogues, including medium-chain fatty acids and glutathione derivatives. The observed inhibition type was non-competitive. Similar to the Michaelis constants for the corresponding omega-hydroxy fatty acids, the inhibition constants for fatty acids were in the micromolar range and showed a clear dependency on chain length with optimal inhibitory capacity for eleven and twelve carbons. The most efficient inhibitors found were undecanoic acid, dodecanoic acid and dodecanedioic acid, with no significant difference in inhibition constant. All glutathione-derived inhibitors displayed inhibition constants in the millimolar range, at least three orders of magnitudes higher than the Michaelis constants of the high-affinity substrates GSNO and S-hydroxymethylglutathione. The experimental results as well as docking simulations with GSNO and S-methylglutathione suggest that for ADH3 ligands with a glutathione scaffold, in contrast to fatty acids, a zinc-binding moiety is imperative for correct orientation and stabilization of the hydrophilic glutathione scaffold within a predominantly hydrophobic active site.
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| 16. |
- Westerling, Ulrika, 1970-, et al.
(author)
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In safe hands : a qualitative study on older adults' experiences of a tailored primary health care unit
- 2022
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In: Scandinavian Journal of Primary Health Care. - : Taylor & Francis Group. - 0281-3432 .- 1502-7724. ; 40:2, s. 271-280
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Journal article (peer-reviewed)abstract
- Objective: Today's health care system faces challenges in meeting the needs of older people with multimorbidity. To better cope with these needs, tailored primary health care with geriatric competence and person-centred care has been suggested. The aim of this study was to explore older patients' experiences of a tailored primary health care unit.Design: This was a qualitative study using semi-structured individual interviews and qualitative content analysis.Setting and patients: Nineteen patients were recruited from a tailored PHC unit for people aged 75 years or older in a region in central Sweden.Methods: The interview data were analysed using inductive category development.Results: In the analysis, the theme In safe hands when in need of primary health care emerged. The interviewees expressed a desire to participate in their own care. Easy access, enough consultation time and a calm environment, along with the PHC professionals' welcoming and attentive approach enhanced their feeling of being in safe hands. PHC professionals were perceived as having geriatric knowledge and taking responsibility for the care of older patients. Although the interviewees experienced that they received attention for their health conditions, a need for a more preventive approach to care emerged.Conclusion: Older patients highly appreciated their tailored PHC unit and they emphasised that it was an improvement compared to the ordinary PHC centre. This study provides insights into older patients' experiences, which may be helpful in the ongoing process of improving care for older patients in PHC.Older patients attending a tailored Primary health care (PHC) unit felt acknowledged, unlike in the ordinary PHC centre, which facilitated their participation in their care.The calm environment, specialist geriatric competence and ample patient contact time enabled them to feel secure and taken care of.Older patients expressed a need for an incorporation of social services and health promotion visits at the tailored PHC unit.
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| 17. |
- Westerling, Ulrika, 1970-, et al.
(author)
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Informal caregivers' experiences of support from a tailored primary healthcare unit for older adults : A focus group study
- 2024
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In: Scandinavian Journal of Caring Sciences. - : Blackwell Publishing. - 0283-9318 .- 1471-6712.
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Journal article (peer-reviewed)abstract
- BACKGROUND: Informal caregivers are an essential part of health and social care systems worldwide. As such, they may need professional support. AIM: The aim of this study was to describe informal caregivers' experiences and need for support from a tailored primary health care (PHC) unit.METHODS: This is a qualitative descriptive study using data collected from five semi-structured focus group discussions with a purposeful sample of 16 informal caregivers of older relatives. Respondents were recruited from a tailored PHC unit for people aged 75 years or older in a region in central Sweden. The data were analysed by qualitative content analysis with an abductive approach, based on the principles of the patient- and family-centred care framework.RESULTS: The overarching theme was 'Striving for partnership'. The findings indicate that informal caregivers to some extent felt supported by the healthcare professionals. However, the caregivers expressed a need to be further acknowledged by the professionals in order to participate in the care of their older relatives in the way they wanted. Moreover, insufficient information regarding the older adult's health condition and care provided by the professionals had a negative impact on the caregiver's participation in care.CONCLUSIONS: Informal caregivers have unmet needs for support and strive for a partnership with the PHC professionals. PHC professionals should be more attentive and invite informal caregivers to participate in the care of the older adult in order to meet their support needs and build an equal partnership. The patient- and family-centred care framework may be of guidance when providing care for older adults in a PHC context.
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