| 1. |
- Sällström, Johan, et al.
(author)
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High-protein-induced glomerular hyperfiltration is independent of the tubuloglomerular feedback mechanism and nitric oxide synthases
- 2010
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In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 299:5, s. R1263-R1268
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Journal article (peer-reviewed)abstract
- A high protein intake is associated with increased glomerular filtration rate (GFR), which has been suggested to be mediated by reduced signaling of the tubuloglomerular feedback (TGF) mechanism. Nitric oxide (NO) has been shown to contribute to high protein-induced glomerular hyperfiltration, but the specific NO synthase (NOS) isoform responsible is not clear. In this study, a model for high-proteininduced hyperfiltration in conscious mice was developed. Using this model, we investigated the role of TGF using adenosine A(1)-receptor knockout mice lacking the TGF mechanism. Furthermore, the role of the different NOS isoforms was studied using neuronal-, inducible-, and endothelial-NOS knockout mice, and furthermore, wild-type mice acutely administered with the unspecific NOS inhibitor N-omega-nitro-L-arginine methyl ester (100 mg/kg). GFR was measured consecutively in mice given a low-protein diet (8% casein) for 10 days, followed by a high-protein diet (50% casein) for 10 days. All mice developed high protein-induced hyperfiltration to a similar degree. These results demonstrate that high protein-induced glomerular hyperfiltration is independent of the TGF mechanism and NOS isoforms.
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| 2. |
- Bamberg, Krister, et al.
(author)
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Electrolyte handling in the isolated perfused rat kidney : demonstration of vasopressin V2-receptor-dependent calcium reabsorption
- 2020
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In: Upsala Journal of Medical Sciences. - : TAYLOR & FRANCIS LTD. - 0300-9734 .- 2000-1967. ; 125:4, s. 274-280
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Journal article (peer-reviewed)abstract
- Background The most profound effect of vasopressin on the kidney is to increase water reabsorption through V-2-receptor (V2R) stimulation, but there are also data suggesting effects on calcium transport. To address this issue, we have established an isolated perfused kidney model with accurate pressure control, to directly study the effects of V2R stimulation on kidney function, isolated from systemic effects. Methods The role of V2R in renal calcium handling was studied in isolated rat kidneys using a new pressure control system that uses a calibration curve to compensate for the internal pressure drop up to the tip of the perfusion cannula. Results Kidneys subjected to V2R stimulation using desmopressin (DDAVP) displayed stable osmolality and calcium reabsorption throughout the experiment, whereas kidneys not administered DDAVP exhibited a simultaneous fall in urine osmolality and calcium reabsorption. Epithelial sodium channel (ENaC) inhibition using amiloride resulted in a marked increase in potassium reabsorption along with decreased sodium reabsorption. Conclusions A stable isolated perfused kidney model with computer-controlled pressure regulation was developed, which retained key physiological functions. The preparation responds to pharmacological inhibition of ENaC channels and activation of V2R. Using the model, the dynamic effects of V2R stimulation on calcium handling and urine osmolality could be visualised. The study thereby provides evidence for a stimulatory role of V2R in renal calcium reabsorption.
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| 3. |
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| 4. |
- Carlström, Mattias, et al.
(author)
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Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice
- 2007
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In: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 189:3, s. 293-301
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Journal article (peer-reviewed)abstract
- Aim: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt-sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt-sensitive hypertension. Methods: PUUO was created in 3-week-old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated. Results: All hydronephrotic animals developed salt-sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes. Conclusion: This study provides a model for PUUO in mice and demonstrates the presence of salt-sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before.
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| 5. |
- Carlström, Mattias, et al.
(author)
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Hydronephrosis causes salt-sensitive hypertension in rats
- 2006
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In: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0263-6352 .- 1473-5598. ; 24:7, s. 1437-1443
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Journal article (peer-reviewed)abstract
- BACKGROUND: Hypertension is a common disease in the Western world and approximately 5% of all cases are secondary to kidney malfunction. It is not clear whether unilateral hydronephrosis due to partial obstruction affects blood pressure. AIM: The aim of this study was to determine whether hypertension develops and to investigate the effects of different salt diets on the blood pressure in hydronephrotic animals. METHODS: Unilateral partial ureteral obstruction was created in 3-week-old Sprague-Dawley rats. A telemetric device was implanted 4-6 weeks later and blood pressure was measured on normal, low- and high-salt diets. Plasma samples were collected on all diets for renin analysis. RESULTS: All hydronephrotic animals developed hypertension that correlated to the degree of hydronephrosis. The blood pressure increased slowly with time and was salt sensitive. In severe hydronephrosis, blood pressure increased from 118 ± 5 mmHg on low salt to 140 ± 6 mmHg on high salt intake, compared to control levels of 82 ± 2 and 84 ± 2 mmHg, respectively. Plasma renin concentration was increased in the hydronephrotic group of animals compared to controls on all diets, but the difference was only significant on a normal salt diet, 165 ± 15 versus 86 ± 12 μGU/ml respectively. In animals with severe hydronephrosis the plasma renin levels were lower, and the changes less, than in those with mild and moderate hydronephrosis. CONCLUSION: This study demonstrates the presence of a salt-sensitive hypertension in hydronephrosis. A systemic effect of the renin-angiotensin system alone cannot be responsible for the hypertension.
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| 6. |
- Carlström, Mattias, et al.
(author)
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Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals
- 2008
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In: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 294:2, s. 362-370
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Journal article (peer-reviewed)abstract
- Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N-G- nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.
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| 7. |
- Carlström, Mattias, et al.
(author)
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SOD1-Deficiency Causes Salt-Sensitivity and Aggravates Hypertension in Hydronephrosis
- 2009
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In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 297:1, s. R82-R92
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Journal article (peer-reviewed)abstract
- Background: Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with NO-deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt-sensitivity and for hypertension in hydronephrosis. Methods: Hydronephrosis was induced in SOD1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko) and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high sodium (4% NaCl) diets and with chronic Tempol supplementation. 8-iso-prostaglandin-F2alpha (F2-IsoPs) and protein excretion profiles and histology were investigated. The acute effects of Tempol on blood pressure and TGF were studied in rats. Results: In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114+/-1 to 120+/-2 mmHg) which was augmented in SOD1-ko (125+/-3 to 135+/-4 mmHg), but abolished in SOD1-tg (109+/-3 to 108+/-3 mmHg). SOD1-ko controls displayed salt-sensitive blood pressure (108+/-1 to 115+/-2 mmHg), which was not found in wild-types or SOD1-tg. Chronic Tempol treatment reduced blood pressure in SOD1-ko controls (-7 mmHg) and in hydronephrotic wild-types (-8 mmHg) and SOD1-ko mice (-16 mmHg), but had no effect on blood pressure in wild-type or SOD1-tg controls. SOD1-ko controls and hydronephrotic wild-type and SOD1-ko mice exhibited increased fluid excretion associated with increased F2-IsoPs and protein excretion. The renal histopathological changes found in hydronephrotic wild-types were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis (DeltaPSF: 15.2+/-1.2 to 9.1+/-0.6 mmHg, TP: 14.3+/-0.8 to 19.7+/-1.4 nl/min). Conclusion: Oxidative stress due to SOD1-deficiency causes salt-sensitivity and plays a pivotal role for the development of hypertension in hydronephrosis. Increased superoxide formation may enhance TGF response and thereby contribute to hypertension.
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| 8. |
- Carlström, Mattias, et al.
(author)
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Uninephrectomy in Young Age or Chronic Salt Loading Causes Salt-Sensitive Hypertension in Adult Rats
- 2007
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In: Hypertension. - 0194-911X .- 1524-4563. ; 49:6, s. 1342-1350
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Journal article (peer-reviewed)abstract
- The importance of nephron endowment and salt intake for the development of hypertension is under debate. The present study was designed to investigate whether reduced nephron number, after completion of nephrogenesis, or chronic salt loading causes renal injury and salt-sensitive hypertension in adulthood. Rats were operated at 3 weeks of age (after completed nephrogenesis) and then subjected to either normal or high-salt diets for 6 to 8 weeks. Four different experimental groups were used: sham-operated animals raised with normal-salt diet (controls) or high-salt diet (HS) and uninephrectomized animals raised with normal-salt diet (UNX) or high-salt diet (UNX+HS). In the adult animals, renal and cardiovascular functions were evaluated and blood pressure recorded telemetrically under different sodium conditions (normal, high, and low). Hypertension was present in UNX+HS (122±9 mm Hg), UNX (101±3 mm Hg), and HS (96± 1 mm Hg) groups on normal-salt diets compared with the controls (84±2 mm Hg), and the blood pressure was salt sensitive (high- versus normal-salt diet; 23±3, 9±2, 7±2, and 1±1 mm Hg, respectively). The hypertensive groups (UNX+HS, UNX, and HS) had increased diuresis and reduced ability to concentrate urine. The glomerular filtration rate (milliliters per minute) in anesthetized rats was reduced in the UNX+HS (2.36±0.30) and UNX animals (2.00±0.31) compared with both HS animals (3.55±0.45) and controls (3.01±0.35). Hypertensive groups displayed reduced plasma renin concentrations during high sodium conditions and hypertrophic kidneys and hearts with various degrees of histopathologic changes. In conclusion, at a young age after completed nephrogenesis, uninephrectomy or chronic salt loading causes renal and cardiovascular injury with salt-sensitive hypertension.
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| 9. |
- Gao, Xiang, et al.
(author)
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Adenosine A(1)-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment
- 2011
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In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 301:6, s. R1669-R1681
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Journal article (peer-reviewed)abstract
- Adenosine mediates tubuloglomerular feedback responses via activation of A(1)-receptors on the renal afferent arteriole. Increased preglomerular reactivity, due to reduced nitric oxide (NO) production or increased levels of ANG II and reactive oxygen species (ROS), has been linked to hypertension. Using A(1)-receptor knockout (A(1)(-/-)) and wild-type (A(1)(+/+)) mice we investigated the hypothesis that A(1)-receptors modulate arteriolar and blood pressure responses during NO synthase (NOS) inhibition or ANG II treatment. Blood pressure and renal afferent arteriolar responses were measured in nontreated mice and in mice with prolonged N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or ANG II treatment. The hypertensive responses to L-NAME and ANG II were clearly attenuated in A(1)(-/-) mice. Arteriolar contractions to L-NAME (10(-4) mol/l; 15 min) and cumulative ANG II application (10(-12) to 10(-6) mol/l) were lower in A(1)(-/-) mice. Simultaneous treatment with tempol (10(-4) mol/l; 15 min) attenuated arteriolar responses in A(1)(+/+) but not in A(1)(-/-) mice, suggesting differences in ROS formation. Chronic treatment with L-NAME or ANG II did not alter arteriolar responses in A(1)(-/-) mice, but enhanced maximal contractions in A(1)(+/+) mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A(1)(+/+) mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A(1)-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A(1)-receptor signaling blunts L-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.
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| 10. |
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| 11. |
- Kinch, Amelie, 1973-, et al.
(author)
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Long-term outcome of Epstein-Barr virus DNAemia and PTLD with the use of preemptive rituximab following allogeneic HSCT
- 2018
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In: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 59:5, s. 1172-1179
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Journal article (peer-reviewed)abstract
- We studied retrospectively the outcome of Epstein-Barr virus (EBV)-related disease with EBV monitoring and preemptive rituximab to prevent post-transplant lymphoproliferative disorder (PTLD) in 319 consecutive allogeneic stem cell transplantations 2004-2012. Patients who received anti-thymocyte globulin (ATG) or alemtuzumab were regarded as high-risk for PTLD (n = 214). EBV DNAemia ≥1000 copies/mL plasma was observed in 50 (23%) of the high-risk patients. Thirty-three of the high-risk (15%) and one of the low-risk (1%) patients received rituximab, in combination with reduction of immunosuppression (n = 24) or chemotherapy (n = 4). Although rituximab was initiated only 5 d after first EBV load ≥1000 copies/mL, 85% of the rituximab-treated patients developed symptoms (lymphadenopathy 50%, fever 76%, and encephalitis/meningitis 12%). Response-rate to EBV treatment was 88%. Overall survival at 1- and 5-year was 71 and 52% for rituximab-treated patients, which was not inferior to all other patients post-transplant. In conclusion, rituximab therapy for EBV DNAemia does not affect long-term survival negatively.
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| 12. |
- Langhammar, Birgitta, et al.
(author)
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Life satisfaction in persons with severe stroke – A longitudinal report from the Sunnaas International Network (SIN) stroke study
- 2017
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In: European stroke journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 2:2, s. 154-162
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Journal article (peer-reviewed)abstract
- Introduction The overall aim of the present study was to explore perceived life satisfaction in persons with stroke, from admission to specialised rehabilitation until follow up 1 year post-discharge. The secondary aim was to evaluate possible external and internal explanatory factors for perceived life satisfaction. Patients and methods A prospective, descriptive study of specialised rehabilitation of persons with stroke. Persons with a primary diagnosis of stroke were enrolled in the study. Results Overall, total score on LiSat-11 showed that life was perceived as satisfying by 11% on admission, 21% at discharge, 25% at 6 and 31% at 12 months after discharge from rehabilitation, reported by 230 participating persons with stroke. Repeated measurement indicated significant differences of total life satisfaction between clinics, also when controlled for disability and severity. The items “sexual life,” “health,” and “vocational life”/“financial” were most dissatisfying at the various reported time points. The linear regression analysis revealed an equal amount of internal and external explanatory factors at the different time points, explaining between 16% and 41% of the variations. Discussion and conclusion The perceived life satisfaction was reported as low/dissatisfying at the four stated time points in all the participating clinics. Four items were especially vulnerable post-stroke: vocational situation, sexual life, physical health and mental health. Both internal and external factors contributed to life satisfaction, such as gender, severity of stroke, marital status, country, models of rehabilitation, occupational status, length of stay (LOS), number of therapies and hours in therapy. However, there were significant differences between clinics, indicating that unidentified factors may also influence life satisfaction.
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| 13. |
- Langhammer, Birgitta, et al.
(author)
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Factors enhancing activities of daily living after stroke in specialized rehabilitation. An observational multicenter study within the Sunnaas International Network.
- 2017
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In: European journal of physical and rehabilitation medicine. - 1973-9095. ; 53:5, s. 725-34
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Journal article (peer-reviewed)abstract
- Stroke may lead to serious, long-term disability. Consequently, many individuals with stroke will be in need of rehabilitation, and some of specialized rehabilitation. The content and organization of rehabilitation vary within and between countries, reflecting the preferences, customs, traditions, and values of a society or community, that may have an impact on outcomes.The main aim of the present study was to evaluate the influence of team models in specialized rehabilitation on outcomes as measured by stroke patients' performance in ADL, at a standardized time and at discharge in the various specialized rehabilitation clinics. Secondary aims were to identify explanatory factors for possible differences in ADL changes at standardized time points.A prospective descriptive cross-sectional explorative, multicentre study.Specialized rehabilitation clinics in Norway, China, the United States, Russia, Israel, Palestine, and Sweden, in total nine clinics.Persons with stroke.Outcomes measures were the modified Rankin Scale (mRS) and the National Institute of Health Stroke Scale (NIHSS), both on admission and at discharge from the inpatient rehabilitation unit, and Barthel Index (BI) or alternatively Functional Independence Measure (FIM), on admittance, 18-22 days into rehabilitation, at discharge, and at 6 and 12 months after discharge.In total 230 persons with stroke from nine clinics were recruited. There were significant differences in change scores of ADL from admittance to standardized time point 18-22 days into rehabilitation, (p<0.001, r2= 0.19) and when controlled for baseline NIHSS and mRS (p<0.001, r2 = 0.18; p=0.01, r2 = 0.9 respectively). Analysis divided into intra-, multi- and interdisciplinary models showed significant differences at 18-22 days (p=0.02) and at discharge (p<0.001), indicating a more favourable outcome in ADL with the multi- disciplinary model. The linear regression analysis explained 55 % of the changes in ADL (R2= 0.55) at the standardized time point and 48% (R2 = 0.48) at discharge. Main explanatory factors were disability (mRS) and severity (NIHSS), team models, hours in therapy, and location at discharge. ADL was maintained for the majority of participants at 6 and 12 months post discharge. The correlations mRS / ADL (r=-0.68, p<0.0001), NIHSS / ADL (r=-0.55, p<0.0001) and NIHSS / mRS (r=0.46, p<0.0001) disclosed medium to large associations at 18-22 days into rehabilitation.The study indicates that the organisation of services in specialized rehabilitation after stroke has a major impact on improvement of ADL outcomes. Main positive predictive factors were models of teamwork, with the multidisciplinary model as most beneficial, and concentrated hours of therapy. Negative predictors were the level of baseline severity and disability post stroke.The results indicate that organization of services should be at target to optimize patients' outcomes in rehabilitation. Furthermore, that concentrated hour's related to specific goals in therapy are preferable to optimize functional recovery.
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| 14. |
- Langhammer, Birgitta, et al.
(author)
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Return to work after specialized rehabilitation-An explorative longitudinal study in a cohort of severely disabled persons with stroke in seven countries: The Sunnaas International Network stroke study.
- 2018
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In: Brain and behavior. - : Wiley. - 2162-3279. ; 8:8
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Journal article (peer-reviewed)abstract
- Stroke may impose disabilities with severe consequences for the individual, with physical, psychological, social, and work-related consequences. The objective with the current study was to investigate to what extent persons with stroke were able to return to work, to maintain their financial situation, and to describe the follow-up services and participation in social networks and recreational activities.The design was a prospective, descriptive study of specialized stroke rehabilitation in nine rehabilitation centers in seven countries. Semistructured interviews, which focused on the return to work, the financial situation, follow-up services, the maintenance of recreational activities, and networks, were performed 6 and 12months post discharge from rehabilitation.The working rate before the onset of stroke ranged from 27% to 86%. At 12 months post stroke, the return to work varied from 11% to 43%. Consequently, many reported a reduced financial situation from 10% to 70% at 6months and from 10% to 80% at 12months. Access to postrehabilitation follow-up services varied in the different countries from 24% to 100% at 6months and from 21% to 100% at 12months. Physical therapy was the most common follow-up services reported. Persons with stroke were less active in recreational activities and experienced reduced social networks. Associations between results from the semistructured interviews and related themes in LiSat-11 were small to moderate. The study shows that education, age, and disability are predictors for return to work. Differences between countries were observed in the extent of unemployment.In this international multicentre study, return to work after severe stroke and specialized/comprehensive rehabilitation was possible, depending on the extent of the disability, age, and education. Altered financial situation, reduced social networks, and reduced satisfaction with life were common psychosocial situations for these patients.
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| 15. |
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| 16. |
- Langhammer, Birgitta, et al.
(author)
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Tilbake til arbeid etter hjerneslag – en studie fra sju land om personer med funksjonsnedsettelse etter hjerneslag SIN (Sunnaas International Network) Stroke Study
- 2018
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In: BestPractice: faglig dialog mellem laeger. - 1902-7583. ; 7:23
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Journal article (other academic/artistic)abstract
- tudien omfatter pasienter som har gjennomgått spesialisert rehabilitering etter et alvorlig hjerneslag, og problemstillingen er hvorvidt disse er kommet tilbake i arbeid med sin moderate funksjonsnedsettelse seks og 12 måneder etter gjennomgått rehabilitering. Studien er en internasjonal multisenterstudie med deltakere fra rehabiliteringsklinikker i sju land (Norge, Sverige, USA, Kina, Russland, Palestina og Israel).1 Hjerneslag medfører i noen tilfeller funksjonsnedsettelser som har alvorlige konsekvenser,2 ikke bare i fysisk og psykologisk forstand, men også i forhold til arbeid, sosial situasjon og familieforhold. Det synes å være et gjensidig forhold mellom det å ha et arbeid og livstilfredshet. Tilbakegang til arbeid er relatert til bedre fysisk og psykisk funksjon etter hjerneslag.3 Det å kunne gå tilbake til et arbeid etter gjennomgått hjerneslag har vist seg å forbedre generell trivsel og økonomi,2,4 mens det motsatte, ikke å ha et arbeid å gå tilbake til, kan ha en negativ innvirkning på familieforhold, seksualliv, økonomi og fritidsaktiviteter.5 Det er nærliggende å anta at bedre fysisk funksjon leder til høyere arbeidsdeltakelse, men noen studier har vist at 53 % av 161 personer med hjerneslag som var uavhengige i henhold til Barthel-indeksen (BI > 19), og 39 % av 96 personer med hjerneslag, som var svært aktive i henhold til Frenchay Activity Index (FAI > 30/45), ikke var i arbeid.6-8 Disse resultatene indikerer at arbeidsstatus er avhengig av andre faktorer enn fysisk funksjon og selvstendighet i dagliglivets aktiviteter, som ofte er de primære målene i rehabilitering.6-8 Arbeid innebærer tilgang til en sosial arena, som medfører økonomisk uavhengighet og sosialt nettverk.3 Det ikke å være i arbeid kan ha økonomiske konsekvenser for den enkelte, for familien og for samfunnet. I tillegg kan man spekulere på om tilbakegang til arbeidet også har konsekvenser for opprettholdelse av et sosialt nettverk og for selvtilliten; tillit til egenmestring, verdighet og evner. Dette kan også relateres til kultur i den forstand at i en kontekst der individuell uavhengighet dyrkes som en vital dyd, blir det også grunnleggende for sosial rolle og posisjon.9 Det er få studier, som har fokus på hvordan den sosiale situasjonen utvikles for personer med moderat til alvorlig slag etter endt rehabilitering, og enda mindre med et multinasjonalt perspektiv. Sunnaas International Network har gjennomført et internasjonalt, multisenter forskningsprosjekt der målet var å kartlegge innholdet av spesialisert rehabilitering, utfall og sosiale konsekvenser under og etter spesialisert rehabilitering av hjerneslag i syv land.10-14 Her rapporteres de sosiale konsekvenser, målet var å undersøke i hvilken grad personer med hjerneslag gikk tilbake til arbeid, om det var viktig for å opprettholde sin økonomiske situasjon, deltakelse i sosialt nettverk og opprettholdelse av fritidsaktiviteter. I tillegg ble oppfølgning fra helsevesenet i de forskjellige land registrert for å få en oversikt over i hvilken monn trening og behov for hjelp ble fulgt opp i tiden etter rehabilitering i de forskjellige land. Metode Designet var en prospektiv, deskriptiv og hypotesegenererende studie, og det ble brukt semi-strukturerte intervjuer med fokus på retur til arbeid, finansiell situasjon, vedlikehold av fritidsaktiviteter, nettverk og registrering av oppfølgingstjenester. Dette ble gjennomført seks og 12 måneder etter utskrivelse fra en klinikk hvor man hadde fått spesialisert rehabilitering etter hjerneslag. De halvstrukturerte spørreskjemaene ble kvalitativt analysert med en induktiv tilnærming ved hjelp av komparativ tekstanalyse.15 To av medforfattere (BL, SS) utførte analysene i fire faser: lesing, tolking, syntetisering i kategorier og konsensus.15 Resultater I ni klinikker fra sju ulike land ble totalt 230 personer med alvorlig hjerneslag involvert i studien. Deltakerne var forholdsvis unge med alder 49-64 år (tabell 1) og med moderate funksjonsnedsettelser, Modified Rankin Scale (mRS), gjennomsnittlig 3,7 (SD 0,8)/median 4 (IQR 1,0), og grad av alvorlighet ved innleggelse etter National Institute of Health Stroke Scale (NIHSS) var gjennomsnittlig 7,8 (SD 4,4)/median 7 (IQR 6,6). Ved innleggelse var 53,4 % yrkesaktive, 29,1 % var pensjonerte og 17,4 % var arbeidsledige. Sysselsettingsstatus varierte mellom de involverte klinikkene, fra 27 % til 86 %. Seks og 12 måneder etter utskrivning fra rehabilitering kunne 200 respektive 182 pasienter følges opp. Av disse hadde henholdsvis 18 % og 20 % gjenopptatt arbeid seks og 12 måneder etter avsluttet rehabilitering. Det var således et flertall som ikke kom tilbake i arbeid. Årsakene til dette ble angitt til å være redusert funksjon (42 % og 33 % ved seks og 12 måneder) og førtidspensjonering (28 % og 45 % ved seks og 12 måneder). Personer yngre enn 60 år gikk tilbake til arbeid i høyere grad etter endt rehabilitering enn personer over 60 år både ved seks og 12 måneder (26,7 %/29,8 % versus 6,1 %/8,2 %). Hjerneslaget medførte, i tillegg til redusert funksjon og tap av arbeid, også redusert livskvalitet med alvorlige konsekvenser for noen med skilsmisse, stridigheter i familien, endring av rolle, tap av sosial posisjon og ”respekt”. Type funksjonsnedsettelser, som gjorde tilbakegang til arbeid vanskelig eller umulig, ble rapportert noe ulik. De ”vestlige” landene rapporterte mer psykologiske og kognitive vanskeligheter etter slag, som fatigue, ensomhet, lav selvtillit, angst, bekymringer, usikkerhet, økt følsomhet for lyd, redusert hukommelse og problemer med konsentrasjon. Det påvirket også sosial deltagelse og nettverk. Flere nevnte at spontanitet ble redusert da alt måtte planlegges, og dette i sin tur førte til lav fysisk og sosial aktivitet. Klinikkene i Midtøsten og Asia fokuserte mer på fysiske funksjonsnedsettelser og sekundære komplikasjoner, som hjerteproblemer, fall og vanskeligheter med mobilitet/gangfunksjon, som reduserte eller hindret tilbakegang til arbeid. Generelt sett var det liten eller ingen forskjell mellom kjønn i forhold til tilbakegang til arbeid, 18,4 %/38,5 % av kvinnene og 17,5 %/39,8 % av mennene var i arbeid seks og 12 måneder etter avsluttet rehabilitering. Kjønnsforskjeller ble rapportert hovedsakelig i Palestina, hvor kvinner generelt var mer avhengige av sine familier når det gjaldt omsorg og økonomi. Menn, derimot, syntes å kunne gå tilbake til arbeid i de små familiebedriftene, men ikke i en ledende funksjon, hvilket for noen innebar tap av sosial posisjon. Den økonomiske situasjonen for de fleste involverte i studien, uavhengig av land, ble påvirket. Det var imidlertid forskjeller mellom land, med en variasjon mellom 29 % til 87 %, som rapporterte forverret finansiell situasjon etter hjerneslaget. I hvilken utstrekning det fantes sosiale sikringsnett i form av privat eller offentlig forsikring, og i hvilken grad disse dekket daglige utgifter, var styrende. For eksempel var det en forskjell mellom sentrene i urbane og landlige områder i Kina, som gjenspeilte ulike lokale sykeforsikringssystemer, og som hadde konsekvenser for enkeltpersoner. En annen forklarende variabel for redusert finansiell situasjon var skiftet fra arbeidsstatus til arbeidsledig eller pensjonert. Sivil status påvirket ikke den økonomiske situasjon, 51 %/54 % av de som var gifte, 51 %/59 % av ugifte og 44 %/67 % av enker/enkemenn opprettholdt sin økonomiske situasjon ved seks og 12 måneder. Tapet av en arbeidsrolle kan påvirke og eventuelt redusere sosiale nettverk, noe som også kan redusere livstilfredsheten3,4,16. I denne studien ble de sosiale nettverkene rapportert å bli redusert 20 %-70 % ved seks til 12 måneder etter avsluttet rehabilitering. Klinikkene i Kina, USA, Palestina og Sverige rapporterte en høyere negativ endring i sosiale nettverk enn klinikkene i Norge og Israel, noe som indikerte mulige kulturelle forskjeller. Faktorer som utdanning, alder og funksjonshemning predikerte for retur til arbeid, men dette var også relatert til faktorer som generell arbeidsledighet i de forskjellige land. Mange ulike barrierer kan hindre arbeidsdeltakelse av funksjonshemmede, pensjonister og andre med redusert arbeidsevne. En felles forklaring på de lave sysselsettingsratene i disse gruppene er holdninger og vilje hos arbeidsgivere til å ansette personer med redusert arbeidsevne.17 I tillegg kan insentiver for å gå tilbake til arbeid være små. Mange personer med redusert funksjon arbeider deltid, noe som innebærer lav lønn. Dette kan også føre til at de kan miste finansiell støtte fra sykeforsikringen, samt at de kan miste pensjonsrettigheter. Andre hindringer som fremholdes er at reiseutgifter overstiger inntjeningen i deltidsarbeid.3,4
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| 17. |
- Luft, Friedrich C., et al.
(author)
-
Amiloride and calciuria
- 2022
-
In: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 37:2, s. 205-207
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Journal article (other academic/artistic)
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| 18. |
- Mozelius, Peter, 1959-, et al.
(author)
-
Teacher Attitudes Toward Game-based Learning in History Education
- 2017
-
In: International Journal of Information and Communication Technologies in Education. - : Walter de Gruyter GmbH. - 1805-3726. ; 5:2, s. 29-50
-
Journal article (peer-reviewed)abstract
- Game-based learning (GBL) is an emerging field reaching new contexts. Research has reported about students’ rich use of digital games and the learning potential of GBL in traditional school subjects. Digital games have been tested as educational tools in various subjects in Swedish schools during the last decade, in areas such as teaching and learning of history and foreign languages. However, there is a lack of detailed research on attitudes toward the use of GBL in history education.Main aim of the study was to examine and discuss attitudes toward an increased use of digital games in formal history education. Earlier studies have analysed students’ opinions and preferences, but this study has a focus on the teacher perspective and on which design factors are important if digital games should be an alternative for self-learning in history education. The research approach has been qualitative cross-sectional study where secondary school teachers have answered questionnaires with open-ended questions on their view of didactics and the use of GBL in formal education. All selected respondents are registered as professional secondary school history teachers. Furthermore, teachers have described their own gaming habits and their game design preferences. Findings show that a majority of the informants have good knowledge about digital games with historical setting and also a positive attitude toward an increased use of GBL. Secondary school teachers also have a tradition of using various media in their teaching and learning activities and there are neither any regulations against an increased use of digital games. An important aspect of history education, where digital games might not the first choice, is in the description of the main changes and influence of a historical époque. Authors’ recommendation is to use games that can enable tangential learning where the gaming sessions could be seen as appetisers for further and deeper learning.
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| 19. |
- Mozelius, Peter, et al.
(author)
-
Teacher Attitudes Toward Game-based Learning in History Education
- 2017
-
In: International Journal of Information and Communication Technologies in Education. - : Walter de Gruyter GmbH. - 1805-3726. ; 6:4, s. 27-35
-
Journal article (peer-reviewed)abstract
- Game-based learning (GBL) is an emerging field reaching new contexts. Research has reported about students’ rich use of digital games and the learning potential of GBL in traditional school subjects. Digital games have been tested as educational tools in various subjects in Swedish schools during the last decade, in areas such as teaching and learning of history and foreign languages. However, there is a lack of detailed research on attitudes toward the use of GBL in history education.Main aim of the study was to examine and discuss attitudes toward an increased use of digital games in formal history education. Earlier studies have analysed students’ opinions and preferences, but this study has a focus on the teacher perspective and on which design factors are important if digital games should be an alternative for self-learning in history education. The research approach has been qualitative cross-sectional study where secondary school teachers have answered questionnaires with open-ended questions on their view of didactics and the use of GBL in formal education. All selected respondents are registered as professional secondary school history teachers. Furthermore, teachers have described their own gaming habits and their game design preferences.Findings show that a majority of the informants have good knowledge about digital games with historical setting and also a positive attitude toward an increased use of GBL. Secondary school teachers also have a tradition of using various media in their teaching and learning activities and there are neither any regulations against an increased use of digital games. An important aspect of history education, where digital games might not the first choice, is in the description of the main changes and influence of a historical époque. Authors’ recommendation is to use games that can enable tangential learning where the gaming sessions could be seen as appetisers for further and deeper learning.
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| 20. |
- Roaldsen, Kirsti Skavberg, et al.
(author)
-
Pediatric spinal cord injury rehabilitation : A protocol for an international multicenter project (SINpedSCI)
- 2022
-
In: Journal of Pediatric Rehabilitation Medicine. - : IOS Press. - 1874-5393 .- 1875-8894. ; 15:2, s. 395-403
-
Journal article (peer-reviewed)abstract
- PURPOSE: Children and adolescents (<18 years old) who sustain a spinal cord injury (SCI) should ideally be managed in specialized rehabilitation services. This project aims to describe the organization of pediatric SCI in ten rehabilitation units in seven countries and to qualitatively explore psychosocial aspects of adolescents living with SCI. METHODS: A multicenter cross-sectional project is planned, using quantitative (web survey) and qualitative (interview) methods in ten rehabilitation units from Norway, Sweden, United States, Israel, PR China, Russia and Palestine. Individual interviews will be conducted with >= 20 adolescents aged 13-17 years at least 6 months post rehabilitation. RESULTS: Units involved will be described and compared, according to funding, attachment to an acute SCI unit, catchment area, number of beds, admittance and discharge procedures, availability of services, staff/patient ratio, content and intensity of rehabilitation programs, length of stay, measurement methods, follow-up services, health promotion services, and pediatric SCI prevention acts. The semi-structured interview guide will include experiences from acute care and primary rehabilitation, daily life, school, contact with friends, leisure time activities, peers, physical and psychological health, and the adolescents plans for the future. CONCLUSION: Based on the present protocol, this project is likely to provide new insight and knowledge on pediatric SCI rehabilitation and increase the understanding of pediatric SCI in adolescents and their families internationally.
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| 21. |
- Schnermann, Jurgen, et al.
(author)
-
Erik Persson (1941-2020) : a Remembrance
- 2020
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In: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 230:4
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Journal article (pop. science, debate, etc.)
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| 22. |
- Stridh, Sara, et al.
(author)
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C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats
- 2009
-
In: Oxygen transport to tissue xxx. - New York : Springer. - 9780387859972 - 0387859977 - 9780387859989 ; , s. 219-225
-
Book chapter (peer-reviewed)abstract
- Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.
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| 23. |
- Sällström, Björn, et al.
(author)
-
A Pharmacodynamic Turnover Model Capturing Asymmetric Circadian Baselines of Body Temperature, Heart Rate and Blood Pressure in Rats : Challenges in Terms of Tolerance and Animal-handling Effects
- 2005
-
In: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 32:5-6, s. 835-859
-
Journal article (peer-reviewed)abstract
- This study presents development and behaviour of a feedback turnover model that mimics asymmetric circadian oscillations of body temperature, blood pressure and heart rate in rats.The study also includes an application to drug-induced hypothermia, tolerance and handling effects. Data were collected inn normotensive Sprague-Dawley rats, housed at 25 degrees C with a 12:12 hr light dark cycle (light on at 06:00 am) and with free access of food and water. The model consisted of two intertwined parallel compartments which captured a free-running rhythm with a period close to but not exactly 24 hrs. The free-running rhythm was synchronised to exactly 24 hrs by the environmental timekeeper (12:12 hr light on/off cycle) in experimental settings. The baseline model was fitted to a standardised 24-hr period derived from mean data of six animals over a period of nine consecutive days. The first-order rate constants related to the turnover of the baseline temperature, alpha and beta, were 0.026 min(-1) (+/-5%) and 0.0037 min(-1) (+/-3%). The alpha and beta parameters are approximately 2/transition time between day and night and 2/night time, respectively. The day:night timekeeper g(t), reference point T(ref) and amplitude were 0.053(+/-2%),37.3(+/-0.02%) and 3.3% (+/-2%), respectively. Simulations with the baseline model revealed stable oscillations (free-running rhythm) in the absence of the timekeeper. This temperature-time profile was then symmetric and had a smaller amplitude, with a slightly shorter period and less pronounced temperature shift as compared to the profile in the presence of an external Timekeeper. Fitting the model to 96 hr mean profiles of blood pressure and heart rate from 10 control animals demonstrated the usefulness of the model.Simulations of the integrated temperature model succeeded in mimicking other modes of administration such as oral dosing.
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| 24. |
- Sällström, Johan, et al.
(author)
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Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism
- 2007
-
In: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 190:3, s. 253-259
-
Journal article (peer-reviewed)abstract
- Aims: Glomerular hyperfiltration is commonly found in diabetic patients early after the onset of disease. This is one of the first indications of the development of progressive diabetic nephropathy. It has been proposed that glomerular hyperfiltration is caused by decreased delivery of electrolytes to the macula densa due to the increased sodium and glucose reabsorption in the proximal tubule, which would increase the glomerular filtration rate (GFR) via the tubuloglomerular feedback (TGF) mechanism. In this study, we investigated the role of TGF in diabetes-induced glomerular hyperfiltration by inducing diabetes in adenosine A1-receptor knockout (A1AR−/−) mice known to lack a functional TGF mechanism. Methods: Diabetes was induced by alloxan (75 mg kg−1 bw) injected into the tail vein. The 24-hour urinary electrolyte excretion was measured in metabolic cages, the GFR determined by inulin clearance under isoflurane-anaesthesia, and histological changes evaluated. Results: All alloxan-treated animals developed hyperglycaemia (≥20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR+/+ 9.3 ± 0.5 vs. A1AR−/− 10.1 ± 0.8 μL min−1g−1 bw) and diabetes resulted in similar glomerular hyperfiltration in both groups (A1AR+/+ 14.0 ± 1.7, n = 9 vs. A1AR−/− 15.3 ± 1.9 μL min−1g−1 bw). Diabetic animals had a similar tendency to develop interstitial fibrosis, whereas the glomerular volume was similar in both genotypes, and unaltered by diabetes. Conclusions: This study shows that the A1AR−/− mice develop diabetes-induced glomerular hyperfiltration, demonstrating that the TGF mechanism is not the major cause of the development of hyperfiltration. Furthermore, the hyperfiltration in the present study was not related to alterations in the glomerular filtration area.
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| 25. |
- Sällström, Johan
(author)
-
Functional Aspects of the Juxtaglomerular Apparatus : Control of Glomerular Filtration and Renin Release
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- The juxtaglomerular apparatus (JGA) is a control unit of the kidney, that regulates glomerular filtration rate (GFR) and renin release, and hence extracellular volume and blood pressure. The tubuloglomerular feedback (TGF) mechanism is a negative feedback loop that regulates GFR. Neuronal nitric oxide synthase (nNOS) is highly expressed in the macula densa cells of the JGA, and regulates the sensitivity of the TGF mechanism. Hypertension has been proposed to be caused by an increased sensitivity of the TGF due to nNOS deficiency. In diabetes, reduced TGF activity due to increased sodium-glucose reabsorption is suggested to cause hyperfiltration. Glomerular hyperfiltration has clinical significance, since it correlates with the risk of developing nephropathy. In this thesis, the role of nNOS in the control of blood pressure and renin release was investigated in nNOS knockout mice (nNOS-/-) treated with low- and high sodium diets. The nNOS-/- were normotensive, but displayed an impaired renin regulation, and failed to increase renin in response to a low sodium diet. A significantly larger renin increase during phosphodiesterase 3 (PDE3) inhibition was found in nNOS-/- compared to the wild types, resulting in similar renin levels. Furthermore, the role of TGF and proximal glucose reabsorption in diabetes-induced hyperfiltration was investigated in adenosine A1-receptor knockout mice (A1AR-/-) that are known to lack a functional TGF mechanism. Diabetes was induced in A1AR-/- and wild types by injection of alloxan. The diabetic A1AR-/- displayed a similar degree of hyperfiltration as their wild-type controls. Inhibition of renal sodium-glucose transporters reduced GFR in both genotypes, but the reduction was even more pronounced in the A1AR-/-. In conclusion, the results indicate that renin secretion during low sodium conditions is mediated by nNOS-derived nitric oxide via cGMP-mediated inhibition of PDE3, whereas deletion of the nNOS gene does not cause hypertension. Diabetes-induced hyperfiltration is not mediated by TGF, but appears to be dependent on increased renal glucose reabsorption.
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| 26. |
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| 27. |
- Sällström, Johan, et al.
(author)
-
Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension
- 2013
-
In: AM J PHYSIOL-RENAL. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 305:1, s. F71-F79
-
Journal article (peer-reviewed)abstract
- Experimental hydronephrosis induced by partial ureteral obstruction at 3 wk of age causes hypertension and renal impairment in adult rats and mice. Signaling by Ephrin receptors (Eph) and their ligands (ephrins) importantly regulates embryonic development. Genetically modified mice, where the cytoplasmic domain of the EphA4 receptor has been substituted by enhanced green fluorescent protein (EphA4(gf/gf)), develop spontaneous hydronephrosis and provide a model for further studies of the disorder. The present study aimed to determine if animals with congenital hydronephrosis develop hypertension and renal injuries, similar to that of experimental hydronephrosis. Ultrasound and Doppler techniques were used to visualize renal impairment in the adult mice. Telemetric blood pressure measurements were performed in EphA4(gf/gf) mice and littermate controls (EphA4(+/+)) during normal (0.7% NaCl)- and high (4% NaCl)-sodium conditions. Renal excretion, renal plasma flow, and glomerular filtration were studied, and histology and morphology of the kidneys and ureters were performed. EphA4(gf/gf) mice developed variable degrees of hydronephrosis that correlated with their blood pressure level. In contrast to EphA4(+/+), the EphA4(gf/gf) mice displayed salt-sensitive hypertension, reduced urine concentrating ability, reduced renal plasma flow, and lower glomerular filtration rate. Kidneys from EphA4(gf/gf) mice showed increased renal injuries, as evidenced by fibrosis, inflammation, and glomerular and tubular changes. In conclusion, congenital hydronephrosis causes hypertension and renal damage, similar to that observed in experimentally induced hydronephrosis. This study further reinforces the supposed causal link between hydronephrosis and later development of hypertension in humans.
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| 28. |
- Sällström, Johan, et al.
(author)
-
Inhibition of sodium-linked glucose reabsorption in the kidney normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A1-receptor-deficient mice
- 2014
-
In: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 210:2, s. 440-445
-
Journal article (peer-reviewed)abstract
- Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. In this study, we investigated the role of the increased tubular sodium/glucose co-transport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback mechanism (TGF), we used adenosine A1-receptor deficient (A1AR-/-) mice known to lack a functional TGF mechanism, and compared the results to corresponding wild-type animals (A1AR+/+). Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose co-transporters were inhibited by phlorizin 30 minutes prior to GFR measurements. Normoglycemic animals had a similar GFR independent of genotype, and induction of diabetes resulted in similar glomerular hyperfiltration in both groups. Phlorizin had no effect on GFR in normoglycemic mice, whereas it reduced GFR in both genotypes during diabetes. Notably, the reduction was more pronounced in the A1AR-/-. This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.
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| 29. |
- Sällström, Johan, et al.
(author)
-
Neuronal nitric oxide synthase-deficient mice have impaired renin release but normal blood pressure
- 2008
-
In: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225. ; 21:1, s. 111-116
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Nitric oxide deficiency is involved in the development of hypertension, but the mechanisms are currently unclear. This study was conducted to further elucidate the role of neuronal nitric oxide synthase (nNOS) in blood pressure regulation and renin release in relation to different sodium loads. METHODS: Blood pressure and heart rate were measured telemetrically and assessed during periods of physical activity and inactivity. Urinary solute excretion was measured by metabolism cages and plasma renin concentration (PRC) was determined by radioimmunoassay; all in nNOS knockout (nNOS(-/-)) and wild-type (nNOS(+/+)) mice after 10 days of low (0.01% NaCl) and high (4% NaCl) sodium diets. RESULTS: The resting heart rate was reduced in nNOS(-/-) mice, but the two genotypes had similar blood pressure during the low (nNOS(+/+) 104 +/- 2 mm Hg; nNOS(-/-) 103 +/- 2 mm Hg) and high (nNOS(+/+) 107 +/- 3 mm Hg; nNOS(-/-) 108 +/- 2 mm Hg) sodium diets. During the high sodium diet, PRC did not differ between the genotypes (nNOS(+/+) 743 +/- 115 10(-5) Goldblatt units; nNOS(-/-) 822 +/- 63 10(-5) Goldblatt units), but during the low sodium diet, nNOS(-/-) mice failed to increase PRC (nNOS(+/+) 2164 +/- 220 10(-5) Goldblatt units; nNOS(-/-) 907 +/- 101 10(-5) Goldblatt units) and renal renin mRNA. On the low sodium diet, nNOS(-/-) mice also showed increased urine flow rate and osmolar excretion, observations not made during a high sodium diet. CONCLUSIONS: Our results show that nNOS is necessary for stimulation of renin in response to sodium restriction. Furthermore, nNOS(-/-) mice are normotensive, and their blood pressure responds normally to an increased dietary sodium intake, indicating that nNOS deficiency does not cause salt-sensitive hypertension.
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| 30. |
- Sällström, Johan, et al.
(author)
-
Neuronal nitric oxide synthase supports renin release during sodium restriction through inhibition of phosphodiesterase 3
- 2010
-
In: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225. ; 23:11, s. 1241-1246
-
Journal article (peer-reviewed)abstract
- Background: Mice with targeted deletion of neuronal nitric oxide synthase (nNOS‑/‑) display inability to increase plasma renin concentration (PRC) in response to sodium restriction. nNOS has a distinct expression at the macula densa, and it has been hypothesized that nNOS supports renin release by cGMP-mediated inhibition of cAMP-specific phosphodiesterase 3 (PDE3) in juxtaglomerular cells. Objective: To test the hypothesis that nNOS-derived NO supports renin release by inhibition of PDE3. Methods: The experiments were performed in conscious nNOS-/- and wild types after ten days on a low sodium diet by acute treatment with the PDE3 inhibitor milrinone, the PDE5 inhibitor zaprinast, or vehicle, using a crossover study protocol. PRC was measured with the antibody-trapping technique and blood pressure with telemetry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were estimated by measurements of inulin- and Para-Amino Hippuric acid clearances, respectively. Results: The basal PRC was reduced in nNOS-/- compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS-/-, resulting in normalized renin levels, while PDE5 inhibition did not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone. Conclusions: The present study provides in vivo evidence supporting the view that NO, selectively derived from nNOS, mediates renin release during sodium restriction by inhibiting PDE3, which would increase renin release by elevating cAMP levels in the juxtaglomerular cells.
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| 31. |
- Sällström, Johan, et al.
(author)
-
Pharmacokinetic-pharmacodynamic modeling of QRS-prolongation by flecainide : Heart rate-dependent effects during sinus rhythm in conscious telemetered dogs
- 2014
-
In: Journal of pharmacological and toxicological methods. - : Elsevier BV. - 1056-8719 .- 1873-488X. ; 69:1, s. 24-29
-
Journal article (peer-reviewed)abstract
- Introduction:The duration of the QRS interval is determined by the ion currents involved in cardiac depolarization. Class I antiarrhythmic drugs reduce cardiac excitability and conduction by inhibiting Nav1.5 channels responsible for I-Na, thus increasing the QRS interval. Previous studies in humans as well as in animal models have demonstrated a more pronounced effect on QRS-prolongation during higher heart rates. In the present study, the effects of the Nav1.5 inhibitor flecainide on cardiovascular parameters, were studied in the telemetered beagle dog under normal autonomic control. The heart rate dependency of QRS prolongation was characterized using pharmacokinetic-pharmacodynamic (PKPD) modeling.Methods:Four male telemetered beagle dogs were administered placebo or flecainide (100, 150 and 200 mg) in a Latin square design. The QRS interval and heart rate were recorded, and blood samples were taken. Plasma concentrations of flecainide were fitted to a one compartment oral model and the intrapolated plasma concentrations were fitted to QRS and heart rate data sampled during 5 h after dosing.Results:Flecainide increased the QRS interval in all dogs, whereas there were no effects on heart rate. Using the PKPD model, a statistically significant heart rate-dependent QRS prolongation was linked to individual concentration-time profiles of flecainide.Discussion:PKPD analysis of QRS interval data from unrestrained dogs with sinus rhythm can elucidate mechanisms previously only described during controlled heart rhythm. Specific questions can therefore be addressed in generically designed cardiovascular telemetry safety studies and different types of relationships between parameters can be uncovered. In addition, the present approach can be used to better characterize drug-induced QRS effects in cardiovascular dog models.
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| 32. |
- Sällström, Johan, et al.
(author)
-
Simultaneous determination of renal plasma flow and glomerular filtration rate in conscious mice using dual bolus injection
- 2013
-
In: Journal of pharmacological and toxicological methods. - : Elsevier BV. - 1056-8719 .- 1873-488X. ; 67:3, s. 187-193
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Journal article (peer-reviewed)abstract
- Introduction: The present report describes and evaluates a simple protocol for serial measurements of glomerular filtration rate (GFR) and renal plasma flow (RPF) in conscious mice. Methods: In conscious mice, a bolus of [H-3] methoxy-inulin and [C-14] para-amino-hippuric (PAH) was injected in the tail vein whereupon eight blood samples were taken during the following 75 min. Plasma concentrations were determined by liquid scintillation and clearances of the injected markers were calculated by non-compartmental pharmacokinetic data analysis of the plasma disappearance curves. In anaesthetized mice, the renal extraction ratio of PAH was determined by infusion of PAH and subsequent analysis of blood taken from the carotid artery and the renal vein. The acquired value (0.70 +/- 0.02) was used for all subsequent calculations of RPF. To evaluate the protocol, a crossover study was performed where either the vehicle or the angiotensin II AT1 receptor antagonist candesartan was given prior to the clearance measurements. Results: Baseline values of GFR and RPF were in line with those earlier reported in mice. Administration of candesartan increased RPF and reduced the filtration fraction, whereas GFR was unaltered. These changes are supported by earlier findings and demonstrate that GFR and RPF can be determined independently. Furthermore, modelling experiments demonstrated that acceptable results are obtained even if the number of blood samples is reduced to four which is a way to further simplify the procedure. Discussion: The method provides an effective way for repeated measurements of GFR and RPF in mice without potentially confounding effects of anaesthesia.
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| 35. |
- Tobin, Gerard, et al.
(author)
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Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia
- 2002
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In: Blood. - 0006-4971 .- 1528-0020. ; 99:6, s. 2262-2264
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Journal article (peer-reviewed)abstract
- Recent studies on the immunoglobulin variable heavy chain (IgV(H)) genes have revealed that B-cell chronic lymphocytic leukemia (B-CLL) consists of at least 2 clinical entities with either somatically mutated or unmutated V(H) genes. We have analyzed the V(H) gene mutation status and V(H) gene usage in 119 B-CLL cases and correlated them to overall survival. A novel finding was the preferential use of the V(H)3-21 gene in mutated cases, whereas biased V(H)1-69 gene usage was found in unmutated cases as previously reported. Interestingly, the subset of mutated cases using the V(H)3-21 gene displayed distinctive genotypic/phenotypic characteristics with shorter average length of the complementarity determining region 3 and clonal expression of lambda light chains. In addition, this mutated subset showed significantly shorter survival than other mutated cases and a similar clinical course to unmutated cases. We therefore suggest that B-CLL cases with mutated V(H)3-21 genes may constitute an additional entity of B-CLL.
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| 36. |
- Visser, Sandra A. G., et al.
(author)
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Modeling drug- and system-related changes in body temperature : application to clomethiazole-induced hypothermia, long-lasting tolerance development, and circadian rhythm in rats
- 2006
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 317:1, s. 209-219
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Journal article (peer-reviewed)abstract
- The aim of the present investigation was to develop a pharmacokinetic-pharmacodynamic model for the characterization of clomethiazole (CMZ)-induced hypothermia and the rapid development of long-lasting tolerance in rats while taking into account circadian rhythm in baseline and the influence of handling. CMZ-induced hypothermia and tolerance was measured using body temperature telemetry in male Sprague-Dawley rats, which were given s.c. bolus injections of 0, 15, 150, 300, and 600 micromol kg(-1) and 24-h s.c. continuous infusions of 0, 20, and 40 micromol kg(-1) h(-1) using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 micromol kg(-1) at 3- to 32-day intervals. Plasma exposure to CMZ was obtained in satellite groups of catheterized rats. Fitted population concentration-time profiles served as input for the pharmacodynamic analysis. The asymmetric circadian rhythm in baseline body temperature was successfully described by a novel negative feedback model incorporating external light-dark conditions. An empirical function characterized the transient increase in temperature upon handling of the animal. A feedback model for temperature regulation and tolerance development allowed estimation of CMZ potency at 30 +/- 1 microM. The delay in onset of tolerance was estimated via a series of four transit compartments at 7.6 +/- 2 h. The long-lasting tolerance was assumed to be caused by inactivation of a mediator with an estimated turnover time of 46 +/- 3 days. This multicomponent turnover model was able to quantify the CMZ-induced hypothermia, circadian rhythm in baseline, and rapid onset of a long-lasting tolerance to CMZ in rats.
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| 37. |
- Yang, Ting, et al.
(author)
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Genetic Abrogation of Adenosine A(3) Receptor Prevents Uninephrectomy and High Salt-Induced Hypertension
- 2016
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In: Journal of the American Heart Association. - 2047-9980. ; 5:7
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Journal article (peer-reviewed)abstract
- Background - Early-life reduction in nephron number (uninephrectomy [UNX]) and chronic high salt (HS) intake increase the risk of hypertension and chronic kidney disease. Adenosine signaling via its different receptors has been implicated in modulating renal, cardiovascular, and metabolic functions as well as inflammatory processes; however, the specific role of the A(3) receptor in cardiovascular diseases is not clear. In this study, gene-modified mice were used to investigate the hypothesis that lack of A(3) signaling prevents the development of hypertension and attenuates renal and cardiovascular injuries following UNX in combination with HS (UNX-HS) in mice.Methods and Results - Wild-type (A(3)(+/+)) mice subjected to UNX-HS developed hypertension compared with controls (mean arterial pressure 106 +/- 3 versus 82 +/- 3 mm Hg; P<0.05) and displayed an impaired metabolic phenotype (eg, increased adiposity, reduced glucose tolerance, hyperinsulinemia). These changes were associated with both cardiac hypertrophy and fibrosis together with renal injuries and proteinuria. All of these pathological hallmarks were significantly attenuated in the A(3)(-/-) mice. Mechanistically, absence of A(3) receptors protected from UNX-HS-associated increase in renal NADPH oxidase activity and Nox2 expression. In addition, circulating cytokines including interleukins 1 beta, 6, 12, and 10 were increased in A(3)(+/+) following UNX-HS, but these cytokines were already elevated in naive A(3)(-/-) mice and did not change following UNX-HS.Conclusions - Reduction in nephron number combined with chronic HS intake is associated with oxidative stress, chronic inflammation, and development of hypertension in mice. Absence of adenosine A(3) receptor signaling was strongly protective in this novel mouse model of renal and cardiovascular disease.
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