| 1. |
- Fälker, Knut, 1971-, et al.
(author)
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ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin-induced ERK2 activation in human platelets
- 2004
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In: Thrombosis and Haemostasis. - Stuttgart, Germany : Schattauer Gmbh. - 0340-6245 .- 2567-689X. ; 92:1, s. 114-23
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Journal article (peer-reviewed)abstract
- Stimulating human platelets with thrombin induces the activation of the extracellular signal-regulated kinase 2 (ERK2). We demonstrate that this effect is highly dependent on ADP secretion and P2Y12 receptor signalling. AR-C69931MX (10 microM), a specific antagonist of the Gi-coupled P2Y12 ADP receptor, inhibits ERK2 activation induced by thrombin. Antagonists of the Gq-coupled P2Y1 ADP receptor, A3P5P (500 microM) and MRS2179 (100 microM), have no effect. ADP and its more potent analogue 2-methylthio-ADP alone (both up to 100 microM) do not induce ERK2 activation. Furthermore, we show that the inhibitory effect of AR-C69931MX on ERK2 activation induced by 0.1 U/ml thrombin as well as on platelet aggregation can be bypassed by epinephrine (1 and 10 microM), whereas epinephrine alone has no effect. Epinephrine acts on platelets mainly via alpha(2A)-adrenergic receptors, which, like P2Y12 receptors, couple to inhibitory G proteins. In addition, 2-methylthio-ADP as well as epinephrine provoke ERK2 activation at a thrombin concentration that alone has no detectable effect (0.05 U/ml). Thromboxane A2 (TXA2), which, like ADP, is released by activated platelets, acts as a positive feedback mediator. Stimulating the Gq-coupled TXA2 -receptor with U46619 (10 microM), which leads to ADP secretion and P2Y12 receptor-dependent platelet aggregation, also induces P2Y12-related ERK2 activation. The inhibition of U46619-induced ERK2 activation and platelet aggregation by AR-C69931MX are also rescued by epinephrine. Pretreatment with aspirin inhibits ERK2 activation induced by 0.1 U/ml thrombin, but has no effect at high concentrations of thrombin. The combination of U46619 and thrombin, at concentrations which alone have no effect, provokes ERK2 activation, suggesting that thrombin and released TXA2 act synergistically. Our data indicate that both primary signalling through Gq, which evokes ADP secretion, as well as subsequent coupling via Gi by the P2Y12 receptor are required for ERK2 activation.
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| 2. |
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| 3. |
- Jahnson, Staffan, et al.
(author)
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Tumor mapping of regional immunostaining for p21, p53, and mdm2 in locally advanced bladder carcinoma
- 2000
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In: Cancer. - New York, USA : John Wiley & Sons. - 0008-543X .- 1097-0142. ; 89:3, s. 619-629
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Journal article (peer-reviewed)abstract
- Background: The aim of this study was to elucidate the associations among immunostaining for p53, p21, and mdm2; their respective expression within each tumor; and the value of these variables for predicting treatment outcome after cystectomy for patients with locally advanced bladder carcinoma.Methods: The hospital records from all 173 patients treated with cystectomy for locally advanced urothelial bladder carcinoma between 1967 and 1992 were retrospectively reviewed. Three consecutive sections from biopsies taken before any treatment were stained using the standard immunohistochemical technique for p53, p21, and mdm2, respectively. The cutoff limit was 20% or more for positive p53 expression and 10% or more for positive p21 and mdm2 expression.Results: Positive immunostaining was observed for p53 in 98 tumors (57%), for p21 in 89 tumors (51%), and for mdm2 in only 16 tumors (9%). The only association found between immunostaining for the three antibodies was that most mdm2-positive tumors had positive p21 expression. Tumor mapping of regional immunostaining showed no association between immunostaining for p53 and p21. In a proportional hazards analysis, no association was found between the results of immunostaining for the three antibodies and treatment outcome.Conclusions: Positive or negative expression of p53, p21, or mdm2, or combinations of these, was not associated with cancer specific mortality after cystectomy for bladder carcinoma. There was no association between immunostaining for p21 and p53, whereas positive immunostaining for mdm2 was observed in a minority of the tumors. These results indicate that, in addition to p21, p53, and mdm2, there are other oncoproteins and tumor suppressor proteins along the p53 pathway that are involved in tumor development and progression.
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| 4. |
- Kadi, Fawzi, et al.
(author)
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Satellite cells and myonuclei in young and elderly women and men
- 2004
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In: Muscle and Nerve. - : Wiley. - 0148-639X .- 1097-4598. ; 29:1, s. 120-127
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Journal article (peer-reviewed)abstract
- The overall aim of this study was to assess the effects of aging on the satellite cell population. Muscle biopsies were taken from the tibialis anterior muscle of healthy, moderately active young (age range, 20-32 years; n = 31) and elderly (age range, 70-83 years; n = 27) women and men with comparable physical activity pattern. Satellite cells and myonuclei were visualized using a monoclonal antibody against neural cell adhesion molecule and counterstained with Mayer's hematoxylin. An average of 211 (range, 192-241) muscle fibers were examined for each individual. Compared with the young women and men, the elderly subjects had a significantly lower (P < 0.011) number of satellite cells per muscle fiber but a significantly higher (P < 0.004) number of myonuclei per muscle fiber. The number of satellite cells relative to the total number of nuclei [satellite cells/(myonuclei + satellite cells)] was significantly lower in the elderly than in the young women and men. These results imply that a reduction in the satellite cell population occurs as a result of increasing age in healthy men and women.
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| 5. |
- Kurland, Lisa, 1960-, et al.
(author)
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Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial
- 2002
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In: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 20:4, s. 657-663
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Journal article (peer-reviewed)abstract
- BACKGROUND: Our aim was to determine if gene polymorphisms in the renin-angiotensin-aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment. METHODS AND RESULTS: Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (-23 +/- 31SD g/m2 for TM and +0.5 +/- 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (-0.1 +/- 19 g/m2 for AA and -18 +/- 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol. DISCUSSION: The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.
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| 6. |
- Larsson, Britt, et al.
(author)
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Blood supply and oxidative metabolism in muscle biopsies of female cleaners with and without myalgia
- 2004
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In: The Clinical Journal of Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0749-8047 .- 1536-5409. ; 20:6, s. 440-446
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Pathomechanisms of work-related myalgia are poorly understood. Myalgia is thought to be caused by excitation of nociceptors present in the muscular tissue but not in the muscle fiber itself. Muscle contraction in combination with hypoxia is known to excite nociceptors. Morphologic analysis can contribute to the knowledge of the excitation of nociceptors. This study thoroughly examines the morphology of the trapezius muscle's capillary supply and signs of disturbed oxidative metabolism to understand their role in work-related myalgia. METHODS: Surgical trapezius muscle biopsies were obtained from 25 female cleaners with long-standing work-related myalgia, 25 female cleaners without trapezius myalgia, and 21 healthy teachers. Enzyme and immunohistochemical stainings were performed to highlight fibers with aberrant intermyofibrillar patterns, indicating a disturbed oxidative metabolism (also known as moth-eaten fibers) and a disturbed capillary supply of different fibers. RESULTS: A significantly lower number of capillaries per fiber area in cleaners suffering from myalgia compared with cleaners without trapezius myalgia was found. Moth-eaten fibers were found in the 3 groups, but these fibers were significantly more prevalent in the groups of cleaners than in the healthy teacher group. CONCLUSION: This work indicates that the capillary supply of trapezius is affected in work-related trapezius myalgia. More studies are needed to understand possible mechanisms that would explain the occurrence of moth-eaten fibers.
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| 7. |
- Liljedahl, Ulrika, et al.
(author)
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A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response
- 2003
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In: Pharmacogenetics. - : Ovid Technologies (Wolters Kluwer Health). - 0960-314X .- 1473-561X. ; 13:1, s. 7-17
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Journal article (peer-reviewed)abstract
- We aimed to develop a microarray genotyping system for multiplex analysis of a panel of single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in blood pressure regulation, and to apply this system in a pilot study demonstrating its feasibility in the pharmacogenetics of hypertension. A panel of 74 SNPs in 25 genes involved in blood pressure regulation was selected from the SNP databases, and genotyped in DNA samples of 97 hypertensive patients. The patients had been randomized to double-blind treatment with either the angiotensin II type 1 receptor blocker irbesartan or the beta 1-adrenergic receptor blocker atenolol. Genotyping was performed using a microarray based DNA polymerase assisted 'minisequencing' single nucleotide primer extension assay with fluorescence detection. The observed genotypes were related to the blood pressure reduction using stepwise multiple regression analysis. The allele frequencies of the selected SNPs were determined in the Swedish population. The established microarray-based genotyping system was validated and allowed unequivocal multiplex genotyping of the panel of 74 SNPs in every patient. Almost 7200 SNP genotypes were generated in the study. Profiles of four or five SNP-genotypes that may be useful as predictors of blood pressure reduction after antihypertensive treatment were identified. Our results highlight the potential of microarray-based technology for SNP genotyping in pharmacogenetics.
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| 8. |
- Ramsey, D. K., et al.
(author)
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Methodological concerns using intra-cortical pins to measure tibiofemoral kinematics
- 2003
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In: Knee Surgery, Sports Traumatology, Arthroscopy. - New York, USA : Springer-Verlag New York. - 0942-2056 .- 1433-7347. ; 11:5, s. 344-349
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Journal article (peer-reviewed)abstract
- The complexity of human tibiofemoral joint motion is now better understood with the advancement of new methodologies to measure tibiofemoral kinematics in vivo. Marker clusters anchored to stainless steel bone pins inserted directly into the femur and tibia provide the most sensitive and accurate means for directly measuring skeletal tibiofemoral joint motion. Despite its invasiveness, this technique has been successful, although complications have been reported with the femoral pin and its insertion site. The purpose of this technical report is twofold: to review the difficulties with the femoral pin and its insertion site from a historical perspective, and to identify the load force required from biological tissue to permanently deform the pin. In addition, proposals in the advancement of this method are discussed in the context of reducing impingement with the femoral pin and the Iliotibial band. Because stainless steel exhibits plastic behaviour with no sharp yield point, Apex self-drilling/self-tapping bone pins underwent incremental loading on an Instron materials testing machine. Loads were transmitted perpendicular to the pin with the threads partially exposed and fully secured in vice. Since the accuracy of our combined stereophotogrammetry and Optoelectric motion analysis was less than 0.4 mm, it was decided that plastic deformation occurred after deflections of 0.4 mm. With exposed threads, deflections larger than 0.4 mm were observed at 150 N and 100 N when loads were applied at 15 mm and 20 mm from the vice (representative of where the tissue came in contact with the pin). Loads greater than 200 N produced deflections less than 0.2 mm when threads were fully inserted. The 90 Hz resonant frequency for the marker cluster-bone pin complex is beyond the spectrum of human movement and can be lowpass filtered. To reduce impingement and pin bending, one solution may be to implant pins with a shorter threaded section. By completely penetrating the bone, only the smooth surface of the pin is exposed which is more resistant to bending. Otherwise pins with larger diameters and longer longitudinal incisions about the femoral insertion site are an alternative. Lengthening the longitudinal incisions about the insertion site, and correctly aligning and inserting the femoral pin between the Iliotibial band and quadriceps tendon may diminish impingement. Performing dynamic open chain flexion and extension movements while on the operating table may aid in aligning the pin at the incision site. This may stretch the IT band and quadriceps tendon and may guide the femoral pin into a more optimal position prior to it being inserted into the cortex of the bone.
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| 9. |
- Tsui, Janice C. S., et al.
(author)
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Localization of nitric oxide synthase in saphenous vein grafts harvested with a novel "no-touch" technique : potential role of nitric oxide contribution to improved early graft patency rates.
- 2002
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In: Journal of Vascular Surgery. - New York, USA : Elsevier. - 0741-5214 .- 1097-6809. ; 35:2, s. 356-362
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Journal article (peer-reviewed)abstract
- Objective: The use of the saphenous vein in coronary artery bypass graft surgery is associated with high 1-year occlusion rates of as much as 30%. A new "no-touch" technique of saphenous vein harvesting in which the vein is harvested with a pedicle of surrounding tissue and not distended may result in improved early patency rates. We hypothesize that nitric oxide synthase is better preserved with the no-touch technique, and the aim of this study was the investigation of whether nitric oxide synthase distribution and quantity in saphenous veins harvested with the no-touch technique differ from those veins harvested with the conventional technique. The separate contribution of perivascular tissue removal and distension to alterations in nitric oxide synthase was also studied.Methods: Segments of 10 saphenous veins were harvested from 10 patients who underwent coronary artery bypass grafting surgery with the no-touch and conventional techniques. Samples were also taken from segments that were stripped of surrounding tissue but not distended. Nitric oxide synthase distribution was studied with reduced nicotinamide adenine dinucleotide phosphate--diaphorase histochemistry, and staining was quantified with image analysis. Immunohistochemistry was used for the identification of specific nitric oxide synthase isoforms, and immunomarkers were used for the identification of associated cell types.Results: Nitric oxide synthase content was higher in no-touch vessels as compared with conventionally harvested vessels (35.5%; P <.05, with analysis of variance). This content was associated with endothelial nitric oxide synthase on the lumen while all three isoforms were present in the media. In the intact adventitia of no-touch vessels, all three isoforms of nitric oxide synthase were also present, associated with microvessels and perivascular nerves. Perivascular tissue stripping and venous distension both contribute to the reduced nitric oxide synthase in conventionally harvested veins.Conclusion: The new no-touch technique of saphenous vein harvesting preserves nitric oxide synthase, which suggests that improved nitric oxide availability may be an important mechanism in the success of this technique.
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| 10. |
- Eldh, Ann Catrine, et al.
(author)
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The phenomena of participation and non-participation in health care : experiences of patients attending a nurse-led clinic for chronic heart failure
- 2004
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In: European Journal of Cardiovascular Nursing. - : Oxford University Press (OUP). - 1474-5151 .- 1873-1953. ; 3:3, s. 239-246
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Journal article (peer-reviewed)abstract
- Background: Patient participation is stressed in the health care acts of many western countries yet a common definition of the concept is lacking. The understanding of experiences of patients with chronic heart failure (CHF) who attend nurse-led specialist clinics, a form of care suggested as beneficiary to this group, may promote a better understanding of participation. Aim: To investigate the meanings of participation and non-participation as experienced by patients living with CHF. Methods: Narrative interviews analysed in the phenomenological hermeneutic tradition inspired by Ricoeur where the interpretation is made in the hermeneutic circle, explaining and understanding the experienced phenomena. Findings: Participation was experienced as to “be confident”, “comprehend” and “seek and maintain a sense of control”. Non-participation was experienced as to “not understand”, “not be in control”, “lack a relationship” and “not be accountable”. The findings indicate that the experiences of participation and non-participation can change over time and phases of the disease and treatment. Conclusion: The study suggests an extended view on the concept of participation. Patients' experiences of participation in health care can vary and should therefore be an issue for dialogue between nurses and patients with CHF in nurse-led specialist clinics.
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