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  • 251.
    Berglund, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Aasa, Björn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Michaelson, Peter
    Luleå Tekniska Universitet, Institutionen för hälsovetenskap, Avdelningen för hälsa och rehabilitering, Fysioterapi .
    Aasa, Ulrika
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    The effects of low-load motor control exercises and a high-load lifting exercise on lumbar multifidus thickness – a randomized controlled trialManuscript (preprint) (Other academic)
    Abstract [en]

    Study Design

    Randomized controlled trial

    Objective

    The aim of this study was to compare the effects of low-load motor control exercises and a high-load lifting exercise on lumbar multifidus thickness among patients with nociceptive mechanical low back pain.

    Summary of Background Data

    There is evidence that patients with low back pain may have a decreased size of the lumbar multifidus muscles with an asymmetry between left/right sides in the lower back. It has also been shown that low-load motor control training can affect this asymmetry; essentially, it is effective in equalizing side differences in lumbar multifidus muscle size. It is, however, not known whether a high-load exercise has the same effect.

    Methods

    Sixty-five participants diagnosed with nociceptive mechanical low back pain were included and randomized into low-load motor control exercises or a high-load lifting exercise, the deadlift. The lumbar multifidus thickness at the fifth lumbar vertebra was measured, using rehabilitative ultrasound imaging, at baseline and after a 2-month training period.

    Results

    There were no differences between interventions regarding effect on lumbar multifidus muscle thickness. However, the linear mixed model analysis showed a significant effect for asymmetry. The thickness of the lumbar multifidus muscle on the small side increased significantly compared to the large side in both intervention groups.

    Conclusions

    There was a difference in thickness of the lumbar multifidus muscles between sides. It seems that exercises focusing on spinal alignment may increase the thickness of the lumbar multifidus muscles on the small side, irrespective of exercise load.

  • 252.
    Berglund, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Hellqvist, Jonas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Aasa, Björn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Holmberg, David
    Luleå Tekniska Universitet, Institutionen för hälsovetenskap, Avdelningen för hälsa och rehabilitering, Fysioterapi.
    Michaelson, Peter
    Luleå Tekniska Universitet, Institutionen för hälsovetenskap, Avdelningen för hälsa och rehabilitering, Fysioterapi.
    Aasa, Ulrika
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Which patients with persistent mechanical low back pain will respond to high load motor control training?2011Conference paper (Refereed)
  • 253.
    Berglund, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Long-term results of patients <65 years of age undergoing Total Knee Arthroplasty with Trabecular Metal Implant2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 254.
    Bergman, Bo
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Studies on patients with ileal conduit diversion with special regard to renal infection1978Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The conditions for retrograde transport of urine and thereby bacteria in the urinary svstem of diverted patients (device and urinary tract) were studied with roentgeno­logical technigue. Back-flow from the urinary collecting device into the conduit occurred in a fifth of those patients who had a flat stoma. A nipple stoma of at least 2 cm height resisted back-flow better than any flat stoma.

    Ureteral reflux occurred to approximately 30 % of the ureters, both in the supine and erect body positions.The intraluminal pressure in the conduit was "low"

    (^12 cm H2O) in approximately 30 % when reflux occurred.

    The autopsy study showed a higher frequency of renal infections in diverted patients than in non-diverted controls. 5 of 11 patients who died more than 2 months after diversion, and without cancer at autopsy, were attributed to death from renal infection.

    There was a relationship between urographical abnormalities, recognized as associated with pyelonephritis, and raised serum antibody titers against E.coli and/or P.mirabilis.

    Most of the ”not normal" renal units deteriorated after the diversion operation.

    The variable "kidney area" was found to be "small" in a higher frequency after a long postoperative period than after a short one.

    Raised -serum antibody titers occurred in 35 % of the patients and were correlated to growth of the corresponding bacteria (E.coli and P.mirabilisrespectively) in the conduit urine. The frequency of raised antibody titers increased with the time after the diversion operation. After treatment with antibiotics of patients with bacteriuria and raised serum antibody titers, the titers were within normal limits («£512), or decreased significantly, in 22 of 25 patients. Serum antibody titer determinations against E.coli and P.mirabilisare suggested as complement to urinary cultures in the follow-up of diverted patients.

    The residual urine volume in the conduit was shown to be of importance for bacteriuria and raised titer against P.mirabilis.

    Some measures, which possibly may reduce bacteriuria and thereby pyelonephritis, are suggested. A nipple stoma of at least 2 cm height ought to be constructed at the operation. To obtain a low residual urine volume the conduit should be short and unobstructed. The urinary collecting device should be emptied often and connected to a uribag during the night.

  • 255. Bergman, Emma Ahlen
    et al.
    Hartana, Ciputra Adijaya
    Linton, Ludvig
    Winerdal, Malin E.
    Krantz, David
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lundgren, Christian
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Epigenetic methylation profiles of CD4 T cell signature loci from patients with urinary bladder cancer2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 264-264Article in journal (Other academic)
  • 256.
    Bergman, Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Anastomosläckage efter främre resektion: Rektalt blodflöde och biomarkörer2015Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 257.
    Bergman, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Invasiveness and metastatic aggressiveness in small differentiated thyroid cancers. - Demography of small papillary thyroid carcinoma (PTC) in the Swedish population2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 258.
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Fragility fractures in fragile people: epidemiology of the age quake2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Osteoporosis-related fracture is already today a major public health problem and the number of hip fractures is expected to double to 2030. Sweden has one of the highest hip fracture incidences worldwide. This may be explained by several factors: e.g. age, genetic, climatologic, geographic and a relative vitamin D deficiency, secondary to the limited sunlight exposure especially during winter months. Intrinsic and extrinsic factors contribute to a fracture, although a prior low energy fracture is one of the strongest predictors for a subsequent one and this should be a target for secondary fracture prevention in an orthopaedic setting.

    Since 1993 all injured patients admitted to the emergency floor and all in-hospital fractures at Umeå University Hospital, Sweden, were registered according to the Injury Data Base, former EHLASS. There were 31,173 fracture events (one or more fractures at the same time), of which 13,931 were in patients’ ≥ 50 years old. The fracture database was co analyzed with the Northern Sweden Health and Disease Study cohort in a nested case-control study for investigations of associations between osteoporotic fracture and serum markers, lifestyle data, nutrition etc. We found that there were differences in fracture pattern depending on age and sex. Both injury mechanism and fracture site were strongly dependent of age. The most severe fragility fracture, hip fracture, had a decreasing incidence. However, the incidence curve was right-shifting leading to an increase, both in numbers and in incidence of hip fractures among the oldest female. To identify people at high risk for fractures, re-fracture patients are useful. No less than 21% of the fracture patients had suffered more than one fracture event, accounting for 38% of all fracture events. The total risk ratio for a subsequent fracture was 2.2 (2.1-2.3 95% CI). In males the highest risk for re fracture was in the age cohort 70-79 years (RR 2.7, 2.3-3.2 95% CI), in females > 90 years (RR 3.9, 3.2-4.8 95% CI). Another possible risk factor in this subarctic population is the lack of sunlight, leading to a vitamin D deficit. The overall adjusted risk of sustaining a hip fracture in this population was 2.7 (95%CI:1.3-5.4) in subjects with a serum 25 hydroxyvitamin D below 50 nmol/l. The association was, however, different according to age at baseline. Thus in subjects aged 60 years and above at baseline, the adjusted odds ratio of sustaining a hip fracture was 6.2 (1.2-32.5 95%CI) for the group of individuals with a serum 25OHD below 50 nmol/l, whereas no significant association was found in the youngest age group.

    In the next 30 years the ongoing demographic changes will accelerate. The World War II baby boomers will cause an age quake. We can already see signs heralding a new fracture pattern: an increasing cohort of mobile but fragile elderly, with considerable co-morbidity is now at risk for fragility fractures. In fracture patients, clinical information is sufficient to pinpoint patients with a high risk for re-fractures. It is therefore clinically important to use the information provided by the fracture event. We suggest that trauma units and primary care units should screen for risk factors and inform patients about the treatment options, and to organize fracture liaison services. This seems to be especially cost-efficient for our oldest and frailest patients. Secondary prophylaxis and follow-up treatment after cardiovascular disorders are now a matter of course worldwide, but the screening for risk factors, in order to prevent a second fracture, is often neglected. This is one of the most important issues of fracture care in the future in order to improve general health.

  • 259.
    Bergström, Ulrica
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Fracture mechanisms and fracture pattern in men and women aged 50 years and older: a study of a 12-year population-based injury register, Umeå, Sweden2008In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 19, no 9, p. 1267-1273Article in journal (Refereed)
    Abstract [en]

    Summary: In a study of a 12-year population-based injury register, Umeå, Sweden, we analyzed the fracture mechanisms and fracture pattern in men and women 50 years and older. Low-energy trauma was responsible for the major and costliest part of the fracture panorama, but the pattern differs between age groups.

    Introduction: Osteoporosis-related fracture is a major health problem: the number of hip fractures is expected to double to 2030. While osteoporosis is one of many risk factors, trauma is almost always involved. Therefore, we analyzed injury mechanisms in patients aged over 50.

    Methods: We registered injury mechanism, cause, diagnosis in all trauma patients at Umeå University hospital, Sweden. This population-based register (1993–2004) comprises a total of 113,668 injuries (29,189 fractures). Patients ≥50 years contributed to 13,279 fractures.

    Results: Low-energy trauma (fall <1 m) caused 53% of all fractures ≥50 years and older. In those over 75 low-energy trauma caused >80%. The seasonal variation of fractures was maximally 25%. With increasing age, proximal fractures became more common, in both upper and lower extremities. Proximal locations predominate in older age groups.

    Conclusions: Low-energy trauma was responsible for the largest and costliest part of the fracture panorama. In fact, almost all fractures in middle-aged and old people were caused by low-energy mechanisms; thus, most fractures in these patients have a fragility component, and the contribution of osteoporosis-related fractures is more important than previously thought. A better understanding of injury mechanisms also in low-energy trauma is a prerequisite for preventive interventions.

  • 260. Bergström, Ulrica
    et al.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Svensson, Olle
    Fracture panorama in Umeå2006In: Läkartidningen, ISSN 0023-7205, Vol. 103, no 40, p. 2967-8Article in journal (Refereed)
  • 261.
    Bergström, Ulrica
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Jonsson, H
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Olofsson, B
    Pettersson, U
    Svensson, O
    Serial fractures - age and fracture site important predictors for a second fracture: results from 13-years population based dataManuscript (Other academic)
  • 262.
    Bergström, Ulrica
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    The hip fracture incidence curve is shifting to the right: a forecast of the age-quake2009In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 80, no 5, p. 520-524Article in journal (Refereed)
    Abstract [en]

    Background The number of hip fractures has doubled in the last 30–40 years in many countries. Age-adjusted incidence has been reported to be decreasing in Europe and North America, but is there a decreasing trend in all age groups? Patients and methods This population-based study included all hip-fracture patients over 50 years of age (a total of 2,919 individuals, 31% of whom were men) admitted to Umeå University Hospital, Sweden, from 1993 through 2005. Results The incidence of hip fracture declined between the periods 1993–1996 and 2001–2005: from 706 to 625 hip fractures per 105 women and from 390 to 317 hip fractures per 105 men. However, there was a 114% increase in the number of fractures in women aged 90 or older (12 and 25 hip fractures/year, respectively, in the two time periods). For the period 2001–05, women ≥ 90 years of age accounted for almost the same numbers of hip fractures as women aged 75–79 (27 fractures/year). The rate increased during this period, from 2,700 per 105 women to 3,900 per 105 women > 90 years. In men there were declining trends for both relative and absolute numbers. Interpretation Although age-adjusted incidence declined in the population > 50 years of age, absolute fracture rate and incidence increased in the very old. Women over 90 now have the same absolute number of hip fractures every year as women aged 75–79 years. There was a right-shift in hip fracture distribution towards the oldest old, probably due to an increased number of octo/nonagenarians, a new population of particularly frail old people that hardly existed earlier. Better health among septuagenarians may also have delayed the age at which fractures occurred. This changing pattern will strain orthopedic and geriatric resources even more.

  • 263. Berndt, Sonja I
    et al.
    Sampson, Joshua
    Yeager, Meredith
    Jacobs, Kevin B
    Wang, Zhaoming
    Hutchinson, Amy
    Chung, Charles
    Orr, Nick
    Wacholder, Sholom
    Chatterjee, Nilanjan
    Yu, Kai
    Kraft, Peter
    Feigelson, Heather Spencer
    Thun, Michael J
    Diver, W Ryan
    Albanes, Demetrius
    Virtamo, Jarmo
    Weinstein, Stephanie
    Schumacher, Fredrick R
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Valeri, Antoine
    Andriole, Gerald L
    Crawford, E David
    Haiman, Christopher
    Henderson, Brian
    Kolonel, Laurence
    Le Marchand, Loic
    Siddiq, Afshan
    Riboli, Elio
    Travis, Ruth C
    Kaaks, Rudolf
    Isaacs, William
    Isaacs, Sarah
    Wiley, Kathleen E
    Gronberg, Henrik
    Wiklund, Fredrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Xu, Jianfeng
    Zheng, S Lilly
    Sun, Jielin
    Vatten, Lars J
    Hveem, Kristian
    Njølstad, Inger
    Gerhard, Daniela S
    Tucker, Margaret
    Hayes, Richard B
    Hoover, Robert N
    Fraumeni, Joseph F
    Hunter, David J
    Thomas, Gilles
    Chanock, Stephen J
    Large-scale fine mapping of the HNF1B locus and prostate cancer risk2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 16, p. 3322-3329Article in journal (Refereed)
    Abstract [en]

    Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

  • 264. Bersani, Cinzia
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Tertipis, Nikolaos
    Haeggblom, Linnea
    Näsman, Anders
    Romanitan, Mircea
    Dalianis, Tina
    Ramqvist, Torbjörn
    MicroRNA-155,-185 and-193b as biomarkers in human papillomavirus positive and negative tonsillar and base of tongue squamous cell carcinoma2018In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 82, p. 8-16Article in journal (Refereed)
    Abstract [en]

    Objective: Three-year disease-free survival (DFS) is 80% for human papillomavirus (HPV) positive tonsillar and base of tongue cancer (TSCC/BOTSCC) treated with radiotherapy alone, and today's intensified therapy does not improve prognosis. More markers are therefore needed to more accurately identify patients with good prognosis or in need of alternative therapy. Here, microRNAs (miRs) 155, 185 and 193b were examined as potential prognostic markers in TSCC/BOTSCC.

    Material and methods: 168 TSCC/BOTSCC patients diagnosed 2000-2013, with known data on HPV-status, CD8(+) tumour infiltrating lymphocytes, tumour staging and survival were examined for expression of miR-155, -185 and -193b using Real-Time PCR. Associations between miR expression and patient and tumour characteristics were analysed using univariate testing and multivariate regression.

    Results: Tumours compared to normal tonsils showed decreased miR-155 and increased miR-193b expression. miR-155 expression was associated with HPV-positivity, low T-stage, high CD8(+) TIL counts and improved survival. miR-185 expression was associated with HPV-negativity and a tendency towards decreased survival, while miR-193b expression was associated with higher T-stage, male gender and lower CD8(+) TIL counts, but not with outcome. Upon Cox regression, miR-185 was the only miR significantly associated with survival. Combining miR-155 and miR-185 to predict outcome in HPV+ patients yielded an area under curve (AUC) of 71%.

    Conclusion: Increased miR-155 expression was found as a positive predictor of survival, with the effect mainly due to its association with high CD8(+) TIL numbers, while miR-185 independently associated with decreased survival. Addition of these miRs to previously validated prognostic biomarkers could improve patient stratification accuracy.

  • 265. Bersani, Cinzia
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Dept. of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Tertipis, Nikolaos
    Haeggblom, Linnea
    Sivars, Lars
    Ährlund-Richter, Andreas
    Vlastos, Andrea
    Smedberg, Cecilia
    Grün, Nathalie
    Munck-Wikland, Eva
    Näsman, Anders
    Ramqvist, Torbjörn
    Dalianis, Tina
    A model using concomitant markers for predicting outcome in human papillomavirus positive oropharyngeal cancer2017In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 68, p. 53-59Article in journal (Refereed)
    Abstract [en]

    Objective: Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. Material and methods: TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8(+) TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. Results: 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8(+) TIL counts and young age were the strongest predictors of survival, followed by T-stage <3 and presence of HPV16 E2 mRNA. The model had an area under curve (AUC) of 76%. A model where the presence of three of four of these markers defined good prognosis captured 56% of non-relapsing patients with a positive predictive value of 98% in the validation set. Furthermore, the model identified 35% of our cohort that was over-treated and could safely have received de-escalated therapy. Conclusion: CD8(+) TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.

  • 266. Bersani, Cinzia
    et al.
    Sivars, Lars
    Haeggblom, Linnea
    DiLorenzo, Sebastian
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahrlund-Richter, Andreas
    Tertipis, Nikolaos
    Munck-Wikland, Eva
    Nasman, Anders
    Ramqvist, Torbjorn
    Dalianis, Tina
    Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR32017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 21, p. 35339-35350Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes.

    PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants.

    RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed.

    CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.

  • 267. Bertelsen, R. J.
    et al.
    Rava, M.
    Carsin, A. E.
    Accordini, S.
    Benediktsdottir, B.
    Dratva, J.
    Franklin, Karl A.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Heinrich, J.
    Holm, M.
    Janson, C.
    Johannessen, A.
    Jarvis, D. L.
    Jogi, R.
    Leynaert, B.
    Norback, D.
    Omenaas, E. R.
    Raherison, C.
    Sanchez-Ramos, J. L.
    Schlunssen, V.
    Sigsgaard, T.
    Dharmage, S. C.
    Svanes, C.
    Clinical markers of asthma and IgE assessed in parents before conception predict asthma and hayfever in the offspring2017In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 47, no 5, p. 627-638Article in journal (Refereed)
    Abstract [en]

    Background: Mice models suggest epigenetic inheritance induced by parental allergic disease activity. However, we know little of how parental disease activity before conception influences offspring's asthma and allergy in humans.

    Objective: We aimed to assess the associations of parental asthma severity, bronchial hyperresponsiveness (BHR), and total and specific IgEs, measured before conception vs. after birth, with offspring asthma and hayfever.

    Methods: The study included 4293 participants (mean age 34, 47% men) from the European Community Respiratory Health Survey (ECRHS) with information on asthma symptom severity, BHR, total and specific IgEs from 1991 to 1993, and data on 9100 offspring born 1972–2012. Adjusted relative risk ratios (aRRR) for associations of parental clinical outcome with offspring allergic disease were estimated with multinomial logistic regressions.

    Results: Offspring asthma with hayfever was more strongly associated with parental BHR and specific IgE measured before conception than after birth [BHR: aRRR = 2.96 (95% CI: 1.92, 4.57) and 1.40 (1.03, 1.91), respectively; specific IgEs: 3.08 (2.13, 4.45) and 1.83 (1.45, 2.31), respectively]. This was confirmed in a sensitivity analysis of a subgroup of offspring aged 11–22 years with information on parental disease activity both before and after birth.

    Conclusion & Clinical Relevance: Parental BHR and specific IgE were associated with offspring asthma and hayfever, with the strongest associations observed with clinical assessment before conception as compared to after birth of the child. If the hypothesis is confirmed in other studies, parental disease activity assessed before conception may prove useful for identifying children at risk for developing asthma with hayfever.

  • 268.
    Bertheim, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Hellström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    The distribution of hyaluronan in human skin and mature, hypertrophic and keloid scars1994In: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 47, no 7, p. 483-489Article in journal (Refereed)
    Abstract [en]

    A hyaluronan-binding protein (HABP) was used to locate the distribution of HA in normal skin and in various types of scar tissue: mature scar tissue, hypertrophic scar tissue and keloids. The study was intended to establish whether or not a deviant HA distribution could explain the different clinical features of these scar tissues. The distribution of HA was found to differ between the various scar tissues. In normal skin an intense HA-staining was observed in the papillary dermis. In mature scar tissue the distribution of HA resembled that of normal uninjured tissue, but the layer of HA was thinner. In hypertrophic scar tissue, HA occurred mainly as a narrow strip in the papillary dermis. Keloid tissue showed the least HA-staining of the papillary layer and resembled that of the bulging reticular dermis. In contrast, the thickened granular and spinous layer of the keloid epidermis exhibited an intense HA-staining. We suggest that the altered distribution and amount of HA in these different scar tissues may contribute to their different clinical characteristics. This histochemical technique for the demonstration of HA in scar tissue could be of use in clinical work to decide on therapeutic strategies.

  • 269.
    Bertilsson, Sandra
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Mortalitet och vårdbehov hos patienter med dialyskrävande njursvikt efter hjärtkirurgi2015Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 270. Bex, Axel
    et al.
    Albiges, Laurence
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bensalah, Karim
    Dabestani, Saeed
    Giles, Rachel H.
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Fernandez-Pello, Sergio
    Tahbaz, Rana
    Abu-Ghanem, Yasmin
    Staehler, Michael
    Volpe, Alessandro
    Powles, Thomas
    Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 805-809Article in journal (Refereed)
    Abstract [en]

    Cytoreductive nephrectomy (CN) has been the standard of care in patients with metastatic clear-cell renal cancer who present with the tumour in place. The CARMENA trial compared systemic therapy alone with CN followed by systemic therapy. This article outlines the new guidelines based on these data.

    Patient summary: The CARMENA trial demonstrates that immediate cytoreductive nephrectomy should no longer be considered the standard of care in patients diagnosed with intermediate and poor risk metastatic renal cell carcinoma when medical treatment is required. However, the psychological burden poor risk patients experience hearing that removal of their primary tumour will not be beneficial, should be carefully considered. 

  • 271. Bex, Axel
    et al.
    Albiges, Laurence
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bensalah, Karim
    Dabestani, Saeed
    Giles, Rachel H.
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Staehler, Michael
    Volpe, Alessandro
    Powles, Thomas
    Updated European Association of Urology Guidelines Regarding Adjuvant Therapy for Renal Cell Carcinoma2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, no 5, p. 719-722Article in journal (Refereed)
    Abstract [en]

    The European Association of Urology Renal Cell Carcinoma (RCC) guidelines panel updated their recommendation on adjuvant therapy in unfavourable, clinically nonmetastatic RCC following the recently reported results of a second randomised controlled phase 3 trial comparing 1-yr sunitinib to placebo for high-risk RCC after nephrectomy (S-TRAC). On the basis of conflicting results from the two available studies, the panel rated the quality of the evidence, the harm-to-benefit ratio, patient preferences, and costs. Finally, the panel, including representatives from a patient advocate group (International Kidney Cancer Coalition) voted and reached a consensus to not recommend adjuvant therapy with sunitinib for patients with high-risk RCC after nephrectomy. Patient summary: In two studies, sunitinib was given for 1 yr and compared to no active treatment (placebo) in patients who had their kidney tumour removed and who had a high risk of cancer coming back after surgery. Although one study demonstrated that 1 yr of sunitinib therapy resulted in a 1.2-yr longer time before the disease recurred, the other study did not show a benefit and it has not been shown that patients live longer. Despite having been diagnosed with high-risk disease, many patients remain without recurrence, and the side effects of sunitinib are high. Therefore, the panel members, including patient representatives, do not recommend sunitinib after tumour removal in these patients.

  • 272. Bex, Axel
    et al.
    Albiges, Laurence
    Staehler, Michael
    Bensalah, Karim
    Giles, Rachel H.
    Dabestani, Saeed
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Fernández-Pello, Sergio
    Tahbaz, Rana
    Abu-Ghanem, Yasmin
    Volpe, Alessandro
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Escudier, Bernard
    Powles, Thomas
    A Joint Statement from the European Association of Urology Renal Cell Cancer Guidelines Panel and the International Kidney Cancer Coalition: The Rejection of Ipilimumab and Nivolumab for Renal Cancer by the Committee for Medicinal Products for Human Use Does not Change Evidence-based Guideline Recommendations2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 849-851, article id S0302-2838(18)30624-9Article in journal (Refereed)
  • 273. Bex, Axel
    et al.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Comparing Everolimus to Sunitinib in Non-clear-cell Renal Cell Carcinoma2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 5, p. 875-876Article in journal (Other academic)
  • 274. Bex, Axel
    et al.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    van Poppel, Hein
    Powles, Thomas
    The Role of Cytoreductive Nephrectomy: European Association of Urology Recommendations in 20162016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 6, p. 901-905Article in journal (Refereed)
    Abstract [en]

    Patient summary: After the introduction of systemic targeted therapies, the use of nephrectomy in patients with metastatic renal cell carcinoma has declined. Currently, systemic therapy is offered to more patients first as a means to select those candidates that will likely benefit from removal of their primary tumour. Although studies consistently demonstrate a survival benefit after nephrectomy, most patients with poor risk metastatic disease are unlikely to benefit from surgery. Soon studies will report on the effect of nephrectomy in patients with metastatic disease at diagnosis.

  • 275. Bhangu, A
    et al.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University Hospital.
    Andersson, Linda
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University Hospital.
    Gunnarsson, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University Hospital.
    Escobar, EG
    Mortality of emergency abdominal surgery in high-, middle- and low-income countries2016In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 103, no 8, p. 971-988Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI).

    METHODS: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression.

    RESULTS: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1·6 per cent at 24 h (high 1·1 per cent, middle 1·9 per cent, low 3·4 per cent; P < 0·001), increasing to 5·4 per cent by 30 days (high 4·5 per cent, middle 6·0 per cent, low 8·6 per cent; P < 0·001). Of the 578 patients who died, 404 (69·9 per cent) did so between 24 h and 30 days following surgery (high 74·2 per cent, middle 68·8 per cent, low 60·5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2·78, 95 per cent c.i. 1·84 to 4·20) and low-income (OR 2·97, 1·84 to 4·81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days.

    CONCLUSION: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role.

  • 276. Bhoo-Pathy, Nirmala
    et al.
    Uiterwaal, Cuno S. P. M.
    Dik, Vincent K.
    Jeurnink, Suzanne M.
    Bech, Bodil H.
    Overvad, Kim
    Halkjær, Jytte
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Racine, Antoine
    Katzke, Verena A.
    Li, Kuanrong
    Boeing, Heiner
    Floegel, Anna
    Androulidaki, Anna
    Bamia, Christina
    Trichopoulou, Antonia
    Masala, Giovanna
    Panico, Salvatore
    Crosignani, Paolo
    Tumino, Rosario
    Vineis, Paolo
    Peeters, Petra H. M.
    Gavrilyuk, Oxana
    Skeie, Guri
    Weiderpass, Elisabete
    Duell, Eric J.
    Arguelles, Marcial
    Molina-Montes, Esther
    Navarro, Carmen
    Ardanaz, Eva
    Dorronsoro, Miren
    Lindkvist, Björn
    Wallström, Peter
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Karolinska institutet.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Duarte-Salles, Talita
    Freisling, Heinz
    Licaj, Idlir
    Gallo, Valentina
    Michaud, Dominique S.
    Riboli, Elio
    Bueno-de-Mesquita, H. Bas
    Intake of Coffee, Decaffeinated Coffee, or Tea Does Not Affect Risk for Pancreatic Cancer: Results From the European Prospective Investigation into Nutrition and Cancer Study2013In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 11, no 11, p. 1486-1492Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Few modifiable risk factors have been implicated in the etiology of pancreatic cancer. There is little evidence for the effects of caffeinated coffee, decaffeinated coffee, or tea intake on risk of pancreatic cancer. We investigated the association of total coffee, caffeinated coffee, decaffeinated coffee, and tea consumption with risk of pancreatic cancer.

    METHODS: This study was conducted within the European Prospective Investigation into Nutrition and Cancer cohort, comprising male and female participants from 10 European countries. Between 1992 and 2000, there were 477,312 participants without cancer who completed a dietary questionnaire, and were followed up to determine pancreatic cancer incidence. Coffee and tea intake was calibrated with a 24-hour dietary recall. Adjusted hazard ratios (HRs) were computed using multivariable Cox regression.

    RESULTS: During a mean follow-up period of 11.6 y, 865 first incidences of pancreatic cancers were reported. When divided into fourths, neither total intake of coffee (HR, 1.03; 95% confidence interval [CI], 0.83-1.27; high vs low intake), decaffeinated coffee (HR, 1.12; 95% CI, 0.76-1.63; high vs low intake), nor tea were associated with risk of pancreatic cancer (HR, 1.22, 95% CI, 0.95-1.56; high vs low intake). Moderately low intake of caffeinated coffee was associated with an increased risk of pancreatic cancer (HR, 1.33; 95% CI, 1.02-1.74), compared with low intake. However, no graded dose response was observed, and the association attenuated after restriction to histologically confirmed pancreatic cancers.

    CONCLUSIONS: Based on an analysis of data from the European Prospective Investigation into Nutrition and Cancer cohort, total coffee, decaffeinated coffee, and tea consumption are not related to the risk of pancreatic cancer.

  • 277. Bill-Axelson, Anna
    et al.
    Garmo, Hans
    Lambe, Mats
    Bratt, Ola
    Adolfsson, Jan
    Nyberg, Ullakarin
    Steineck, Gunnar
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Suicide risk in men with prostate-specific antigen-detected early prostate cancer: a nationwide population-based cohort study from PCBaSe Sweden.2010In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 57, no 3, p. 390-395Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The risk of suicide is increased among cancer patients including men with prostate cancer (PCa). However, whether this increased risk applies to men diagnosed subsequent to prostate-specific antigen (PSA) testing is not known. OBJECTIVE: To assess the risk of suicide among men diagnosed with PCa subsequent to PSA testing. DESIGN, SETTING, AND PARTICIPANTS: The Prostate Cancer Base Sweden (PCBaSe Sweden) database, the Swedish Cause of Death Register, and the Swedish census database were used. The PCBaSe Sweden is a merged database that includes data from the Swedish National Prostate Cancer Register (NPCR) for cases diagnosed between January 1, 1997, and December 31, 2006. The number of suicides registered for cases in the PCBaSe cohort was compared with the expected number of suicides in an age-matched general male Swedish population. MEASUREMENTS: Standardised mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated for different categories of cases. RESULTS AND LIMITATIONS: There were 128 suicides among the 77,439 PCa cases in the NPCR compared with an expected number of 85 (SMR: 1.5; 95% CI, 1.3-1.8). The risk of suicide was not increased for the 22,405 men with PSA-detected T1c tumours (SMR: 1.0; 95% CI, 0.6-1.5), whereas the 22,929 men with locally advanced nonmetastatic tumours (SMR: 2.2; 95% CI, 1.6-2.9) and the 8350 men with distant metastases (SMR: 2.1; 95% CI, 1.2-3.6) had statistically significant increased SMRs for suicide. Potential effects of comorbid medical and psychiatric conditions could not be investigated. CONCLUSIONS: No increased risk of committing suicide was observed among men with PCa diagnosed subsequent to PSA testing, whereas the risk was twice as high among men with locally advanced or metastatic disease, compared with an age-matched male population.

  • 278. Bill-Axelson, Anna
    et al.
    Garmo, Hans
    Nyberg, Ullakarin
    Lambe, Mats
    Bratt, Ola
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Adolfsson, Jan
    Steineck, Gunnar
    Psychiatric treatment in men with prostate cancer: results from a Nation-wide, population-based cohort study from PCBaSe Sweden.2011In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, no 14, p. 2195-201Article in journal (Refereed)
    Abstract [en]

    Aim: To explore whether the self-reported psychological distress among men with prostate cancer was to the extent that it required psychiatric treatment.

    Methods: PCBaSe Sweden, a merged database based on the National Prostate Cancer Register including 97% of allprostate cancers registered as well as age-matched controls. We calculated relative risks and 95% confidence intervals to compare risks of psychiatric treatment due to depression, anxiety, and post-traumatic stress disordercontrolling for age and socio-economic factors. We used odds ratios to compare use or no use of antidepressants.

    Findings: In total 72,613 men with prostate cancer and 217,839 men without prostate cancer were included for analyses. Psychiatric hospitalisation due to depression, anxiety and post-traumatic stress disorder were significantly increased (RR 1.29, (95% CI 1.14–1.45), RR 1.42 (95% CI 1.12–1.80) and RR 1.61 (95% CI 1.16–2.24), respectively). However, hospitalisations due to anxiety were only increased in men with more advanced tumours RR 2.28 (95% CI 1.45–3.57). The use of antidepressants was increased for all men with prostate cancer RR 1.65 (95% CI 1.54–1.77) and treatment strategies RR 1.93 (95% CI 1.75–2.13).

    Interpretation: Men diagnosed with prostate cancer had increased risk of psychiatric treatment for depression, post-traumatic stress disorder and use of antidepressants regardless of risk group and treatment strategy compared to age-matched controls, whilst more advanced prostate cancer was associated with severe anxiety disorders.

  • 279.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Insulin secretion and ASNA-1-dependent function of the endoplasmic reticulum in C. elegans2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    ASNA1 is a well-conserved ATPase involved in a wide range of functions, including cisplatin resistance, growth control, insulin secretion and targeting of tail-anchored (TA) proteins to membranes. It is a positive regulator of insulin secretion both in the roundworm Caenorhabditis elegans and in humans. Insulin secretion and downstream insulin/IGF signalling (IIS) stands at the heart of many human pathologies, such as diabetes, Alzheimer’s disease and cancer. A better understanding of IIS may therefore prove vital for treatment and cure of these diseases. This thesis aims to further investigate the function of asna-1, and to identify new regulators of IIS based on the asna-1 phenotype in C. elegans.

    Worms lacking ASNA-1 arrest growth in the first larval stage, L1, with reduced insulin secretion. The L1 arrest represents the strongest of the IIS phenotypes in worms. Most regulators of the insulin pathway have been identified in screens for other IIS phenotypes, influencing lifespan or the dauer diapause. Therefore, new regulators could be found by screening for genes which, when inactivated, cause an asna-1-like L1 arrest. Using bioinformatic approaches, a set of 143 putative asna-1 interactors were identified, based on their predicted or confirmed interaction with asna-1 in various organisms. Depletion of the Golgi SNARE homologue YKT-6 or the mitochondrial translocase homologue TOMM-40 caused asna-1-like larval arrests. Using several criteria, including genetic suppression by daf-16/Foxo, it was established that YKT-6 and TOMM-40 are positive regulators of IIS. Both proteins were also required for normal DAF-28/insulin secretion.

    Further investigation of TOMM-40 identified it as a ubiquitously expressed mitochondrial translocase in C. elegans: It localized to mitochondrial membranes and was required for importing a tagged mitochondrial reporter across mitochondrial membranes. Depletion of TOMM-40 caused a collapse of the proton gradient across the inner mitochondrial membrane and triggered the mitochondrial unfolded protein response (UPR). Worms with defective mitochondria failed to grow normally in presence of food, but this growth defect was suppressed by daf-16(mgDf50). In addition, tomm-40(RNAi) led to DAF-16/FOXO activation, an effect that was suppressed by over expression of DAF-28/insulin. Taken together, these findings support a model whereby signals of food availability are conveyed through respiring mitochondria to promote DAF-28/insulin secretion, which in turn promotes growth.

    Biochemical studies have identified ASNA-1 as a chaperone that targets a subset of newly synthesized TA proteins to a receptor at the endoplasmic reticulum (ER) membrane. However, these findings have not been tested in vivo in a metazoan model. A reporter-based system to analyse TA protein targeting into the ER in live animals using confocal microscopy was set up. A model asna-1-dependent TA protein, Y38F2AR.9/SEC-61β, required functional ASNA-1 for correct targeting to the ER. Conversely, a model asna-1-independent TA protein, CYTB5.1/cytochrome B5, did not. This phenotype was shared with the predicted asna-1 receptor homologue, wrb-1. Consistently, WRB-1 was found to localize to the ER. However, other wrb-1 mutant phenotypes only partially overlap with those of asna-1 mutants, suggesting that ASNA-1 is either partially independent of WRB-1 for TA protein targeting or that ASNA-1 has additional functions besides its role in TA protein targeting.

    Confocal microscopy also indicated that the ER morphology was aberrant in asna-1 and wrb-1 mutants. ER UPR was elevated in the asna-1 mutants, as indicated by the upregulation of an hsp-4/BiP reporter. Transmission and immuno-electron microscopy of these mutants revealed a swollen ER lumen, which is another hallmark of ER stress. High levels of autophagy in asna-1 animals and the presence of ER-containing autophagosomes in both asna-1 and wrb-1 mutants indicated a stress-induced remodelling of the ER membrane in these two mutants. In addition, both mutants had normal mitochondrial morphology, but showed severe effects on Golgi compartment morphology. Hypothetically, all these phenotypes could be due to defects in the signal recognition particle (SRP) pathway. This is because Y38F2AR.9/SEC-61β is both a TA protein and a component of the SEC-61 translocon. However, both Golgi and ER morphology was normal in Y38F2AR.9/sec-61β(tm1986) mutant animals, suggesting that the organellar defects seen in asna-1 and wrb-1 were due to a TA protein-dependent mechanism rather than an SRP-dependent mechanism. In addition, asna-1 mutants displayed numerous protein aggregates, consistent with a proposed role for ASNA-1 in shielding aggregation-prone TA protein membrane anchors from the hydrophilic environment of the cytosol.

    In conclusion, YKT-6 and TOMM-40 are positive regulators of IIS and DAF-28/insulin secretion, implicating roles for Golgi and mitochondria in IIS. DAF-28 is a metabolically regulated insulin in C. elegans, since its secretion depends on active mitochondria. Mutants for asna-1 and its predicted receptor wrb-1 show severe defects in ER and Golgi morphology. These defects may occur because TA protein targeting in asna-1 and wrb-1 mutants is defective, which is also demonstrated here in the first analysis of this process in live animals.

  • 280.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Naredi, Peter
    ASNA-1 acts independently of its endoplasmic reticulum receptor WRB-1 to promote insulin/IGF signallingManuscript (preprint) (Other academic)
  • 281.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mitochondrial function is required for secretion of DAF-28/insulin in C. elegans.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e14507-Article in journal (Refereed)
    Abstract [en]

    While insulin signaling has been extensively studied in Caenorhabditis elegans in the context of ageing and stress response, less is known about the factors underlying the secretion of insulin ligands upstream of the insulin receptor. Activation of the receptor governs the decision whether to progress through the reproductive lifecycle or to arrest growth and enter hibernation. We find that animals with reduced levels of the mitochondrial outer membrane translocase homologue TOMM-40 arrest growth as larvae and have decreased insulin signaling strength. TOMM-40 acts as a mitochondrial translocase in C. elegans and in its absence animals fail to import a mitochondrial protein reporter across the mitochondrial membrane(s). Inactivation of TOMM-40 evokes the mitochondrial unfolded protein response and causes a collapse of the proton gradient across the inner mitochondrial membrane. Consequently these broadly dysfunctional mitochondria render an inability to couple food abundance to secretion of DAF-28/insulin. The secretion defect is not general in nature since two other neuropeptides, ANF::GFP and INS-22::VENUS, are secreted normally. RNAi against two other putative members of the TOMM complex give similar phenotypes, implying that DAF-28 secretion is sensitive to mitochondrial dysfunction in general. We conclude that mitochondrial function is required for C. elegans to secrete DAF-28/insulin when food is abundant. This modulation of secretion likely represents an additional level of control over DAF-28/insulin function.

  • 282.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Natarajan, Balasubramanian
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mohammed, Ateequrrahman
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    A directed RNAi screen based on larval growth arrest reveals new modifiers of C. elegans insulin signaling2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34507-Article in journal (Refereed)
    Abstract [en]

    Genes regulating Caenorhabditis elegans insulin/IGF signaling (IIS) have largely been identified on the basis of their involvement in dauer development or longevity. A third IIS phenotype is the first larval stage (L1) diapause, which is also influenced by asna-1, a regulator of DAF-28/insulin secretion. We reasoned that new regulators of IIS strength might be identified in screens based on the L1 diapause and the asna-1 phenotype. Eighty-six genes were selected for analysis by virtue of their predicted interaction with ASNA-1 and screened for asna-1-like larval arrest. ykt-6, mrps-2, mrps-10 and mrpl-43 were identified as genes which, when inactivated, caused larval arrest without any associated feeding defects. Several tests indicated that IIS strength was weaker and that insulin secretion was defective in these animals. This study highlights the role of the Golgi network and the mitochondria in insulin secretion and provides a new list of genes that modulate IIS in C. elegans.

  • 283. Bjartell, Anders
    et al.
    Bottai, Matteo
    Persson, Josefin
    Bratt, Ola
    Damber, Jan-Erik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Akre, Olof
    Prediction of clinical progression after radical prostatectomy in a nationwide population-based cohort2016In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 50, no 4, p. 255-259Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to create a model for predicting progression-free survival after radical prostatectomy for localized prostate cancer. Material and methods: The risk of biochemical recurrence (BCR) was modelled in a cohort of 3452 men aged 70 years or younger who were primarily treated with radical prostatectomy after being diagnosed between 2003 and 2006 with localized prostate cancer [clinical stage T1c-T2, Gleason score 5-10, N0/NX, M0/MX, prostate-specific antigen (PSA)<20 ng/ml]. The cohort was split into two: one cohort for model development (n = 3452) and one for validation (n = 1762). BCR was defined as two increasing PSA values of at least 0.2 ng/ml, initiation of secondary therapy, distant metastases or death from prostate cancer. Multivariable Cox proportional hazard regression was applied, predictive performance was assessed using the bootstrap resampling technique to calculate the c index, and calibration of the model was evaluated by comparing predicted and observed Kaplan-Meier 1 year BCR. Results: The overall 5 year progression-free survival was 83% after a median follow-up time of 6.8 years in the development cohort and 7.3 years in the validation cohort. The final model included T stage, PSA level, primary and secondary Gleason grade, and number of positive and negative biopsies. The c index for discrimination between high and low risk of recurrence was 0.68. The probability of progression-free survival ranged from 22% to 97% over the range of risk scores in the study population. Conclusions: This model is based on nationwide population-based data and can be used with a fair predictive accuracy to guide decisions on clinical follow-up after prostatectomy. An online calculator for convenient clinical use of the model is available at www.npcr.se/nomogram

  • 284.
    Bjelkedal, Malte
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    A Genealogical Study of Prostate Cancer in Västerbotten2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 285. Bjerg, Anders
    et al.
    Ekerljung, Linda
    Eriksson, Jonas
    Olafsdóttir, Inga Sif
    Middelveld, Roelinde
    Franklin, Karl A.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Larsson, Kjell
    Lötvall, Jan
    Torén, Kjell
    Dahlén, Sven-Erik
    Lundbäck, Bo
    Janson, Christer
    Higher risk of wheeze in female than male smokers: results from the Swedish GA(2)LEN study2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, article id e54137Article in journal (Refereed)
    Abstract [en]

    Background: Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders.

    Methods: In 2008 the Global Allergy and Asthma European Network (GA2LEN) questionnaire was mailed to 45.000 Swedes (age 16–75 years), and 26.851 (60%) participated. “Any wheeze”: any wheeze during the last 12 months. “Asthmatic wheeze”: wheeze with breathlessness apart from colds.

    Results: Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56–2.19) vs. 1.60 (1.30–1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age ≥53 years.

    Discussion: In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women.

  • 286.
    Bjerg, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Ekerljung, Linda
    Middelveld, Roelinde
    Dahlén, Sven-Erik
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Franklin, Karl
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Larsson, Kjell
    Lötvall, Jan
    Ólafsdóttir, Inga Sif
    Torén, Kjell
    Lundbäck, Bo
    Janson, Christer
    Increased prevalence of symptoms of rhinitis but not of asthma between 1990 and 2008 in Swedish adults: comparisons of the ECRHS and GA2LEN surveys2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16082-Article in journal (Refereed)
    Abstract [en]

    Background

    The increase in asthma prevalence until 1990 has been well described. Thereafter, time trends are poorly known, due to the low number of high quality studies. The preferred method for studying time trends in prevalence is repeated surveys of similar populations. This study aimed to compare the prevalence of asthma symptoms and their major determinants, rhinitis and smoking, in Swedish young adults in 1990 and 2008.

    Methods

    In 1990 the European Community Respiratory Health Survey (ECRHS) studied respiratory symptoms, asthma, rhinitis and smoking in a population-based sample (86% participation) in Sweden. In 2008 the same symptom questions were included in the Global Allergy and Asthma European Network (GA2LEN) survey (60% participation). Smoking questions were however differently worded. The regions (Gothenburg, Uppsala, Umeå) and age interval (20–44 years) surveyed both in 1990 (n = 8,982) and 2008 (n = 9,156) were analysed.

    Results

    The prevalence of any wheeze last 12 months decreased from 20% to 16% (p<0.001), and the prevalence of “asthma-related symptoms” was unchanged at 7%. However, either having asthma attacks or using asthma medications increased from 6% to 8% (p<0.001), and their major risk factor, rhinitis, increased from 22% to 31%. Past and present smoking decreased.

    Conclusion

    From 1990 to 2008 the prevalence of obstructive airway symptoms common in asthma did not increase in Swedish young adults. This supports the few available international findings suggesting the previous upward trend in asthma has recently reached a plateau. The fact that wheeze did not increase despite the significant increment in rhinitis, may at least in part be due to the decrease in smoking.

  • 287. Bjerg, Anders
    et al.
    Eriksson, Jonas
    Ólafsdóttir, Inga Sif
    Middelveld, Roelinde
    Franklin, Karl
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Larsson, Kjell
    Torén, Kjell
    Dahlén, Sven-Erik
    Janson, Christer
    The association between asthma and rhinitis is stable over time despite diverging trends in prevalence2015In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 109, no 3, p. 312-319Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite the well-known association between asthma and rhinitis, in Swedish adults the prevalence of rhinitis rose from 22% to 31% between 1990 and 2008 while asthma prevalence was unchanged. We tested whether the association of rhinitis with asthma was stable over time using the same population-based databases.

    METHODS: Two surveys of adults (20-44 years) living in three regions of Sweden, carried out in 1990 (n = 8982) and 2008 (n = 9156) were compared. Identical questions regarding respiratory symptoms, asthma and rhinitis were used. Asthmatic wheeze: Wheeze with breathlessness apart from colds. Current asthma: Asthma attacks and/or asthma medication use.

    RESULTS: Subjects with rhinitis had level time trends in asthmatic wheeze, current asthma and most nocturnal respiratory symptoms between 1990 and 2008, adjusted for age, sex, area and smoking. Any wheeze however decreased slightly. In never-smokers asthma symptoms were similarly associated with rhinitis in 1990 and 2008: any wheeze OR 4.0 vs. 4.4 (p = 0.339); asthmatic wheeze OR 6.0 vs. 5.9 (p = 0.937); and current asthma OR 9.6 vs. 7.7 (p = 0.213). In the whole population there were decreases in the asthma symptoms most closely associated to smoking, which decreased by half 1990-2008. Conversely current asthma, which was strongly associated with rhinitis and not with smoking, increased (p < 0.001).

    CONCLUSIONS: The association of rhinitis with asthma was stable between 1990 and 2008. The pattern in the time trends of asthma outcomes strongly suggests that decreased smoking counterbalanced the driving effect of increased rhinitis on asthma prevalence. The findings illustrate the public health benefits of decreased smoking.

  • 288.
    Bjerke, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Department of Physiotherapy, School of Health Education & Social Work, Sør-Trøndelag University College, Trondheim, Norway.
    Öhberg, Fredrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nilsson, Kjell G
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Foss, Olav A
    Orthopaedic Research Centre, Trondheim University Hospital, Trondheim, Norway.
    Stensdotter, Ann-Katrin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Department of Physiotherapy, School of Health Education & Social Work, Sør-Trøndelag University College, Trondheim, Norway.
    Peak knee flexion angles during stair descent in TKA patients2014In: The Journal of Arthroplasty, ISSN 0883-5403, E-ISSN 1532-8406, Vol. 29, no 4, p. 707-711Article in journal (Refereed)
    Abstract [en]

    Reduced peak knee flexion during stair descent (PKSD) is demonstrated in subjects with total knee arthroplasty (TKA), but the underlying factors are not well studied. 3D gait patterns during stair descent, peak passive knee flexion (PPKF), quadriceps strength, pain, proprioception, demographics, and anthropometrics were assessed in 23 unilateral TKA-subjects ~ 19 months post-operatively, and in 23 controls. PKSD, PPKF and quadriceps strength were reduced in the TKA-side, but also in the contralateral side. A multiple regression analysis identified PPKF as the only predictor (57%) to explain the relationship with PKSD. PPKF was, however sufficient for normal PKSD. Deficits in quadriceps strength in TKA-group suggest that strength is also contributing to smaller PKSD. Increased hip adduction at PKSD may indicate both compensatory strategy and reduced hip strength.

  • 289.
    Bjerke, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Department of Physiotherapy, School of Health Education & Social Work, Sør-Trøndelag University College, Trondheim, Norway.
    Öhberg, Fredrik
    Department of Biomedical Engineering & Informatics, Umeå University Hospital, Umeå, Sweden.
    Nilsson, Kjell G
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Stensdotter, Ann-Katrin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Department of Physiotherapy, School of Health Education & Social Work, Sør-Trøndelag University College, Trondheim, Norway.
    Compensatory strategies for muscle weakness during stair ascent in subjects with total knee arthroplasty2014In: The Journal of Arthroplasty, ISSN 0883-5403, E-ISSN 1532-8406, Vol. 29, no 7, p. 1499-1502Article in journal (Refereed)
    Abstract [en]

    Subjects with total knee arthroplasty (TKA) exhibit decreased quadriceps and hamstring strength. This may bring about greater relative effort or compensatory strategies to reduce knee joint moments in daily activities. To study gait and map out the resource capacity, knee muscle strength was assessed by maximal voluntary concentric contractions, and whole body kinematics and root mean square (RMS) electromyography (EMG) of vastus lateralis and semitendinosus were recorded during stair ascent in 23 unilateral TKA-subjects ~19months post-operation, and in 23 healthy controls. Muscle strength and gait velocity were lower in the TKA group, but no significant group differences were found in RMS EMG or forward trunk lean. The results suggest that reduced walking velocity sufficiently compensated for reduced knee muscle strength.

  • 290.
    Bjerke, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Department of Physiotherapy, School of Health Education & Social Work, Sør-Trøndelag University College, Trondheim, Norway.
    Öhberg, Fredrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nilsson, Kjell G
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Stensdotter, Ann-Katrin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Department of Physiotherapy, School of Health Education & Social Work, Sør-Trøndelag University College, Trondheim, Norway.
    Gait on soft versus hard surface after total knee arthroplastyManuscript (preprint) (Other academic)
    Abstract [en]

    Asymmetric gait patterns are common following total knee arthroplasty (TKA). Gait on even and hard surface is primarily characterized by reduced peak knee flexion in the prosthetic knee, increased contralateral knee adduction angle, and decreased walking speed compared to controls. Natural conditions may however lead to different strategies. Therefore, the objective of the present study was to explore how gait patterns may differ when walking on a soft surface. Methods: 3D kinematics during gait on hard and soft surface were assessed in 23 unilateral TKA-subjects ~19 months post-operative, and in 23 controls. Results: Gait characteristics in TKA-subjects that differed from controls observed on hard surface were amplified on soft surface. Flexion in the prosthetic knee was further decreased and a tendency towards reduced flexion in the contralateral knee was observed. Knee and hip adduction were not affected by surface conditions nevertheless there was a difference between groups, in particular with regard to the prosthetic side. In addition, step width increased on soft surface in TKA-subjects. Conclusion: Gait on an even and soft surface did not amplify asymmetries in TKA-subjects, but decreased knee flexion and increased step-width, albeit with similar gait speed as the control group suggests that the soft surface provided a small but significant challenge making the TKA-subjects precautious.

  • 291.
    Bjerke, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Department of Physiotherapy, Faculty of Health and Social Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
    Öhberg, Fredrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nilsson, Kjell G
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Stensdotter, Ann-Katrin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. epartment of Physiotherapy, Faculty of Health and Social Sciences, Norwegian University of Science and Technology, Trondheim, Norway .
    Walking on a compliant surface does not enhance kinematic gait asymmetries after unilateral total knee arthroplasty2016In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 24, no 8, p. 2606-2613Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate gait asymmetries and the effect of walking on compliant surfaces in individuals with unilateral total knee arthroplasty (TKA), hypothesizing that asymmetries would increase as an effect of the compliant surface.

    METHODS: Individuals with unilateral TKA ~19 months post-operative (n = 23, median age 59 years) recruited from one orthopaedic clinic and age- and gender-matched healthy individuals without knee complaints (n = 23, median age 56 years) walked at comfortable speed on a hard surface and on a compliant surface. 3D kinematic analyses were made for knee and hip angles in sagittal and frontal planes, stance time, step length, and gait velocity.

    RESULTS: Shorter stance time (p < 0.01) and less peak knee flexion (p < 0.001) at weight bearing acceptance was found in the prosthetic side compared with the contralateral side. Larger knee (p < 0.01) and hip (p < 0.001) adduction was found compared with healthy controls. Neither asymmetries between the prosthetic and the contralateral side nor differences compared with healthy controls were enhanced when walking on compliant surfaces compared with hard surfaces.

    CONCLUSION: The TKA group adapted their gait to compliant surfaces similarly to healthy controls. Gait asymmetries in the TKA group observed on hard surface were not enhanced, and adduction in hip and knee joints did not increase further as an effect of walking on compliant surfaces. Thus, unfavourable knee joint loading did not increase when walking on a compliant surface. This implies that recommendations for walking on soft surfaces to reduce knee joint loading are not counteracted by increased gait asymmetries and unfavourable joint loading configurations.

    LEVEL OF EVIDENCE: III.

  • 292.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    The human Achilles tendon: innervation and intratendinous production of nerve signal substances - of importance in understanding the processes of Achilles tendinosis2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tendinopathies are painful tendon conditions of presumably multifactorial genesis. In tendinosis, as in Achilles tendinosis, there is apart from pain also morphological changes which are described as degenerative with no signs of inflammation. The exact mechanisms behind these conditions are still, to a large extent, unknown. Pain, being the foremost impairing symptom, leads us to the hypothesis that nerves are deeply involved in the symptoms and processes of Achilles tendinosis. Locally produced nerve signal substances may also be involved in the processes. Knowledge of the innervation patterns within the tendon and knowledge on a possible local nerve signal substance production are therefore of utmost importance. There is a lack of information on these aspects.

    The specific aims of this thesis were 1) to investigate the innervation patterns regarding general, sensory, cholinergic and sympathetic innervations, and 2) to examine for the possible occurrence of a production of nerve signal substances and a presence of receptors related to these in the tendon cells, the tenocytes. Painfree normal and tendinosis Achilles tendons were examined.

    Immunohistochemistry, using antibodies against the general nerve marker PGP9.5, the synthesizing enzymes for acetylcholine (choline acetyltransferase; ChAT), and catecholamines (tyrosine hydroxylase; TH), the vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), substance P and calcitonin gene-related peptide, was applied. Immunohistochemistry was also used for the delineation of muscarinic (M2R), adrenergic (α1-AR) and NPY-ergic (Y1 and Y2) receptors. To detect mRNA for TH and ChAT, in situ hybridization was used.

    In normal Achilles tendons, as well as in the tendinosis tendons, there was a very scanty innervation within the tendon tissue proper, the main general, sensory and sympathetic innervations being found in the paratendinous loose connective tissue. Interestingly, the tenocytes showed immunoreactions for ChAT, VAChT, TH, M2R, α1-AR and Y1R. The reactions were clearly more observable in tendons of tendinosis patients than in those of controls. The tenocytes of tendinosis patients also displayed mRNA reactions for ChAT and TH. Nevertheless, all tenocytes in the tendinosis specimens did not show these reactions. Immunoreactions for α1-AR, M2R and Y1R were also seen for blood vessel walls.

    The present thesis shows that there is a very limited innervation within tendon tissue proper, whilst there is a substantial innervation in the paratendinous loose connective tissue. It also gives evidence for an occurrence of production of catecholamines and acetylcholine in tenocytes, especially for tendinosis tendons. Furthermore, that ACh, catecholamines and NPY can have effects on these, as well as on blood vessels, via the receptors observed.

    The observations suggest that Achilles tendon tissue, whilst containing a very scarce innervation, exhibits autocrine/paracrine cholinergic/catecholaminergic/NPY-ergic effects that are upregulated in tendinosis. These findings are of great importance as the results of such effects may mimic processes that are known to occur in tendinosis. That includes effects related to proliferation and angiogenesis, and blood vessel and collagen regulating effects.

    In conclusion, within the Achilles tendon there is a very scarce innervation, whilst there appears to be a marked local production of nerve signal substances in Achilles tendinosis, namely in the tenocytes, the cells also harbouring receptors for these substances. The observations give a new insight into how the tendon tissue of the Achilles tendon is influenced by signal substances and may give options for new treatments of Achilles tendinosis.

  • 293.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of the neuropeptide Y 1 receptor in tenocytes and blood vessel walls in the human Achilles tendon2009In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 43, no 13, p. 1136-1142Article in journal (Refereed)
    Abstract [en]

    Background: There are still questions concerning the mechanisms of development of chronic pain and impaired function of tendons (tendinosis). Aspects that are known to occur are cell proliferation, angiogenesis and altered blood flow regulation. Neuropeptide NPY (NPY) is widely distributed in the body and has powerful effects in relation to these processes. NPY has its effects via the G-protein-coupled Y receptors. There is no information concerning the presence or absence of NPY receptors in Achilles tendons or other tendons.

    Objective: To clarify the expression patterns of the NPY receptors Y1 and Y2 in normal and tendinosis Achilles tendons of man.

    Methods: Immunohistochemical methods were used. Examination on NPY was carried out in parallel.

    Results: The tenocytes showed strong immunoreactions for the Y1 receptor. The immunoreactions were more intense in the tenocytes of the tendinosis tendons than in those of the non-tendinosis tendons. The rounded/oval tenocytes typically seen in tendinosis tendons exhibited marked Y1 receptor reactions on their exterior. Pronounced Y1 reactions were seen in the smooth muscle of the arterioles of both tendinosis and non-tendinosis tendons. No reactions for the Y2 receptor were noted. NPY was detected in nerve fascicles and in the perivascular innervation.

    Conclusions: The present study shows that there is a morphologic correlate for the occurrence of pronounced NPY effects via the Y1 receptor in both tenocytes, this especially being a fact for tendinosis tendons, and blood vessel walls in the Achilles tendon. The findings are of particular interest as NPY is known to have proliferative, angiogenic and blood vessel regulating effects. The effects of targeting the Y1 receptor in tendinosis is an interesting task to be further evaluated.

  • 294.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The innervation pattern of the human Achilles tendon: studies of the normal and tendinosis tendon with markers for general and sensory innervation2005In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 320, no 1, p. 201-206Article in journal (Refereed)
    Abstract [en]

    Pain-free normal Achilles tendons and chronic painful Achilles tendons were examined by the use of antibodies against a general nerve marker (protein gene-product 9.5, PGP9.5), sensory markers (substance P, SP; calcitonin gene-related peptide, CGRP), and immunohistochemistry. In the normal tendons, immunoreactions against PGP9.5 and against SP/CGRP were encountered in the paratendinous loose connective tissue, being confined to nerve fascicles and to nerve fibers located in the vicinity of blood vessels. To some extent, these immunoreactions also occurred in the tendon tissue proper. Immunoreaction against PGP9.5 and against SP/CGRP was also observed in the tendinosis samples and included immunoreactive nerve fibers that were intimately associated with small blood vessels. In conclusion, Mechanoreceptors (sensory corpuscles) were occasionally observed, nerve-related components are present in association with blood vessels in both the normal and the tendinosis tendon.

  • 295.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Immunohistochemical and in situ hybridization observations favor a local catecholamine production in the human Achilles tendon2008In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 23, no 2, p. 197-208Article in journal (Refereed)
    Abstract [en]

    Results of recent studies using immunohistochemistry show evidence of an occurrence of catecholamine production in the cells (tenocytes) of patellar tendons exhibiting tendinopathy (tendinosis). In the present study, antibodies against the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) and alpha1-adrenoreceptors were applied to sections of specimens of normal and tendinosis Achilles tendons. In situ hybridization using a probe detecting human TH mRNA was also utilized. It was found that sympathetic innervation was very scarce. On the other hand, there were distinct alpha1-adrenoreceptor immunoreactions in blood vessel walls. Interestingly, tenocytes, particularly from tendinosis samples in which the tenocytes showed an abnormal shape (not the typical slender appearance), displayed TH immunoreactions and reactions for TH mRNA. Of further interest was the finding of alpha1-adrenoreceptor immunoreactions in tenocytes. The observations show not only evidence of local catecholamine production at the protein level, which was the case in recent studies for the patellar tendon, but also at the mRNA level. The observations suggest that the tenocytes, especially those with disfigured appearances in tendinosis, can produce catecholamines and also that they can respond to sympathetic transmitters. This is of interest as adrenergic stimulation in other parts of the body is known to induce degenerative/apoptotic and proliferative events, features which are seen in Achilles tendinosis. These observations are completely new findings concerning the human Achilles tendon. It is likely that locally produced catecholamines and the occurrence of autocrine/paracrine effects of these substances are of great relevance during the process of tendinosis.

  • 296.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Observations in favor of a presence of local catecholamine production in the human Achilles tendon - of importance when understanding potential adrenergic effects in Achilles tendinosis.2006Conference paper (Refereed)
    Abstract [en]

    The mid-portion of the Achilles tendon is a frequently injured and pathologically affected tendon region. Achilles tendinosis presents with chronic tendon pain and impaired function, and most often occurs in the mid-portion of the tendon. Nerve-related effects are likely to be of great significance in the pathogenesis of this condition, and information on innervation patterns is therefore of importance. However, the available information on these aspects is limited for the human Achilles tendon. Via staining for a general nerve marker it has previously been shown that there is a presence of innervation in the loose paratendinous connective tissue and to some extent also within the tendon tissue proper. This innervation has been found to partly conform to sensory innervation. There is no information at all on the patterns of sympathetic innervation in the human Achilles tendon. This is a drawback as it is crucial to know the basis for adrenergic effects on blood vessel regulation in tendinosis and as efferent sympathetic nerve activities may be related to pain symptoms. In the present study, therefore, specimens of tendon tissue from the human Achilles tendon of both tendinosis patients and normal controls were immunohistochemically examined concerning expression of the rate limiting enzyme in catecholamine production, tyrosine hydroxylase (TH), and of neuropeptide Y (NPY). In normal tendons, TH- and NPY-immunoreactive nerve fibers were occasionally detected in nerve fascicles and in arterial walls in the paratendinous tissue, but were not detected with certainty within the tendon tissue proper. In the specimens of tendinosis affected tendons, TH-and NPY-immunoreactive nerve fibers were almost non-existent. Surprisingly, however, TH-immunoreactions could be seen in the tendon cells (tenocytes) themselves. Sections were also processed for demonstration of α1-, α2a-, and β1- adrenoreceptors. It was hereby seen that there were immunoreactions for adrenergic receptors in the walls of some of the blood vessels, as well as in some of the tenocytes. The observations show that there is a limited sympathetic innervation at the level of the paratendinous tissue and in principle a non-existent such innervation within the tendon tissue proper. On the other hand, as evidenced by findings of TH-immunoreaction in tenocytes, it appears as if there is a local production of catecholamines within the tendon tissue proper itself. Thus, the tenocytes might be an important source of mediators that bind to the adrenergic receptors in the tissue. The observations of adrenergic receptors on tenocytes are furthermore of interest as adrenergic stimulation in other situations can lead to degenerative/apoptotic events and an affection on cell growth. These facts are thus highly interesting when trying to understand how such events can occur in Achilles tendinosis. Similarly, cartilage and menisci have in recent studies been found to harbor cells that express adrenergic receptors, but nevertheless to be very scarcely equipped with nerves. Although there is a very limited sympathetic innervation in the Achilles tendon, our observations show that there is a morphologic correlate for the occurrence of adrenergic actions in the tendon, via effects of locally produced catecholamines.

  • 297.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Presence of a non-neuronal cholinergic system and occurrence of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance regarding Achilles tendon tendinosis (tendinopathy)2008In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 331, no 2, p. 385-400Article in journal (Refereed)
    Abstract [en]

    Limited information is available concerning the existence of a cholinergic system in the human Achilles tendon. We have studied pain-free normal Achilles tendons and chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2) muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M(2)R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M(2)R immunoreactivity was present in the endothelium. M(2)R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M(2)R immunoreactivity was highly variable, tendinosis tendons that exhibit hypercellularity and hypervascularity showing the highest levels of immunostaining. Immunoreaction for ChAT and VAChT was detected in tenocytes in tendinosis specimens, particularly in aberrant cells. In situ hybridization revealed that mRNA for ChAT is present in tenocytes in tendinosis specimens. Our results suggest that autocrine/paracrine effects occur concerning the tenocytes in tendinosis. Up-regulation/down-regulation in the levels of M(2)R immunoreactivity possibly take place in tenocytes and blood vessel cells during the various stages of tendinosis. The presumed local production of acetylcholine (ACh), as evidenced by immunoreactivity for ChAT and VAChT and the detection of ChAT mRNA, appears to evolve in response to tendinosis. These observations are of importance because of the well-known vasoactive, trophic, and pain-modulating effects that ACh is known to have and do unexpectedly establish the presence of a non-neuronal cholinergic system in the Achilles tendon.

  • 298.
    Björck van Dijken, Christina
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics. Umeå University, Faculty of Medicine, Community Medicine and Rehabilitation, Physiotherapy.
    Fjellman-Wiklund, Anncristine
    Umeå University, Faculty of Medicine, Community Medicine and Rehabilitation.
    Hildingsson, Christer
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Low back pain, lifestyle factors and physical activity: a population-based study.2008In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 40, no 10, p. 864-869Article in journal (Refereed)
    Abstract [en]

    Objective and designThe prevalence of low back pain was assessed in relation to physical activity, for both work and leisure activities, in a randomly selected population in the northern part of Sweden. Additionally, the associations between age, sex, level of education, lifestyle factors, demographic characteristics, and low back pain were evaluated. Subjects: A total of 5798 subjects aged 25–79 years were selected randomly from a geographically well-defined area in northern Sweden. Methods: Additional questions concerning people's experience of low back pain were added to the questionnaire of the World Health Organization MONICA (MONItoring of trends and determinants in CArdiovascular disease) health survey with the aim of investigating prevalence rates and factors associated with low back pain. Results: Forty-one percent of the participants reported having low back pain (of these 55% were women and 45% men). The prevalence rate was highest in the age group 55–64 years. Chronic low back pain was the most frequent occurring problem. Of those with low back pain, 43% of the women and 37% of the men reported having continuous low back pain for more than 6 months. Individuals with low back pain often experienced a more physically heavy workload at work and lower physical activity during leisure time, and they were also more likely to have been smokers, have had higher body mass index, lived in smaller communities, and were less educated than people without low back pain. Conclusion: Low back pain seems to be associated with physical activity at work and in leisure time, certain lifestyle factors and demographic characteristics.

  • 299.
    Björklin, Josefin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    The effect of spinal anaesthesia in postoperative analgesia after caesarean sections - comparison between adjuvant morphine and fentanyl2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 300.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Increased expression of cannabinoid CB(1) receptors in achilles tendinosis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24731-Article in journal (Refereed)
    Abstract [en]

    Background: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB(1)) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis.

    Methodology: Cannabinoid CB(1) receptor immunoreactivity (CB(1)IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons.

    Principal Findings: CB(1)IR was seen as a granular pattern in the tenocytes. CB(1)IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB(1) receptor expression in tendinosis tissue compared to control tissue.

    Conclusion: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder.

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