| 1. |
- Baumgartner, Ruth, et al.
(författare)
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Impact of post-hepatectomy liver failure on morbidity and short- and long-term survival after major hepatectomy
- 2022
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Ingår i: BJS Open. - : Oxford University Press. - 2474-9842. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- Background Post-hepatectomy liver failure (PHLF) is one of the most serious postoperative complications after hepatectomy. The aim of this study was to assess the impact of the International Study Group of Liver Surgery (ISGLS) definition of PHLF on morbidity and short- and long-term survival after major hepatectomy. Methods This was a retrospective review of all patients who underwent major hepatectomy (three or more liver segments) for various liver tumours between 2010 and 2018 at two Swedish tertiary centres for hepatopancreatobiliary surgery. Descriptive statistics, regression models, and survival analyses were used. Results A total of 799 patients underwent major hepatectomy, of which 218 patients (27 per cent) developed ISGLS-defined PHLF, including 115 patients (14 per cent) with ISGLS grade A, 76 patients (10 per cent) with grade B, and 27 patients (3 per cent) with grade C. The presence of cirrhosis, perihilar cholangiocarcinoma, and gallbladder cancer, right-sided hemihepatectomy and trisectionectomy all significantly increased the risk of clinically relevant PHLF (grades B and C). Clinically relevant PHLF increased the risk of 90-day mortality and was associated with impaired long-term survival. ISGLS grade A had more major postoperative complications compared with no PHLF but failed to be an independent predictor of both 90-day mortality and long-term survival. The impact of PHLF grade B/C on long-term survival was no longer present in patients surviving the first 90 days after surgery. Conclusions The presently used ISGLS definition for PHLF should be reconsidered regarding mortality as only PHLF grade B/C was associated with a negative impact on short-term survival; however, even ISGLS grade A had clinical implications. The aim was to assess the ISGLS criteria for post-hepatectomy liver failure (PHLF) in a cohort of patients with major hepatectomy. The presently used ISGLS definition for PHLF should be reconsidered regarding mortality as only PHLF grade B/C was associated with a negative impact on short-term survival.
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| 2. |
- Granberg, I, et al.
(författare)
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Capillary supply in relation to myosin heavy chain fibre composition of human intrinsic tongue muscles
- 2010
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Ingår i: Cells Tissues Organs. - : S. Karger AG. - 1422-6405 .- 1422-6421. ; 192:5, s. 303-313
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Tidskriftsartikel (refereegranskat)abstract
- The capillary supply and myosin heavy chain (MyHC) composition of three different intrinsic tongue muscles was analysed in the anterior and posterior regions of the human tongue with biochemical and immunohistochemical techniques. Mean capillary density for the whole tongue was 796 ± 82 cap/mm², without regional differences. The overall number of capillaries around each fibre (CAF) was higher in the posterior than in the anterior region (2.5 vs. 2.1, p = 0.009). However, correcting for regional differences in fibre size, CAF per fibre area was higher in the anterior region (4.3 vs. 3.0, p < 0.001). Muscle fibres containing fast MyHCs predominated in the anterior region (78.7%), consisting of MyHCIIa (58.5%), MyHCIIx (1.0%), MyHCIIa+MyHCIIx (11.3%) and MyHCI+MyHCIIa (7.9%). Fibres containing slow MyHC predominated in the posterior region (65.2%), consisting of MyHCI (45.5%) and MyHCI+MyHCIIa (19.7%). A minor fibre population (<2%) contained unusual MyHC isoforms, namely MyHC foetal, MyHC slow-tonic, MyHC α-cardiac or MyHC embryonic. The microvascularization of the human tongue was twice as high as in human limb muscles. Regional similarities in capillary supply, but differences in fibre phenotype composition, suggest that human tongue muscle fibres are fatigue resistant independently of MyHC content. High frequency of hybrid fibres, that is fibres co-expressing two or more MyHC isoforms, indicates a wider spectrum of fibre contractile properties than in limb muscles. In conclusion, human intrinsic tongue muscles showed internal specialization in distribution of MyHC isoforms and capillary supply, but not in the expression of unusual MyHCs.
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| 3. |
- Levin, Sara, 1974-
(författare)
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The challenges of using structured risk assessment instruments in forensic psychiatric care
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The purpose of psychiatric forensic care is to provide treatment for mentally ill offenders and to prevent future acts of violence and other adverse events. During care, the type of restrictions of freedom, the patient’s continuous need for involuntary treatment and readiness for discharge, are continuously evaluated based on the assessment of risk the patient pose to themselves and others as well as the progress achieved with treatment. The use of structured risk assessment instruments is recommended in clinical guidelines to assess such risks. However, unstructured clinical assessments, considered to be less valid, are often used in clinical practice. There is insufficient research evidence concerning several aspects related to the clinical use of structured risk assessment instruments in terms of guiding the planning and realization of care and risk management interventions. There is also a lack of knowledge about what patients themselves perceive to be mediating factors for their use of violence. Overall aim: The overarching aim of this thesis was to investigate the implementation and use of structured risk assessment instruments to prevent violence and other adverse events in forensic settings and to improve understanding of the factors that influence such events among forensic patients.Methods: Several methods were used for data collection and data were analysed by different types of content analysis. In the first paper, a systematic review of previous research studies on implementation determinants for structured risk assessment instruments in forensic settings was conducted to investigate implementation determinants for such instruments. The second paper evaluates a pilot project of the implementation of a structured risk assessment instrument at a forensic clinic in Östergötland using focus group interviews with staff members who had used the instrument. Their perceptions of the instrument and barriers and facilitators to its implementation and clinical use were investigated. The third paper investigated the actual clinical use of structured risk assessments to guide the planning and realization of care and risk management interventions documented in forensic patients’ records. In the fourth paper, patient perspectives of factors increasing and decreasing the risk for violence were investigated by individual semi-structured interviews with forensic patients.Results: There is a wide variety of determinants for the implementation and clinical use of structured risk assessment instruments, which make such missions complicated. The determinants relate to the characteristics of the implementation object, characteristics of users, the inner setting in which the implementation occurs and the implementation process. Limiting the need to change current routines, and hence the strain on the organization by reducing complexity, and the need for resource allocation seem especially important. Most of the planned risk management interventions in structured risk assessments were realized according to patient records. However, structured risk assessments largely overlap with unstructured risk assessments in terms of planned care and risk management interventions. Noteworthy, most of the interventions realized were not documented as planned. Forensic patients described several risk factors that increased and decreased their use of violence. These factors related to themselves, external influences, social and relational aspects and situational factors. Most patient accounts of mediating factors overlapped with those listed in commonly used risk assessment instruments and previous research. Additional factors identified by patients related to the outer context and interpersonal aspects.Conclusions: There are many barriers and facilitators to the implementation and use of structured risk assessment instruments, implying the need for a multifaceted approach to address determinants at several system levels. Considering the clinical context is important when selecting a structured risk assessment instrument to be implemented, but also the complexity of the instrument, the required change of routines and the provision of continuous resources and interventions to achieve and maintain clinical use. Despite the many barriers, there is evidence of clinical use of both unstructured clinical and structured risk assessments in terms of informing and guiding care and risk management interventions. The large overlap, however, makes it difficult to draw definite conclusion about which type of assessment actually influenced the interventions that were realized. Realized care and risk management interventions are most often not documented as planned. This increases the risk of subjective decisions and provision of interventions, which also make such interventions difficult to evaluate. Forensic patients are actively managing their risk of violence and are capable of identifying and communicating many different mediating factors for their violence risk. They are knowledgeable and important stakeholders and should be involved in their own risk assessments, as well as in research.
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| 4. |
- Nielsen, Rasmus Oestergaard, et al.
(författare)
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Collagen content in the vastus lateralis and the soleus muscle following a 90-day bed rest period with or without resistance exercises
- 2015
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Ingår i: MLTJ - Muscles Ligaments and Tendons Journal. - : Edra SpA. - 2240-4554. ; 5:4, s. 305-309
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: spaceflight seems associated with deterioration of the function of the skeletal muscles. Since muscle collagen is critical for muscle function, an improved understanding of the content of the muscle collagen during long-term inactivity seems important. Bed-rest with in-bed resistance training serves as a proxy for the conditions in space. Therefore, ground-based studies may improve the understanding of the consequences of long-term inactivity.Purpose: the purpose is to compare the change in collagen protein in the vastus lateralis (VL) and the soleus (SOL) muscle amongst persons exposed to a 90-day bed rest with or without resistance exercise.Methods: an explorative analysis was completed based on data from a randomized, controlled trial.The intervention group (BRE, SOL n=4, VL n=8) performed supine-based squat exercises, whereas the controls (BE, SOL n=6, VL n=12) remained inactive during follow-up. Muscle biopsies from vastus lateralis and soleus were taken at baseline(pre) and after 90-days’ follow-up (post). Muscle collagen (μg collagen/mg protein) was quantified. Two-way repeated measurements ANOVA was used to compare the interaction between the intervention (BRE/BR) and time (pre/post) for each muscle.Results: the collagen content of VL was similar between pre and post in the BRE group (-3.8 μg collagen/mg protein [95% CI: -22.0; 14.4], p=0.68) while it rose amongst individuals in the BR group (14.9 μg collagen/mg protein [95% CI: -0.01; 29.7], p=0.05). The difference of 18.66 [95% CI: -6.5; 43.9] between BRE and BR across time was, however, not significant (p=0.14). No significant reduction in SOL muscle collagen content was observed from pre to post in the BR group (-9.3 μg collagen/mg protein [95% CI: -24.9; 6.4], p=0.25) or in the BRE group (-6.5 μg collagen/mg protein [95% CI: -25.6; 12.6], p=0.50). There was no difference in the effect of BR versus BRE over time (mean difference -2.78 μg collagen/mg protein[95% CI: -29.7; 24.1], p=0.82).Conclusion: muscle collagen content in the VL or SOL muscle does not seem to differ after a 90-day bed rest period with or without squat exercises.
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| 5. |
- Niméus, Emma, et al.
(författare)
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Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionSome patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.MethodsWe performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.ResultsWithin the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).ConclusionA highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.
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| 6. |
- Sjöström, Martin, et al.
(författare)
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Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast-conserving surgery : a long-term follow-up of the SweBCG91-RT randomised trial
- 2020
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 14:11, s. 2713-2726
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Tidskriftsartikel (refereegranskat)abstract
- Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91-RT trial, which randomly assigned patients to breast-conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGFstr); pMet in the membrane (pMetmem); HGF, pMet and pAkt in the cytoplasm (HGFcyt, pMetcyt, pAktcyt); and pAkt in the nucleus (pAktnuc). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGFcyt and pMetcyt and high levels of pAktnuc derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037–0.30), 0.066 (0.016–0.28) and 0.094 (0.028–0.31), respectively] compared to patients with high expression of HGFcyt and pMetcyt, and low pAktnuc [HR: 0.36 (0.19–0.67), 0.35 (0.20–0.64) and 0.47 (0.32–0.71), respectively; interaction analyses: P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis, P-values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGFcyt, low pMetcyt and high pAktnuc may derive an increased benefit from RT after breast-conserving surgery concerning the risk of developing IBTR.
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| 7. |
- Skoglund, Elisabeth, et al.
(författare)
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Skeletal muscle morphology, satellite cells, and oxidative profile in relation to physical function and lifelong endurance training in very old men
- 2023
-
Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 134:2, s. 264-275
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Tidskriftsartikel (refereegranskat)abstract
- In the current study, we compared muscle morphology in three advanced aging cohorts that differed in physical function, includ-ing a unique cohort of lifelong endurance athletes. Biopsies from the vastus lateralis muscle of seven lifelong endurance athletes (EAs) aged 82-92 yr, and 19 subjects from the Uppsala Longitudinal Study of Adult Men (ULSAM) aged 87-91 yr were analyzed. ULSAM subjects were divided into high-(n = 9, HF) and low-(n = 10, LF) function groups based on strength and physical function tests. The analysis included general morphology, fiber type and cross-sectional area, capillarization, deficient cytochrome c oxi-dase (COX) activity, number of myonuclei and satellite cells, and markers of regeneration and denervation. Fibers with central nuclei and/or nuclear clumps were observed in all groups. EA differed from LF and HF by having a higher proportion of type I fibers, 52% more capillaries in relation to fiber area, fewer COX-negative fibers, and less variation in fiber sizes (all P < 0.05). There were no differences between the groups in the number of myonuclei and satellite cells per fiber, and no significant differ-ences between LF and HF (P > 0.05). In conclusion, signs of aging were evident in the muscle morphology of all groups, but neither endurance training status nor physical function influenced signs of regeneration and denervation processes. Lifelong en-durance training, but not higher physical function, was associated with higher muscle oxidative capacity, even beyond the age of 80.NEW & NOTEWORTHY Here we show that lifelong endurance training, but not physical function, is associated with higher mus-cle oxidative capacity, even beyond the age of 80 yr. Neither endurance training status nor physical function was significantly associated with satellite cells or markers of regeneration and denervation in muscle biopsies from these very old men.
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| 8. |
- Stål, Per, et al.
(författare)
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Fibre composition of human intrinsic tongue muscles.
- 2003
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Ingår i: Cells Tissues Organs. - : S. Karger AG. - 1422-6405 .- 1422-6421. ; 173:3, s. 147-161
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Tidskriftsartikel (refereegranskat)abstract
- The muscle fibre composition of three human intrinsic tongue muscles, the longitudinalis, verticalis and transversus, was investigated in four anterior to posterior regions of the tongue using morphological and enzyme- and immunohistochemical techniques. All three muscles typically contained type I, IIA and IM/IIC fibres. Type I fibres expressed slow myosin heavy chain (MyHC), type II fibres fast MyHC, mainly fast A MyHC, whereas type IM/IIC coexpressed slow and fast MyHCs. Type II fibres were in the majority (60%), but regional differences in proportion and diameter of fibre types were obvious. The anterior region of the tongue contained a predominance of relatively small type II fibres (71%), in contrast to the posterior region which instead showed a majority of larger type I and type IM/IIC fibres (66%). In general, the fibre diameter was larger in the posterior region. This muscle fibre composition of the tongue differs from those of limb, orofacial and masticatory muscles, probably reflecting genotypic as well as phenotypic functional specialization in oral function. The predominance of type II fibres and the regional differences in fibre composition, together with intricate muscle structure, suggest generally fast and flexible actions in positioning and shaping the tongue, during vital tasks such as mastication, swallowing, respiration and speech. Copyright 2003 S. Karger AG, Basel
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| 9. |
- Thornell, Lars-Eric, et al.
(författare)
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Fibre typing of intrafusal fibres
- 2015
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Ingår i: Journal of Anatomy. - : John Wiley & Sons. - 0021-8782 .- 1469-7580. ; 227:2, s. 136-156
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Forskningsöversikt (refereegranskat)abstract
- The first descriptions of muscle spindles with intrafusal fibres containing striated myofibrils and nervous elements were given approximately 150years ago. It took, however, another 100years to establish the presence of two types of intrafusal muscle fibres: nuclear bag and nuclear chain fibres. The present paper highlights primarily the contribution of Robert Banks in fibre typing of intrafusal fibres: the confirmation of the principle of two types of nuclear bag fibres in mammalian spindles and the variation in occurrence of a dense M-band along the fibres. Furthermore, this paper summarizes how studies from the Umea University group (Laboratory of Muscle Biology in the Department of Integrative Medical Biology) on fibre typing and the structure and composition of M-bands have contributed to the current understanding of muscle spindle complexity in adult humans as well as to muscle spindle development and effects of ageing. The variable molecular composition of the intrafusal sarcomeres with respect to myosin heavy chains and M-band proteins gives new perspectives on the role of the intrafusal myofibrils as stretch-activated sensors influencing tension/stiffness and signalling to nuclei.
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| 10. |
- Österlund, Catharina, 1965-
(författare)
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Extra- and intrafusal muscle fibre type compositions of the human masseter at young age. : In perspective of growth and functional maturation of the jaw-face motor system.
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Muscles control body posture and movement by extrafusal and intrafusal (muscle spindle) fibres. The purpose of this thesis was to provide insight into the muscular basis for human jaw function at young age. Extrafusal and intrafusal fibres in the young masseter, and for comparison young biceps, were examined for composition of fibre types and myosin heavy chain (MyHC) isoforms by means of morphological, enzyme-histochemical, biochemical and immuno-histochemical techniques. For evaluation of plasticity during life span the data for young muscles were compared with previous reported data for adult and elderly muscles.The results showed significant differences in extrafusal fibre types and MyHC expression between young masseter and young biceps and between young masseter and masseter in adults and elderly. Compared with young biceps, young masseter was more intricate in composition of extrafusal MyHC expression. Muscle spindles were larger and more frequent in the masseter than in the biceps. Masseter and biceps muscle spindles showed fundamental similarities but also marked differences in MyHC expression.The results suggest that the young masseter is specialized in fibre types already at young age and shows a unique fibre type growth pattern. Whereas masseter extrafusal fibres display marked plasticity in fibre types and MyHC isoforms during life span muscle spindles/intrafusal fibres are morphologically mature already at young age and precede extrafusal fibres in growth and maturation. Results showed similarities in intrafusal MyHC expression between young masseter and biceps, but also differences implying muscle specific proprioceptive control. Differences in fibre types and MyHC expression between young masseter and young biceps extrafusal fibres are proposed to reflect diverse evolutionary and developmental origins and accord with the masseter and biceps being separate allotypes of muscle.
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| 11. |
- Adam, Iris, et al.
(författare)
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Daily vocal exercise is necessary for peak performance singing in a songbird
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Vocal signals, including human speech and birdsong, are produced by complicated, precisely coordinated body movements, whose execution is fitness-determining in resource competition and mate choice. While the acquisition and maintenance of motor skills generally requires practice to develop and maintain both motor circuitry and muscle performance, it is unknown whether vocal muscles, like limb muscles, exhibit exercise-induced plasticity. Here, we show that juvenile and adult zebra finches (Taeniopygia castanotis) require daily vocal exercise to first gain and subsequently maintain peak vocal muscle performance. Experimentally preventing male birds from singing alters both vocal muscle physiology and vocal performance within days. Furthermore, we find females prefer song of vocally exercised males in choice experiments. Vocal output thus contains information on recent exercise status, and acts as an honest indicator of past exercise investment in songbirds, and possibly in all vocalising vertebrates.
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| 12. |
- Ahmadi, Mahboobah, et al.
(författare)
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Human extraocular muscles in ALS
- 2010
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 51:7, s. 3494-3501
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. To investigate the general morphology, fiber type content, and myosin heavy chain (MyHC) composition of extraocular muscles (EOMs) from postmortem donors with amyotrophic lateral sclerosis (ALS) and to evaluate whether EOMs are affected or truly spared in this disease. METHODS. EOM and limb muscle samples obtained at autopsy from ALS donors and EOM samples from four control donors were processed for immunohistochemistry with monoclonal antibodies against distinct MyHC isoforms and analyzed by SDS-PAGE. In addition, hematoxylin and eosin staining and nicotinamide tetrazolium reductase (NADH-TR) activity were studied. RESULTS. Wide heterogeneity was observed in the appearance of the different EOMs from each single donor and between donors, irrespective of ALS type or onset. Pathologic morphologic findings in ALS EOMs included presence of atrophic and hypertrophic fibers, either clustered in groups or scattered; increased amounts of connective tissue; and areas of fatty replacement. The population of fibers stained with anti-MyHCslow tonic was smaller than that of MyHCIpositive fibers and was mostly located in the orbital layer in most of the ALS EOM samples, whereas an identical staining pattern for both fiber populations was observed in the control specimens. MyHCembryonic was notably absent from the ALS EOMs. CONCLUSIONS. The EOMs showed signs of involvement with altered fiber type composition, contractile protein content, and cellular architecture. However, when compared to the limb muscles, the EOMs were remarkably preserved. EOMs are a useful model for the study of the pathophysiology of ALS.
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| 13. |
- Akbari, Camilla, et al.
(författare)
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Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD
- 2024
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Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 6:2
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Tidskriftsartikel (refereegranskat)abstract
- Background & AimsLong-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD.MethodsWe conducted a cohort study with data from Swedish university hospitals. Patients (n = 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n = 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression.ResultsMALO occurred in 111 (8.8%, incidence rate = 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate = 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio = 6.6; 95% CI = 5.2–8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72 at 10 years).ConclusionsThis study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy.Impact and implicationsSeveral implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.
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| 14. |
- Aleman, Soo, et al.
(författare)
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Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population
- 2011
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 46:9, s. 1118-1126
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. Patients and methods. 373 patients with hemochromatosis detected through routine health checkups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 +/- 5.8 years. The degree of liver fibrosis and survival were analyzed. Results. Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. Conclusion. Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.
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| 15. |
- Bergström, Per, 1980, et al.
(författare)
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Inventering, metodutveckling och modellering i marin miljö i Marstrandsskärgården
- 2009
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Länsstyrelsen i Västra Götalands län uppdrog år 2007 åt Institutionen för Marin ekologi att med stöd av Marbipp-verktyget dels inventera grundområdena i Marstrandsskärgården i Kungälvs kommun dels utveckla/utvärdera olika inventeringsmetoder i grunda områden. År 2008 erhölls ett tilläggsuppdrag avseende arbete med habitatmodellering med data från 2007 och från nya inventeringar genomförda år 2008 av länsstyrelsen. Inventeringen har dels utförts med småbåt och vattenkikare på sedvanligt vis, dessutom har punkter slumpats ut i området till grund för en efterföljande modellering. En ny metod med transekter och avläsning med hjälp av ekolod har också prövats. Med stöd från resultat från inventeringarna och information om bland annat vågexponering är det möjligt att klassificera olika bottenhabitat enligt det europeiska systemet för habitatklassificering EUNIS (European Nature Information System). Denna klassificering har efter modellering av substrat och vegetation i icke inventerade områden genomförts för hela undersökningsområdet. Modelleringen utfördes på två separata dataset, ett innehållande inventeringsinformation från punktlokaler (dyk, bottenhugg, droppvideo och vattenkikare) samt ett med information från inventeringar över större ytor (vattenkikare och ekolodsmätningar). Modelleringen visar på att Marstrandsområdet domineras av vegetationsfria lerbottnar (A5.3) följt av moderat exponerade infralittorala hårdbottnar (A3.2) och makrofyt dominerade sublittorala sediment. I modellen som baseras på punktlokaler dominerar mjukbottnarna helt, medan i den andra modellen är det jämnare fördelat mellan mjukbottnarna och de infralittorala hårdbottnarna.
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| 16. |
- Bojmar, Linda
(författare)
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Metastatic Mechanisms in Malignant Tumors
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.
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| 17. |
- Bojmar, Linda, et al.
(författare)
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miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome
- 2015
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.
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| 18. |
- Bojmar, Linda, et al.
(författare)
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The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12, s. 84815-
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Tidskriftsartikel (refereegranskat)abstract
- The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200 ZEB E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMTmarkers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 - ZEB - E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.
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| 19. |
- Dahl, Morten, et al.
(författare)
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Stiffness and thickness of Fascia do not explain chronic exertional compartment syndrome
- 2011
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Ingår i: Clinical Orthopaedics and Related Research. - : Ovid Technologies (Wolters Kluwer Health). - 0009-921X .- 1528-1132. ; 469:12, s. 3495-3500
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Tidskriftsartikel (refereegranskat)abstract
- Background Chronic exertional compartment syndrome is diagnosed based on symptoms and elevated intramuscular pressure and often is treated with fasciotomy. However, what contributes to the increased intramuscular pressure remains unknown. Questions/purposes We investigated whether the stiffness or thickness of the muscle fascia could help explain the raised intramuscular pressure and thus the associated chronic compartment syndrome symptoms. Patients and Methods We performed plain radiography, bone scan, and intramuscular pressure measurement to diagnose chronic compartment syndrome and to exclude other disorders. Anterior tibialis muscle fascial biopsy specimens from six healthy individuals, 11 patients with chronic compartment syndrome, and 10 patients with diabetes mellitus and chronic compartment syndrome were obtained. Weight-normalized fascial stiffness was assessed mechanically in a microtensile machine, and fascial thickness was analyzed microscopically. Results Mean fascial stiffness did not differ between healthy individuals (0.120 N/mg/mm; SD, 0.77 N/mg/mm), patients with chronic compartment syndrome (0.070 N/mg/mm; SD, 0.052 N/mg/mm), and patients with chronic compartment syndrome and diabetes (0.097 N/mg/mm; SD, 0.073 N/mg/mm). Similarly, no differences in fascial thickness were present. There was a negative correlation between fascial stiffness and intramuscular pressure in the patients with chronic compartment syndrome and diabetes. Conclusions The lack of difference in fascial thickness and stiffness in patients with chronic compartment syndrome and patients with chronic compartment syndrome and diabetes compared with healthy individuals suggests structural and mechanical properties are unlikely to explain chronic compartment syndrome. To prevent chronic exertional compartment syndrome, it is necessary to address aspects other than the muscle fascia.
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| 20. |
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| 21. |
- Edmundsson, David, 1956-
(författare)
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Chronic exertional compartment syndrome of the lower leg : a novel diagnosis in diabetes mellitus: a clinical and morphological study of diabetic and non-diabetic patients
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic exertional compartment syndrome (CECS) of the lower leg, defined as a condition with exercise-induced pain due to increased intramuscular pressure (IMP), has previously mainly been described in running athletes, and etiologic factors are poorly described. CECS has not been reported to occur together with other diseases and information about consequences on muscles morphology after treatment with fasciotomy is largely unknown. We investigated etiologic and pathophysiologic aspects to CECS in a consecutive series of 63 patients with exercise-related leg pain and in 17 diabetic patients with symptoms of intermittent claudication but no circulatory insufficiency. Clinical examination, radiography, scintigraphy and IMP measurements at rest and after reproduction of symptoms were done. Patients with CECS were recommended treatment with fasciotomy. Biopsies were taken from the tibialis anterior muscle at time of fasciotomy and at follow-up 1 year later. For comparison muscle samples were taken from normal controls. Enzyme- and immunohistochemical and morphometric methods were used for analysis of muscle fiber morphology/pathology, fiber phenotype composition, mitochondrial oxidative capacity and capillary supply. Thirty-six of the 63 patients fulfilled the criteria for diagnosis of CECS in the anterior tibial compartment. The CECS patients could be divided into different etiologic groups: 18 healthy, 10 with history of trauma against the lower leg, 4 diabetic patients and 4 others. Only 5 of 36 CECS patients were athletes. The results after fasciotomy were good or excellent in 41 of 57 treated legs. Sixteen of the 17 diabetic patients were diagnosed with CECS, 11 with diabetes type 1 and 5 with type 2. The diabetic patients differed from the other groups with longer symptom-duration, shorter pain-free walking distance, firm and tender lower leg muscles and higher IMP. The postoperative outcome was good or excellent in 15 of 18 treated legs. The muscle biopsies taken at fasciotomy showed frequent histopathological changes including small and large sized fibers, fiber atrophy, internal myonuclei, split fibers, fibrosis, disorganization of mitochondria in contrast to healthy CECS subjects having low muscle capillarization as the main finding. Muscular abnormalities were generally more complex, severe and widespread in diabetic patients. After 1 year, the majority of CECS patients could return to unrestricted physical activity and the histopathological muscle changes were clearly reduced. The muscle fiber size was larger and the muscles contained signs of regeneration and repair. Remaining muscle abnormalities were present mainly in diabetic patients. CECS is a new differential-diagnosis in diabetic patients with symptoms of claudication without signs of vascular disease. A low ability for physical activity, reflected by the signs of both myopathy and neuropathy, indicates that high IMP and circulatory impairment has deleterious effects for the involved muscles. Increased physical activity and normalization of muscle morphology 1 year after treatment shows the benefit of fasciotomy. The more severe clinical and morphological findings in diabetic compared to healthy subjects with CECS indicate differences in the pathogenesis. The unrestricted physical ability after treatment is very important for diabetic patients, since physical activity is an essential part of the therapy of the disease.
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| 22. |
- Edmundsson, David, 1956-, et al.
(författare)
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Evidence for low muscle capillary supply as a pathogenic factor in chronic compartment syndrome
- 2010
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - Copenhagen : Munksgaard. - 0905-7188 .- 1600-0838. ; 20:6, s. 805-813
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Tidskriftsartikel (refereegranskat)abstract
- There is a paucity of data regarding the pathogenesis of chronic exertional compartment syndrome (CECS), its consequences for the muscles and the effects of treatment with fasciotomy. We analyzed biopsies from the tibialis anterior muscle, from nine patients, obtained during a decompressing fasciotomy and during follow-up 1 year later. Control biopsies were obtained from nine normal subjects. Muscle capillarity, fiber-type composition and fiber area were analyzed with enzyme- and immunohistochemistry and morphometry. At baseline, CECS patients had lower capillary density (273 vs 378 capillaries/mm(2), P=0.008), lower number of capillaries around muscle fibers (4.5 vs 5.7, P=0.004) and lower number of capillaries in relation to the muscle fiber area (1.1 vs 1.5, P=0.01) compared with normal controls. The fiber-type composition and fiber area did not differ, but focal signs of neuromuscular damage were observed in the CECS samples. At 1-year follow-up after fasciotomy, the fiber area and the number of fibers containing developmental myosin heavy chains were increased, but no enhancement of the capillary network was detected. Thus, morphologically, patients with CECS seemed to have reduced microcirculation capacity. Fasciotomy appeared to trigger a regenerative response in the muscle, however, without any increase in the capillary bed.
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| 23. |
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| 24. |
- Edmundsson, David S., et al.
(författare)
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Muscle changes in patients with diabetes and chronic exertional compartment syndrome before and after treatment with fasciotomy
- 2018
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Ingår i: Muscle and Nerve. - : John Wiley & Sons. - 0148-639X .- 1097-4598. ; 57:2, s. 229-239
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Muscle changes in patients with diabetes and lower leg pain due to chronic exertional compartment syndrome (CECS) were investigated before and after fasciotomy.Methods: The tibialis anterior muscle was analyzed with histochemical and morphological techniques in 7 patients with diabetes and CECS before fasciotomy and in 5 of them 1 year after fasciotomy. Nondiabetic patients with CECS and healthy participants served as references.Results: Before treatment, walking distance until occurrence of pain was limited (<0.2 km). Intramuscular pressure was significantly higher than in reference participants. Muscle analysis showed changes pathognomonic for neuropathy and myopathy and a restricted capillary network, with significantly more severe changes in the muscles of patients with diabetes than in the muscles of nondiabetic patients. Treatment with fasciotomy improved clinical signs, increased walking ability, and reduced muscle abnormalities, but muscle capillarization remained low.Discussion: Patients with diabetes and CECS have distinct pathological changes in affected muscles. Pressure-relieving fasciotomy triggers a regenerative response in the muscle tissue but not in the capillary bed.
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| 25. |
- Ehinger, Anna, et al.
(författare)
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Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 2013
- 2017
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Ingår i: Acta Oncologica. - : TAYLOR & FRANCIS LTD. - 0284-186X .- 1651-226X. ; 56:1, s. 68-74
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Tidskriftsartikel (refereegranskat)abstract
- Background: The St Gallen surrogate definition of the intrinsic subtypes of breast cancer consist of five subgroups based on estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki-67. PgR and Ki-67 are used for discriminating between the Luminal A-like and Luminal B-like (HER2-negative) subtypes. Histological grade (G) has prognostic value in breast cancer; however, its relationship to the St Gallen subtypes is not clear. Based on a previous pilot study, we hypothesized that G could be a primary discriminator for ER-positive/HER2-negative breast cancers that were G1 or G3, whereas Ki-67 and PgR could provide additional prognostic information specifically for patients with G2 tumors. To test this hypothesis, a larger patient cohort was examined. Patients and methods: Six hundred seventy-one patients (amp;gt;= 35 years of age, pT1-2, pN0-1) with ER-positive/HER2-negative breast cancer and complete data for PgR, Ki-67, G, lymph node status, tumor size, age, and distant disease-free survival (DDFS; median follow-up 9.2 years) were included. Results: Luminal A-like tumors were mostly G1 or G2 (90%) whereas Luminal B-like tumors were mostly G2 or G3 (87%) and corresponded with good and poor DDFS, respectively. In Luminal B-like tumors that were G1 (n = 23), no metastasis occurred, whereas 14 of 40 Luminal A-like tumors that were G3 metastasized. In the G2 subgroup, low PgR and high Ki-67 were associated with an increased risk of distant metastases, hazard ratio (HR) and 95% confidence interval (CI) 1.8 (0.95-3.4) and 1.5 (0.80-2.8), respectively. Conclusions: Patients with ER-positive/HER2-negative/G1 breast cancer have a good prognosis, similar to that of Luminal A-like, while those with ER-positive/HER2-negative/G3 breast cancer have a worse prognosis, similar to that of Luminal B-like, when assessed independently of PgR and Ki-67. Therapy decisions based on Ki-67 and PgR might thus be restricted to the subgroup G2.
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