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There is an urgent need for new high‐quality markers for the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2‐bound α1‐acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated the predictive advantage of S2‐bound AGP in the early detection of HCC. In a retrospective case–control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct‐acting antiviral agents (n = 93), we measured S2‐bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at the start of treatment, end of treatment and follow‐up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). Thirty‐one patients chronically infected with HCV developed HCC after a sustained virological response, while 62 did not. In addition, samples of patients with chronic hepatitis B virus infection, metabolic dysfunction‐associated steatotic liver disease and HCC of different etiologies were analysed. S2‐bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2‐bound AGP for the early detection of HCC during treatment and follow‐up. Interestingly, S2‐bound AGP levels correlated with aspartate aminotransferase (ρ =.56, p = 9.5×10−15) and liver elastography (ρ =.67, p = 2.2×10−16). Of note, S2‐bound AGP decreased in patients chronically infected with HCV after treatment‐induced HCV clearance. Fucosylated S2‐bound AGP levels were elevated in patients with chronic HCV and HCC. The potential role of S2‐bound AGP as a novel tumour marker requires further investigation. [ABSTRACT FROM AUTHOR]

Background and Aims: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. Methods: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti‐HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti‐HDV testing was analysed in relation to liver‐related outcomes with logistic regression. Results: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti‐HDV screening; within a median of 1.8 months (range 0.0–57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti‐HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty‐five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow‐up. The predictive factors for anti‐HDV screening were Asian origin, diagnosis after the year 2012, HIV co‐infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co‐infection was the only remaining factor in multivariable analysis. Delayed anti‐HDV test >5 years was independently associated with worsened liver‐related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8–31.6). Conclusion: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low‐endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis. [ABSTRACT FROM AUTHOR]

The middle ear muscles have vital roles, yet their precise function in hearing and protection remains unclear. To better understand the function of these muscles in humans, the morphology, fiber composition, and metabolic properties of nine tensor tympani and eight stapedius muscles were analyzed with immunohistochemical, enzyme‐histochemical, biochemical, and morphometric techniques. Human orofacial, jaw, extraocular, and limb muscles were used as references. The immunohistochemical analysis showed that the stapedius and tensor tympani muscles were markedly dominated by fibers expressing fast contracting myosin heavy chain MyHC‐2A and MyHC‐2X (79 ± 6% vs. 86 ± 9%, respectively, p = 0.04). In fact, the middle ear muscles had one of the highest proportions of MyHC‐2 fibers ever reported for human muscles. Interestingly, the biochemical analysis revealed a MyHC isoform of unknown identity in both the stapedius and tensor tympani muscles. Muscle fibers containing two or more MyHC isoforms were relatively frequently observed in both muscles. A proportion of these hybrid fibers expressed a developmental MyHC isoform that is normally absent in adult human limb muscles. The middle ear muscles differed from orofacial, jaw, and limb muscles by having significantly smaller fibers (220 vs. 360 μm2, respectively) and significantly higher variability in fiber size, capillarization per fiber area, mitochondrial oxidative activity, and density of nerve fascicles. Muscle spindles were observed in the tensor tympani muscle but not in the stapedius muscle. We conclude that the middle ear muscles have a highly specialized muscle morphology, fiber composition, and metabolic properties that generally showed more similarities to orofacial than jaw and limb muscles. Although the muscle fiber characteristics in the tensor tympani and stapedius muscles suggest a capacity for fast, fine‐tuned, and sustainable contractions, their difference in proprioceptive control reflects different functions in hearing and protection of the inner ear. [ABSTRACT FROM AUTHOR]

Background and Aims: Several genotypes associate with a worse histopathological profile in patients with non‐alcoholic fatty liver disease (NAFLD). Whether genotypes impact long‐term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD. Method: DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non‐alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population‐based registers. Events of severe liver disease and all‐cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression. Results: In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66–8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79–4.14). After up to 40 years of follow‐up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15–4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85–11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14–59.47). Overall mortality was not affected by any genetic variant. Conclusion: The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: Previous reports of muscle changes in the upper airways of obstructive sleep apnea (OSA) patients have primarily been attributed to acquired nerve lesions due to snoring vibrations. The aim of this study was to investigate whether alterations reflecting muscle fiber injuries also occur in the upper respiratory tract of snoring and OSA patients and if these changes relate to upper airway dysfunction. Methods: Muscle changes in biopsies from the soft palate of 20 patients suffering from snoring and OSA were investigated with enzyme, immunohistochemical, and morphometric techniques. Biopsies from eight healthy non‐snoring subjects were used as controls. Swallowing dysfunction was assessed with videoradiography. Results: Fourteen patients had various degrees of swallowing dysfunction. The muscle samples from all the patients showed changes typical for both motor‐nerve lesions and muscle fiber injuries. The most common alterations reflecting myopathy were fibers having aggregates and disorganization of cytoskeletal proteins (15.5 ± 10.7%). Other changes were fibers with vacuole‐like structures (5.0 ± 4.4%), centrally positioned myonuclei (7.9 ± 4.8%), subsarcolemmal accumulations of nuclei, and various forms and sizes of ring fibers, that is, fibers where the myofilaments were disorganized peripherally (2.8 ± 2.8%). Conclusion: The results show that muscle changes mirroring both myopathy and neuropathy co‐exist in the upper airway of snoring OSA patients. These findings suggest muscle weakness as a contributing factor to the upper airway dysfunction in OSA patients. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) infection causes a severe chronic viral hepatitis with accelerated development of liver cirrhosis and decompensation, but whether it further increases the risk of hepatocellular carcinoma (HCC) is unclear. We performed a comprehensive systematic review of the published literature and meta‐analysis to assess the risk of HCC in HDV and hepatitis B virus (HBV) co‐infected, compared to HBV mono‐infected patients. The study was conducted per a priori defined protocol, including only longitudinal studies, thus excluding cross‐sectional studies. Random‐effects models were used to determine aggregate effect sizes (ES) with 95% confidence intervals (CI). Meta‐regression was used to examine the associations among study level characteristics. Twelve cohort studies comprising a total of 6099 HBV/HDV co‐infected and 57,620 chronic HBV mono‐infected patients were analysed. The overall pooled ES showed that HBV/HDV co‐infected patients were at 2‐fold increased risk of HCC compared to HBV mono‐infected patients (ES = 2.12, 95% CI 1.14–3.95, I2 = 72%, N = 12). A six‐fold significant increased risk of HCC was noted among HIV/HBV/HDV triple‐infected, compared to HIV/HBV co‐infected patients. The magnitude of ES did not differ significantly after adjustment for study design and quality, publication year and follow‐up duration in univariable meta‐regression analysis. This systematic review and meta‐analysis shows that infection with HDV is associated with a 2‐fold higher risk of HCC development compared to HBV mono‐infection. HCC surveillance strategies taking this increased risk into account, and new treatment options against HDV, are warranted. [ABSTRACT FROM AUTHOR]

Skeletal muscle in individuals with CP also contains lower amounts of mtDNA, potentially indicating fewer mitochondria in CP skeletal muscle compared with typically developing muscle. We compared skeletal muscle samples from children with cerebral palsy (CP) and typically developing children and observed evidence of reduced mtDNA and OXPHOS protein content in CP skeletal muscle, indicating reduced mitochondrial abundance. Cerebral palsy (CP) muscle contains fewer energy-generating organelles than typically developing muscle. [Extracted from the article]

Background & Aims: Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra‐hepatic diseases, especially breast and colorectal cancer. Here we investigated long‐term outcomes of Swedish patients with HFE mutations. Methods: We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinson's disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes. Results: Median age at diagnosis was 52 years, 44% were females. During a mean follow‐up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver‐related outcomes were rare, with a cumulative incidence of <1%. Conclusions: Individuals found to be HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed. [ABSTRACT FROM AUTHOR]

Background and Aims: Non‐alcoholic fatty liver disease (NAFLD) is a growing cause of hepatocellular carcinoma (HCC). In NAFLD, HCC occurs more commonly in the absence of cirrhosis compared with other liver diseases; yet, patients with non‐cirrhotic NAFLD‐HCC are poorly characterized. Here, we characterized a large cohort of HCC cases and assessed the outcomes of patients with non‐cirrhotic NAFLD‐HCC. Methods: We identified all cases of HCC treated at the Karolinska University Hospital, Stockholm, Sweden from 2004 to 2017. Patient charts were manually reviewed for variable extraction. Cases were followed passively for all‐cause and HCC‐related mortality until the end of April 2018. Cox regression was performed to estimate mortality rates and identify mortality risk factors in patients with non‐cirrhotic NAFLD‐HCC. Results: Totally, 1562 cases with HCC were identified. Of these, 225 (14.4%) had NAFLD‐HCC, of which 83 (37%) did not have cirrhosis. Compared with patients with cirrhotic NAFLD‐HCC, patients with non‐cirrhotic NAFLD‐HCC were older (74 vs 70 years, P < 0.001), had a lower prevalence of type 2 diabetes (T2DM) (66% vs 80%, P = 0.02), larger tumours, less frequently underwent liver transplantation (0% vs 11%, P = 0.002), but more frequently underwent resection (35% vs 8%, P < 0.001). Mortality was similar (aHR for non‐cirrhotic NAFLD‐HCC vs cirrhotic NAFLD‐HCC 0.93, 95% CI 0.58‐1.51, P = 0.78). Parameters independently associated with increased mortality included the Barcelona Clinic Liver Cancer stage, number of tumours, lower albumin and presence of T2DM. Conclusions: Patients with non‐cirrhotic NAFLD‐HCC differ from those with cirrhosis in age, tumour size and allocated treatments. Despite these differences, survival is similar. [ABSTRACT FROM AUTHOR]

Objectives: Neuromuscular injuries are suggested to contribute to upper airway collapse and swallowing dysfunction in patients with sleep apnea. Neurotrophins, a family of proteins involved in survival, development, and function of neurons, are reported to be upregulated in limb muscle fibers in response to overload and nerve damage. We aimed to investigate the expression of two important neurotrophins, brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in muscle fibers of uvula from snorers and sleep apnea patients and to compare these findings with pharyngeal function. Methods: Uvula muscle biopsies from 22 patients and 10 controls were analyzed for BDNF, NGF, and cytoskeletal protein desmin using immunohistochemistry. Pharyngeal swallowing function was assessed using videoradiography. Results: BDNF, but not NGF, was significantly upregulated in a subpopulation of muscle fibers in snoring and sleep apnea patients. Two major immunoreaction patterns for BDNF were observed; a fine grainy point like BDNF staining was displayed in muscle fibers of both patients and controls (41 ± 23 vs. 25 ± 17%, respectively, P =.06), while an abnormal upregulated intense‐dotted or disorganized reaction was mainly observed in patients (8 ± 8 vs. 2 ± 2%, P =.02). The latter fibers, which often displayed an abnormal immunoreaction for desmin, were more frequent in patients with than without swallowing dysfunction (10 ± 8 vs. 3 ± 3%, P =.05). Conclusion: BDNF is upregulated in the upper airway muscles of snorers and sleep apnea patients, and especially in patients with swallowing dysfunction. Upregulation of BDNF is suggested to be a response to denervation, reinnervation, and repair of injured muscle fibers. Our findings propose that damaged upper airway muscles might heal following treatment for snoring and sleep apnea. Level of Evidence: NA [ABSTRACT FROM AUTHOR]

Background & Aims: Patients with non‐alcoholic fatty liver disease (NAFLD) are at an increased risk for cardiovascular disease (CVD). It is unclear whether histological variables may help predict CVD risk. We evaluated histology and traditional CV risk factors as predictors of CVD outcomes in a large NAFLD cohort. Methods: We included 603 biopsy‐proven NAFLD patients free of baseline CVD and matched these (1:10, by age, sex and municipality) to 6269 population controls. All individuals were cross‐linked to national registries to ascertain incident CVD events, defined as acute ischaemic heart disease or stroke. The presence of CV risk factors and liver histology were available in NAFLD patients only. Cox regression models were used to estimate hazard ratios (HR) for incident CVD. Results: During a mean follow‐up of 18.6 years, 168 (28%) of NAFLD patients and 1325 (21%) of controls experienced a CVD event (HR 1.54, 95%CI 1.30‐1.83). Within the NAFLD cohort, age, male sex, type 2 diabetes, smoking and triglycerides were associated with risk of CVD. Taking these CV risk factors into account, no histological parameter, including presence of NASH and fibrosis stage, were associated with incident CVD. Conclusions: Patients with NAFLD are at an increased risk for CVD compared to matched controls, but histological parameters do not seem to independently predict this risk. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease(NAFLD) is the second most common cause of liver transplantation in the US. Data on NAFLD as a liver transplantation indication from countries with lower prevalences of obesity are lacking. We studied the temporal trends of NAFLD as an indication for liver transplantation in the Nordic countries, and compared outcomes for patients with NAFLD to patients with other indications for liver transplantation. Method: Population‐based cohort study using data from the Nordic Liver Transplant Registry on adults listed for liver transplantation between 1994 and 2015. NAFLD as the underlying indication for liver transplantation was defined as a listing diagnosis of NAFLD/nonalcoholic steatohepatitis, or cryptogenic cirrhosis with a body mass index ≥25 kg/m2 and absence of other liver diseases. Waiting time for liver transplantation, mortality and withdrawal from the transplant waiting list were registered. Survival after liver transplantation was calculated using multivariable Cox regression, adjusted for age, sex, body mass index and model for end‐stage liver disease. Results: A total of 4609 patients listed for liver transplantation were included. NAFLD as the underlying indication for liver transplantation increased from 2.0% in 1994‐1995 to 6.2% in 2011‐2015 (P = .01) and was the second most rapidly increasing indication. NAFLD patients had higher age, model for end‐stage liver disease and body mass index when listed for liver transplantation, but overall survival after liver transplantation was comparable to non‐‐NAFLD patients (aHR 1.03, 95% CI 0.70‐1.53 P = .87). Conclusion: NAFLD is an increasing indication for liver transplantation in the Nordic countries. Despite more advanced liver disease, NAFLD patients have a comparable survival to other patients listed for liver transplantation. [ABSTRACT FROM AUTHOR]

Introduction: Children with cerebral palsy (CP) and acquired brain injury (ABI) commonly develop muscle contractures with advancing age. An underlying growth defect contributing to skeletal muscle contracture formation in CP/ABI has been suggested.Methods: The biceps muscles of children and adolescents with CP/ABI (n = 20) and typically developing controls (n = 10) were investigated. We used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blotting to assess gene expression relevant to growth and size homeostasis.Results: Classical pro-inflammatory cytokines and genes involved in extracellular matrix (ECM) production were elevated in skeletal muscle of children with CP/ABI. Intramuscular collagen content was increased and satellite cell number decreased and this was associated with reduced levels of RNA polymerase I transcription factors, 45s pre-rRNA and 28S rRNA.Discussion: The present study provides novel data suggesting a role for pro-inflammatory cytokines and reduced ribosomal production in the development/maintenance of muscle contractures, possibly underlying stunted growth and perimysial ECM expansion. Muscle Nerve 58: 277-285, 2018. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Prognostication in hepatocellular carcinoma (HCC) is demanding. Not only tumour extent and performance status are to be considered, but also liver function, which is often limiting for both survival itself and for treatment possibilities. This study was conducted to assess whether patient‐reported questionnaires containing general and liver‐specific questions could improve prognostication of survival. Methods: 185 patients with hepatocellular carcinoma in Norway and Sweden were prospectively included. Patients completed the quality‐of‐life questionnaires EORTC QLQ C30 and HCC18, and clinical, radiological and laboratory parameters were registered. Multivariate Cox regression and Harrell's C‐statistics were used to identify the model that best predicted mortality. Results: Quality‐of‐life data were prognostic for overall survival. Fatigue and nutrition scales were prognostic in the multivariable analyses alone and in combination with clinical parameters. The prognostic value of established scoring systems was increased by the addition of QoL data. The best prognostic power was achieved by combining HCC18 nutrition scale with selected background parameters. Conclusion: Quality‐of‐life questionnaires can prognosticate mortality in HCC patients. When combined with established scoring systems, both the general cancer questionnaire EORTC QLQ C30, and the additional liver cancer‐specific HCC18 increased the prognostic accuracy slightly. [ABSTRACT FROM AUTHOR]

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. Muscle Nerve 57: 229-239, 2018. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a common response to many chronic liver diseases. The aim of our study was to explore whether pharmacotherapy for concurrent diseases affects overall mortality, liver-related mortality and liver-related morbidity in patients with chronic liver disease. We performed a register-based cohort study of all patients with a first-time diagnosis of chronic liver disease between 2005 and 2012 in Sweden (n = 70 546). Data from the Patient Register, the Prescribed Drug Register and the Death Certificate Register were linked. We studied whether the use of statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and antibiotics affected the risk of total mortality, liver-specific mortality and morbidity. We found a reduction in mortality risk for statin users (n = 11,245) with hazard ratios from 0.57 (95% CI: 0.32-0.99) for patients with autoimmune hepatitis to 0.84 (95% CI: 0.75-0.95) for patients with alcoholic liver disease. There was a significantly reduced liver-related mortality for patients with alcoholic liver disease who used angiotensin-converting enzyme inhibitors, 0.85 (95% CI: 0.65-0.96). There were increased overall mortality risks for antibiotic users (n = 44,572), with hazard ratios up to 1.67 (95% CI, 1.55-1.80) for viral hepatitis. Statin use was associated with decreased risks of liver-specific mortality and morbidity, and reduced total mortality foremost among patients with alcoholic liver disease. Angiotensin-converting enzyme inhibitors was associated with reduced liver-related mortality among patients with alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Background & Aims High levels of ferritin in patients with non-alcoholic fatty liver disease ( NAFLD) are associated with significant fibrosis and higher NAFLD activity score ( NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD. Methods We included 222 patients between 1979 and 2009 with biopsy-proven NAFLD and available serum ferritin concentrations. The cohort was divided into 'high' ( n = 89) and 'normal' ( n = 133) ferritin values, using a cut-point of 350 μg/L in males, and 150 μg/L in females, and stratified upon iron overload status. Data on mortality were obtained from a national, population-based register. Poisson regression was used to estimate hazard ratios for mortality. The estimates were adjusted for age at biopsy, sex, smoking, BMI, diabetes, hypertension, cardiovascular disease and fibrosis stage at the time of biopsy. Results The median follow-up time was 15.6 years (range: 0.5-34.2). Patients with high ferritin had more advanced fibrosis and higher NAS than patients with normal ferritin ( P < 0.05). Fifteen years after diagnosis, and after adjusting for confounders, the high-ferritin group showed an increasingly higher mortality that was statistically significant (Hazard ratio = 1.10 per year, 95% Confidence interval 1.01-1.21, P < 0.05). There was no difference in mortality between patients with different iron overload patterns. Conclusions High levels of ferritin are associated with a long-term increased risk of death. [ABSTRACT FROM AUTHOR]

The human oropharyngeal muscles have a unique anatomy with diverse and intricate functions. To investigate if this specialization is also reflected in the cytoarchitecture of muscle fibers, intermediate filament proteins and the dystrophin-associated protein complex have been analyzed in two human palate muscles, musculus uvula ( UV) and musculus palatopharyngeus ( PP), with immunohistochenmical and morphological techniques. Human limb muscles were used as reference. The findings show that the soft palate muscle fibers have a cytoskeletal architecture that differs from the limb muscles. While all limb muscles showed immunoreaction for a panel of antibodies directed against different domains of cytoskeletal proteins desmin and dystrophin, a subpopulation of palate muscle fibers lacked or had a faint immunoreaction for desmin ( UV 11.7% and PP 9.8%) and the C-terminal of the dystrophin molecule ( UV 4.2% and PP 6.4%). The vast majority of these fibers expressed slow contractile protein myosin heavy chain I. Furthermore, an unusual staining pattern was also observed in these fibers for β-dystroglycan, caveolin-3 and neuronal nitric oxide synthase nNOS, which are all membrane-linking proteins associated with the dystrophin C-terminus. While the immunoreaction for nNOS was generally weak or absent, β-dystroglycan and caveolin-3 showed a stronger immunostaining. The absence or a low expression of cytoskeletal proteins otherwise considered ubiquitous and important for integration and contraction of muscle cells indicate a unique cytoarchitecture designed to meet the intricate demands of the upper airway muscles. It can be concluded that a subgroup of muscle fibers in the human soft palate appears to have special biomechanical properties, and their unique cytoarchitecture must be taken into account while assessing function and pathology in oropharyngeal muscles. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin-V and PI and 40,6-diamidino-2-phenylindole-staining of nuclei. In addition, signs of both caspase-dependent and - independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly-ADP ribose polymerase-cleavage as well as translocation of Apoptosis-inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3-II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC. [ABSTRACT FROM AUTHOR]

The first descriptions of muscle spindles with intrafusal fibres containing striated myofibrils and nervous elements were given approximately 150 years ago. It took, however, another 100 years 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 Umeå 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. [ABSTRACT FROM AUTHOR]

Background & Aims Surveillance for hepatocellular carcinoma ( HCC) in patients with cirrhosis is recommended in clinical guidelines. In real-life management, surveillance rates below 20% have been reported from the United States. We aimed to determine the use of HCC-surveillance in patients diagnosed with HCC in a European setting, and to identify the reasons for surveillance failures. Methods Age, gender, tumour characteristics, BCLC classification, Child-Pugh stage, pre-existing liver disease, treatment, survival, frequency of HCC surveillance and reasons for surveillance failures were retrospectively determined in 616 patients diagnosed with HCC at Karolinska University Hospital 2005-2012. Results Hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease ( NAFLD) were the most common diagnoses. The proportion of HCC patients diagnosed through surveillance was 22%. In 35% of cases, surveillance was missed due to doctor′s failure to order surveillance or to diagnose the underlying liver disease. Diagnosis of NAFLD or alcoholic liver disease increased the risk of not receiving surveillance more than two-fold. Undiagnosed liver disease was most common in NAFLD patients. Patients who underwent surveillance had smaller tumours, more frequently received curative treatment, and had better survival compared to those in whom surveillance was indicated but missed. Conclusion In a European setting, only 22% of HCCs were diagnosed by surveillance, and in more than one-third of cases, surveillance was indicated but missed. NAFLD and alcoholic liver disease were associated with deficient surveillance. Survival was significantly better in patients who underwent surveillance compared with those in whom surveillance was missed although indicated. [ABSTRACT FROM AUTHOR]

Neural cell adhesion molecule (N-CAM) is expressed by activated hepatic stellate cells (HSC), portal fibroblasts, cholangiocytes and hepatic progenitor cells during liver injury. Its functional role in liver disease and fibrogenesis is unknown. The aim of this study was to investigate the role of N-CAM in liver fibrogenesis. To induce fibrosis, N-CAM knockout mice and wild-type controls were subjected to bile duct ligation (BDL) or repeated carbon tetrachloride (CCl) injections. Fibrosis was quantified by hydroxyproline, immunhistochemistry staining and image analysis. Protein levels were determined with immunoblotting. HSCs were isolated by ultracentrifugation in a Larcoll gradient and thereafter in vitro stimulated with recombinant transforming growth factor (TGF)-β1. Two weeks after BDL, wild-type mice had developed pronounced liver fibrosis while N-CAM−/− mice had less such alterations. N-CAM−/− mice had less deposition of collagen and fibronectin seen in immunhistochemistry. The protein levels of fibronectin were higher in the liver from the wild type, while laminin were unaltered. CCl-treated N-CAM−/− and wild-type mice showed no significant difference in the extent of liver fibrosis or the expression levels of the above-mentioned genes. HSC isolated from N-CAM−/− mice showed declined levels of smooth muscle actin and desmin after stimulation in vitro with TGF-β1. Loss of N-CAM results in decreased hepatic collagen and fibronectin deposition in mice subjected to BDL, but not in animals exposed to repeated CCl injections. HSC isolated from N-CAM null mice show impaired activation in vitro. This indicates a role of N-CAM in cholestatic liver disease and HSC activation. [ABSTRACT FROM AUTHOR]

Background: Hyperbiliverdinaemia is a poorly defined clinical sign that has been infrequently reported in cases of liver cirrhosis or liver carcinoma, usually indicating a poor long-term prognosis. Aims: To clarify the pathogenesis of hyperbiliverdinaemia in an extended case report. Methods: A 64-year-old man with alcoholic cirrhosis was admitted to hospital with severe bleeding from oesophageal varices. Ultrasonography showed ascites, but no dilatation of the biliary tree. The skin, sclerae, plasma, urine and ascites of the patient showed a greenish appearance. Bilirubin levels were normal, and there were no signs of haemolysis. Biliverdin was analysed in plasma and urine with liquid chromatography coupled to mass spectrometry. The seven exonic regions of the biliverdin reductase-A (BVR-A) gene was amplified by polymerase chain reaction and sequenced. Results: Biliverdin was present in plasma and urine. In nucleotide 52 of exon I of the DNA isolated from the hyperbiliverdinaemic patient, we discovered a novel heterozygous C→T nonsense mutation converting an arginine ( GA) in position 18 into a stop codon ( GA) (R18Stop) predicted to truncate the protein N-terminally to the active site Tyr97. Two children of the proband were heterozygous for the identical mutation in the BVR-A gene, but had no clinical signs of liver disease and had normal levels of biliverdin. The BVR-A gene mutation was not found in 200 healthy volunteers or nine patients with end-stage liver cirrhosis. Conclusion: Hyperbiliverdinaemia (green jaundice) with green plasma and urine may be caused by a genetic defect in the BVR-A gene in conjunction with decompensated liver cirrhosis. [ABSTRACT FROM AUTHOR]

The altered iron metabolism in hepatocellular carcinomas (HCCs), characterized by the iron-deficient phenotype, is suggested to be of importance for tumour growth. However, the underlying molecular mechanisms remain poorly understood. We asked whether these iron perturbations would involve altered expression of genes controlling iron homeostasis. Methods: HCCs were induced in rats by the Solt and Farber protocol of chemical hepatocarcinogenesis, and to evaluate the effects of iron loading, one group of animals were supplemented with dietary iron during tumour progression. Tissue iron contents were determined, labelling indices of S-phase nuclei were calculated, and mRNA levels of iron-regulatory genes were quantitated. Protein levels of ferroportin1 were determined with Western blot. Results: HCCs displayed reduced amount of tissue iron and lack of histologically stainable iron. HCCs expressed significantly higher mRNA levels of genes involved in iron uptake (transferrin receptor-1, divalent metal ion transporter-1), ferroxidase activity (Ferritin-H), and iron extrusion (ferroportin1). The protein levels of ferroportin1 in iron-deficient HCCs were similar as in control livers, and did not increase in HCCs exposed to iron. Hepcidin mRNA levels were decreased in iron-deficient HCCs, rose in response to iron loading and correlated to the tissue iron content. Conclusions: Taken together, the altered expressions of iron-regulatory genes in HCCs possibly reflect an increased demand for bioavailable iron and a high iron turnover in neoplastic cells. [ABSTRACT FROM AUTHOR]

Aim: The present study was undertaken to investigate possible effects of dietary iron during the progression step in hepatocarcinogenesis. Methods: Two experiments were performed, in which preneoplastic foci were produced in rat liver using the Solt & Farber protocol, with diethylnitrosamine as initiator and partial hepatectomy + 2-acetyl-aminofluorene as promoter. Two weeks after promotion, animals were fed 1.25-2.5% dietary carbonyl iron or a control diet until sacrifice. In the first experiment, animals were killed at different time points when they developed an abdominal mass in combination with weight loss. In the second experiment, animals were sacrificed 45 weeks post-promotion. Liver tumours were counted and histologically graded. Tumour levels of ubiquinone-9 and α-tocopherol were determined with HPLC, and labelling and apoptotic indices calculated using immunohistochemistry. The number and area of glutathione S-transferase 7,7 (GST-7,7)-positive foci were determined. Results: In experiment number 1, survival and tumour differentiation were similar in iron-treated animals and controls. In the second experiment, iron-treated rats had an increased number of GST-7,7-positive foci compared to controls. Number and size of carcinomas were similar between the groups, whereas tumour differentiation was higher in rats exposed to iron. Cell proliferation, apoptosis and concentrations of α-tocopherol in tumours were not altered by iron. The ratio of reduced/oxidized ubiquinone-9 was decreased in tumours from iron-treated animals. Conclusion: In this model, dietary iron overload resulted in an increased number of preneoplastic foci but did not enhance the progression of these into hepatocellular carcinomas. Iron decreased the ratio of reduced/oxidized ubiquinone-9 in tumours, indicating that neoplastic liver cells utilize intracellular ubiquinones as a defense mechanism against iron-induced oxidative stress. [ABSTRACT FROM AUTHOR]