Browsing by Subject "LIVER"

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  • Lluch, Aina; Veiga, Sonia R.; Latorre, Jèssica; Moreno-Navarrete, José M.; Bonifaci, Núria; Nguyen, Van Dien; Zhou, You; Höring, Marcus; Liebisch, Gerhard; Olkkonen, Vesa M.; Llobet-Navas, David; Thomas, George; Rodríguez-Barrueco, Ruth; Fernández-Real, José M.; Kozma, Sara C.; Ortega, Francisco J. (2022)
    The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
  • Berger, Claudia; Heyne, Henrike O.; Heiland, Tina; Dommel, Sebastian; Hoefling, Corinna; Guiu-Jurado, Esther; Lorenz, Jana; Rossner, Steffen; Dannemann, Michael; Kelso, Janet; Kovacs, Peter; Blueher, Matthias; Kloeting, Nora (2021)
    The leptin receptor (Lepr) pathway is important for food intake regulation, energy expen-diture, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/ 6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chro-mosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-Lepr(L536Hfs*6-1NKB)), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, Lepr(L536Hfs*6) develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the Lepr(L536Hfs*6) model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Leprdb/wt with Lepr(L536Hfs*6/wt) mice results in compound heterozygous Lepr(L536Hfs*6/db) mice, which develop even higher body weight and fat mass than both homozygous Lepr(db/db) and Lepr(L536Hfs*6) mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.
  • Dillard, Kati J.; Hytönen, Marjo K.; Fischer, Daniel; Tanhuanpää, Kimmo; Lehti, Mari S.; Vainio-Siukola, Katri; Sironen, Anu; Anttila, Marjukka (2018)
    Ciliopathies presenting as inherited hepatorenal fibrocystic disorders are rare in humans and in dogs. We describe here a novel lethal ciliopathy in Norwich Terrier puppies that was diagnosed at necropsy and characterized as diffuse cystic renal disease and hepatic fibrosis. The histopathological findings were typical for cystic renal dysplasia in which the cysts were located in the straight portion of the proximal tubule, and thin descending and ascending limbs of Henle's loop. The pedigree of the affected puppies was suggestive of an autosomal recessive inheritance and therefore, whole exome sequencing and homozygosity mapping were used for identification of the causative variant. The analyses revealed a case-specific homozygous splice donor site variant in a cilia related gene, INPP5E: c.1572+5G>A. Association of the variant with the defect was validated in a large cohort of Norwich Terriers with 3 cases and 480 controls, the carrier frequency being 6%. We observed that the identified variant introduces a novel splice site in INPP5E causing a frameshift and formation of a premature stop codon. In conclusion, our results suggest that the INPP5E: c.1572+5G>A variant is causal for the ciliopathy in Norwich Terriers. Therefore, genetic testing can be carried out in the future for the eradication of the disease from the breed.
  • Lavilla-Alonso, Sergio; Bauerschmitz, Gerd; Abo-Ramadan, Usama; Halavaara, Juha; Escutenaire, Sophie; Diaconu, Iulia; Tatlisumak, Turgut; Kanerva, Anna; Hemminki, Akseli; Pesonen, Sari (2010)
  • Koivusalo, Antti; Mutanen, Annika; Nissinen, Markku; Gylling, Helena; Pakarinen, Mikko (2019)
    Objectives: We elucidated pathophysiology of pediatric gallstone disease by assessing liver expression of bile transporters in relation to bile acids and surrogates of cholesterol absorption and synthesis in serum and gallstones. Methods: RNA expression of canalicular bile transporters in liver biopsies from 32 pediatric gallstone patients and from 6 liver donors (controls) was measured by qRT-PCR (quantitative real-time reverse transcription polymerase chain reaction). Concentrations of cholesterol and precursors, plant sterols and bile acids in gallstones, and in serum of the patients and 82 healthy children were measured. Primary outcomes were the difference in RNA expressions and serum sterol profiles between patients and controls. Results: Cholesterol stones (CS; n = 15) contained cholesterol >42% and pigment stones (PS; n = 17)
  • Kettunen, Jarno L. T.; Parviainen, Helka; Miettinen, Päivi J.; Färkkilä, Martti; Tamminen, Marjo; Salonen, Pia; Lantto, Eila; Tuomi, Tiinamaija (2017)
    Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.
  • CAPP2 Investigators; Mathers, John C.; Elliott, Faye; Macrae, Finlay; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Burn, John (2022)
    The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P= 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. Prevention Relevance: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.
  • Wang, Liang; Li, Menglu; Bu, Qian; Li, Hongchun; Xu, Wei; Liu, Chunqi; Gu, Hui; Zhang, Jiamei; Wan, Xuemei; Zhao, Yinglan; Cen, Xiaobo (2019)
    Much efforts have been tried to clarify the molecular mechanism of alcohol-induced brain damage from the perspective of genome and protein; however, the effect of chronic alcohol exposure on global lipid profiling of brain is unclear. In the present study, by using Q-TOF/MS-based lipidomics approach, we investigated the comprehensive lipidome profiling of brain from the rats orally administrated with alcohol daily, continuously for one year. Through systematically analysis of all lipids in prefrontal cortex (PFC) and striatum region, we found that long-term alcohol exposure profoundly modified brain lipidome profiling. Notably, three kinds of lipid classes, glycerophospholipid (GP), glycerolipid (GL) and fatty acyls (FA), were significantly increased in these two brain regions. Interestingly, most of the modified lipids were involved in synthetic pathways of endoplasmic reticulum (ER), which may result in ER stress-related metabolic disruption. Moreover, alcohol-modified lipid species displayed long length of carbon chain with high degree of unsaturation. Taken together, our results firstly present that chronic alcohol exposure markedly modifies brain lipidomic profiling, which may activate ER stress and eventually result in neurotoxicity. These findings provide a new insight into the mechanism of alcohol-related brain damage.
  • Bossen, Lars; Vesterhus, Mette; Hov, Johannes R.; Färkkilä, Martti; Rosenberg, William M.; Moller, Holger J.; Boberg, Kirsten M.; Karlsen, Tom H.; Gronbaek, Henning (2021)
    INTRODUCTION: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC. METHODS: We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison. RESULTS: Median (interquartile range) sCD163 was 3.32 (2.27-5.60) and 1.96 (1.47-2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22-0.44) and 0.28 mg/L (0.20-0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients. DISCUSSION: Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516). [GRAPHICS]
  • Becker, Anna; Backman, Janne T.; Itkonen, Outi (2020)
    Introduction: Life-long monitoring of immunosuppressive drugs (ISDs) in blood is essential after organ transplantation. However, the ISD concentrations vary depending on the assay employed. ISDs are strongly bound to cytoplasmic proteins in erythrocytes in circulation. Therefore, the relatively rapid sedimentation of blood cells in whole blood samples may affect the results when using liquid handling robots. Methods: We used 1115 blood samples from outpatients and ward patients with kidney (n = 373), liver (n = 101), heart (n = 29) and bone marrow (n = 155) transplant. Whole blood samples were pretreated by protein precipitation. Alternatively, the samples were hemolyzed by freezing prior to precipitation. ISDs were analyzed by a 2-plexing liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and commercial chemiluminescent microparticle immunoassays (CMIA). Results: The difference between the two sample preparation practices was negligible (<2%). Overall, the measured ISD concentrations in patient samples were lower by LC-MS/MS than by CMIA. The difference was the largest (20.2%) and the smallest (9.1%) in samples from liver and from heart transplant patients, respectively. Conclusions: CMIA overestimates blood ISD concentrations as compared to LC-MS/MS. The extent of the difference was found to be organ transplant dependent. The ISDs can be quantitated either from intact or hemolyzed blood samples.
  • Grunewald, M.; Kumar, S.; Sharife, H.; Volinsky, E.; Gileles-Hillel, A.; Licht, T.; Permyakova, A.; Hinden, L.; Azar, S.; Friedmann, Y.; Kupetz, P.; Tzuberi, R.; Anisimov, A.; Alitalo, K.; Horwitz, M.; Leebhoff, S.; Khoma, O. Z.; Hlushchuk, R.; Djonov, Valentin G; Abramovitch, R.; Tam, J.; Keshet, E. (2021)
    Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, "inflammaging" (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.
  • Kiamehr, Mostafa; Heiskanen, Laura; Laufer, Thomas; Duesterloh, Aneta; Kahraman, Mustafa; Kakela, Reijo; Laaksonen, Reijo; Aalto-Setala, Katriina (2019)
    Aim: Primary human hepatocytes (PHHs) undergo dedifferentiation upon the two-dimensional (2D) culture, which particularly hinders their utility in long-term in vitro studies. Lipids, as a major class of biomolecules, play crucial roles in cellular energy storage, structure, and signaling. Here, for the first time, we mapped the alterations in the lipid profile of the dedifferentiating PHHs and studied the possible role of lipids in the loss of the phenotype of PHHs. Simultaneously, differentially expressed miRNAs associated with changes in the lipids and fatty acids (FAs) of the dedifferentiating PHHs were investigated. Methods: PHHs were cultured in monolayer and their phenotype was monitored morphologically, genetically, and biochemically for five days. The lipid and miRNA profile of the PHHs were analyzed by mass spectrometry and Agilent microarray, respectively. In addition, 24 key genes involved in the metabolism of lipids and FAs were investigated by qPCR. Results: The typical morphology of PHHs was lost from day 3 onward. Additionally, ALB and CYP genes were downregulated in the cultured PHHs. Lipidomics revealed a clear increase in the saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) containing lipids, but a decrease in the polyunsaturated fatty acids (PUFA) containing lipids during the dedifferentiation of PHHs. In line with this, FASN, SCD, ELOVL1, ELOVL3, and ELOVL7 were upregulated but ELOVL2 was downregulated in the dedifferentiated PHHs. Furthermore, differentially expressed miRNAs were identified, and the constantly upregulated miR-27a and miR-21, and downregulated miR-30 may have regulated the synthesis, accumulation and secretion of PHH lipids during the dedifferentiation. Conclusion: Our results showed major alterations in the molecular lipid species profiles, lipid-metabolizing enzyme expression as wells as miRNA profiles of the PHHs during their prolonged culture, which in concert could play important roles in the PHHs' loss of phenotype. These findings promote the understanding from the dedifferentiation process and could help in developing optimal culture conditions, which better meet the needs of the PHHs and support their original phenotype.
  • Corbacioglu, Selim; Carreras, Enric; Mohty, Mohamad; Pagliuca, Antonio; Boelens, Jaap Jan; Damaj, Gandhi; Iacobelli, Massimo; Niederwieser, Dietger; Olavarria, Eduardo; Suarez, Felipe; Ruutu, Tapani; Verdonck, Leo; Hume, Robin; Nejadnik, Bijan; Lai, Chinglin; Finetto, Giorgia; Richardson, Paul (2016)
    Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy results were consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose. (C) 2016 American Society for Blood and Marrow Transplantation.
  • Jyväkorpi , Satu K.; Suominen , Merja H.; Strandberg, Timo E.; Salminen, Karoliina; Niskanen, Riikka T.; Roitto, Hanna-Maria; Saarela, Riitta K. T.; Pitkälä, Kaisu H. (2022)
    Purpose To describe and compare detailed dietary fat intake, fat quality and associative factors between two measuring points 10 years apart of residents living in long-term care facilities, and to reflect how fat composition and fat quality corresponds to current nutrition recommendations. Methods In 2007 long-term care residents (n = 374) of 25 assisted-living facilities and nursing homes and in 2017-18 long-term care residents (n = 486) of 17 respective facilities in Helsinki metropolitan area were recruited for this study. Information on the residents' heights, demographic information and use of calcium and vitamin D supplementation were retrieved from medical records. Residents' clinical assessment included Clinical Dementia Rating (CDR), the Mini Nutritional Assessment (MNA) and questionnaire related to nutrition care. Participants' energy and fat intake were determined from 1--2-day food diaries kept by the ward nurses, and fat quality indicators calculated. Results Age, gender distribution, MNA score or body mass index did not differ between the two cohorts. Residents' cognitive status, subjective health and mobility were poorer in 2017 compared to 2007. Total fat and saturated fatty acid (SFA) intakes were higher and fat quality indicators lower in the 2017 cohort residents than in the 2007 cohort residents. Sugar intake, male gender, eating independently, eating larger amounts and not having dry mouth predicted higher SFA intake in the 2017 cohort. Conclusions The fat quality in long-term care residents in our study worsened in spite of official recommendations between the two measurement points.
  • Bogacheva, Mariia S.; Khan, Sofia; Kanninen, Liisa K.; Yliperttula, Marjo; Leung, Alan W.; Lou, Yan-Ru (2018)
    Definitive endoderm (DE) is the first stage of human pluripotent stem cell (hPSC) differentiation into hepatocyte-like cells. Developing human liver cell models for pharmaceutical applications is highly demanding. Due to the vast number of existing protocols to generate DE cells from hPSCs, we aimed to compare the specificity and efficiency of selected published differentiation conditions. We differentiated two hPSC lines (induced PSC and embryonic stem cell) to DE cells on Matrigel matrix using growth factors (Activin A and Wnt-3a) and small molecules (sodium butyrate and IDE 1) in different combinations. By studying dynamic changes during 6 days in cell morphology and the expression of markers for pluripotency, DE, and other germ layer lineages, we found that Activin A is essential for DE differentiation, while Wnt-3a and sodium butyrate are dispensable. Although sodium butyrate exerted rapid DE differentiation kinetics, it caused massive cell death and could not generate sufficient cells for further differentiation and applications. We further discover that IDE 1 could not induce DE as reported previously. Hereby, we compared different conditions for DE induction and found an effective six day-protocol to obtain DE cells for the further differentiation and applications.
  • Nissinen, Markku J.; Pitkänen, Niina; Simonen, Piia; Gylling, Helena; Viikari, Jorma; Raitakari, Olli; Lehtimäki, Terho; Juonala, Markus; Pakarinen, Mikko P. (2018)
    Background & aims: Gallstone disease is related to hypersecretion of cholesterol in bile, and low serum phytosterol levels. We examined how genetic polymorphisms of sterol transporters affect childhood cholesterol metabolism trait predicting adult gallstone disease. Patients and methods: In retrospective controlled study, we determined D19H polymorphism of ABCG8 gene, genetic variation at Niemann-Pick C1-like 1 (NPC1L1) gene locus (rs41279633, rs17655652, rs2072183, rs217434 and rs2073548), and serum cholesterol, noncholesterol sterols and lipids in children affected by gallstones decades later (n = 66) and controls (n = 126). Results: In childhood, phytosterols were lower (9.7%-23.4%) in carriers of risk allele 19H compared to 19D homozygotes. Lowest campesterol/cholesterol tertile consisted of 1.9-times more future gallstone subjects, and 3.7-times more 19H carriers than highest one. Campesterol/cholesterol-ratio was highest in 19D homozygote controls, but similar to 11% lower in gallstone 19D homozygotes and similar to 25% lower among gallstone and control carriers of 19H. Gallstone subjects with alleles CC of rs41279633 and TT of rs217434 of NPC1L1 had similar to 18% lower campesterol/cholesterol-ratio compared to mutation carriers. Conclusions: Risk trait of cholesterol metabolism (low phytosterols) in childhood favouring cholesterol gallstone disease later in adulthood is influenced by risk variant 19H of ABCG8 and obviously also other factors. NPC1L1 variants have minor influence on noncholesterol sterols. (c) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
  • Lundbom, Jesper; Bierwagen, Alessandra; Bodis, Kalman; Apostolopoulou, Maria; Szendroedi, Julia; Müssig, Karsten; Hwang, Jong-Hee; Roden, Michael (2019)
    Objectives There is a discrepancy between studies suggesting that higher bone marrow fat saturation is associated with impaired health, and studies suggesting that erythropoiesis increases red bone marrow (RBM) fat saturation in young healthy individuals. Here, we seeked to elucidate these discrepancies by using long TE magnetic resonance spectroscopy (MRS) to study both yellow bone marrow (YBM) and RBM in the femur of healthy volunteers. Materials and methods Thirty-three young healthy volunteers (17 females), age range 20-31 years, underwent long TE H-1 MRS at 3.0 T of RBM and YBM fat composition in the left femur. The water content of the bone marrow depots was measured using short TE MRS. Results The female participants displayed a lower unsaturation in the sampled RBM volume (RBMV) than the males (P <0.01) without displaying a concomitant difference in YBM (P = 0.42). They also showed a higher water content and broader spectral linewidths in RBM (P = 0.04). The water content in RBM strongly associated with broader spectral linewidths (R = 0.887, P MUCH LESS-THAN 0.01) and inversely with RBMV fat unsaturation (R = - 0.365, P = 0.04). Discussion These results partly support the notion that females display higher rate of erythropoiesis and lower fat unsaturation in RBM.
  • Purhonen, Janne; Rajendran, Jayasimman; Morgelin, Matthias; Uusi-Rauva, Kristiina; Katayama, Shintaro; Krjutskov, Kaarel; Einarsdottir, Elisabet; Velagapudi, Vidya; Kere, Juha; Jauhiainen, Matti; Fellman, Vineta; Kallijarvi, Jukka (2017)
    Mitochondrial disorders are among the most prevalent inborn errors of metabolism but largely lack treatments and have poor outcomes. High-fat, low-carbohydrate ketogenic diets (KDs) have shown beneficial effects in mouse models of mitochondrial myopathies, with induction of mitochondrial biogenesis as the suggested main mechanism. We fed KD to mice with respiratory chain complex III (CIII) deficiency and progressive hepatopathy due to mutated BCS1L, a CIII assembly factor. The mutant mice became persistently ketotic and tolerated the KD for up to 11 weeks. Liver disease progression was attenuated by KD as shown by delayed fibrosis, reduced cell death, inhibition of hepatic progenitor cell response and stellate cell activation, and normalization of liver enzyme activities. Despite no clear signs of increased mitochondrial biogenesis in the liver, CIII assembly and activity were improved and mitochondrial morphology in hepatocytes normalized. Induction of hepatic glutathione transferase genes and elevated total glutathione level were normalized by KD. Histological findings and transcriptome changes indicated modulation of liver macrophage populations by the mutation and the diet. These results reveal a striking beneficial hepatic response to KD in mice with mitochondrial hepatopathy and warrant further investigations of dietary modification in the management of these conditions in patients.
  • Färkkilä, Martti; Karvonen, Anna-Liisa; Nurmi, Heimo; Nuutinen, Hannu; Taavitsainen, Matti; Pikkarainen, Pekka; Kärkkäinen, Päivi (2004)
    No effective medical therapy is currently available for primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA) improves liver enzymes, but its effect on liver histology is controversial. Metronidazole (MTZ) prevents PSC-like liver damage in animal models and reduces intestinal permeability. We recruited 80 patients with PSC into a randomized placebo-controlled study to evaluate the effect of UDCA and MTZ (UDCA/MTZ) compared with UDCA/placebo on the progression of PSC. Patients (41 UDCA/placebo and 39 UDCA/ MTZ) were followed every third month. Assessment of liver function test, histological stage and grade, and cholangiography (via ERCP) at baseline showed no differences between the groups. After 36 months, serum aminotransferases gamma-glutamyltransferase, and alkaline phosphatase (ALP) decreased markedly in both groups, serum ALP more significantly in the UDCA/MTZ group (-337 +/- 54 U/L, P
  • Leppäniemi, A. (2019)
    Background and aims: Today, a significant proportion of solid abdominal organ injuries, whether caused by penetrating or blunt trauma, are managed nonoperatively. However, the controversy over operative versus nonoperative management started more than a hundred years ago. The aim of this review is to highlight some of the key past observations and summarize the current knowledge and guidelines in the management of solid abdominal organ injuries. Materials and Methods: A non-systematic search through historical articles and references on the management practices of abdominal injuries was conducted utilizing early printed volumes of major surgical and medical journals from the late 19th century onwards. Results: Until the late 19th century, the standard treatment of penetrating abdominal injuries was nonoperative. The first article advocating formal laparotomy for abdominal gunshot wounds was published in 1881 by Sims. After World War I, the policy of mandatory laparotomy became standard practice for penetrating abdominal trauma. During the latter half of the 20th century, the concept of selective nonoperative management, initially for anterior abdominal stab wounds and later also gunshot wounds, was adopted by major trauma centers in South Africa, the United States, and little later in Europe. In blunt solid abdominal organ injuries, the evolution from surgery to nonoperative management in hemodynamically stable patients aided by the development of modern imaging techniques was rapid from 1980s onwards. Conclusion: With the help of modern imaging techniques and adjunctive radiological and endoscopic interventions, a major shift from mandatory to selective surgical approach to solid abdominal organ injuries has occurred during the last 30-50 years.