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  • 151.
    Horie, Masafumi
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan;RIKEN, Ctr Life Sci Technol, DGT, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa, Japan.
    Miyashita, Naoya
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mikami, Yu
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Sandelin, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Lab Med Reg Skane, Pathol, Lund, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan.
    An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer2018Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, nr 2, s. 154-165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC.

  • 152. Horne, B D
    et al.
    Lenzini, P A
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Jorgensen, A L
    Kimmel, S E
    Ridker, P M
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Anderson, J L
    Pirmohamed, M
    Limdi, N A
    Pendleton, R C
    McMillin, G A
    Burmester, J K
    Kurnik, D
    Stein, C M
    Caldwell, M D
    Eby, C S
    Rane, A
    Lindh, J D
    Shin, J-G
    Kim, H-S
    Angchaisuksiri, P
    Glynn, R J
    Kronquist, K E
    Carlquist, J F
    Grice, G R
    Barrack, R L
    Li, J
    Gage, B F
    Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy2012Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 107, nr 2, s. 232-240Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.

  • 153.
    Hotz, A.
    et al.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Fagerberg, C.
    Odense Univ Hosp, Dept Clin Genet, Odense, Denmark..
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Bygum, A.
    Odense Univ Hosp, Dept Dermatol, Odense, Denmark.;Odense Univ Hosp, Allergy Ctr, Odense, Denmark..
    Törmä, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Rauschendorf, M-A
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Zhang, Hanqian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Heinz, L.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany.;Univ Freiburg, Fac Biol, Freiburg, Germany..
    Bourrat, E.
    Hop St Louis, Ctr Reference Genodermatoses, Paris, France..
    Hausser, I.
    Univ Hosp Heidelberg, Inst Pathol, Heidelberg, Germany..
    Vestergaard, V.
    Odense Univ Hosp, Dept Clin Pathol, Odense, Denmark..
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Zimmer, A. D.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Fischer, J.
    Univ Freiburg, Inst Human Genet, Fac Med, Med Ctr, Freiburg, Germany..
    Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis2018Inngår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 178, nr 3, s. E207-E209Artikkel i tidsskrift (Annet vitenskapelig)
  • 154. Husby, Simon
    et al.
    Ralfkiaer, Ulrik
    Garde, Christian
    Zandi, Roza
    Ek, Sara
    Kolstad, Arne
    Jerkeman, Mats
    Laurell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Raety, Riikka
    Pedersen, Lone B.
    Pedersen, Anja
    Ehinger, Mats
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Karjalainen-Lindsberg, Marja-Liisa
    Delabie, Jan
    Clasen-Linde, Erik
    Brown, Peter
    Cowland, Jack B.
    Workman, Christopher T.
    Geisler, Christian H.
    Gronbaek, Kirsten
    miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, nr 17, s. 2669-2677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2trial (screening cohort). Prognosticmi RNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.

  • 155.
    Hårdstedt, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning Dalarna.
    Lindblom, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Hong, Jaan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    A novel model for studies of blood-mediated long-term responses to cellular transplants2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 1, s. 28-39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims

    Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h.

    Methods

    Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability.

    Results

    Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen.

    Conclusion

    A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.

  • 156.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B).  In this thesis, the clinical importance of the two types of amyloid fibrils was investigated.

    We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients.

    The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development.

    By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations.

    In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.

    Delarbeid
    1. Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
    Åpne denne publikasjonen i ny fane eller vindu >>Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
    Vise andre…
    2008 (engelsk)Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 216, nr 2, s. 253-61Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.

    Emneord
    amyloid, transthyretin, fibril, familial, heart, phenotype, age of onset
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-103613 (URN)10.1002/path.2411 (DOI)000259510000015 ()18729067 (PubMedID)
    Tilgjengelig fra: 2009-05-20 Laget: 2009-05-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Proportion between wild-type and mutant protein in truncated compared to full-length ATTR: an analysis on transplanted transthyretin T60A amyloidosis patients
    Åpne denne publikasjonen i ny fane eller vindu >>Proportion between wild-type and mutant protein in truncated compared to full-length ATTR: an analysis on transplanted transthyretin T60A amyloidosis patients
    Vise andre…
    2009 (engelsk)Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 379, nr 4, s. 846-850Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Familial ATTR amyloidosis is caused by point mutations in the transthyretin gene. The clinical manifestations are highly varied but polyneuropathy and/or cardiomyopathy are generally the main symptoms. The amyloid fibrils can either be composed of only intact ATTR molecules or intact together with fragmented ATTR species. As plasma TTR is almost exclusively synthesized in the liver, liver transplantation is performed in order to eliminate the mutant plasma TTR. The procedure has shown best results among patients with the V30M mutation, while a rapid continued cardiac deposition of wild-type (wt) TTR has been seen for many other mutations. In this paper we investigated the proportion of wtATTR in two TTRT60A patients that underwent liver transplantation; one patient died 3 weeks after surgery, the other patient survived for 12 months. As the role of fragmented TTR species in the pathogenesis is far from understood, we investigated the proportion of wt in these species separately to the full-length molecules, which has not been done before in transplanted patients. The results show a higher proportion of wtTTR in the 12-months-surviving patient than the 3-weeks-surviving patient, but interestingly this difference in wt proportion is mainly seen among the full-length, and not the fragmented, molecules.

    Emneord
    Amyloid, Transthyretin, Familial amyloidotic polyneuropathy, ATTRT60A, Liver transplantation, Fibril, Cardiomyopathy, Wild-type
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-103620 (URN)10.1016/j.bbrc.2008.12.095 (DOI)000263336700009 ()19118530 (PubMedID)
    Tilgjengelig fra: 2009-05-20 Laget: 2009-05-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
    Åpne denne publikasjonen i ny fane eller vindu >>Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
    2011 (engelsk)Inngår i: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 89, nr 2, s. 171-180Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Familial transthyretin (TTR) amyloidosis is caused by a mutation in the TTR gene, although wild-type (wt) TTR is also incorporated into the amyloid fibrils. Liver transplantation (LT) is the prevailing treatment of the disease and is performed in order to eliminate the mutant TTR from plasma. The outcome of the procedure is varied; especially problematic is a progressive cardiomyopathy seen in some patients, presumably caused by continued incorporation of wtTTR. What determines the discrepancy in outcome is not clear. We have previously shown that two structurally distinct amyloid fibrils (with or without fragmented ATTR) are found among ATTRV30M patients. In this study, we investigated the proportion of wtATTR in cardiac and adipose amyloid from patients having either fibril type. It was found that cardiac amyloid more easily incorporates wtTTR than adipose amyloid, offering a potential explanation for the vulnerability of cardiac tissue for continued amyloidosis after LT. In cardiac tissue, fibrils with fragmented ATTR contained a higher wt proportion than fibrils without, suggesting that continued incorporation of wtTTR after LT, perhaps, can take place more easily in these patients. In adipose tissue, a rapid increase in wt proportion after LT indicates that a rather fast turnover of the deposits must occur. A difference in wt proportion between the fibril types was seen post-LT but not pre-LT, possibly caused by differences in turnover rate. Conclusively, this study further establishes the basic dissimilarities between the two fibril types and demonstrates that their role in LT outcome needs to be further investigated.

    Emneord
    Amyloid, Transthyretin, Familial amyloidotic polyneuropathy, Liver transplantation, Wild-type
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-150732 (URN)10.1007/s00109-010-0695-1 (DOI)000288363300008 ()21107516 (PubMedID)
    Tilgjengelig fra: 2011-04-05 Laget: 2011-04-05 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    4. Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
    Åpne denne publikasjonen i ny fane eller vindu >>Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one composed of only intact ATTR (type B). Patients with type A fibrils have a late age of onset and signs of cardiomyopathy, while patients with type B fibrils have an early onset and much less myocardial involvement.

    The present study aimed to determine if the correlation between fibril type and clinical phenotype is true for familial amyloidosis in general. Cardiac and/or adipose tissue from 48 patients carrying 21 different non-TTRV30M mutations were examined, as well as 7 non-Swedish ATTRV30M patients. Fibril type was determined with western blotting and compared to the patients´ age of onset and degree of cardiomyopathy.

    Non-Swedish V30M patients showed the same correlation as described for Swedish V30M patients, with fibrils of only full-length ATTR (type B) linked to less myocardial involvement. In contrast, all patients with non-V30M mutations had a fibril composition with ATTR fragments (type A). Some of these patients had onset of disease at young age. The vast majority had increased thickness of left cardiac ventricle, but a few individuals had values within normal limits.

    This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis. It also suggests that fibrils composed of only full-length ATTR is an exception, perhaps only found among young ATTRV30M amyloidosis patients.

    Emneord
    amyloid, transthyretin, familial amyloidotic polyneuropathy, non-TTRV30M, TTRV30M, cardiomyopathy, fibril composition
    HSV kategori
    Forskningsprogram
    Biokemi; Biologi med inriktning mot molekylärbiologi; Biomedicinsk laboratorievetenskap; Experimentell patologi; Medicinsk biokemi; Molekylärbiologi; Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-160979 (URN)
    Tilgjengelig fra: 2011-11-27 Laget: 2011-11-03 Sist oppdatert: 2018-01-12
  • 157.
    Ihse, Elisabet
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Rapezzi, Claudio
    Cardiovascular Dept, University of Bologna, Italy.
    Merlini, Giampaolo
    Amyloid Research and Treatment Center, Scientific Institute Policlinico San Matteo, University of Pavia, Italy.
    Benson, Merrill D
    Dept of Pathology and Laboratory Medicine, Indiana University School of Medicine and Roudebush VA medical Center, Indianapolis, IN, USA.
    Ando, Yukio
    Dept of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
    Suhr, Ole B
    Dept of Public Health and Clinical Medicine, Umeå University.
    Leone, Ornella
    Pathology Department, S.Orsola-Malpighi Hospital, Bologna, Italy.
    Lorenzini, Massimiliano
    Cardiovascular Dept, University of Bologna, Italy.
    Quarta, Candida Cristina
    Cardiovascular Dept, University of Bologna, Italy.
    Obici, Laura
    Amyloid Research and Treatment Center, Scientific Institute Policlinico San Matteo, University of Pavia, Italy.
    Lavatelli, Francesca
    Amyloid Research and Treatment Center, Scientific Institute Policlinico San Matteo, University of Pavia, Italy.
    Liepnieks, Juris
    Dept of Pathology and Laboratory Medicine, Indiana University School of Medicine and Roudebush VA medical Center, Indianapolis, IN, USA.
    Ohshima, Toshinori
    Dept of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan.
    Jono, Hirofumi
    Dept of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosisManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one composed of only intact ATTR (type B). Patients with type A fibrils have a late age of onset and signs of cardiomyopathy, while patients with type B fibrils have an early onset and much less myocardial involvement.

    The present study aimed to determine if the correlation between fibril type and clinical phenotype is true for familial amyloidosis in general. Cardiac and/or adipose tissue from 48 patients carrying 21 different non-TTRV30M mutations were examined, as well as 7 non-Swedish ATTRV30M patients. Fibril type was determined with western blotting and compared to the patients´ age of onset and degree of cardiomyopathy.

    Non-Swedish V30M patients showed the same correlation as described for Swedish V30M patients, with fibrils of only full-length ATTR (type B) linked to less myocardial involvement. In contrast, all patients with non-V30M mutations had a fibril composition with ATTR fragments (type A). Some of these patients had onset of disease at young age. The vast majority had increased thickness of left cardiac ventricle, but a few individuals had values within normal limits.

    This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis. It also suggests that fibrils composed of only full-length ATTR is an exception, perhaps only found among young ATTRV30M amyloidosis patients.

  • 158. Isfoss, Björn L
    et al.
    Majak, Bernard
    Busch, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Braathen, Geir J
    Diagnosis of intraurothelial neoplasia: Interobserver variation and the value of individual histopathologic attributes2011Inngår i: Analytical and Quantitative Cytology and Histology, ISSN 0884-6812, Vol. 33, nr 2, s. 75-81Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To determine interobserver variation in histopathologic diagnosis of carcinoma in situ (CIS) and dysplasia (collectively intraurothelial neoplasia [IUN]) of the bladder and identify histomorphologic features important for diagnosis.

    STUDY DESIGN:

    A total of 272 consecutive bladder tissue samples were re-evaluated blindly by two general pathologists and one uropathologist for IUN. Discrepancies were resolved jointly. Fifteen histopathologic attributes were evaluated for prediction of diagnosis. Followup revealed recurrence and progression rates for each diagnostic category.

    RESULTS:

    Thirty-six percent of specimens contained no evaluable flat mucosa; 51% percent of specimens from papillary urothelial neoplasia (PUN) cases showed CIS. General pathologists detected 56-69% of CIS and 8-42% of dysplasia. Histopathologic features most predictive for CIS were nuclear size, variation in nuclear shape, loss of maturation, loss of polarity, and architectural disorder. None of these individually or in combination exceeded general pathologists' diagnostic accuracy. IUN was not predictive of recurrence or progress.

    CONCLUSION:

    Using material mostly consisting of flat mucosa gratuitously provided in PUN resection specimens, IUN carries no prognostic value. General histopathologists detect IUN poorly to moderately, and the five most discriminatory histomorphologic features are insufficient for diagnosis. Interobserver agreement for dysplasia is dismal. Absent flat mucosa in PUN resections predicts recurrence.

  • 159. Isfoss, Björn L
    et al.
    Majak, Bernard
    Busch, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Braathen, Geir J
    Simplification of grading papillary urothelial neoplasia using a reduced set of diagnostic features2011Inngår i: Analytical and Quantitative Cytology and Histology, ISSN 0884-6812, Vol. 33, nr 2, s. 68-74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To determine whether a reduced set of the histopathologic features used in internationally accepted classifications is capable of accurately grading papillary urothelial neoplasms (PUN).

    STUDY DESIGN:

    All surgical specimens from urinary bladders received during a 2-year period were reexamined by an expert uropathologist for assessing the accuracy of original nonexpert PUN grading and staging. Thirteen histopathologic features entailing 32 attributes were evaluated with regard to prediction of expert grade. Patients were followed for 35-59 months (mean, 47).

    RESULTS:

    A total of 88 PUN specimens could be analyzed completely including follow-up specimens. Agreement between original and expert grade was 71% for low-grade and 87% for high-grade PUN, with overall kappa = 0.53. The histomorphologic features most predictive of expert grade were architectural disorder, variability of nuclear enlargement, and absence of umbrella cells. Neither individual histomorphologic attributes nor their combinations were as predictive of expert pathologist grade as original diagnoses.

    CONCLUSION:

    Improvements in PUN grading and prognostication are not likely to be accomplished by only reducing the number of histomorphologic features currently recommended by the World Health Organization and International Society of Urological Pathology.

  • 160.
    Jabs, Verena
    et al.
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Edlund, Karolina
    Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Koenig, Helena
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Grinberg, Marianna
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Madjar, Katrin
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Rahnenfuehrer, Joerg
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Ekman, Simon
    Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden..
    Bergkvist, Michael
    Gavle Cent Hosp, Dept Oncol, Gavle, Sweden..
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Reg Canc Ctr Uppsala Orebro, Uppsala, Sweden.;Kings Coll London, Fac Life Sci & Med, Div Canc Studies, London, England..
    Ickstadt, Katja
    TU Dortmund Univ, Fac Stat, Dortmund, Germany..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hengstler, Jan G.
    Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikkel-id e0187246Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-small cell lung cancer (NSCLC) represents a genomically unstable cancer type with extensive copy number aberrations. The relationship of gene copy number alterations and subsequent mRNA levels has only fragmentarily been described. The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190) and their association with survival. While more than half of all analyzed gene copy number-gene expression pairs showed statistically significant correlations (10,296 of 18,756 genes), high correlations, with a correlation coefficient >0.7, were obtained only in a subset of 301 genes (1.6%), including KRAS, EGFR and MDM2. Higher correlation coefficients were associated with higher copy number and expression levels. Strong correlations were frequently based on few tumors with high copy number gains and correspondingly increased mRNA expression. Among the highly correlating genes, GO groups associated with posttranslational protein modifications were particularly frequent, including ubiquitination and neddylation. In a meta-analysis including 1,779 patients we found that survival associated genes were overrepresented among highly correlating genes (61 of the 301 highly correlating genes, FDR adjusted p<0.05). Among them are the chaperone CCT2, the core complex protein NUP107 and the ubiquitination and neddylation associated protein CAND1. In conclusion, in a comprehensive analysis we described a distinct set of highly correlating genes. These genes were found to be overrepresented among survival-associated genes based on gene expression in a large collection of publicly available datasets.

  • 161.
    Jansson, Desiree S.
    et al.
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Bröjer, Caroline
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, Uppsala, Sweden..
    Neimanis, Aleksija
    Natl Vet Inst SVA, Dept Pathol & Wildlife Dis, Uppsala, Sweden..
    Mörner, Torsten
    Natl Vet Inst SVA, Dept Dis Control & Epidemiol, Uppsala, Sweden..
    Murphy, Charles L.
    Univ Tennessee, Med Ctr, Dept Med, Knoxville, TN USA..
    Otman, Faruk
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Post mortem findings and their relation to AA amyloidosis in free-ranging Herring gulls (Larus argentatus)2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 3, artikkel-id e0193265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Since the late 1990s, high mortality and declining populations have been reported among sea birds including Herring gulls ( Larus argentatus) from the Baltic Sea area in Northern Europe. Repeated BoNT type C/D botulism outbreaks have occurred, but it remains unclear whether this is the sole and primary cause of mortality. Thiamine deficiency has also been suggested as a causal or contributing factor. With this study, we aimed to investigate gross and microscopic pathology in Herring gulls from affected breeding sites in Sweden in search of contributing diseases. Herring gulls from Iceland served as controls. Necropsies and histopathology were performed on 75 birds, of which 12 showed signs of disease at the time of necropsy. Parasites of various classes and tissues were commonly observed independent of host age, e.g. oesophageal capillariosis and nematode infection in the proventriculus and gizzard with severe inflammation, air sac larid pentastomes and bursal trematodiasis in pre-fledglings. Gross and microscopic findings are described. Notably, amyloidosis was diagnosed in 93 and 33% of the adult birds from Sweden and Iceland, respectively ( p<0.001), with more pronounced deposits in Swedish birds ( p<0.001). Gastrointestinal deposits were observed in the walls of arteries or arterioles, and occasionally in villi near the mucosal surface. Amyloid was identified within the intestinal lumen in one severely affected gull suggesting the possibility of oral seeding and the existence of a primed state as previously described in some mammals and chickens. This could speculatively explain the high occurrence and previously reported rapid onset of amyloidosis upon inflammation or captivity in Herring gulls. Amyloid-induced malabsorbtion is also a possibility. The Herring gull SAA/AA protein sequence was shown to be highly conserved but differed at the N-terminus from other avian species.

  • 162. Jardin, Fabrice
    et al.
    Pujals, Anais
    Pelletier, Laura
    Bohers, Elodie
    Camus, Vincent
    Mareschal, Sylvain
    Dubois, Sydney
    Sola, Brigitte
    Ochmann, Marlène
    Lemonnier, François
    Viailly, Pierre-Julien
    Bertrand, Philippe
    Maingonnat, Catherine
    Traverse-Glehen, Alexandra
    Gaulard, Philippe
    Damotte, Diane
    Delarue, Richard
    Haioun, Corinne
    Argueta, Christian
    Landesman, Yosef
    Salles, Gilles
    Jais, Jean-Philippe
    Figeac, Martin
    Copie-Bergman, Christiane
    Molina, Thierry Jo
    Picquenot, Jean Michel
    Cornic, Marie
    Fest, Thierry
    Milpied, Noel
    Lemasle, Emilie
    Stamatoullas, Aspasia
    Moeller, Peter
    Dyer, Martin J S
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bastard, Christian
    Tilly, Hervé
    Leroy, Karen
    Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.2016Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 91, nr 9, s. 923-30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.

  • 163.
    Jiang, Yiwen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Marinescu, Voichita Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Maturi, Naga Prathyusha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Olofsson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindberg, Nanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Natl Board Forens Med, Dept Forens Med, Box 1024, S-75140 Uppsala, Sweden..
    Leijonmarck, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin2017Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, nr 4, s. 977-990Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

  • 164. Jin, J-P
    et al.
    Bloch, Robert J
    Huang, Xupei
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Muscle contractility and cell motility2012Inngår i: Journal of Biomedicine and Biotechnology, ISSN 1110-7243, E-ISSN 1110-7251, nr Article ID 257812Artikkel i tidsskrift (Fagfellevurdert)
  • 165. Johnson, JA
    et al.
    Caudle, KE
    Gong, L
    Whirl-Carrillo, M
    Stein, CM
    Scott, SA
    Lee, MT
    Gage, BF
    Kimmel, SE
    Perera, MA
    Anderson, JL
    Pirmohamed, M
    Klein, TE
    Limdi, NA
    Cavallari, LH
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update2017Inngår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, nr 3, s. 397-404Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

  • 166.
    Jonsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Reference interval for urinary catecholamines and methylated catecholamines analysed using HPLC2012Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Catecholamines are stress hormones that are produced and released by a rare tumor called pheochromocytoma. This tumor can cause hypertension which if undiagnosed and untreated leads to death. Since good therapy is available, it is important to find the tumor in time. The most common way to diagnose the tumor is measurement of the biochemical markers; catecholamines and their metabolites, methylated catecholamines.

    After observation that almost all normetanephrine results for women were higher than the upper reference limit and therefore pathological, the accuracy of the present reference intervals was questioned. Therefore new reference intervals for both urinary catecholamines and methylated catecholamines were developed by analysis of 46 samples using HPLC. Creatinine was analysed in acidified urine in order to see if the results became the same as when analysed in non-acidified urine.

    Urinary catecholamines and methylated catecholamines were analysed using HPLC. Comparison between measurement of creatinine in acidified urine and non-acidified urine with an enzymatic method was performed using Architect ci 8200, Abbott.

    As suspected, there was a difference between the present and new intervals. Therefore the new intervals will be used for future diagnosis. There was no difference between the two treatments of creatinine samples wherefore it can be measured in both.In conclusion reference intervals determind in this study will be used and it was shown that creatinine can be measured in acidified urine.

  • 167. Jonsson, M
    et al.
    Hansson, L-O
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Grubb, Anders
    Plasmaproteiner, inflammation och amyloidos2018Inngår i: Laurells klinisk kemi i praktisk medicin. / [ed] Theodorsson E. ; Berggren Söderlund, M., Lund: Studentlitteratur AB, 2018, 10, s. 87-130Kapittel i bok, del av antologi (Fagfellevurdert)
  • 168.
    Kaden, Rene
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi. National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden.
    Ferrari, Sevinc
    National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden.
    Jinnerot, Tomas
    National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden.
    Lindberg, Martina
    National Veterinary Institute, Uppsala, Sweden; Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden; National Food Agency, Uppsala, Sweden.
    Wahab, Tara
    Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Public Health Agency of Sweden Solna, Sweden..
    Lavander, Moa
    Swedish Forum for Biopreparedness Diagnostics, Umeå, Uppsala and Solna, Sweden; Swedish Joint Laboratory for Food Safety and Biopreparedness, Uppsala, Sweden; National Food Agency, Uppsala, Sweden..
    Brucella abortus: determination of survival times and evaluation of methods for detection in several matrices2018Inngår i: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 18, artikkel-id 259Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Brucella abortus is a highly pathogenic zoonotic agent, tempting for the development of a rapid diagnostic method to enable adequate treatment and prevent further spread. Enrichment of the bacteria is often used as a first step in diagnostics to increase the bacterial number above the detection limit of the real-time PCR. The enrichment of Brucella spp. takes at least 3 days, which might be avoidable if sensitive PCR methods can be used. Since many matrices contain PCR inhibitors, the limit of detection (LOD) must be determined for each separate matrix. Another aim of this study was the determination of survival of Brucella abortus in the analyzed matrices. METHODS: The LOD for the detection of B. abortus in 14 matrices, relevant for human medicine, veterinary medicine and food and feed safety, was determined to evaluate the need of a pre-enrichment step prior to real-time PCR. The survival of B. abortus in the spiked matrices was tested by plate count in a 7-day interval for 132 days. RESULTS: The limit of detection for B. abortus in most matrices was in the range of 10(3)-10(4) CFU/g for cultivation and 10(4)-10(5) CFU/g for direct real-time PCR. The survival time of B. abortus was less than 21 days in apple puree and stomach content and 28 days in water while B. abortus remained viable at day 132 in milk, blood, spinach and minced meat. CONCLUSIONS: A direct PCR analysis without enrichment of bacteria saves at least 3 days. However, the limit of detection between direct PCR and plate count differs in a 10 fold range. We conclude that this lower sensitivity is acceptable in most cases especially if quick analysis are required.

  • 169. Kankel, Jennifer
    et al.
    Obreja, Otilia
    Kleggetveit, Inge Petter
    Schmidt, Roland
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Jørum, Ellen
    Schmelz, Martin
    Namer, Barbara
    Differential effects of low dose lidocaine on C-fiber classes in humans2012Inngår i: Journal of Pain, ISSN 1526-5900, E-ISSN 1528-8447, Vol. 13, nr 12, s. 1232-1241Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The nonselective sodium channel blocker lidocaine is widely used as a local anesthetic but also systemically for treatment of postoperative and neuropathic pain. Voltage-gated sodium channels are crucial for action potential generation and conduction, and their availability controls the amount of activity-dependent conduction velocity slowing. This important axonal property, as assessed by microneurography, is used to differentiate human mechanoinsensitive (silent) nociceptors from the classical polymodal nociceptors. In the current study, microneurography was used to assess axonal properties of the 2 main nociceptor classes in humans, before and after intradermal injection of lidocaine .1% or control saline solution in the receptive field. In mechanosensitive nociceptors, lidocaine reduced baseline conduction velocity and turned activity-dependent slowing into speeding of conduction. In contrast, mechanoinsensitive fibers were not affected in their baseline conduction velocity or their activity-dependent slowing, but probability of conduction block with repetitive stimulation increased. Recovery cycles showed reduced hyperpolarization in all C-fiber classes after lidocaine injections. These results support our hypothesis that sodium channel subtypes are differentially expressed in the 2 nociceptor classes of mechanosensitive C-fibers (CMs) and mechanoinsensitive C-fibers (CMis).

    Perspective: This study reveals that microneurography can be used to assess pharmacologicaleffects on single C-fibers directly in humans. 

  • 170.
    Karakatsanis, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Bergkvist, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Abdsaleh, S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Simplifying Logistics and Avoiding the Unnecessary in Patients with Breast Cancer Undergoing Sentinel Node Biopsy. A Prospective Feasibility Trial of the Preoperative Injection of Super Paramagnetic Iron Oxide Nanoparticles2018Inngår i: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 107, nr 2, s. 130-137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Sentinel node is routinely localized with the intraoperative use of a radioactive tracer, involving challenging logistics. Super paramagnetic iron oxide nanoparticle is a non-radioactive tracer with comparable performance that could allow for preoperative localization, would simplify the procedure, and possibly be of value in axillary mapping before neoadjuvant treatment. The current trial aimed to determine the a priori hypothesis that the injection of super paramagnetic iron oxide nanoparticles in the preoperative period for the localization of the sentinel node is feasible.

    METHODS: This is a prospective feasibility trial, conducted from 9 September 2014 to 22 October 2014 at Uppsala University Hospital. In all, 12 consecutive patients with primary breast cancer planned for resection of the primary and sentinel node biopsy were recruited. Super paramagnetic iron oxide nanoparticles were injected in the preoperative visit in the outpatient clinic. The radioactive tracer (99mTc) and the blue dye were injected perioperatively in standard fashion. A volunteer was injected with super paramagnetic iron oxide nanoparticles to follow the decline in the magnetic signal in the sentinel node over time. The primary outcome was successful sentinel node detection.

    RESULTS: Super paramagnetic iron oxide nanoparticles' detection after preoperative injection (3-15 days) was successful in all cases (100%). In the volunteer, axillary signal was presented for 4 weeks. No adverse effects were noted. Conclusion and relevance: Preoperative super paramagnetic iron oxide nanoparticles' injection is feasible and leads to successful detection of the sentinel node. That may lead to simplified logistics as well as the identification, sampling, and marking of the sentinel node in patients planned for neoadjuvant treatment.

  • 171. Karamanakos, Petros N.
    et al.
    Jaaskelainen, Juha E.
    Alafuzoff, Irina
    Department of Clinical Pathology, University Hospital, Kuopio, Finland.
    Pirinen, Elina
    Vanninen, Ritva
    Silvennoinen, Sanna
    Sankilampi, Ulla
    Immonen, Arto
    Malignant giant cell tumor in the posterior fossa of a neonate: case report2010Inngår i: Journal of Neurosurgery: Pediatrics, ISSN 1933-0707, E-ISSN 1933-0715, Vol. 5, nr 3, s. 277-282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Giant cell tumors (GCTs) of the bone are rare, usually benign but locally aggressive neoplasms that primarily occur in the epiphyses of long bones. They seldom develop in the cranium; when they do, they involve principally the sphenoid and temporal bones. These tumors usually affect young adults, and few reports in children have been published. Primary malignant GCTs of the skull are even more uncommon. The 3 published cases all involved adults over 40 years of age. Herein, the authors present a case of a highly aggressive primary malignant GCT of the posterior fossa in a 5-week old preterm infant. One month after the gross-total resection of the tumor found in the bone, the infant's condition rapidly deteriorated and she died. Magnetic resonance imaging and postmortem examination revealed a tumor larger than it had been before the operation, with expansion toward the brain. To the best of the authors' knowledge, this is the youngest patient reported with a primary malignant GCT of the skull, and actually the first case in a pediatric patient. In addition, the extremely high growth rate of the tumor in the postoperative period renders this case the most aggressive primary malignant GCT of the cranium described so far.

  • 172.
    Karawajczyk, Malgorzata
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Point-of-care instruments need to offer high levels of accuracy2017Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, nr 10, artikkel-id 1707Artikkel i tidsskrift (Annet vitenskapelig)
  • 173.
    Karlsson, Anna
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Veerla, Srinivas
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jönsson, Mats
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Reuterswärd, Christel
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Skane Univ Hosp, Dept Resp Med & Allergol, Lund, Sweden..
    Staaf, Johan
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification2017Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, nr 8, s. 1257-1267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) constitute a small proportion of NSCLC. The WHO 2015 classification guidelines changed the definition of the debated histological subtype LCLC to be based on immunomarkers for adenocarcinoma and squamous cancer. We sought to determine whether these new guidelines also translate into the transcriptional landscape of lung cancer, and LCLC specifically.

    Methods: Gene expression profiling was performed by using Illumina V4 HT12 microarrays (Illumina, San Diego, CA) on samples from 159 cases (comprising all histological subtypes, including 10 classified as LCLC WHO 2015 and 14 classified as LCNEC according to the WHO 2015 guidelines), with complimentary mutational and immunohistochemical data. Derived transcriptional phenotypes were validated in 199 independent tumors, including six WHO 2015 LCLCs and five LCNECs.

    Results: Unsupervised analysis of gene expression data identified a phenotype comprising 90% of WHO 2015 LCLC tumors, with characteristics of poorly differentiated proliferatiVe cancer, a 90% tumor protein p53 gene (TP53) mutation rate, and lack of well-known NSCLC oncogene driver alterations. Validation in independent data confirmed aggregation of WHO 2015 LCLCs in the specific phenotype. For LCNEC tumors, the unsupervised gene expression analysis suggested two different transcriptional patterns corresponding to a proposed genetic division of LCNEC tumors into SCLC-like and NSCLC-like cancer on the basis of TP53 and retinoblastoma 1 gene (RB1) alteration patterns.

    Conclusions: Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining driven classification with the transcriptional landscape of lung cancer.

  • 174.
    Karlsson, Terese
    et al.
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Kvarnbrink, Samuel
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Holmlund, Camilla
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Henriksson, Roger
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Johansson, Mikael
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Hedman, Hakan
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease2018Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, s. 174-184Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.

    Materials and methods: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.

    Results: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.

    Conclusion: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.

  • 175. Kerr, Keith M
    et al.
    Tsao, Ming-Sound
    Nicholson, Andrew G
    Yatabe, Yasushi
    Wistuba, Ignacio I
    Hirsch, Fred R
    Botling, Johan
    IASLC Pathology Committee.
    Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer: In what state is this art?2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 7, s. 985-989Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Therapeutic antibodies to programmed death receptor 1 (PD-1) and its ligand PD-L1 show promising clinical results. Anti-PD-L1 immunohistochemistry (IHC) may be a biomarker to select patients more likely to respond to these treatments. However, the development of at least four different therapeutics, each with a different anti-PD-L1 IHC assay, has raised concerns among pathologists and oncologists alike. This article reviews existing data on the IHC biomarker aspects of studies using these drugs in non-small-cell lung cancer (NSCLC) and considers the challenges ahead, should these drug/IHC assay combinations reach routine practice. For each the known biomarker assays in development, there is a different monoclonal IHC antibody clone, produced by one of two diagnostics companies. Each test requires proprietary staining platforms and uses different definitions of a "positive" test for PD-L1 expression, on tumor cells and, in one test, also on tumor infiltrating immune cells. There are still considerable gaps in our knowledge of the technical aspects of these tests, and of the biological implications and associations of PD-L1 expression in NSCLC, considering heterogeneity of expression, dynamic changes in expression, and prognostic implications among other factors. The International Association for the Study of Lung Cancer Pathology Committee raises the prospect of trying not only to harmonize and standardize testing for PD-L1 by IHC, at least at a technical level, but also, ideally, as a predictive marker, to facilitate availability of this test and a promising treatment for patients with NSCLC.

  • 176.
    Khezri, Banafsheh
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Helmersson-Karlqvist, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Estimation of the possible economic effects of a sequential testing strategy with NT-proBNP before echocardiography in primary care2014Inngår i: Clinical Laboratory, ISSN 1433-6510, Vol. 60, nr 7-8, s. 881-886Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    The object of the study was to estimate the possible economic effects of a sequential testing strategy with NT-proBNP from a primary care payer perspective.

    METHODS:

    The study data were collected from primary care physicians in the County of Uppland from 2005 through 2012. Two different cut-off levels were used for negative NT-proBNP in the rule-out test: 300 and 400 pg/mL. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for echocardiographies.

    RESULTS:

    The female patients were slightly older than the males. Based on the data from 2012, the estimated costs for NT-proBNP tests and echocardiographies per county were reduced by EUR 300000/100000 inhabitants with the 300 pg/mL cut-off and EUR 350000/100000 inhabitants with the 400 pg/mL.

    CONCLUSIONS:

    The use of NT-proBNP as a rule-out test in a sequential testing strategy reduced the cost for diagnostic work-up of primary care patients with suspected heart failure.

  • 177. Kimby, Eva
    et al.
    Östenstad, Björn
    Brown, Peter
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Erlanson, Martin
    Holte, Harald
    Linden, Ola
    Johansson, Ann-Sofie
    Ahlgren, Tomas
    Wader, Karin
    Wahlin, Björn Engelbrekt
    Delabie, Jan
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas2015Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, nr 9, s. 2598-2607Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with advanced CD20 + indolent lymphoma, requiring therapy, were randomized to rituximab (four weekly infusions of 375 mg/m(2)) or to rituximab combined with 5 weeks of interferon-α2a (IFN-α2a) (3-4.5 MIU daily) as priming. Responding patients were eligible for a second cycle with the same allocated treatment. In total, 156 patients were randomized to rituximab and 157 to rituximab + IFN-α2a. In the intention-to treat (ITT) population, 244 patients (78%) responded to cycle 1. After a second cycle the complete remission/complete remission unconfirmed (CR/CRu) rate was 41% with the combination versus 24% with monotherapy (p = 0.005). The median time to treatment failure (primary endpoint) in ITT patients was 28 vs. 21.5 months, respectively (p = 0.302). After a long median follow-up (61 months), 33% (42% of patients responding to cycle 1) were still failure-free with an overall survival rate of 88% and with no difference between the treatment groups. The trial was registered at ClinicalTrials.gov Identifier: NCT01609010.

  • 178.
    Kinch, Amelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Tufveson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Association between HLA-A1 and -A2 types and Epstein-Barr virus status of post-transplant lymphoproliferative disorder2016Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 57, nr 10, s. 2351-2358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The susceptibility to Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) may be affected by the human leukocyte antigen (HLA) type. We investigated HLA-A and HLA-B allele frequencies, focusing on HLA-A1 and -A2, in a population-based case series of EBV + (n = 60) and EBV- (n = 44) PTLD after solid organ transplantation. The proportion of EBV + PTLD was highest in HLA-A1 homozygotes (100%), lower in carriers of HLA-A1/AX (79%), HLA-A1/A2 (55%), HLA-A2/AX (54%), and lowest in HLA-A2 homozygotes (37%). HLA-A1 type was overrepresented (22% versus 7%, p = 0.05) and HLA-A2 type underrepresented (57% versus 80%, p = 0.01) in patients with EBV + compared with EBV - PTLD. EBV + PTLD in HLA-A1 carriers developed almost exclusively in already EBV-seropositive individuals. EBV status of PTLD was not related to any other HLA-A or HLA-B type. Our findings suggest that HLA-A1 carriers may have an increased risk of EBV + PTLD due to a decreased ability to control the latent EBV infection.

  • 179.
    Knight, Ann
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hjorton, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Smedby, Karin E
    Askling, Johan
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Leukemia and Myelodysplastic Syndrome in Granulomatosis with Polyangiitis: Subtypes, Clinical Characteristics, and Outcome2015Inngår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, nr 4, s. 690-694Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Previous studies have shown that patients with granulomatosis with polyangiitis (GPA) have an increased risk of hematological malignancies, especially leukemia. Our aim was to assess clinical characteristics and treatment of patients with GPA complicated by hematological malignancies with focus on leukemia and to describe these malignancies in more detail.

    METHODS: From the Swedish population-based patient register, all individuals with a diagnosis of GPA from 1964-2012 were identified (n = 3224). Through linkage with the Swedish Cancer Register, we searched for all cases of leukemia [International Classification of Diseases (ICD) 7: 204-207 and corresponding codes ICD 8-10] registered after the first discharge listing GPA. The GPA diagnosis was evaluated using the European Medical Association classification algorithm. To confirm the hematological malignancy, all diagnostic bone marrow samples were reclassified. Clinical data of both the GPA and hematological malignancy were collected from medical files.

    RESULTS: Twenty-one cases were identified, all of myeloid origin, including 9 with myelodysplastic syndrome developing to acute myeloid leukemia (MDS-AML), 7 AML, 3 MDS, and 2 chronic myeloid leukemia. The median time from GPA diagnosis to hematological malignancy was 8 years (range 5-21). All patients had severe generalized GPA and had received high doses of cyclophosphamide (CYC; median cumulative dose 96.5 g). Cytopenia occurred in 76% of the patients prior to the hematological malignancy.

    CONCLUSION: The findings emphasize the longterm risk of leukemia and MDS in CYC-treated, severely ill patients with GPA. Cytopenia during the course of GPA may be a warning sign and warrants a liberal attitude toward bone marrow examination.

  • 180. Koivisto, Anne M
    et al.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Savolainen, Sakari
    Sutela, Anna
    Rummukainen, Jaana
    Kurki, Mitja
    Jääskeläinen, Juha E
    Soininen, Hilkka
    Rinne, Jaakko
    Leinonen, Ville
    Poor Cognitive Outcome in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus2013Inngår i: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 72, nr 1, s. 1-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. OBJECTIVE:: To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. METHODS:: The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. RESULTS:: At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition. CONCLUSION:: The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH-related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities. ABBREVIATIONS:: Aβ, amyloid betaAD, Alzheimer diseaseCI, confidence intervalHPτ, hyperphosphorylated tauICP, intracranial pressureiNPH, idiopathic normal pressure hydrocephalusKUH, Kuopio University HospitalNPH, normal pressure hydrocephalusVaD, vascular dementia.

  • 181.
    Kollmer, Marius
    et al.
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Meinhardt, Katrin
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Haupt, Christian
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Liberta, Falk
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Wulff, Melanie
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Linder, Julia
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Handl, Lisa
    Univ Ulm, Inst Stochast, D-89081 Ulm, Germany..
    Heinrich, Liesa
    Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany..
    Loos, Cornelia
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Schmidt, Matthias
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Syrovets, Tatiana
    Univ Ulm, Inst Pharmacol Nat Prod & Clin Pharmacol, D-89081 Ulm, Germany..
    Simmet, Thomas
    Univ Ulm, Inst Pharmacol Nat Prod & Clin Pharmacol, D-89081 Ulm, Germany..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Westermark, Gunilla T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Horn, Uwe
    Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany..
    Schmidt, Volker
    Univ Ulm, Inst Stochast, D-89081 Ulm, Germany..
    Walther, Paul
    Univ Ulm, Cent Electron Microscopy Facil, D-89081 Ulm, Germany..
    Faendrich, Marcus
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits2016Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 20, s. 5604-5609Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.

  • 182. Kolstad, Arne
    et al.
    Laurell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Jerkeman, Mats
    Grønbæk, Kirsten
    Elonen, Erkki
    Räty, Riikka
    Pedersen, Lone Bredo
    Loft, Annika
    Bogsrud, Trond Velde
    Kimby, Eva
    Hansen, Per Boye
    Fagerli, Unn Merete
    Nilsson-Ehle, Herman
    Lauritzsen, Grete Fossum
    Lehmann, Anne Kristine
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Karjalainen-Lindsberg, Marja-Liisa
    Ralfkiaer, Elisabeth
    Ehinger, Mats
    Delabie, Jan
    Bentzen, Hans
    Schildt, Jukka
    Kostova-Aherdan, Kamelia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Frederiksen, Henrik
    Brown, Peter de Nully
    Geisler, Christian H
    Nordic MCL-3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, nr 19, s. 2953-2959Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The main objective of the MCL3 study was to improve outcome for patients not in CR before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. 160 consecutive, untreated stage II-IV MCL patients < 66 years received rituximab (R)- maxi-CHOP alternating with R-high-dose Ara-C (6 cycles total), followed by high-dose BEAM or BEAC and autologous stem cell transplantation 2005-2009. Zevalin (0.4 mCi/kg) was given to responders in only CRu/PR prior to high-dose therapy. The overall response rate (ORR) pre-transplant was 97%. After a median follow-up of 4.4 years the outcome did not differ from that of the historic control, the MCL2 trial with the same treatment except for Zevalin. Overall (OS), event free (EFS), and progression-free survival (PFS) at 4 years were 78, 62 and 71%, respectively. For patients in CRu/PR before transplant who received Zevalin duration of response was shorter than in the CR group. Inferior PFS, EFS- and OS were predicted by PET-positivity pre-transplant and detectable minimal residual disease (MRD) before and after transplant. In conclusion, a positive PET prior to transplant and MRD are strong predictors of outcome. Late intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant.

  • 183.
    Kolstad, Arne
    et al.
    Oslo Univ Hosp, Radiumhospitalet, Dept Oncol, Oslo, Norway..
    Pedersen, Lone Bredo
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Eskelund, Christian W.
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Husby, Simon
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Jerkeman, Mats
    Skane Univ Hosp, Dept Oncol, Lund, Sweden..
    Laurell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Raty, Riikka
    Univ Helsinki, Cent Hosp, Dept Hematol & Oncol, Helsinki, Finland..
    Elonen, Erkki
    Univ Helsinki, Cent Hosp, Dept Hematol & Oncol, Helsinki, Finland..
    Andersen, Niels Smedegaard
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Brown, Peter deNully
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Kimby, Eva
    Karolinska Inst, Dept Hematol, S-10401 Stockholm, Sweden..
    Bentzen, Hans
    Aarhus Univ Hosp, Dept Hematol, DK-8000 Aarhus, Denmark..
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden..
    Ehinger, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Karjalainen-Lindsberg, Marja-Liisa
    Skane Univ Hosp, Dept Pathol, Lund, Sweden..
    Delabie, Jan
    Helsinki Univ Cent Hosp, Dept Pathol, Helsinki, Finland..
    Ralfkiaer, Elisabeth
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark.;Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Fagerli, Unn-Merete
    Copenhagen Univ Hosp, Rigshospitalet, Dept Pathol, Copenhagen, Denmark..
    Nilsson-Ehle, Herman
    St Olavs Univ Hosp, Dept Oncol, Trondheim, Norway..
    Lauritzsen, Grete Fossum
    Oslo Univ Hosp, Radiumhospitalet, Dept Oncol, Oslo, Norway..
    Kuittinen, Outi
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden. Oulu Univ Hosp, Dept Oncol, Oulu, Finland..
    Niemann, Carsten
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Geisler, Christian Hartman
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years2017Inngår i: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 23, nr 3, s. 428-435Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rear-rangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P <.0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P <.0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.

  • 184. Kovacs, Gabor G
    et al.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Preface.2017Inngår i: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, artikkel-id ixArtikkel i tidsskrift (Fagfellevurdert)
  • 185.
    Kovacs, Gabor G
    et al.
    Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    Ferrer, Isidro
    Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Spain.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Concomitant pathologies II: neurodegenerative conditions2015Inngår i: Neuropathology of neurodegenerative diseases A practical guide / [ed] Gabor G Kovacs, Cambridge University Press, 2015, s. 292-298Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Introduction The term “mixed or concomitant” pathologies in neurodegenerative disease means that, in addition to the hallmark lesions of a neurodegenerative disease entity, further pathological alterations can be observed in the same brain. The term mixed pathology was originally used when describing accompanying vascular pathology. Later, Lewy body pathology was also described as concomitant pathology when seen together with other neurodegenerative diseases. Currently, we classify neurodegenerative diseases according to the predominant protein that shows pathological depositions in the brain. During the diagnostic process, detecting hallmark lesions of a certain disease, like neuritic plaques in the cortex, spongiform change in the cortex, globose tangles in the brainstem nuclei or Lewy bodies in the brainstem or cortex, can lead to negligence of further lesions or performance of further stains. However, deposition of multiple proteins, in addition to co-occurrence of non-neurodegenerative pathology (e.g. vascular, metabolic), is a frequent event. In fact, overlapping neurodegeneration may be more the rule than the exception. This concept is supported by observations in genetic forms of neurodegenerative disorders where various proteins may show pathological deposits in the same brain [1–3]. Complex constellations of clinical symptoms (movement disorders and cognitive decline) may associate with the accompanying presence of diverse neurodegenerative disorders. There are several factors determining overlap between neurodegenerative disorders as proposed by Armstrong et al. [4]): (i) historical factors, which means that the original descriptions of key disorders were based on the descriptions of relatively small numbers of cases; furthermore, the original investigators interpreted these as ‘syndromes’ rather than distinct diseases; (ii) disease heterogeneity; (iii) age-related changes;(iv) apolipoprotein ɛ genotype, especially in cases with significant Aβ deposition but without further features of Alzheimer’s disease (AD); (v) co-occurrence of common diseases, like AD and Parkinson’s disease (PD), as both are more likely to occur in the elderly and thus are more likely to co-occur.

  • 186. Kovacs, Gabor G
    et al.
    Rozemuller, Annemieke J M
    van Swieten, John C
    Gelpi, Ellen
    Majtenyi, Katalin
    Al-Sarraj, Safa
    Troakes, Claire
    Bódi, István
    King, Andrew
    Hortobágyi, Tibor
    Esiri, Margaret M
    Ansorge, Olaf
    Giaccone, Giorgio
    Ferrer, Isidre
    Arzberger, Thomas
    Bogdanovic, Nenad
    Nilsson, Tatjana
    Leisser, Irene
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Ironside, James W
    Kretzschmar, Hans
    Budka, Herbert
    Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: A study of the BrainNet Europe Consortium2013Inngår i: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 39, nr 2, s. 166-178Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

  • 187. Kovacs, Gabor G.
    et al.
    Wagner, Uta
    Dumont, Benoit
    Pikkarainen, Maria
    Osman, Awad A.
    Streichenberger, Nathalie
    Leisser, Irene
    Verchère, Jérémy
    Baron, Thierry
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Budka, Herbert
    Perret-Liaudet, Armand
    Lachmann, Ingolf
    An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology2012Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, nr 1, s. 37-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    α-Synuclein is the major protein associated with Lewy body dementia, Parkinson's disease and multiple system atrophy. Since α-synuclein is present in the brain in physiological conditions as a presynaptic protein, it is crucial to characterize disease-associated modifications to develop an in vivo biomarker. With the aim to develop antibodies showing high specificity and sensitivity for disease-associated α-synuclein, synthetic peptides containing different amino acid sequences were used for immunization of mice. After generation of α-synuclein aggregates, ELISA and immunoblotting were used to test the specificity of antibodies. Tissue microarray sections originating from different human α-synucleinopathies were used to compare immunostaining with other, commercially available antibodies. Immunization of mice with the peptide TKEGVVHGVATVAE (amino acid 44-57 of α-synuclein) resulted in the generation of a monoclonal antibody (5G4), which was able to bind aggregated α-synuclein preparation in sandwich ELISA or coated on magnetic beads. 5G4 proved to be superior to other antibodies in comparative immunohistochemical studies by revealing more widespread and distinct α-synuclein pathology. Immunoblotting of human brain tissue revealed an additional band seen in dementia with Lewy bodies, whereas the band representing monomeric α-synuclein was very weak or lacking. In summary, the 5G4 antibody is most promising for re-evaluation of archival material and may offer new perspective for the development of in vivo diagnostic assays for detecting disease-associated α-synuclein in body fluids.

  • 188. Kuusisto, E
    et al.
    Kauppinen, T
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Use of p62/SQSTM1 antibodies for neuropathological diagnosis.2008Inngår i: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 34, nr 2, s. 169-80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The demonstration of proteinaceous inclusions in the brain is the key step in the pathological diagnosis of degenerative dementias. The diversity of these diseases has necessitated the use of a panel of (immuno)stains to visualize all suspect pathologies, elevating diagnostic costs. Immunodetection of p62 (sequestosome 1), an abundant constituent in diverse pathological inclusions, holds the potential for a broad-specificity, high-contrast inclusion label. In the brain, pathological p62-positive aggregates comprise both cytoplasmic and nuclear types in neurones and glia, with abnormal tau, alpha-synuclein, TAR DNA-binding protein 43 or polyglutamine proteins as primary components. We therefore set out to evaluate the performance of p62 antibodies for diagnostic immunohistochemistry. We optimized the application conditions and compared the staining profiles of eight commercial p62 antibodies with each other and with reference immunostains, using 2-mm tissue multiarrays representing the major tauo- and synucleinopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The lesions were best visualized using monoclonal antibodies, displaying most types of hallmark inclusions with excellent contrast. Expanding the list of p62-containing aggregates, we demonstrated p62 in tufted astrocytes, coiled bodies, astrocytic plaques, and variform neocortical inclusions and pathological processes in FTLD-U. Polyclonal antibodies exhibited lower sensitivities with variable background levels. We also noted more subtle p62-immunoreactive features lacking overt disease associations. Emphasizing the importance of proper antibody and epitope unmasking methods for maximum sensitivity, we recommend p62 immunodetection as a screening stain for diagnostic practice.

  • 189.
    Källberg, Linnéa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Evaluation of lithium-heparintube analyses performance2013Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Today, some kind of laboratory results is required for around 70% of the diagnostics and follow-ups for diseases. In many of the cases the time from sampling to a result is very critical. Therefore the discussion of how to improve this situation has begun. For many analyses serum has been the routine choice for a long time but now it is disputed. After blood collection in a serum tube it is essential to wait 30-60 minutes before centrifugation and analysis of the sample, a long time for someone in an acute state. Other problems like post centrifugation clots of fibrin causing false results or time-consuming reruns of the sample have also been reported. These problems have initiated the laboratory in Hudiksvall’s hospital to find out an alternative to the common serum sampling.In this report, the differences between serum and lithium heparin plasma for 31 analyses has been evaluated. Paired blood samples, one serum and one plasma, were collected for routine, hormonal and for tumor markers analyses and analyzed in a Cobas c501, e411 or e601 (ROCHE). The results of the analyzed samples were compared to each other by statistical analysis.The results prove that serum and lithium heparin plasma is equal for ALT, GGT, NT-proBNP, FT3, FT4, cobalamin, LH, prolactin, TSH, CA19-9, CEA and PSA. The results also prove that serum and lithium heparin plasma is not equal for 19 other analyses. Therefore, a shift between different types of sampling is not to be recommended without further evaluations.

  • 190. Kämäläinen, Anna
    et al.
    Viswanathan, Jayashree
    Natunen, Teemu
    Helisalmi, Seppo
    Kauppinen, Tarja
    Pikkarainen, Maria
    Pursiheimo, Juha-Pekka
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Kivipelto, Miia
    Haapasalo, Annakaisa
    Soininen, Hilkka
    Herukka, Sanna-Kaisa
    Hiltunen, Mikko
    GRN Variant rs5848 Reduces Plasma and Brain Levels of Granulin in Alzheimer's Disease Patients.2013Inngår i: Journal of Alzheimer's disease : JAD, ISSN 1875-8908, Vol. 33, nr 1, s. 23-7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.

  • 191.
    La Fleur, Linnea
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Boura, Vanessa F.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Alexeyenko, Andrey
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden;Natl Bioinformat Infrastruct Sweden, Sci Life Lab, Solna, Sweden.
    Berglund, Anders
    Epistat, Uppsala, Sweden.
    Ponten, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Persson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Brunnström, Hans
    Lund Univ, Skane Univ Hosp, Div Pathol, Lund, Sweden.
    Isaksson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karlsson, Mikael C. I.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer2018Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, nr 7, s. 1741-1752Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.

  • 192.
    La Fleur, Linnéa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Falk-Sörqvist, Elin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Smeds, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berglund, Anders
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mattsson, Johanna SM
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Isaksson, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Brunnström, Hans
    Nilsson, Mats
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Moens, Lotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK112019Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 130, s. 50-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.

    MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.

    RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.

    CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.

  • 193. Lafuente, Jose Vicente
    et al.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Patnaik, Ranjana
    Muresanu, Dafin Fior
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Diabetes Exacerbates Nanoparticles Induced Brain Pathology2012Inngår i: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 11, nr 1, s. 26-39Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Long term exposure of nanoparticles e.g., silica dust (SiO2) from desert environments, or engineered nanoparticles from metals viz., Cu, Al or Ag from industry, ammunition, military equipment and related products may lead to adverse effects on mental health. However, it is unclear whether these nanoparticles may further adversely affect human health in cardiovascular or metabolic diseases e.g., hypertension or diabetes. It is quite likely that in diabetes or hypertension where the body immune system is already compromised there will be greater adverse effects following nanoparticles exposure on human health as compared to their exposure to healthy individuals. Previous experiments from our laboratory showed that diabetic or hypertensive animals are more susceptible to heat stress-induced neurotoxicity. Furthermore, traumatic injury to the spinal cord in SiO2 exposed rats resulted in exacerbation of cord pathology. However, whether nanoparticles such as Cu, Ag or SiO2 exposure will lead to enhanced neurotoxicity in diabetic animals are still not well investigated. Previous data from our laboratory showed that Cu or Ag intoxication (50 mg/kg, i.p. per day for 7 days) in streptozotocine induced diabetic rats exhibited enhanced neurotoxicity and exacerbation of sensory, motor and cognitive function as compared to normal animals under identical conditions. Thus the diabetic animals showed exacerbation of regional blood-brain barrier (BBB) disruption, edema formation and cell injuries along with greater reduction in the local cerebral blood flow (CBF) as compared to normal rats. These observations suggest that diabetic animals are more vulnerable to nanoparticles induced brain damage than healthy rats. The possible mechanisms and functional significance of these findings are discussed in this review largely based on our own investigations.

  • 194. Laiterä, Tiina
    et al.
    Paananen, Jussi
    Helisalmi, Seppo
    Sarajärvi, Timo
    Huovinen, Joel
    Laitinen, Marjo
    Rauramaa, Tuomas
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Remes, Anne M
    Soininen, Hilkka
    Haapasalo, Annakaisa
    Jääskeläinen, Juha E
    Leinonen, Ville
    Hiltunen, Mikko
    Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients2017Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 55, nr 3, s. 995-1003Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects.

    OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients.

    METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition.

    RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition.

    CONCLUSION: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.

  • 195.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    What can we learn from studies on regional differences in the utilization of laboratory tests?2011Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, nr 4, s. 225-226Artikkel i tidsskrift (Fagfellevurdert)
  • 196.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Breimer, Lars
    Örebro Universitet.
    Anpassa utredningen av diabetes hos patienter med invandrarbakgrund.2018Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115, s. FFIZ-FFIZArtikkel i tidsskrift (Fagfellevurdert)
  • 197.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Breimer, Lars
    Örebro Universiet.
    Bra att läkare inte stirrar sig blinda på HbA1c2019Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, s. FIEW-Artikkel i tidsskrift (Annet vitenskapelig)
  • 198.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Carlsson, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Bodolea, Constantin
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid2015Inngår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, nr 2, s. 514-518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.

  • 199.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Greig-Pylypczuk, Roman
    Huisman, Albert
    The state of point-of-care testing: a european perspective2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 1, s. 1-10Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Abstract Point-of-care testing (POCT) refers to any diagnostic test administered outside the central laboratory at or near the location of the patient. By performing the sample collection and data analysis steps in the same location POCT cuts down on transport and processing delays, resulting in the rapid feedback of test results to medical decision-makers. Over the past decades the availability and use of POCT have steadily increased in Europe and throughout the international community. However, concerns about overall utility and the reliability of benefits to patient care have impeded the growth of POCT in some areas. While there is no agreed-upon standard for how success should be judged, the increases in speed and mobility provided by POCT can lead to substantial advantages over traditional laboratory testing. When properly utilized, POCT has been shown to yield measurable improvements in patient care, workflow efficiency, and even provide significant financial benefits. However, important organizational and quality assurance challenges must be addressed with the implementation of POCT in any health care environment. To ensure maximal benefits it may be necessary to evaluate critically and restructure existing clinical pathways to capitalize better on the rapid test turnaround times provided by POCT.

  • 200.
    Larsson, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Nordin, Gunnar
    För kort ”bäst före-datum” ett hot mot patientsäkerheten2014Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, artikkel-id C9A6Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
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