Publications by authors named "T Salonen"

40 Publications

Modulating dream experience: Noninvasive brain stimulation over the sensorimotor cortex reduces dream movement.

Sci Rep 2020 04 21;10(1):6735. Epub 2020 Apr 21.

Department of Psychology, University of Zurich, 8050, Zurich, Switzerland.

Recently, cortical correlates of specific dream contents have been reported, such as the activation of the sensorimotor cortex during dreamed hand clenching. Yet, despite a close resemblance of such activation patterns to those seen during the corresponding wakeful behaviour, the causal mechanisms underlying specific dream contents remain largely elusive. Here, we aimed to investigate the causal role of the sensorimotor cortex in generating movement and bodily sensations during REM sleep dreaming. Following bihemispheric transcranial direct current stimulation (tDCS) or sham stimulation, guided by functional mapping of the primary motor cortex, naive participants were awakened from REM sleep and responded to a questionnaire on bodily sensations in dreams. Electromyographic (EMG) and electroencephalographic (EEG) recordings were used to quantify physiological changes during the preceding REM period. We found that tDCS, compared to sham stimulation, significantly decreased reports of dream movement, especially of repetitive actions. Other types of bodily experiences, such as tactile or vestibular sensations, were not affected by tDCS, confirming the specificity of stimulation effects to movement sensations. In addition, tDCS reduced EEG interhemispheric coherence in parietal areas and affected the phasic EMG correlation between both arms. These findings show that a complex temporal reorganization of the motor network co-occurred with the reduction of dream movement, revealing a link between central and peripheral motor processes and movement sensations of the dream self. tDCS over the sensorimotor cortex interferes with dream movement during REM sleep, which is consistent with a causal contribution to dream experience and has broader implications for understanding the neural basis of self-experience in dreams.
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http://dx.doi.org/10.1038/s41598-020-63479-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174293PMC
April 2020

Standardised spider (Arachnida, Araneae) inventory of Lammi, Finland.

Biodivers Data J 2020 13;8:e50775. Epub 2020 Mar 13.

Laboratory for Integrative Biodiversity Research (LIBRe), Finnish Museum of Natural History (LUOMUS), University of Helsinki, Helsinki, Finland Laboratory for Integrative Biodiversity Research (LIBRe), Finnish Museum of Natural History (LUOMUS), University of Helsinki Helsinki Finland.

Background: In June 2019, an ecology field course of the University of Helsinki was held at Lammi Biological Station, Southern Finland. Within this course, the students familiarised themselves with field work and identification of spiders and explored the diversity of species in the area. Three sampling plots were chosen, one in grassland and two in boreal forest, to demonstrate the sampling techniques and, by applying a standardised protocol (COBRA), contribute to a global spider biodiversity project.

New Information: The collected samples contained a total of 3445 spiders, of which 1956 (57%) were adult. Only adult spiders were accounted for in the inventory due to the impossibility of identification of juveniles. A total of 115 species belonging to 17 families were identified, of which the majority (58 species, 50%) were Linyphiidae. Lycosidae and Theridiidae both had 11 species (10%) and all the other families had seven or fewer species. Linyphiidae were also dominant in terms of adult individuals captured, with 756 (39%), followed by 705 (36%) Lycosidae. Other families with more than 100 individuals were Thomisidae (196, 10%) and Tetragnathidae (102, 5%). The most abundant species were the lycosids (362, 19%) and (290, 15%) and the linyphiid (123, 6%).
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http://dx.doi.org/10.3897/BDJ.8.e50775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083949PMC
March 2020

Chemometrics in forensic chemistry - Part II: Standardized applications - Three examples involving illicit drugs.

Forensic Sci Int 2020 Feb 26;307:110138. Epub 2019 Dec 26.

Netherlands Forensic Institute, Laan van Ypenburg 6, 2497 GB, The Hague, the Netherlands. Electronic address:

In the recently published article "Chemometrics in forensic chemistry - Part I: Implications to the forensic workflow" the application of chemometric methods in forensic casework was described. The steps to facilitate standardized chemometric procedures and the availability of chemometric tools such as software and a guideline are under development. Three examples of typical illicit drugs casework, wherein chemometric methods were applied, are presented in the current paper. The kind of questions presented in these examples cover identification, classification, comparison and quantification of illicit drugs. The examples include several types of data (low- or high-dimensional), pre-processing and chemometric analyses that are applied to answer the questions presented. The performance measures for the chemometric methods are described based on separate datasets for training and testing (validation) purposes. In this way it is illustrated how a chemometric method is set up and data analysis may be performed. The presented methods are intended to be easily translatable to questions in forensic chemistry that are not drug-related.
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http://dx.doi.org/10.1016/j.forsciint.2019.110138DOI Listing
February 2020

Chemometrics in forensic chemistry - Part I: Implications to the forensic workflow.

Forensic Sci Int 2019 Aug 19;301:82-90. Epub 2019 May 19.

National Bureau of Investigation, Jokiniemenkuja 4, 01370 Vantaa, Finland.

The forensic literature shows a clear trend towards increasing use of chemometrics (i.e. multivariate analysis and other statistical methods). This can be seen in different disciplines such as drug profiling, arson debris analysis, spectral imaging, glass analysis, age determination, and more. In particular, current chemometric applications cover low-dimensional (e.g. drug impurity profiles) and high-dimensional data (e.g. Infrared and Raman spectra) and are therefore useful in many forensic disciplines. There is a dominant and increasing need in forensic chemistry for reliable and structured processing and interpretation of analytical data. This is especially true when classification (grouping) or profiling (batch comparison) is of interest. Chemometrics can provide additional information in complex crime cases and enhance productivity by improving the processes of data handling and interpretation in various applications. However, the use of chemometrics in everyday work tasks is often considered demanding by forensic scientists and, consequently, they are only reluctantly used. This article and following planned contributions are dedicated to those forensic chemists, interested in applying chemometrics but for any reasons are limited in the proper application of statistical tools - usually made for professionals - or the direct support of statisticians. Without claiming to be comprehensive, the literature reviewed revealed a sufficient overview towards the preferably used data handling and chemometric methods used to answer the forensic question. With this basis, a software tool will be designed (part of the EU project STEFA-G02) and handed out to forensic chemist with all necessary elements of data handling and evaluation. Because practical casework is less and less accompanied from the beginning to the end out of the same hand, more and more interfaces are built in through specialization of individuals. This article presents key influencing elements in the forensic workflow related to the most meaningful chemometric application and evaluation.
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http://dx.doi.org/10.1016/j.forsciint.2019.05.030DOI Listing
August 2019

Establishment of a spontaneously transformed cell line (JU-PI) from a myxoinflammatory fibroblastic sarcoma.

Tumour Biol 2018 May;40(5):1010428318777936

1 Department of Pathology, University of Helsinki, Helsinki, Finland.

Myxoinflammatory fibroblastic sarcoma is a soft-tissue neoplasm most frequently found in the distal extremities of middle-aged adults. Most myxoinflammatory fibroblastic sarcoma are low-grade tumors with propensity for local recurrence after incomplete removal. We report a myxoinflammatory fibroblastic sarcoma which developed in the foot of a 41-year-old male and showed an exceptionally aggressive course with metastatic spread and fatal outcome within 16 months. We managed to establish a spontaneously transformed continuous cell line, called JU-PI, from a metastatic lesion. The JU-PI cells have a sub-tetraploid karyotype including the 1;10 chromosomal translocation and amplification of the proximal end of 3p; these features are considered genetic signatures of myxoinflammatory fibroblastic sarcoma. Both the primary tumor and the JU-PI cells showed nuclear expression of the TFE3 transcription factor but TFE3-activating chromosomal rearrangements were not found. To our knowledge, JU-PI is the first established myxoinflammatory fibroblastic sarcoma cell line. JU-PI cells offer a tool for investigating the molecular oncology of myxoinflammatory fibroblastic sarcoma.
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http://dx.doi.org/10.1177/1010428318777936DOI Listing
May 2018

Molecular alterations in pediatric brainstem gliomas.

Pediatr Blood Cancer 2018 Jan 9;65(1). Epub 2017 Aug 9.

Department of Children and Adolescents, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Background: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group.

Methods: We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC).

Results: H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies.

Conclusions: Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.
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http://dx.doi.org/10.1002/pbc.26751DOI Listing
January 2018

Cloning, characterization, and inhibition studies of a β-carbonic anhydrase from Leishmania donovani chagasi, the protozoan parasite responsible for leishmaniasis.

J Med Chem 2013 Sep 13;56(18):7372-81. Epub 2013 Sep 13.

Institute of Biomedical Technology and BioMediTech, University of Tampere , 33520 Tampere, Finland.

Leishmaniasis is an infection provoked by protozoans belonging to the genus Leishmania. Among the many species and subsepecies of such protozoa, Leishmania donovani chagasi causes visceral leishmaniasis. A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized from this organism, denominated here LdcCA. LdcCA possesses effective catalytic activity for the CO2 hydration reaction, with kcat of 9.35 × 10(5) s(-1) and kcat/KM of 5.9 × 10(7) M(-1) s(-1). A large number of aromatic/heterocyclic sulfonamides and 5-mercapto-1,3,4-thiadiazoles were investigated as LdcCA inhibitors. The sulfonamides were medium potency to weak inhibitors (KI values of 50.2 nM-9.25 μM), whereas some heterocyclic thiols inhibited the enzyme with KIs in the range of 13.4-152 nM. Some of the investigated thiols efficiently inhibited the in vivo growth of Leishmania chagasi and Leishmania amazonensis promastigotes, by impairing the flagellar pocket and movement of the parasites and causing their death. The β-CA from Leishmania spp. is proposed here as a new antileishmanial drug target.
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http://dx.doi.org/10.1021/jm400939kDOI Listing
September 2013

Structured outpatient peritoneal dialysis catheter insertion is safe and cost-saving.

Perit Dial Int 2014 Sep-Oct;34(6):612-7. Epub 2013 Jul 1.

Department of Medicine, Tampere University Hospital, and Medical School, University of Tampere, Tampere, Finland.

Background: Data about outcomes and costs for peritoneal catheter insertion on an outpatient basis are scarce.

Methods: Using patient files, all peritoneal dialysis (PD) catheter insertions performed between 2004 and 2009 in a single-center tertiary care institution for adult patients were located. Patient demographics, complications, hospitalizations, survival, and treatment modality changes were recorded. Procedure-related expenses were valued as actual production costs.

Results: During the study period, 106 PD catheters were inserted. In 46 cases, the patients were admitted electively for catheter insertion; 19 catheters were placed during admission for other medical reasons; and 41 catheters were placed on an outpatient basis. Among the study patients (54.7 ± 16.0 years of age), 45% were diabetic. Early (<30 days) catheter-related complications occurred in 22% of patients. The incidences of technique failure and any complication within 90 days were 10% and 38% respectively. The occurrence of complications was not statistically significantly different for outpatients and electively admitted patients. Average costs for catheter insertion were higher in electively hospitalized patients than in outpatients (€2320 ± €960 vs €1346 ± €208, p < 0.000).

Conclusions: Compared with an inpatient procedure, outpatient insertion of a PD catheter results in similar outcomes at a lower cost.
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http://dx.doi.org/10.3747/pdi.2012.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164405PMC
June 2015

Increased expression of CIP2A in aggressive subtypes of B-cell lymphoma.

Histopathology 2013 Sep 26;63(3):438-9. Epub 2013 Jun 26.

Department of Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, Oulu, Finland.

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http://dx.doi.org/10.1111/his.12162DOI Listing
September 2013

Cerebral small vessel disease and kidney function predict long-term survival in patients with acute stroke.

Stroke 2010 Sep 29;41(9):1914-20. Epub 2010 Jul 29.

Division of Vascular Surgery, Department of Surgery, University of Tampere and Tampere University Hospital, Tampere, Finland.

Background And Purpose: Cerebral small vessel disease reflected by white matter lesions (WMLs) in MRI and kidney function reflected by estimated glomerular filtration rate (eGFR) is closely associated in patients without stroke. We studied whether eGFR and WMLs predict long-term survival in patients with acute stroke.

Methods: After exclusion of patients with low eGFR (N=5 [1.3%]; <30 mL/min/1.73 m(2)), consecutive patients with acute stroke (N=378) subjected to MRI and serum creatinine determination were included in the study and prospectively followed-up up to 12 years.

Results: Of the patients, 71.2% had died during the follow-up, 152 (40.2%) had moderate (eGFR <60 mL/min/1.73 m(2)), and 226 (59.8%) had normal or mildly impaired eGFR (>or=60 mL/min/1.73 m(2)). Of the patients, 108 (28.6%) had mild, 68 (18.0%) had moderate, and 202 (53.4%) had severe WMLs. In logistic regression analysis adjusted with age and sex, eGFR <60 mL/min/1.73 m(2) was associated with severe WMLs (relative risk 2.77, 95% CI 1.10 to 6.98, P=0.030). In Cox regression survival analysis adjusted with significant covariates, eGFR <60 mL/min/1.73 m(2) (1.30, 95% CI 1.00 to 1.68, P=0.047) and severe WMLs (hazard ratio 1.32, 95% CI 1.02 to 1.71, P=0.033) were associated with poor survival, whereas they were not independent from each other. In further analyses, presence of either eGFR >or=60 mL/min/1.73 m(2) or only mild to moderate WMLs, or both, was associated with improved survival compared with all other combinations.

Conclusions: Cerebral small vessel disease is closely associated with kidney function in patients with acute stroke. Cerebral small vessel disease and kidney function are closely associated predictors of poor poststroke survival.
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http://dx.doi.org/10.1161/STROKEAHA.110.587352DOI Listing
September 2010

Self-repair of speech by four-year-old Finnish children.

J Child Lang 2009 Sep 15;36(4):855-82. Epub 2008 Dec 15.

University of Helsinki, Finland.

ABSTRACTThe aim of this study was to examine what four-year-old children repair in their speech. For this purpose, conversational self-repairs (N=316) made by two typically developing Finnish-speaking children (aged 4 ; 8 and 4 ; 11) were examined. The data comprised eight hours of natural interactions videotaped at the children's homes. The tapes were analyzed using conversation analysis. The children made phonological, morphological, syntactic, lexical and non-linguistic self-repairs, and also inserted additional material into their utterances. Finnish-speaking children made more syntactic and fewer morphological self-repairs than the previous research on English-speaking children suggests. Furthermore, most self-repairs were found in talk during pretend play. In designing and engaging in such play, the children skilfully used self-repair to match their talk to meet the requirements of different interactive activities and co-participants. Finally, contextual analysis of children's self-repairs showed that these were also socially motivated, and not just related to slips or errors in speech.
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http://dx.doi.org/10.1017/S0305000908009240DOI Listing
September 2009

Glycosylation, transport, and complex formation of palmitoyl protein thioesterase 1 (PPT1)--distinct characteristics in neurons.

BMC Cell Biol 2007 Jun 12;8:22. Epub 2007 Jun 12.

Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, Finland.

Background: Neuronal ceroid lipofuscinoses (NCLs) are collectively the most common type of recessively inherited childhood encephalopathies. The most severe form of NCL, infantile neuronal ceroid lipofuscinosis (INCL), is caused by mutations in the CLN1 gene, resulting in a deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). The deficiency of PPT1 causes a specific death of neocortical neurons by a mechanism, which is currently unclear. To understand the function of PPT1 in more detail, we have further analyzed the basic properties of the protein, especially focusing on possible differences in non-neuronal and neuronal cells.

Results: Our study shows that the N-glycosylation of N197 and N232, but not N212, is essential for PPT1's activity and intracellular transport. Deglycosylation of overexpressed PPT1 produced in neurons and fibroblasts demonstrates differentially modified PPT1 in different cell types. Furthermore, antibody internalization assays showed differences in PPT1 transport when compared with a thoroughly characterized lysosomal enzyme aspartylglucosaminidase (AGA), an important observation potentially influencing therapeutic strategies. PPT1 was also demonstrated to form oligomers by size-exclusion chromatography and co-immunoprecipitation assays. Finally, the consequences of disease mutations were analyzed in the perspective of our new results, suggesting that the mutations increase both the degree of glycosylation of PPT1 and its ability to form complexes.

Conclusion: Our current study describes novel properties for PPT1. We observe differences in PPT1 processing and trafficking in neuronal and non-neuronal cells, and describe for the first time the ability of PPT1 to form complexes. Understanding the basic characteristics of PPT1 is fundamental in order to clarify the molecular pathogenesis behind neurodegeneration in INCL.
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http://dx.doi.org/10.1186/1471-2121-8-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906764PMC
June 2007

Implications of levels of serum mineral metabolism markers, albumin and C-reactive protein for treatment costs of patients on maintenance dialysis.

Nephron Clin Pract 2007 7;106(1):c17-23. Epub 2007 Mar 7.

Medical School, University of Tampere, Tampere, Finland.

Background: Secondary hyperparathyroidism, malnutrition and inflammation have been reported to associate with adverse outcomes in dialysis patients. However, little is known about the implications of these conditions for treatment costs.

Methods: The cost data of all adult patients who had entered dialysis therapy at Tampere University Hospital between 1991 and 1996 and had remained on dialysis for at least 1 year were collected. results of measurements of parathyroid hormone (PTH), calcium, phosphorus, albumin and C-reactive protein (CRP) were obtained from the database of the hospital.

Results: Patients (n = 109), aged 57.0 +/- 14.9 years, included 57% men and 37% diabetics; 62% started on hemodialysis and 38% on peritoneal dialysis. Average daily costs were USD 161 (range 95-360). After controlling for patients' age, body mass index, gender, dialysis modality and primary renal disease, there was a positive correlation between average CRP and average costs and a negative correlation between albumin and costs. Correlations between mineral metabolism markers and costs were not found, but there was a trend towards lower cost among patients who achieved the Kidney Disease Outcomes Quality Initiative targets of calcium, phosphorus and PTH (USD 145 +/- 31) compared with those with nonoptimal levels (USD 165 +/- 48; p = 0.095). Costs of patients with at least one in-target PTH measurement were lower than costs of patients with constantly low PTH (USD 148 +/- 31 vs. 170 +/- 48; p = 0.01).

Conclusion: Serum levels of albumin and CRP correlated with dialysis patients' treatment costs. Achieving the Kidney Disease Outcomes Quality Initiative targets may be associated with lower costs.
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http://dx.doi.org/10.1159/000100497DOI Listing
May 2007

Alternative strategies to evaluate the cost-effectiveness of peritoneal dialysis and hemodialysis.

Int Urol Nephrol 2007 27;39(1):289-98. Epub 2007 Feb 27.

Medical School, University of Tampere, Tampere FIN-33014, Finland.

Background: Dialysis treatment requires considerable resources and it is important to improve the efficiency of care.

Methods: Files of all adult end-stage renal disease (ESRD) patients who entered dialysis therapy between 1991 and 1996, were studied and all use of health care resources was recorded. A total of 138 patients started with in-center hemodialysis (HD) and 76 patients with continuous ambulatory peritoneal dialysis (CAPD). Four alternative perspectives were applied to assess effectiveness. An additional analysis of 68 matched CAPD-HD pairs with similar characteristics was completed.

Results: Cost-effectiveness ratios (CER; cost per life-year gained) were different in alternative observation strategies. If modality changes and cadaveric transplantations were ignored, annual first three years' CERs varied between $41220-61465 on CAPD and $44540-85688 on HD. If CAPD-failure was considered as death, CERs were $34466-81197 on CAPD. When follow-up censored at transplantation but dialysis modality changes were ignored, CERs were $59409-95858 on CAPD and $70042-85546 on HD. If observation censored at any change of primarily selected modality, figures were $57731-66710 on CAPD and $74671-91942 on HD. There was a trend of lower costs and better survival on CAPD, the only exception was the strategy in which technical failure of modality was considered as death. Figures of the matched CAPD-HD pairs were very close to the figures of the entire study population.

Conclusions: Compared to HD, CERs were slightly lower on CAPD.
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http://dx.doi.org/10.1007/s11255-006-9141-2DOI Listing
November 2007

Type I interferon response against viral and non-viral gene transfer in human tumor and primary cell lines.

J Gene Med 2007 Feb;9(2):122-35

A. I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.

Background: Type I interferon (IFN-alpha/beta) response is one of the major host defence mechanisms against viruses. Some recent reports suggest that IFNs may interfere with the efficacy of both non-viral and virus-vector-mediated therapeutic gene transfer.

Methods: The type I IFN response upon different gene transfer methods in human tumor and primary cell lines was studied by analysing IFN-beta mRNA expression, secretion of type I IFNs and accumulation of IFN-alpha/beta-induced MxA protein (myxovirus resistance protein A).

Results: Infection with avirulent Semliki Forest virus A7[74] induced MxA protein accumulation and increased the IFN-beta mRNA level, whereas none of the studied virus vectors (adenovirus, CRAd, lentivirus or AAV) induced IFN response. However, plasmid DNA induced the accumulation of MxA protein when transfected with several commercial transfection reagents. RNA transfection appeared to be an efficient inducer of type I IFN response: replicating alphaviral RNA, eukaryotic total RNA, or mRNA all induced both MxA protein accumulation and IFN-beta expression. siRNA transfection failed to induce MxA response.

Conclusions: The non-viral gene transfer methods have gained more interest in recent years due to their better safety profiles when compared to their viral counterparts. However, the efficiency of non-viral gene transfer is well below those reached by viral vector systems. The type I interferon response induced by non-viral methods may in part contribute to this inefficiency, while most currently used viral gene transfer vectors fail to induce or are able to suppress type I IFN response.
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http://dx.doi.org/10.1002/jgm.997DOI Listing
February 2007

[Not Available].

Duodecim 2006 ;122(14):1799-800

Kanta-Hämeen keskussairaala, keuhkosairaudet.

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April 2008

Inhibition of classical PKC isoenzymes downregulates STAT1 activation and iNOS expression in LPS-treated murine J774 macrophages.

Br J Pharmacol 2006 Apr;147(7):790-9

The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, Tampere, Finland.

Proinflammatory cytokines and bacterial products trigger inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in inflammatory and tissue cells. In inflammation, NO acts as an important mediator having both proinflammatory and destructive effects. Protein kinase C (PKC) is a family of serine-threonine protein kinase isoenzymes involved in signal transduction pathways related to inflammatory responses. The aim of the present study was to investigate the role of classical PKC (cPKC) isoenzymes in the regulation of iNOS expression and NO production in murine J774 macrophages and the mechanisms involved. RO318220 (inhibits PKCbeta, PKCgamma and PKCvarepsilon), GO6976 (inhibits cPKC isoenzymes PKCalpha and PKCbeta) and LY333531 (inhibits PKCbeta) reduced lipopolysaccharide (LPS)-induced NO production and iNOS expression in a dose-dependent manner as did 6 h pretreatment with 1 microM phorbol 12-myristate 13-acetate (PMA) (which was shown to downregulate PKC expression). PKC inhibitors also reduced LPS-induced iNOS mRNA levels, but they did not affect the half-life of iNOS mRNA. PKC inhibitors did not alter LPS-induced activation of NF-kappaB as measured by electrophoretic mobility shift assay. All PKC inhibitors used and pretreatment with 1 microM PMA inhibited signal transducer and activator of transcription 1 (STAT1) activation as measured by the translocation of STAT1alpha from the cytosol to the nucleus by Western blot. In addition, inhibition of STAT1 activation by AG-490, an inhibitor of JAK-2, also reduced NO production. These results suggest that cPKC isoenzymes, especially PKCbeta, mediate the upregulation of iNOS expression and NO production in activated macrophages in an NF-kappaB-independent manner, possibly through the activation of transcription factor STAT1.
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http://dx.doi.org/10.1038/sj.bjp.0706672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751509PMC
April 2006

Two novel CLN6 mutations in variant late-infantile neuronal ceroid lipofuscinosis patients of Turkish origin.

Clin Genet 2005 Aug;68(2):167-73

Folkhälsan Institute of Genetics, Department of Medical Genetics and Neuroscience Center, Biomedicum Helsinki, University of Helsinki, Finland.

Neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative childhood-onset disorders characterized by autosomal recessive inheritance, epileptic seizures, progressive psychomotor deterioration, visual failure, and premature death. At least seven subtypes of childhood-onset NCLs have been identified of which the late-infantile-onset forms (LINCLs) are genetically the most heterogeneous with four underlying genes identified. A variant form of LINCL (vLINCL) present in Turkish patients has been considered a distinct clinical and genetic entity (CLN7). However, we recently showed that mutations in the CLN8 gene account for a subset of Turkish vLINCL. Toward identifying the CLN7 gene we here screened the known NCL loci for homozygosity in nine Turkish vLINCL families. These loci were excluded in seven families that are likely to represent the 'true' Turkish vLINCL. In two families, we identified two novel homozygous mutations in the CLN6 gene: an intronic base substitution (c.542+5G>T) affecting the splicing of the transcript and a nonsense mutation (c.663C>G) creating a stop codon at tyrosine 221. These data indicate that CLN6 mutations, in addition to those of CLN8, should be considered a diagnostic alternative in Turkish vLINCL patients. The genetic background of the 'true' Turkish vLINCL, CLN7, remains to be defined.
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http://dx.doi.org/10.1111/j.1399-0004.2005.00471.xDOI Listing
August 2005

Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons.

Neurobiol Dis 2005 Feb;18(1):226-41

Department of Medical Genetics and Molecular Medicine, University of Helsinki and National Public Health Institute, Biomedicum Helsinki, FIN-00251 Helsinki, Finland.

Infantile Neuronal Ceroid Lipofuscinosis (INCL) results from mutations in the palmitoyl protein thioesterase (PPT1, CLN1) gene and is characterized by dramatic death of cortical neurons. We generated Ppt1Deltaex4 mice by a targeted deletion of exon 4 of the mouse Ppt1 gene. Similar to the clinical phenotype, the homozygous mutants show loss of vision from the age of 8 weeks, seizures after 4 months and paralysis of hind limbs at the age of 5 months. Autopsy revealed a dramatic loss of brain mass and histopathology demonstrated accumulation of autofluorescent granular osmiophilic deposits (GRODS), both characteristic of INCL. At 6 months, the homozygous Ppt1Deltaex4 mice showed a prominent loss of GABAergic interneurons in several brain areas. The transcript profiles of wild-type and mutant mouse brains revealed that most prominent alterations involved parts of the immune response, implicating alterations similar to those of the aging brain and neurodegeneration. These findings make the Ppt1Deltaex4 mouse an interesting model for the inflammation-associated death of interneurons.
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http://dx.doi.org/10.1016/j.nbd.2004.08.013DOI Listing
February 2005

Cancer cells as targets for lentivirus-mediated gene transfer and gene therapy.

Int J Oncol 2004 Dec;25(6):1753-62

A.I. Virtanen Institute, Department of Biotechnology and Molecular Medicine, University of Kuopio, Kuopio, Finland.

Lentiviruses have been used as gene transfer vectors for almost 10 years and their utility has been demonstrated in a variety of different applications. However, their value in cancer gene therapy has not been studied thoroughly. Here we show that VSV-G pseudotyped HIV-1-based lentiviruses are efficient vectors for human tumor cells in vitro and in vivo. Lentiviral gene transfer efficiency was demonstrated by transducing 42 different cell lines, representing 10 different human tumor types. It was shown that most of the cell lines were good or excellent targets for lentiviral transduction, allowing 50-95% gene transfer efficiency. These results were comparable to those obtained with an E1/E3 deleted, serotype 5 adenovirus vector. Analysis of lentivirus vector structure revealed that virus particles devoid of HIV-1 accessory proteins appeared to be more efficient, but the presence of enhancing elements cPPT and WPRE did not play a major role in transduction efficiency to four different human tumor cell lines. However, their effect on the gene expression level in these cells was apparent. To examine the impact of lentiviral gene expression level on suicide gene therapy approach, human osteosarcoma cells were transduced with lentivirus- or adenovirus vectors carrying the fusion gene HSV-TK-GFP and exposed to ganciclovir. Cell viability analysis after the treatment revealed that both vector types induced similar level of cytotoxicity, suggesting that lentiviral expression of a suicide gene is adequate for tumor cell destruction. Finally, in vivo transduction studies with subcutaneous tumors showed that lentivirus vectors can yield similar gene transfer efficiency than adenovirus vector, despite three orders of magnitude lower titer of the lentiviral preparation. In conclusion, these data show that lentiviruses are efficient gene transfer vehicles for human tumor cells and justify their use in further preclinical cancer gene therapy studies.
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December 2004

Localization of wild-type and mutant neuronal ceroid lipofuscinosis CLN8 proteins in non-neuronal and neuronal cells.

J Neurosci Res 2004 Jun;76(6):862-71

Folkhälsan Institute of Genetics, Department of Medical Genetics and Neuroscience Center, University of Helsinki, Finland.

Neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative disorders characterized by accumulation of autofluorescent lipopigment in many tissues, especially in neurons. Mutations in the CLN8 gene underlie Northern epilepsy (progressive epilepsy with mental retardation [EPMR], OMIM 600143) and a subset of Turkish variant late infantile NCL, but the pathogenetic mechanisms have remained elusive. The CLN8 transmembrane protein is an endoplasmic reticulum (ER) resident protein that recycles between ER and ER-Golgi intermediate compartment (ERGIC) in non-neuronal cells. To explore the disease mechanisms, we have characterized the neuronal localization of wild-type CLN8 protein as well as CLN8 proteins representing patient mutations. Semliki Forest virus-mediated CLN8 protein localized in the ER of mouse hippocampal primary neurons when compared to subcellular markers by immunofluorescence analysis. We also analyzed the possible polarized targeting of CLN8 and observed basolateral targeting in polarized epithelial CaCo-2 cells, suggesting that CLN8 may locate outside the ER or in a specialized subcompartment of the ER. We were not able, however, to demonstrate differential distribution of CLN8 between axons and dendrites of neurons. Fractionation of mouse brain tissue indicated that endogenous mouse Cln8 is observed in light membrane fractions, different from ER, which further suggested differential localization for CLN8 in polarized cells. The disease mutations did not affect intracellular localization of CLN8 in non-neuronal or neuronal cells. Consequently, there is no obvious genotype-phenotype correlation at the level of protein localization and thus mutations most likely directly affect functionally important domains of CLN8.
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http://dx.doi.org/10.1002/jnr.20133DOI Listing
June 2004

Cost analysis of renal replacement therapies in Finland.

Am J Kidney Dis 2003 Dec;42(6):1228-38

Medical School, University of Tampere, Tampere, Finland.

Background: Costs for treating patients with end-stage renal disease (ESRD) have grown noticeably. However, most of the cost estimates to date have taken the perspective of the payers. Hence, direct costs of treating ESRD are not accurately known.

Methods: Files of all adult patients with ESRD who entered dialysis therapy between January 1, 1991, and December 31, 1996, were studied retrospectively, and all use of health care resources and services was recorded. Follow-up continued until December 31, 1996.

Results: Two hundred fourteen patients fulfilled the study criteria, 138 patients started with in-center hemodialysis (HD) therapy, and 76 patients started with continuous ambulatory peritoneal dialysis (CAPD) therapy. Patients were followed up until death (72 patients) or treatment modality changed for more than 1 month. Fifty-five patients received a cadaveric transplant, and after transplantation (TX), they were examined as a separate group of TX patients. Direct health care costs for the first 6 months in the HD, CAPD, and TX groups were 32,566 US dollars, 25,504 dollars, and 38,265 dollars, and for the next 6 months, 26,272 dollars, 24,218 dollars, and 7,420 dollars, respectively. During subsequent years, annual costs were 54,140 US dollars and 54,490 dollars in the HD group, 45,262 dollars and 49,299 dollars in the CAPD group, and 11,446 dollars and 9,989 dollars in the TX group. Regression analyses showed 4 variables significantly associated with greater daily costs in dialysis patients: age, ischemic heart disease, nonprimary renal disease, and HD treatment.

Conclusion: Compared with HD, CAPD may be associated with lower costs, yet the absolute difference is not striking. After the TX procedure is performed once, annual costs decline remarkably, and cadaveric TX is less costly than both dialysis modalities.
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http://dx.doi.org/10.1053/j.ajkd.2003.08.024DOI Listing
December 2003

[Blue lips].

Duodecim 1999 ;115(19):2117,2119

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May 2002

New mutations in the neuronal ceroid lipofuscinosis genes.

Eur J Paediatr Neurol 2001 ;5 Suppl A:7-10

Department of Paediatrics and Child Health, University College London, Rayne Institute, 5 University Street, London WC1E 6JJ, UK.

Thirty-eight mutations and seven polymorphisms have recently been reported in the genes underlying the neuronal ceroid lipofuscinoses (NCLs) including 11 new mutations described here. A total of 114 mutations and 28 polymorphisms have now been described in the five human genes identified which cause NCL. Thirty-eight mutations are recorded for CLN1/PPT; 40 for CLN2/TTP-1, 31 for CLN3, four for CLN5, one for CLN8. Two mutations have been described in animal genes (cln8/mnd, CTSD). All mutations in NCL genes are contained in the NCL Mutation Database (http://www.ucl.ac.uk/NCL).
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http://dx.doi.org/10.1053/ejpn.2000.0427DOI Listing
November 2001

Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations which cause infantile neuronal ceroid lipofuscinocis.

Mol Cell Neurosci 2001 Aug;18(2):131-40

Department of Molecular Medicine, National Public Health Institute, Haartmaninkatu 8, 00290 Helsinki, Finland.

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative storage disorder in children caused by mutations in the palmitoyl protein thioesterase gene (PPT1). We have investigated here four naturally occurring previously described PPT1 mutations and show that all cause severe effects on PPT1 enzyme activity in transiently transfected COS-1 cells. Two of the mutations (delPhe84 and insCys45) cause a classical INCL phenotype and two (Thr75Pro and Leu219Gln) result in a late onset disease phenotype. All these mutated PPT1 molecules have severely altered intracellular localization in transiently transfected BHK-cells, whereas in mouse primary neuron cultures different effects were observed. In neurons the delPhe84 and insCys45 mutant polypeptides were targeted to the ER. Interestingly the Thr75Pro and Leu219Gln mutations had only minor effects on the neuronal trafficking of PPT1 and the mutated polypeptides were observed in neuronal shafts and showed colocalization with the presynaptic marker SV2. Our data indicates that neuronal cells provide an excellent model to study the genotype-phenotype correlation in INCL.
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http://dx.doi.org/10.1006/mcne.2001.1010DOI Listing
August 2001

Reversible posterior leukoencephalopathy after combination chemotherapy.

Neuroradiology 2000 Dec;42(12):895-9

Department of Neurology and Rehabilitation, University of Tampere, 33521 Tampere, Finland.

We describe a young woman with Burkitt's lymphoma, treated with intravenous adriamycine and cyclophosphamide and intrathecal cytarabine. She developed a reversible posterior leukoencephalopathy syndrome (RPLS) with typical MRI findings. Diffusion-weighted images during the first days after the onset of symptoms predicted a small irreversible lesion in the frontal lobe, verified on T2-weighted images 1 month later. The patient showed full recovery after high-dose steroid treatment.
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http://dx.doi.org/10.1007/s002340000482DOI Listing
December 2000

CLN-1 and CLN-5, genes for infantile and variant late infantile neuronal ceroid lipofuscinoses, are expressed in the embryonic human brain.

J Comp Neurol 2000 Oct;426(3):406-12

National Public Health Institute, Department of Human Molecular Genetics, FIN-00300 Helsinki, Finland.

Mutations in the CLN-1 and CLN-5 genes underlie the infantile, and Finnish variant of the late-infantile, neuronal ceroid lipofuscinoses, respectively. These disorders are characterized by a massive neuronal death early in childhood. We have studied mRNA and protein expression of CLN-1 and CLN-5 in embryonic human brains. The spatial and temporal distributions of CLN-1 and CLN-5 were similar in the embryonic human brain. Both genes are expressed at the beginning of cortical neurogenesis, and this expression increases as cortical development proceeds. In the developing cortical plate, expression is found in postmitotic migrating neuroblasts and neuroblasts that have completed migration. Expression was intense also in cells of the thalamus as well as in the future Purkinje cell layer of the cerebellum. These findings indicate that expression of CLN-1 and CLN-5 may be significant for development of a wide range of maturating neurons.
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http://dx.doi.org/10.1002/1096-9861(20001023)426:3<406::aid-cne5>3.0.co;2-5DOI Listing
October 2000

Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1).

Hum Mutat 2000 ;15(3):273-9

National Public Health Institute, Department of Human Molecular Genetics, Helsinki, Finland.

The infantile form of neuronal ceroid lipofuscinosis (INCL; CLN1) is the earliest onset form of the neuronal ceroid lipofuscinoses (NCL), a group of progressive encephalopathies of children. INCL is caused by mutations in the palmitoyl protein thioesterase (PPT) gene, and we report here eight novel INCL mutations in PPT. Five of the mutations, c.456C>A, c.162-163insA, c.174-175delG, c.774-775insA, and a splice acceptor mutation IVS1-2A>G in intron 1, caused the generation of a premature STOP codon either directly or after a frameshift. One mutation was a three-bp insertion in exon 2 (c. 132-133insTGT) leading to insertion of one extra cysteine (Ser44-insCys-Cys45), and another mutation, a 3-bp deletion in exon 3 (c.249-251delCTT), led to deletion of Phe84 in PPT. A splice acceptor mutation IVS6-1G>T in intron 6 can be predicted to cause skipping of exon 7 in PPT. All of these novel mutations were associated with the classical phenotype of INCL, with the first symptoms starting around 12 months of age. The severe phenotypes could be explained by the nature of the novel mutations: five are predicted to lead to premature translational termination, thus abolishing the active site of PPT, and three will probably cause a misfolding of the nascent polypeptide. Thirty-five percent (7/20) of the disease alleles in these 11 families contained the most prevalent c.451C>T missense mutation outside Finland [Das et al., 1998]. Consequently, 31 different mutations underlying INCL have been found so far, the majority leading to classical INCL.
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http://dx.doi.org/10.1002/(SICI)1098-1004(200003)15:3<273::AID-HUMU8>3.0.CO;2-LDOI Listing
May 2000

Mouse palmitoyl protein thioesterase: gene structure and expression of cDNA.

Genome Res 1998 Jul;8(7):724-30

National Public Health Institute and Institute of Biomedicine, Department of Human Molecular Genetics, University of Helsinki, FIN-00300 Helsinki, Finland.

Palmitoyl protein thioesterase (PPT) is the defective enzyme in infantile neuronal ceroid lipofuscinosis (INCL), which is a recessively inherited, progressive neurodegenerative disorder. We present here the cloning, chromosomal mapping, genomic structure, and the expression of the cDNA of mouse PPT. The mouse PPT gene spans >21 kb of genomic DNA and contains nine exons with a coding sequence of 918 bp. Fluorescence in situ hybridization to metaphase chromosomes localized the mouse PPT gene to the chromosome 4 conserved syntenic region with human chromosome 1p32 where the human PPT is located. PPT is expressed widely in a variety of mouse tissues. The mouse PPT cDNA is conserved highly with the human and rat PPT both at the nucleotide and amino acid sequence level. Transient expression of mouse PPT in COS-1 cells yielded a 38/36-kD differentially glycosylated polypeptide that was also secreted into culture media. Immunofluorescence analysis of transiently transfected HeLa cells indicated lysosomal localization of mouse PPT. Based on the high conservation of the gene and polypeptide structure as well as similar processing and intracellular localization, the function of PPT in mouse and human are likely to be very similar.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC310755PMC
http://dx.doi.org/10.1101/gr.8.7.724DOI Listing
July 1998

Monoamine oxidase B inhibitor selegiline protects young and aged rat peripheral sympathetic neurons against 6-hydroxydopamine-induced neurotoxicity.

Acta Neuropathol 1996 ;91(5):466-74

University of Tampere, School of Public Health, Laboratory of Gerontology, Finland.

Selegiline is a selective and irreversible monoamine B inhibitor with the capacity to increase the level of several antioxidative enzymes in rat brain. It can protect adrenergic neurons against injury induced by neurotoxins such as MPTP, DSP-4 and AF64A in animal studies. In addition, the protective action is not limited to catecholaminergic cells, as selegiline can also minimize the loss of developing motoneurons after axotomy. The aim of this study was to determine whether selegiline can protect peripheral catecholaminergic neurons against the neurotoxic effect of 6-OHDA. This kind of protective effect against 6-OHDA neurotoxicity has not been reported before. Wistar albino male rats aged 4 or 24 months were treated with selegiline or saline solution 1 h before 6-OHDA injection. At 2 weeks after the 6-OHDA injection, the superior cervical ganglia (SCG) and submandibular glands (SMG) were studied using catecholamine histofluorescence and immunohistochemistry for tyrosine hydroxylase (TH). The number of TH-positive cells in the SCG and the length and number of adrenergic nerve fibers in the SMG were quantified. Our findings showed that 6-OHDA caused a reduction of TH immunoreactivity and catecholamine histofluorescence in neuronal somata, as well as a decrease in the number and length of adrenergic nerve fibers in the submandibular gland. Selegiline pretreatment protected SCG neurons and their postganglionic nerve fibers in SMG against these changes in a dose-dependent manner. The mechanism through which selegiline exerts its neuroprotective effect is as yet unknown.
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http://dx.doi.org/10.1007/s004010050453DOI Listing
January 1997