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Now showing items 1 - 16 of 89



    Deregulated expression of myc proto-oncogenes is implicated in several human neoplasias. We analysed the expression of c-myc, N-myc, L-myc, max and RBI mRNAs in a panel of human gliomas and glioma cell lines and compared the findings with normal neural cells. The max and RB1 genes were included in the study because their protein products can interact with the Myc proteins, being thus putative modulators of Myc activity. Several gliomas contained c/L-myc mRNAs at levels higher than those in fetal brain, L-myc predominantly in grade II/III and c-myc in grade III gliomas. High-level N-myc expression was detected in one small-cell glioblastoma and lower levels in five other gliomas. In contrast, glioma cell lines totally lacked N/L-myc expression. The in situ hybridisations revealed mutually exclusive topographic distribution of myc and glial fibrillary acidic protein (GFAP) mRNAs, and a lack of correlation between myc expression and proliferative activity. max and RBI mRNAs were detected in most tumours and cell lines. The glioma cells displayed interesting alternative splicing patterns of max mRNAs encoding Max proteins which either suppress (Max) or augment (Delta Max) the transforming activity of Myc. We conclude that (1) glioma cells in vivo may coexpress several,nye genes, thus resembling fetal neural cells; but (2) cultured glioma cells expression only c-myc; (3) myc, max and RBI are regulated independently in glioma cells; and (4) alternative processing of max mRNA in some glioma cells results in Delta Max encoding mRNAs not seen in normal fetal brain.
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  • Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: A randomized double-blind study

    Valtonen, S   Timonen, U   Toivanen, P   Kalimo, H   Kivipelto, L   Heiskanen, O   Unsgaard, G   Kuurne, T  

    OBJECTIVE: To find out the effect of carmustine (bischloroethyl-nitrosourea) combined with a biodegradable polymer in the treatment of malignant (Grades III and IV) gliomas, applied locally, at the time of the primary operation. METHODS: Prospective, randomized double-blind study of an active treatment group versus a placebo group. Conducted at the Departments of Neurosurgery of the University Hospitals of Helsinki, Tampere, and Turku in Finland and Trondheim in Norway. The study consisted of 32 patients (16 in each treatment group) enrolled between March 23, 1992, and March 19, 1993. The study was planned to include 100 patients but had to be terminated prematurely, because the drug that was being used had become unobtainable. The main outcome measures included the survival times of patients after the operations and the application of an active drug or placebo. RESULTS: The median time from surgery to death was 58.1 weeks for the active treatment group versus 39.9 weeks for the placebo group (P = 0.012). For 27 patients with Grade IV tumors, the corresponding times were 39.9 weeks for the placebo group and 53.3 weeks for the active treatment group (P = 0.008). At the end of the study, six patients were still alive, five of whom belonged to the active treatment group. CONCLUSION: Carmustine applied locally in a biodegradable polymer at the time of primary operation, seems to have a favorable effect on the life span of patients with high-grade gliomas.
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  • Dynamic changes of excitatory amino acid receptors in the rat hippocampus following transient cerebral ischemia

    Westerberg, E   Monaghan, DT   Kalimo, H   Cotman, CW   Wieloch, TW  

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  • Remarks on the papers by C.-D. agardh et al./H. Kalimo et al.

    J. B. Brierley   A. W. Brown  

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  • Discharge characteristics of motor units in healthy, myopathic and neuropathic muscle : J.-P. Halonen, B. Falck and H. Kalimo (Turku, Finland)

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  • Lumbar muscle fiber size and type distribution in normal subjects.

    Rantanen, J   Rissanen, A   Kalimo, H  

    The macroanatomy of the clinically important lumbar muscles has recently been investigated in detail, whereas the information about their microscopic structure in healthy persons is still scanty. In this study we have analysed lumbar multifidus and erector spinae muscles from 21 previously healthy persons who died suddenly and were of working age (range 23-65 years, mean 44.7 years). The microscopic structure of myofibers within the lumbar muscles was found to be regionally uniform, which renders in vivo biopsies representative of the whole muscle bulk. Somewhat surprisingly, age did not significantly influence fiber type composition, fiber size, or proportion of nonmuscular tissue. There was a slight predominance of type 1 fibers. The size of type 1 fibers (mean lesser diameter 54.0 microns) corresponded to that in other skeletal muscles, with no significant sex difference (55.1/51.6 microns male/female). Selective type 2 fiber atrophy was a common finding in both sexes, but significantly less so in men (mean diameter 38.8/28.4 microns male/female). We suggest that the values of fiber type proportions and fiber size in the deep multifidus presented in this study can be used as reference values for healthy adults in the present society with limited physical activity.
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  • The Arctic Alzheimer mutation facilitates early intraneuronal A beta aggregation and senile plaque formation in transgenic mice

    Lord, A   Kalimo, H   Eckman, C   Zhang, XQ   Lannfelt, L   Nilsson, LNG  

    The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (A beta) sequence and leads to Alzheimer's disease (AD). Arctic A beta peptides more easily form A beta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APP(ArcSwe)) and transgenic mice with the Swedish mutation alone (tg-APP(Swe)). Intense intraneuronal A beta-immunoreactive staining was present in young tg-APP(ArcSwe) mice, but not in tg-APP(Swe) mice. Intracellular A beta aggregates in tg-APP(ArcSwe) were strongly stained by antibodies recognizing the N-terminus of A beta, while those recognizing the C-terminus of A beta stained weakly. The A beta aggregates inside neurons increased with age and predated extracellular A beta deposition in both tg-APP(ArcSwe) and tg-APP(Swe) mice. Senile plaque deposition was markedly accelerated in tg-APP(ArcSwe) mice, as compared to tg-APP(Swe) mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular A beta aggregates in association with a rapid onset of senile plaque deposition. (C) 2005 Elsevier Inc. All rights reserved.
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  • Pathogenesis of coxsackievirus A9 in mice: role of the viral arginine-glycine-aspartic acid motif

    Harvala, H   Kalimo, H   Stanway, G   Hyypia, T  

    Coxsackievirus A9 (CAV9) contains an arginine-glycine-aspartic acid (RGD) motif which participates in cell entry. Mutants with alterations in the RGD-containing region were utilized to explore the importance of the tripeptide in the pathogenesis of CAV9 in mice. Using in situ hybridization, the parental CAV9 strain was observed to infect skeletal muscle (intercostal, platysma, lingual and thigh muscles) of newborn mice, whereas the RGD-less mutants were detectable only in platysma and lingual muscles. In addition, newborn mice infected with the mutants survived longer than CAV9-infected mice. In adult mice, the parental strain of CAV9, but not the mutants, achieved moderately high titres in the pancreas. These results suggest that the RGD motif has a significant role in the pathogenesis of CAV9 in mice but also that RGD-independent entry routes can be utilized in the infection of murine tissue.
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  • Relation between myofibers and connective tissue during muscle injury repair

    Kaariainen, M   Jarvinen, T   Jarvinen, M   Rantanen, J   Kalimo, H  

    The connective tissue framework in skeletal muscle combines the contractile myofibers into a functional unit, in which the contraction of myofibers is transformed into movement via myotendinous junctions (MTJs) at their ends, where myofibers attach to tendons/fascia. The cytoskeletal contractile myofilament apparatus adheres through subsarcolemmal and transmembrane molecules to the surrounding extracellular matrix, with integrin and dystrophin associated chains of molecules being the two main adhesion complexes. In shearing type of muscle injury both myofibers and the connective tissue framework are ruptured and thereby the functional tendon-muscle-tendon units are disrupted. The stumps of the ruptured myofibers are separated and at the same time joined by a connective tissue scar, through which the ends of regenerating myofibers try to pierce, but as the scar becomes more compact the ends attach to the scar by new mini-MTJs. During the early phase ruptured myofibers try to compensate for the lost MTJ attachment by reinforcing their integrin mediated lateral adhesion, which returns to normal low level after formation of the mini-MTJs and at which time complementary increase of dystrophin and associated molecules on lateral sarcolemma takes place. The stumps appear to remain separated by and attached to the interposed scar for many months, possibly for ever, i.e. the original tendon-muscle-tendon units may have become permanently divided into two consecutive units. Remarkably, axon sprouts are able to penetrate through the interposed scar to form new neuromuscular junctions on those abjunctional stumps which were denervated by the rupture.
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    KALIMO, H  

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  • Cdk5 regulates the organization of nestin and its association with p35

    Sahlgren, CM   Mikhailov, A   Vaittinen, S   Pallari, HM   Kalimo, H   Pant, HC   Eriksson, JE  

    The intermediate filament protein nestin is characterized by its specific expression during the development of neuronal and myogenic tissues. We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. Ectopic expression of cdk5 and p35 in central nervous system progenitor cells and in myogenic precursor cells induced elevated phosphorylation and reorganization of nestin. The kinetics of nestin expression corresponded to elevated expression and activation of cdk5 during differentiation of myoblast cell cultures and during regeneration of skeletal muscle. In the myoblasts, a disassembly-linked phosphorylation of Thr-316 indicated active phosphorylation of nestin by cdk5. Moreover, cdk5 occurred in physical association with nestin. Inhibition of cdk5 activity-either by transfection with dominant-negative cdk5 or by using a specific cdk5 inhibitor-blocked myoblast differentiation and phosphorylation of nestin at Thr-316, and this inhibition markedly disturbed the organization of nestin. Interestingly, the interaction between p35, the cdk5 activator, and nestin appeared to be regulated by cdk5. In differentiating myoblasts, p35 was not complexed with nestin phosphorylated at Thr-316, and inhibition of cdk5 activity during differentiation induced a marked association of p35 with nestin. These results demonstrate that there is a continuous turnover of cdk5 and p35 activity on a scaffold formed by nestin. This association is likely to affect the organization and operation of both cdk5 and nestin during development.
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  • Proximal myotonic dystrophy - A family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: Heterogeneity of proximal myotonic syndromes?

    Udd, B   Krahe, R   WallgrenPettersson, C   Falck, B   Kalimo, H  

    We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed in medical records. Molecular examination of genomic DNA showed no expansion of the unstable (CTG)n trinucleotide repeat on chromosome 19q13.3 associated with myotonic dystrophy (DM). Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCNI) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded. The clinical findings differ from those described in proximal myotonic myopathy (PROMM), in terms of the more severe muscle involvement with atrophy of affected muscles and the hearing loss. These findings suggest phenotypic and probably genetic heterogeneity among the proximal myotonic syndromes. (C) 1997 Elsevier Science B.V.
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  • Metabolic characterization of childhood brain tumors - Comparison of F-18-fluorodeoxyglucose and C-11-methionine positron emission tomography

    Utriainen, M   Metsahonkala, L   Salmi, TT   Utriainen, T   Kalimo, H   Pihko, H   Makipernaa, A   Harila-Saari, A   Jyrkkio, S   Laine, J   Nagren, K   Minn, H  

    BACKGROUND. Positron emission tomography (PET) scans of primary brain tumors were performed in pediatric patients to examine whether metabolic characteristics could be used as an index of clinical aggressiveness. METHODS. Twenty-seven pediatric patients with untreated primary central nervous system neoplasms were studied with PET scans using 2-[F-18] fluoro-2-deoxy-D-glucose (FDG) and/or L-[methyl-C-11] methionine (MET). Metabolic characteristics as assessed with FDG and MET standardized uptake values (SUV) and SUV-to-normal brain ratios were compared with histopathology and selected histochemical features such as proliferation activity (Ki-67(MIB-1)) and apoptotic, vascular, and cell density indices. The median followup time was 43 months. RESULTS. The accumulation of both FDG and MET was significantly higher in high-grade than in low-grade tumors, but a considerable overlap was found. The accumulation of both tracers was associated positively with age. High-grade tumors showed higher proliferative activity and vascularity than the low-grade tumors. In univariate analysis, FDG-PET, MET-PET, and apoptotic index were independent predictors of event-free survival. CONCLUSION. We found that both FDG and MET uptake in pediatric brain tumors are associated with malignancy grade. However, no clear limits of SUVs and SUV-to-normal brain ratios can be set between low-grade and high-grade tumors, which makes the assessment of malignancy grade using metabolic imaging with PET scan difficult in individual cases. Although FDG-PET and MET-PET do not compensate for histopathologic evaluation, they may give valuable additional information especially if invasive procedures to obtain histopathologic samples are not feasible. (C) 2002 American Cancer Society.
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