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  • Panahi, Mahmod; Mesri, Naeimeh Yousefi; Samuelsson, Eva-Britt; Coupland, Kirsten G.; Forsell, Charlotte; Graff, Caroline; Tikka, Saara; Winblad, Bengt; Viitanen, Matti; Karlström, Helena; Sundström, Erik; Behbahani, Homira (2018)
    Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT-PCR analysis, we observed increased Transforming growth factor-beta (TGF beta) gene expression in CADASIL VSMCs. Adding TGF beta-neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGF beta-neutralizing antibody in ECs co-cultured with VSMCs. ECs co-cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co-cultured with control VSMCs, and neutralization of TGF beta normalized the proliferation rate of ECs co-cultured with CADASIL VSMCs. We suggest that increased TGF beta expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature.
  • Tuominen, Susanna; Miao, Qing; Kurki, Timo; Tuisku, Seppo; Pöyhönen, Minna; Kalimo, Hannu; Viitanen, Matti; Sipila, Hannu T.; Bergman, Jörgen; Rinne, JO (2004)
    Background and Purpose - CADASIL causes repeated ischemic strokes leading to subcortical vascular dementia. The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR(gluc)) in CADASIL patients are affected in early adulthood. Methods - CBF and rCMR(gluc) were examined with positron emission tomography in correlation with magnetic resonance imaging (MRI) in 14 adult ( 19 to 41 years) CADASIL patients with the Notch3 R133C mutation. Seven patients had experienced transient ischemic attack and 3 had experienced greater than or equal to1 strokes. Results - The mean CBF in the CADASIL patients was significantly lower in both frontal (P = 0.019) and occipital (P = 0.009) white matter (WM) than those in the controls. CBF decreased significantly with increased severity of the disease. The patients had lower mean rCMR(gluc) values than the controls, although differences were not statistically significant. Sum scores of semiquantitative MRI rating scale (Scheltens) correlated significantly with WM CBF but not with rCMR(gluc). Conclusions - In CADASIL, there is an early and significant decrease in the CBF of WM associated with simultaneous MRI changes. These are obviously caused by the arteriopathy in long penetrating arteries and indicate early tissue damage, also expressed as impaired rCMR(gluc) in the WM.
  • van der Meijden, Els; Horvath, Barbara; Nijland, Marcel; de Vries, Karin; Raez, Emoke; Diercks, Gilles F.; de Weerd, Annelies E.; Clahsen-van Groningen, Marian C.; van der Blij-de Brouwer, Caroline S.; van der Zon, Arnulfo J.; Kroes, Aloys C. M.; Hedman, Klaus; van Kampen, Jeroen J. A.; Riezebos-Brilman, Annelies; Feltkamp, Mariet C. W. (2017)
    Classic human polyomaviruses (JC and BK viruses) become pathogenic when reactivating from latency. For the rare skin disease trichodysplasia spinulosa, we show that manifestations of the causative polyomavirus (TSPyV) occur during primary infection of the immunosuppressed host. High TSPyV loads in blood and cerebrospinal fluid, sometimes coinciding with cerebral lesions and neuroendocrine symptoms, marked the acute phase of trichodysplasia spinulosa, whereas initiation and maturation of TSPyV seroresponses occurred in the convalescent phase. TSPyV genomes lacked the rearrangements typical for reactivating polyomaviruses. These findings demonstrate the clinical importance of primary infection with this rapidly expanding group of human viruses and explain the rarity of some novel polyomavirus-associated diseases.
  • Anastasopoulou, Stavroula; Heyman, Mats; Eriksson, Mats A.; Niinimäki, Riitta; Taskinen, Mervi; Mikkel, Sirje; Vaitkeviciene, Goda E.; Johannsdottir, Inga Maria; Myrberg, Ida Hed; Jonsson, Olafur Gisli; Als-Nielsen, Bodil; Schmiegelow, Kjeld; Banerjee, Joanna; Ranta, Susanna; Harila-Saari, Arja (2020)
    Background Seizures are common in children with acute lymphoblastic leukemia (ALL). As ALL survival rates are improving, the challenge to minimize treatment related side effects and late sequelae rises. Here, we studied the frequency, timing, etiology and risk factors of seizures in ALL patients. Methods The study included children aged 1–17.9 years at diagnosis of B-cell-precursor and T cell ALL who were treated according to the Nordic Society of Pediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2015. Detailed patient data were acquired from the NOPHO ALL2008 registry and by review of medical records. Results Seizures occurred in 81/1464 (5.5%) patients. The cumulative incidence of seizures at one months was 1.7% (95% CI: 1.2–2.5) and at one year 5.3% (95% CI 4.2–6.5%). Patients aged 10–17.9 years, those with T cell immunophenotype, CNS involvement, or high-risk induction with dexamethasone had higher risk for seizures in univariable analyses. Only age remained a risk factor in multivariable analyses (the cumulative incidence of seizures for patients 10–17.9 years old at one year was 9.0% (95% CI: 6.2–12.9)). Of the 81 patients with seizures, 43 had posterior reversible encephalopathy syndrome (PRES), 15 had isolated seizures, nine had sinus venous thrombosis (SVT), three had stroke-like syndrome, and 11 had other neurotoxicities. Epilepsy diagnosis was reported in totally 11 ALL survivors at last follow up. Conclusion Seizures are relatively common in ALL patients and occur most often in patients with PRES, SVT, or as an isolated symptom. Older children have higher risk of seizures.