Serum tissue inhibitor of matrix metalloproteinase-1 levels are associated with mortality in patients with malignant middle cerebral artery infarction

Background: In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study. Methods: This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality. Results: Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95 % CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95 % CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001). Conclusions: The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients

Herpes simplex encephalitis is linked with selective mitochondrial damage; a post-mortem and in vitro study

Herpes simplex virus type-1 (HSV-1) encephalitis (HSE) is the most commonly diagnosed cause of viral encephalitis in western countries. Despite antiviral treatment, HSE remains a devastating disease with high morbidity and mortality. Improved understanding of pathogenesis may lead to more effective therapies. Mitochondrial damage has been reported during HSV infection in vitro. However, whether it occurs in the human brain and whether this contributes to the pathogenesis has not been fully explored. Minocycline, an antibiotic, has been reported to protect mitochondria and limit brain damage. Minocycline has not been studied in HSV infection. In the first genome-wide transcriptomic study of post-mortem human HSE brain tissue, we demonstrated a highly preferential reduction in mitochondrial genome (MtDNA) encoded transcripts in HSE cases (n = 3) compared to controls (n = 5). Brain tissue exhibited a significant inverse correlation for immunostaining between cytochrome c oxidase subunit 1 (CO1), a MtDNA encoded enzyme subunit, and HSV-1; with lower abundance for mitochondrial protein in regions where HSV-1 was abundant. Preferential loss of mitochondrial function, among MtDNA encoded components, was confirmed using an in vitro primary human astrocyte HSV-1 infection model. Dysfunction of cytochrome c oxidase (CO), a mitochondrial enzyme composed predominantly of MtDNA encoded subunits, preceded that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Minocycline treated astrocytes exhibited higher CO1 transcript abundance, sustained CO activity and cell viability compared to non-treated astrocytes. Based on observations from HSE patient tissue, this study highlights mitochondrial damage as a critical and early event during HSV-1 infection. We demonstrate minocycline preserves mitochondrial function and cell viability during HSV-1 infection. Minocycline, and mitochondrial protection, offers a novel adjunctive therapeutic approach for limiting brain cell damage and potentially improving outcome among HSE patients

Työhyvinvoinnin yliopistotasoinen opetus:selvitys työtieteiden opetuksen muutostarpeista Oulun yliopistossa:raportti Pohjois-Suomen elinkeinoelämälle tehdystä kysely- ja haastattelututkimuksesta

Tiivistelmä Tämä on raportti työtieteiden opetusta koskevista muutostarpeista Oulun yliopistossa. Selvityksen toteutti Oulun yliopiston kutsuma selvitysmies FT, dosentti Erkki Yrjänheikki. Yliopiston puolesta hanketta valvoi seurantaryhmä, johon kuuluivat professori Jaakko Kujala ja koulutusalajohtaja Jukka Majava. Ensimmäisessä vaiheessa selvitettiin opetusohjelman ja keskustelujen avulla Oulun yliopiston nykyisen työtieteiden opetuksen sisältöä ja laajuutta. Lisäksi selvitettiin lähinnä internet-sivustojen avulla myös muiden yliopistojen ja korkeakoulujen sekä muiden koulutusorganisaatioiden työhyvinvoinnin ja työtieteiden opetuksen luonnetta ja sisältöjä. Varsinainen käytännön elinkeinoelämään kohdennettu selvitys toteutettiin suunnattuna kyselynä ja valittujen työyhteisöjen haastattelujen avulla. Kirjallisena tehtyyn kyselyyn valittiin yhteensä 112 työyhteisöä, jotka edustavat mahdollisimman hyvin Pohjois-Suomen elinkeinoelämän rakenteita ja alueellista edustavuutta eri puolilta Pohjois-Suomea.Abstract This is a report of change needs in work science education at the University of Oulu. The study was carried out by the PhD, Adjunct Professor Erkki Yrjänheikki. The study project steering group included Professor Jaakko Kujala and Head of Undergraduate and Graduate Programs Jukka Majava. In the first phase of the study current work science teaching content and scope at the University of Oulu was clarified. In addition, the nature and content of other work science and well-being at work education at other universities and colleges was studied. The empirical survey was conducted by a mail survey and interviews at selected organisations. The survey was sent to 112 organisations in Northern Finland

Interleukin-1 beta-induced expression of the prostaglandin E-receptor subtype EP3 in U373 astrocytoma cells depends on protein kinase C and nuclear factor-kappaB

Both interleukin-1beta (IL-1beta) and prostaglandins (PGs) are important mediators of physiological and pathophysiological processes in the brain. PGE2 exerts its effects by binding to four different types of PGE2 receptors named EP1-EP4. EP3 has found to be expressed in neurons, whereas expression of EP3 in glial cells has not been reported in the brain yet. Here we describe IL-1beta-induced EP3 receptor expression in human astrocytoma cells, primary astrocytes of rat and human origin and in rat brain. Using western blot, we found a marked up-regulation of EP3 receptor synthesis in human and rat primary glial cells. Intracerebroventricular administration of IL-1beta stimulated EP3 receptor synthesis in rat hippocampus. The analysis of involved signal transduction pathways by pathway-specific inhibitors revealed an essential role of protein kinase C and nuclear factor-kappaB in astrocytic IL-1beta-induced EP3 synthesis. Our data suggest that PGE2 signaling in the brain may be altered after IL-1beta release due to up-regulation of EP3 receptors. This might play an important role in acute and chronic conditions such as cerebral ischemia, traumatic brain injury, HIV-encephalitis, Alzheimer's disease and prion diseases in which a marked up-regulation of IL-1beta is followed by a prolonged increase of PGE2 levels in the brain

The radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) decreases mortality, enhances cognitive functions in water maze and reduces amyloid plaque burden in hA&#946;PP transgenic mice.

The purpose of this study was to evaluate the efficacy of the radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) in alleviating behavioral deficits and reducing amyloid-β (Aβ) accumulation in an Alzheimer's disease (AD) transgenic Tg2576 mouse model. Daily treatment with IAC (3-30 mg/kg, i.p.) was started at the age of 6 months and continued until the mice were 13 months old. At the age of 9 months and again at 12 months, the mice were tested in open field and water maze tests. At the age of 13 months, the mice were sacrificed and the brains processed for immunohistochemistry. Mortality was significantly reduced in all IAC-treated groups. In addition, IAC treatment improved the water maze hidden platform training performance but had no effect on motor activity in the open field or water maze swim speed in transgenic mice. Lastly, IAC treatment (10 mg/kg) significantly reduced the cortical Aβ plaque burden. In vitro, IAC is able to increase the number of neurites and neurite branches in cultured cortical primary neurons. In conclusion, IAC slowed down the development of the AD-like phenotype in Tg2576 mice and accelerated neurite growth in cultured neurons

Characterization of Neurophysiological and Behavioral Changes, MRI Brain Volumetry and 1H MRS in zQ175 Knock-In Mouse Model of Huntington's Disease

<div><p>Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the <em>huntingtin</em> gene (<em>HTT</em>) mutation that causes the disease, several mouse lines have been developed using different gene constructs of <em>Htt</em>. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050717#pone.0050717-Menalled1">[1]</a>) in an attempt to have the <em>Htt</em> gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050717#pone.0050717-Menalled1">[1]</a>, and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease.</p> </div