Kasvutekijöiden ilmentyminen nikamavälilevykudoksessa : havaintoja nikamavälilevykudoksen degeneraation ja mukautumisen perusmekanismeista

The intervertebral disc is composed of concentrically arranged components: annulus fibrosus, the transition zone, and central nucleus pulposus. The major disc cell type differs in various parts of the intervertebral disc. In annulus fibrosus a spindle shaped fibroblast-like cell mainly dominates, whereas in central nucleus pulposus the more rounded chondrocyte-like disc cell is the major cell type. At birth the intervertebral disc is well vascularized, but during childhood and adolescence blood vessels become smaller and less numerous. The adult intervertebral disc is avascular and is nourished via the cartilage endplates. On the other hand, degenerated and prolapsed intervertebral discs are again vascularized, and show many changes compared to normal discs, including: nerve ingrowth, change in collagen turnover, and change in water content. Furthermore, the prolapsed intervertebral disc tissue has a tendency to decrease in size over time. Growth factors are polypeptides which regulate cell growth, extracellular matrix protease activity, and vascularization. Oncoproteins c-Fos and c-Jun heterodimerize, forming the AP-1 transcription factor which is expressed in activated cells. In this thesis the differences of growth factor expression in normal intervertebral disc, the degenerated intervertebral disc and herniated intervertebral disc were analyzed. Growth factors of particular interest were basic fibroblast growth factor (bFGF or FGF-2), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGFβ). Cell activation was visualized by the expression of the AP-1 transcription promoters c-Fos and c-Jun. The expression was shown with either mono- or polyclonal antibodies by indirect avidin-biotin-peroxidase immunohistochemical staining method. The normal control material was collected from a tissue bank of five organ donors. The degenerated disc material was from twelve patients operated on for painful degenerative disc disease, and herniated disc tissue material was obtained from 115 patients operated on for sciatica. Normal control discs showed only TGFβ immunopositivity. All other factors studied were immunonegative in the control material. Prolapsed disc material was immunopositive for all factors studied, and this positivity was located either in the disc cells or in blood vessels. Furthermore, neovascularization was noted. Disc cell immunoreaction was shown in chondrocyte-like disc cells or in fibroblast-like disc cells, the former being expressed especially in conglomerates (clusters of disc cells). TGFβ receptor induction was prominent in prolapsed intervertebral disc tissue. In degenerated disc material, the expression of growth factors was analyzed in greater detail in various parts of the disc: nucleus pulposus, anterior annulus fibrosus and posterior annulus fibrosus. PDGF did not show any immunoreactivity, whereas all other studied growth factors were localized either in chondrocyte-like disc cells, often forming clusters, in fibroblast-like disc cells, or in small capillaries. Many of the studied degenerated discs showed tears in the posterior region of annulus fibrosus, but expression of immunopositive growth factors was detected throughout the entire disc. Furthermore, there was a difference in immunopositive cell types for different growth factors. The main conclusion of the thesis, supported by all substudies, is the occurrence of growth factors in disc cells. They may be actively participating in a network regulating disc cell growth, proliferation, extracellular matrix turnover, and neovascularization. Chondrocyte-like disc cells, in particular, expressed growth factors and oncoproteins, highlighting the importance of this cell type in the basic pathophysiologic events involved in disc degeneration and disc rearrangement. The thesis proposes a hypothesis for cellular remodelling in intervertebral disc tissue. In summary, the model presents an activation pattern of different growth factors at different intervertebral disc stages, mechanisms leading to neovascularization of the intervertebral disc in pathological conditions, and alteration of disc cell shape, especially in annulus fibrosus. Chondrocyte-like disc cells become more numerous, and these cells are capable of forming clusters, which appear to be regionally active within the disc. The alteration of the phenotype of disc cells expressing growth factors from fibroblast-like disc cells to chondrocyte-like cells in annulus fibrosus, and the numerous expression of growth factor expressing disc cells in nucleus pulposus, may be a key element both during pathological degeneration of the intervertebral disc, and during the healing process after trauma.Nikamavälilevykudos koostuu geelimäisestä ytimestä (nucleus pulpousus) ja tämän ympärille rengasmaisesti rakentuvasta annulus fibrosuksesta. Nikamavälilevykudossolu on erilainen eri osissa välilevykudosta: ulommassa vyöhykkeessä solu muistuttaa sidekudossolua ja geelimäisessä sisävyöhykkeessä solutyyppi on enemmänkin rustosolumainen. Sikiönkehityksen aikana ja syntymän jälkeen nikamavälilevykudos on verisuonitettua. Kasvun aikana verisuonitus vähenee ja häviää kokonaan aikuisikään tultaessa. Aikuisiässä nikamavälilevykudoksen ravinnonsaanti tapahtuu päätelevyjen kautta. Toisaalta nikamavälilevykudoksen degeneroituessa (rappeutuessa) kudokseen ilmaantuu jälleen uusia verisuonia ja uudissuonten muodostumista havaitaan nikamavälilevytilasta ulospullahtaneessa (prolaboituneessa) nikamavälilevykudoksessa. Prolaboituneella nikamavälikudosmassalla on todettu selkeä taipumus spontaaniin pienenemiseen ajan kuluessa. Kasvutekijät ovat proteiinirakenteisia tekijöitä, jotka säätelevät solun kasvua, verisuonitusta ja solunulkoisen tukirakenteen entsyymiaktiviteettia. Onkoproteiinit c-Fos ja c-Jun muodostavat proteiinirakenteen, joka tarvitaan tumaan solun transkription käynnistämiseen. Tässä väitöskirjassa tutkittiin kasvutekijöiden ilmentymistä nikamavälilevykudoksessa; normaalissa kudoksessa, rappeutuneessa kudoksessa ja ulospullahtaneessa kudoksessa. Erityisen mielenkiinnon kohteena olivat kasvutekijät FGF-2 (fibroblastikasvutekijä 2), PDGF ( verihiutalekasvutekijä), VEGF (verisuonen endoteelikasvutekijä) ja TGF-beta (transformoiva kasvutekijä beta). Soluaktivaatiota osoitti mahdollinen onkoproteiinien c-Fos ja c-Jun esiintyminen. Kasvutekijät ja onkoproteiinit osoitettiin immunohistokemiallisesti joko polyklonaalisten tai monoklonaalisten vasta-aineiden avulla. Normaali kontrolli välilevykudosmateriaali oli saatu viideltä elinluovuttajalta. Prolaboituneet nikamavälilevykudosnäytteet oli saatu 115 iskiasvaivan vuoksi leikatulta potilaalta ja degeneroituneet näytteet 12 kivuliaan degeneraatio-ongelman vuoksi leikatulta potilaalta. Normaalissa nikamavälilevykudoksessa esiintyi ainostaan TGF beta -kasvutekijää. Prolaboituneissa näytteissä esiintyi kaikkia tekijöitä, joko nikamavälilevykudossolussa tai verisuonissa. Uudissuonitusta osoitettiin. Soluihin paikantuva immunoreaktio oli joko sidekudostyyppisissä soluissa tai rustosolutyyppisissä soluissa. Jälkimmäiset muodostivat usein soluryhmiä. Yksi erityishavainto oli TGF-beta kasvutekijän reseptorin ilmentymisen selkeä lisääntyminen prolaboituneissa näytteissä verrattuna normaaliin kontrollikudokseen. Degeneroituneissä nikamavälilevynäytteissä oli mahdollista tutkia tarkemmin eri tekijöiden esiintymistä nikamavälilevykudoksen eri osissa. PDGF ei pystytty osoittamaan degeneroituneista näytteistä, muut tutkitut kasvutekijät olivat immunopositiivisia. Monissa degeneroituneissa näytteissä todettiin repeämiä nikamavälilevykudoksen takaosassa. Immunopositiivisuus kasvutekijöille todettiin kuitenkin koko nikamavälilevykudoksen alueella. Eri solutyypeissä kasvutekijäilmentymä vaihteli eri osissa välilevykudosta. Päähavaintona väitöskirjassa osoitettiin tutkittujen kasvutekijöiden esiintyminen erityisesti nikamavälilevykudossoluissa. Erityisesti esille nousi rustosolutyyppinen solu muodostaen myös ryhmiä. On todennäköistä, että kasvutekijät säätelevät nikamavälilevykudoksessa solujen kasvua, proliferaatiota, solunulkoisen väliaineen ylläpitoa ja uudisverisuonitusta. Väitöskirja esittää lopuksi hypoteesin nikamavälilevykudossolun mukautumiselle. Tätä mukautumista tapahtuu erityisesti kudoksen ulkokerroksissa (annulus fibrosus), jossa normaalin kudostyypin sidekudossolutyyppinen solu muuntuu rustosolutyyppiseksi soluksi muodosten myös aktivaatiokeskuksia. Tämä solutyypin muuntuminen saattaa olla keskeinen prosessi, joka mahdollistaa muutokset nikamavälilevykudoksessa: uudissuonituksen, rappeutumisprosessin ja trauman paranemisprosessin prolaboitumisen jälkeen

Red cell distribution width and mortality in older patients with frailty in the emergency department

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Low body temperature and mortality in older patients with frailty in the emergency department

Purpose The aim of this study was to assess the association between low body temperature and mortality in frail older adults in the emergency department (ED). Methods Inclusion criteria were: >= 75 years of age, Clinical Frailty Scale (CFS) score of 4-8, and temperature documented at ED admission. Patients were allocated to three groups by body temperature: low = 38.1. Odds ratios (OR) for 30-day and 90-day mortality were analysed. Results 1577 patients, 61.2% female, were included. Overall mortalities were 85/1577 (5.4%) and 144/1557 (9.2%) in the 30-day and 90-day follow-ups, respectively. The ORs for low body temperature were 3.03 (1.72-5.35; P < 0.001) and 2.71 (1.68-4.38; P < 0.001) for 30-day and 90-day mortality, respectively. This association remained when adjusted for age, CFS score and gender. Mortality of the high-temperature group did not differ significantly when compared to the normal-temperature group. Conclusions Low body temperature in frail older ED patients was associated with significantly higher 30- and 90-day mortality.Peer reviewe

National Early Warning Score 2 (NEWS2) and 3-Level Triage Scale as Risk Predictors in Frail Older Adults in the Emergency Department

Background The aim of the emergency department (ED) triage is to recognize critically ill patients and to allocate resources. No strong evidence for accuracy of the current triage instruments, especially for the older adults, exists. We evaluated the National Early Warning Score 2 (NEWS2) and a 3-level triage assessment as risk predictors for frail older adults visiting the ED. Methods This prospective, observational study was performed in a Finnish ED. The data were collected in a six-month period and included were >= 75-year-old residents with Clinical Frailty Scale score of at least four. We analyzed the predictive values of NEWS2 and the three-level triage scale for 30-day mortality, hospital admission, high dependency unit (HDU) and intensive care unit (ICU) admissions, a count of 72-h and 30-day revisits, and ED length-of-stay (LOS). Results A total of 1711 ED visits were included. Median for age, CFS, LOS and NEWS2 were 85 years, 6 points, 6.2 h and 1 point, respectively. 30-day mortality was 96/1711. At triage, 69, 356 and 1278 of patients were assessed as red, yellow and green, respectively. There were 1103 admissions, of them 31 to an HDU facility, none to ICU. With NEWS2 and triage score, AUCs for 30-day mortality prediction were 0.70 (0.64-0.76) and 0.62 (0.56-0.68); for hospital admission prediction 0.62 (0.60-0.65) and 0.55 (0.52-0.56), and for HDU admission 0.72 (0.61-0.83) and 0.80 (0.70-0.90), respectively. The NEWS2 divided into risk groups of low, medium and high did not predict the ED LOS (p = 0.095). There was a difference in ED LOS between the red/yellow and as red/green patient groups (p <0.001) but not between the yellow/green groups (p = 0.59). There were 48 and 351 revisits within 72 h and 30 days, respectively. With NEWS2 AUCs for 72-h and 30-day revisit prediction were 0.48 (95% CI 0.40-0.56) and 0.47 (0.44-0.51), respectively; with triage score 0.48 (0.40-0.56) and 0.49 (0.46-0.52), respectively. Conclusions The NEWS2 and a local 3-level triage scale are statistically significant, but poor in accuracy, in predicting 30-day mortality, and HDU admission but not ED LOS or revisit rates for frail older adults. NEWS2 also seems to predict hospital admission.Peer reviewe

Systematic geriatric assessment for older patients with frailty in the emergency department: a randomised controlled trial

BackgroundComprehensive geriatric assessment provided in hospital wards in frail patients admitted to hospital has been shown to reduce mortality and increase the likelihood of living at home later. Systematic geriatric assessment provided in emergency departments (ED) may be effective for reducing days in hospital and unnecessary hospital admissions, but this has not yet been proven in randomised trials.MethodsWe conducted a single-centre, randomised controlled trial with a parallel-group, superiority design in an academic hospital ED.ED patients aged >= 75 years who were frail, or at risk of frailty, as defined by the Clinical Frailty Scale, were included in the trial. Patients were recruited during the period between December 11, 2018 and June 7, 2019, and followed up for 365 days.For the intervention group, systematic geriatric assessment was added to their standard care in the ED, whereas the control group received standard care only.The primary outcome was cumulative hospital stay during 365-day follow-up. The secondary outcomes included: admission rate from the index visit, total hospital admissions, ED-readmissions, proportion of patients living at home at 365 days, 365-day mortality, and fall-related ED-visits.ResultsA total of 432 patients, 63% female, with median age of 85 years, formed the analytic sample of 213 patients in the intervention group and 219 patients in the control group.Cumulative hospital stay during one-year follow-up as rate per 100 person-years for the intervention and control groups were: 3470 and 3149 days, respectively, with rate ratio of 1.10 (95% confidence interval, 0.55-2.19, P=.78). Admission rates to hospital wards from the index ED visit for the intervention and control groups were: 62 and 70%, respectively (P=.10). No significant differences were observed between the groups for any outcomes.ConclusionSystematic geriatric assessment for older adults with frailty in the ED did not reduce hospital stay during one-year follow-up. No statistically significant difference was observed for any secondary outcomes. More coordinated, continuous interventions should be tested for potential benefits in long-term outcomes.Trial registrationThe trial was registered in the ClinicalTrials.gov (registration number and date NCT03751319 23/11/2018).Peer reviewe

The emergency department arrival mode and its relations to ED management and 30-day mortality in acute heart failure : an ancillary analysis from the EURODEM study

Background Acute heart failure patients are often encountered in emergency departments (ED) from 11% to 57% using emergency medical services (EMS). Our aim was to evaluate the association of EMS use with acute heart failure patients' ED management and short-term outcomes. Methods This was a sub-analysis of a European EURODEM study. Data on patients presenting with dyspnoea were collected prospectively from European EDs. Patients with ED diagnosis of acute heart failure were categorized into two groups: those using EMS and those self-presenting (non- EMS). The independent association between EMS use and 30-day mortality was evaluated with logistic regression. Results Of the 500 acute heart failure patients, with information about the arrival mode to the ED, 309 (61.8%) arrived by EMS. These patients were older (median age 80 vs. 75 years, p 30/min in 17.1% patients vs. 7.5%, p = 0.005). The only difference in ED management appeared in the use of ventilatory support: 78.3% of EMS patients vs. 67.5% of non- EMS patients received supplementary oxygen (p = 0.007), and non-invasive ventilation was administered to 12.5% of EMS patients vs. 4.2% non- EMS patients (p = 0.002). EMS patients were more often hospitalized (82.4% vs. 65.9%, p < 0.001), had higher in-hospital mortality (8.7% vs. 3.1%, p = 0.014) and 30-day mortality (14.3% vs. 4.9%, p < 0.001). The use of EMS was an independent predictor of 30-day mortality (OR = 2.54, 95% CI 1.11-5.81, p = 0.027). Conclusion Most acute heart failure patients arrive at ED by EMS. These patients suffer from more severe respiratory distress and receive more often ventilatory support. EMS use is an independent predictor of 30-day mortality.Peer reviewe

Soluble triggering receptor expressed on myeloid cells-1 is a marker of organ injuries in cardiogenic shock : results from the CardShock Study

Aims Optimal outcome after cardiogenic shock (CS) depends on a coordinated healing response in which both debris removal and extracellular matrix tissue repair play a crucial role. Excessive inflammation can perpetuate a vicious circle, positioning leucocytes as central protagonists and potential therapeutic targets. High levels of circulating Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), were associated with death in acute myocardial infarction confirming excessive inflammation as determinant of bad outcome. The present study aims to describe the association of soluble TREM-1 with 90-day mortality and with various organ injuries in patients with CS. Methods and results This is a post-hoc study of CardShock, a prospective, multicenter study assessing the clinical presentation and management in patients with CS. At the time of this study, 87 patients had available plasma samples at either baseline, and/or 48 h and/or 96-120 h for soluble TREM-1 (sTREM-1) measurements. Plasma concentration of sTREM-1 was higher in 90-day non-survivors than survivors at baseline [median: 1392 IQR: (724-2128) vs. 621 (525-1233) pg/mL, p = 0.008), 48 h (p = 0.019) and 96-120 h (p = 0.029). The highest tertile of sTREM-1 at baseline (threshold: 1347 pg/mL) was associated with 90-day mortality with an unadjusted HR 3.08 CI 95% (1.48-6.42). sTREM-1 at baseline was not associated to hemodynamic parameters (heart rate, blood pressure, use of vasopressors or inotropes) but rather with organ injury markers: renal (estimated glomerular filtration rate, p = 0.0002), endothelial (bio-adrenomedullin, p = 0.018), myocardial (Suppression of Tumourigenicity 2, p = 0.002) or hepatic (bilirubin, p = 0.008). Conclusion In CS patients TREM-1 pathway is highly activated and gives an early prediction of vital organ injuries and outcome. [GRAPHICS] .Peer reviewe

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism

Background and Purpose Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved.Experimental Approach We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis.Key Results Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation.Conclusion and Implications PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia

Clinical practice selectively follows acute appendicitis guidelines

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Åtgärdsprogram för vattenvården för åren 2022–2027 i Södra Österbotten, Österbotten och Mellersta Österbotten.

Det centrala syftet med vattenvården är att hindra att tillståndet i vattendragen, sjöarna och kustvattnen försämras och att sträva efter att alla vatten uppnår åtminstone god status. Tillståndet i vatten som bedömts ha hög eller god status får inte försämras. För att nå målet planerar och vidtar man åtgärder som förbättrar vattnens status samt följer upp effekterna. I vattenvården beaktar man också målen för havsvården, för hanteringen av översvämnings-risker och för naturskyddet. Vattenvården planeras enligt vattenförvaltningsområden, av vilka det finns sju i Fastlandsfinland. Ett vattenför-valtningsområde bildas av ett eller flera vattendragsområden. Planeringen av vattenvården framskrider i sexårspe-rioder. De första åtgärdsprogrammen som sträcker sig fram till 2015 utarbetades i ett brett samarbete under 2008–2009. Mer information om vattenvården och organiseringen av den inom vattenförvaltningsområdet finns på https://www.ymparisto.fi/sv-FI/Vatten/Vattenskydd/Vattenvardsplanering_och_samarbete/Vattenforvaltningsomraden/Kumo_alvSkargardshavetBottenhavet och i förvaltningsplanen för Kumo älvs-Skärgårdshavets-Bottenhavets vattenförvaltningsområde. I förvaltningsplanen för vattenvården beskrivs lagstiftningen och andra planer och strategier som rör vattenvården mer i detalj. Dessutom har man i vattenförvaltningsplanen gjort en granskning av alternativ för vattenvårdsåtgär-derna i hela vattenförvaltningsområdet