Novel therapeutic and modeling approaches to experimental intracerebral hemorrhage

Intracerebral hemorrhage (ICH) represents the subtype of stroke carrying the most detrimental outcome and highest mortality. It is clearly underinvestigated and lacks an effective treatment except supportive management measures. The dismal outcomes of ICH are clearly associated with the mass effect of hematoma accompanied with dynamic perihematomal edema (PHE) and potential intraventricular bleeding (IVH), which is often complicated by development of hydrocephalus. In this thesis, we aimed to develop novel therapy modalities, which apart from experimental conditions, might be found effective in clinical scenario, and successfully implemented in ICH treatment clinical protocols in the future. In study (I), we utilized autologous blood injection model and magnetic resonance imaging (MRI) follow-up. Following the induction of deep right hemispheric hematoma of 75uL of volume, we performed decompressive craniectomy (DC) at 1 h, 6 h, and 24 h time points, aiming at diminishing high intracranial pressure (ICP) after the bleeding event. Control group did not undergo DC procedure. Decompressive craniectomy was found effective in reducing mortality and improving overall neurobehavioral outcome and mortality in all the 3 treatment groups. Effect of DC was most pronounced in the early craniectomy group (1 h). In study (II), we aimed to examine how deleterious is the influence of tissue plasminogen activator (tPA) in experimental ICH scenario, and whether the adverse tPA effects could be antagonized by the clinically safe mast-cell stabilizer chromoglycate. Animals were divided in four groups. We utilized intrahemispheric collagenase injection rat ICH model and MRI follow-up imaging up to 72h. Group 1 received tPA only, whereas Group 2 and Group 3 besides tPA received chromoglycate in single or double dose. Group 4 was used as a control having ICH, but receiving saline only. TPA-treated animals did not have significantly larger hematomas or hemispheric expansion even though been characterized by worse overall outcome. Application of chromoglycate in high dose mitigated detrimental outcomes present in the group being treated with tPA only, and diminished the extent of hemispheric expansion. This encourages further research to potentially establish "blind" thrombolysis concept coupled with concomitant application of MC inhibitors, as we could show that injurious tPA effects were successfully abolished by concomitant MC stabilization in experimental ICH scenario. In the third study (III), we decided to develop a novel combined ICH + intraventricular hemorrhage (IVH) model in the rat as such a model does not exist besides the fact that approximately 40% of all ICHs in human patients are complicated by presence of intraventricular hemorrhage which is known to worsen prognosis. We utilized different blood volumes of 100-250uL in modified autologous blood injection model to induce deep intrahemispheric ICH to establish a fully novel experimental approach of ICH followed by IVH. We performed 1-week MRI follow-up and consistent neurobehavioral evaluation at 24 h, 48 h, 72 h, and 1 week after hemorrhage. Using MRI, we identified the presence of hydrocephalus in all experimental subjects, and its progressive tendency during entire follow-up. The most prominent hemispheric expansion and the most pronounced hydrocephalus were present in experimental groups with >200uL blood injection. This model was reliable and highly reproducible, demonstrating promising initial point for ICH+IVH experimental research. These two novel treatment strategies established in our studies give promise for further refinements and potential applications in human patients. The novel ICH+IVH model we established in rat models may serve as an improved model for future experimental studies as it mimics human disease scenarios better than the existing models.Aivojen sisäinen verenvuoto (ICH) on aivoverenkiertohäiriön muoto, jossa on huonoin ennuste ja korkein kuolleisuus. Se on selvästi alitutkittu ja siihen ei ole kehitetty varsinaisia spesifisiä hoitoja, tukitoimenpiteitä lukuun ottamatta. ICH:n huono ennuste johtuu vuodon massavaikutuksesta, vuodon ympärille kehittyvästä turvotuksesta sekä potentiaalisesta aivokammion sisäisestä vuodosta jonka seurauksena kehittyy usein vesipää. Tässä työssä pyrittiin kehittämään koeolosuhteissa uusia hoidon mahdollisuuksia, jotka saattavat olla tehokkaita myös kliinisessä tilanteessa, ja jotka voisivat toimia pohjatietona uusissa ICH:n kliinisissä tutkimuksissa. Osatyössä (I) käytettiin autologisen veren injektiomallia ja magneettikuvausseurantaa (MRI). Vuodon induktion jälkeen (tilavuus 75 uL) teimme dekompressiivisen kraniektomian (DC) 1, 6 ja 24 tunnin kuluttua verenvuodosta. DC:n tavoitteena oli vähentää korkeaa kallonsisäistä painetta (ICP). Kontrolliryhmässä kraniektomiaa ei tehty. DC toimii tehokkaana menetelmänä kuolleisuuden vähentämisessä ja neurologisten statuslöydösten parantamisessa kaikissa hoitoryhmissä. DC:n vaikutus oli voimakkainta 1 tunnin kraniektomia-ryhmässä. Osatyössä (II) tavoitteena oli tutkia, miten haitallista on kudosplasminogeeniaktivaattorin (tPA) vaikutus kokeellisessa ICH-skenaariossa, ja voiko tPA:n haittavaikutuksia antagonisoida kliinisesti turvallisella mast-solustabilisaattorilla (kromoglikaatti). Eläimet jaettiin neljään ryhmään. Osatyössä käytettiin rotan kollagenaasin injektiomallia ja suoritettiin MRI-seuranta 72 tuntiin asti. Ryhmä 1 sai vain tPA:ta, kun puolestaan ryhmät 2 ja 3 saivat tPA:n lisäksi joko yksi tai kaksi annosta kromoglikaattia. Ryhmää 4 käytettiin kontrollina, jossa eläimillä oli pelkkä ICH, ja jotka saivat ainoastaan suolaliuosta. TPA:ta saaneilla eläimillä ei esiintynyt tilastollisesti suurempia vuotoja, eikä merkittävämpää aivopuoliskon ekspansiota, vaikka niiden yleinen vointi oli huonompi. Kromoglikaattihoito annettuna riittävän suurina annoksina lievensi haitallisia tPA:n vaikutuksia ja vaikutti myönteisesti aivopuoliskon ekspansioon. Tämä avaa uudet mahdollisuudet tutkia blind -liuotushoito -konseptia tulevaisuudessa kliinisissä olosuhteissa juuri siksi, että vahingollisia tPA:n vaikutuksia onnistuttiin kokeellisissa olosuhteissa poistamaan ICH-rotilta. Osatyössä (III) kehitettiin täysin uusi yhdistetty aivojen sisäisen ja aivokammioiden sisäisen vuodon kokeellinen verenvuotomalli (ICH + IVH) rotilla. IVH tunnetusti pahentaa ICH-potilaiden ennustetta ja selkeästi lisää kuolleisuutta. Eri ryhmille on käyttämällä muokatun autologisen veren injektiomallia annettu stereotaktisesti 100 - 250 uL verta, minkä seurauksena kaikille eläimille kehittyi ICH, jossa oli IVH-jatke. Suoritimme 1 viikon MRI-seurannan ja johdonmukaiset neurologiset arvioinnit 24 h:n, 48 h:n, 72 h:n ja 1 viikon kuluttua verenvuodosta. Käyttämällä MRI:tä tunnistimme merkkejä vesipäästä kaikissa koe-eläimissä, ja sen kehittymisen dynamiikka pystyttiin osoittamaan koko seuranta-aikana. Merkittävin aivopuoliskon ekspansio ja selvin vesipää oli yli 200 uL verta saaneilla eläimillä. Tämä malli osoittautui varsin luotettavaksi, mikä tarjoaa lupaavaa pohjaa tuleviin ICH + IVH -kokeisiin

Kohtausoireet ja ajoterveys

Vertaisarvioitu.• Toimintakyvyn hetkellisesti lamauttava kohtausoire liikenteessä on harvinainen mutta voi johtaa vaaratilanteeseen. • Osa kohtauksista johtuu tiedossa olevasta sairaudesta. • Useimmat kohtaukset ovat synkopaalisia, ja ne johtuvat sydän- ja verenkiertojärjestelmän säätelyn pettämisestä. Neurologiset ja psykogeeniset kohtaukset ovat harvinaisempia. • Liikenneturvallisuuden takia ratista on pysyttävä pois diagnostiikan ja tehoavan hoidon ajan. Nopea tutkiminen ja hoito on siksi keskeistä, etenkin kun kyseessä on ammattikuljettaja.Peer reviewe

Retrospective evaluation of the incidental finding of 403 papillary thyroid microcarcinomas in 2466 patients undergoing thyroid surgery for presumed benign thyroid disease

This research was aimed to describe the effectiveness of discovery learning model to increase student’s fluency thinking skills on chemical equilibrium subject matter.  The method of the research was quasi-experimental with  Non Equivalent Control Group Design.  The population of this research was all students in XI science class of MA Negeri 1 Metro whose sit in odd semester of academic year 2013-2014.  The sample were taken by purposive sampling technique then obtained XI IPA2 dan XI IPA3 class as sample of the research.  The effectiveness of discovery learning model was showed by the significant difference of n-Gain between control and experiment class.The result of research showed that the average n-Gain score for experiment class was  0,32 and the average n-Gain score for control class was 0,21.  Proving the hypothesis showed that discovery learning model is effective to increase student’s fluency thinking skills on chemical equilibrium subject matter. Tujuan penelitian ini adalah untuk mendiskripsikan efektivitas model discovery learning dalam meningkatkan keterampilan berpikir lancar siswa pada materi kesetimbangan kimia.  Metode dalam penelitian ini adalah kuasi eksperimen.  Populasi dalam peneliian ini adalah semua siswa kelas XI IPA MA Negeri 1 Metro semester ganjil Tahun Pelajaran 2013-2014.  Sampel diambil dengan tehnik purposive sampling sehingga diperoleh kelas XI IPA2 dan XI IPA3 sebagai sampel penelitian.  Efektivitas model discovery learning ditunjukan berdasarkan perbedaan nilai n-Gain yang signifikan antara kelas eksperimen dan kelas kontrol. Hasil penelitian menunjukan rata-rata nilai n-Gain untuk kelas eksperimen adalah 0,32 dan rata-rata nilai n-Gain  untuk kelas kontrol adalah 0,21.  Pengujian hipotesis menunjukan bahwa model discovery learning efektif dalam meningkatkan keterampilan berpikir lancar siswa pada materi kesetimbangan kimia. Kata kunci : kesetimbangan kimia, keterampilan berpikir lancar, model discovery learnin

Prognosis after Mild Traumatic Brain Injury: Influence of Psychiatric Disorders

Background: We evaluated the prevalence of psychiatric disorders in mild traumatic brain injury (MTBI) patients and investigated psychiatric comorbidity in relation to subjective symptoms and return to work (RTW). Methods: We recruited 103 MTBI patients (mean age 40.8 years, SD 3.1) prospectively from University Hospital. The patients were followed up for one year. The Rivermead Post-Concussion Symptom Questionnaire (RPQ) and Extended Glasgow Outcome Scale (GOSE) were administered one month after MTBI. Three months after MTBI, any psychiatric disorders were assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders. Results: Psychiatric disorders were diagnosed in 26 patients (25.2%). The most common disorders were previous/current depression. At three months, there was no difference between patients with psychiatric disorders versus those without them in RTW (95.7% vs. 87.3%, p = 0.260) or at least in part-time work (100% vs. 94.4%, p = 0.245). In Kaplan–Meier analysis, the median time to RTW was 10 days for both groups. The median RPQ score was 13.0 (Interquartile range (IQR) 6.5–19.0) in patients with a psychiatric disorder compared to 8.5 (IQR 2.3–14.0) in those without one (p = 0.021); respectively, the median GOSE was 7.0 (IQR 7.0–8.0) compared to 8.0 (IQR 7.0–8.0, p = 0.003). Conclusions: Approximately every fourth patient with MTBI had a psychiatric disorder. These patients reported more symptoms, and their functional outcome measured with GOSE at one month after MTBI was worse. However, presence of any psychiatric disorder did not affect RTW. Early contact and adequate follow-up are important when supporting the patient’s return to work

Prognosis after Mild Traumatic Brain Injury: Influence of Psychiatric Disorders

Background: We evaluated the prevalence of psychiatric disorders in mild traumatic brain injury (MTBI) patients and investigated psychiatric comorbidity in relation to subjective symptoms and return to work (RTW). Methods: We recruited 103 MTBI patients (mean age 40.8 years, SD 3.1) prospectively from University Hospital. The patients were followed up for one year. The Rivermead Post-Concussion Symptom Questionnaire (RPQ) and Extended Glasgow Outcome Scale (GOSE) were administered one month after MTBI. Three months after MTBI, any psychiatric disorders were assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders. Results: Psychiatric disorders were diagnosed in 26 patients (25.2%). The most common disorders were previous/current depression. At three months, there was no difference between patients with psychiatric disorders versus those without them in RTW (95.7% vs. 87.3%, p = 0.260) or at least in part-time work (100% vs. 94.4%, p = 0.245). In Kaplan–Meier analysis, the median time to RTW was 10 days for both groups. The median RPQ score was 13.0 (Interquartile range (IQR) 6.5–19.0) in patients with a psychiatric disorder compared to 8.5 (IQR 2.3–14.0) in those without one (p = 0.021); respectively, the median GOSE was 7.0 (IQR 7.0–8.0) compared to 8.0 (IQR 7.0–8.0, p = 0.003). Conclusions: Approximately every fourth patient with MTBI had a psychiatric disorder. These patients reported more symptoms, and their functional outcome measured with GOSE at one month after MTBI was worse. However, presence of any psychiatric disorder did not affect RTW. Early contact and adequate follow-up are important when supporting the patient’s return to work

Anatomic and MRI bases for pontine infarctions with patients presentation

Objectives: There are scarce data regarding pontine arteries anatomy, which is the basis for ischemic lesions following their occlusion. The aim of this study was to examine pontine vasculature and its relationships with the radiologic and neuro-logic features of pontine infarctions. Materials and methods: Branches of eight basilar arteries and their twigs, including the larger intrapontine branches, were microdis-sected following an injection of a 10% mixture of India ink and gelatin. Two addi-tional brain stems were prepared for microscopic examination after being stained with luxol fast blue and cresyl violet. Finally, 30 patients with pontine infarctions underwent magnetic resonance imaging (MRI) in order to determine the position and size of the infarctions. Results: The perforating arteries, which averaged 5.8 in number and 0.39 mm in diameter, gave rise to paramedian and anteromedial branches, and also to anterolateral twigs (62.5%). The longer leptomeningeal and cere-bellar arteries occasionally gave off perforating and anterolateral twigs, and either the lateral or posterior branches. Occlusion of some of these vessels resulted in the para-median (30%), anterolateral (26.7%), lateral (20%), and combined infarctions (23.3%), which were most often isolated and unilateral, and rarely bilateral (10%). They were located in the lower pons (23.3%), middle (10%) or rostral (26.7%), or in two or three portions (40%). Each type of infarction usually produced characteristic neurologic signs. The clinical significance of the anatomic findings was discussed. Conclusions: There was a good correlation between the intrapontine vascular territories, the position, size and shape of the infarctions, and the type of neurologic manifestations. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Anatomic and MRI bases for medullary infarctions with patients' presentation

Objective: There is a low incidence of the medullary infarctions and sparse data about the vascular territories, as well as a correlation among the anatomic, magnetic resonance imaging (MRI) and neurologic signs. Materials and methods: Arteries of the 10 right and left sides of the brain stem were injected with India ink, fixed in formalin and microdissected. The enrolled 34 patients with medullary infarctions underwent a neurologic, MRI and Doppler examination. Results: Four types of the infarctions were distinguished according to the involved vascular territories. The isolated medial medullary infarctions (MMIs) were present in 14.7%. The complete MMIs comprised one bilateral infarction (2.9%), whilst the incomplete and partial MMIs were observed in 5.9% and 8.9%, respectively. The anterolateral infarctions (ALMIs) were very rare (2.9%). The complete and incomplete lateral infarctions (LMIs), noted in 35.3%, comprised 11.8% and 23.6%, respectively, that is, the anterior (5.9%), posterior (8.9%), deep (2.9%), and peripheral (5.9%). Dorsal ischemic lesions (DMIs) occurred in 11.8%, either as a complete (2.9%), or isolated lateral (5.9%) or medial infarctions (2.9%). The remaining ischemic regions belonged to various combined infarctions of the MMI, ALMI, LMI and DMI (35.3%). The infarctions most often affected the upper medulla (47.1%), middle (11.8%), or both (29.5%). Several motor and sensory signs were manifested following infarctions, including vestibular, cerebellar, ocular, sympathetic, respiratory and auditory symptoms. Conclusions: There was a good correlation among the vascular territories, MRI ischemia features, and neurologic findings regarding the medullary infarctions.Peer reviewe

Perceived Injustice After Mild Traumatic Brain Injury

Objective: To examine perceived injustice and its associations with self-reported symptoms and return to work at 3months after injury in a prospectively recruited sample of patients with mild traumatic brain injury (mTBI). Design: Observational study. Setting: TBI outpatient unit. Participants: Adult patients aged 18 to 68 years with mTBI (n = 100) or orthopedic injury ([OI]; n = 34). Main Measures: The Injustice Experience Questionnaire (IEQ) and its associations with the Rivermead Post Concussion Questionnaire (RPQ), Beck Depression Inventory-Second Edition (BDI-II), PTSD Checklist-Civilian Version (PCL-C), and Pain Visual Analog Scale (PVAS). Information on injury-related characteristics, compensation seeking and litigation, and return-to-work status was also collected. Results: Median IEQ total score was 3 (range, 0-23) in the mTBI group and 2.5 (range, 0-25) in the OI group. In the mTBI group, IEQ was significantly correlated with RPQ (rs = 0.638, PPeer reviewe

Return to work after mild traumatic brain injury : association with positive CT and MRI findings

Background Return to work (RTW) might be delayed in patients with complicated mild traumatic brain injury (MTBI), i.e., MTBI patients with associated traumatic intracranial lesions. However, the effect of different types of lesions on RTW has not studied before. We investigated whether traumatic intracranial lesions detected by CT and MRI are associated with return to work and post-concussion symptoms in patients with MTBI. Methods We prospectively followed up 113 adult patients with MTBI that underwent a brain MRI within 3-17 days after injury. Return to work was assessed with one-day accuracy up to one year after injury. Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Glasgow Outcome Scale Extended (GOS-E) were conducted one month after injury. A Kaplan-Meier log-rank analysis was performed to analyze the differences in RTW. Results Full RTW-% one year after injury was 98%. There were 38 patients with complicated MTBI, who had delayed median RTW compared to uncomplicated MTBI group (17 vs. 6 days), and more post-concussion symptoms (median RPQ 12.0 vs. 6.5). Further, RTW was more delayed in patients with multiple types of traumatic intracranial lesions visible in MRI (31 days, n = 19) and when lesions were detected in the primary CT (31 days, n = 24). There were no significant differences in GOS-E. Conclusions The imaging results that were most clearly associated with delayed RTW were positive primary CT and multiple types of lesions in MRI. RTW-% of patients with MTBI was excellent and a single intracranial lesion does not seem to be a predictive factor of disability to work.Peer reviewe