Intracranial Nimodipine Implant: Feasibility and Implications for the Treatment of Subarachnoid Hemorrhage – A Pre-Clinical Study

Intracranial aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition requiring immediate neurocritical care. A ruptured aneurysm must be isolated from arterial circulation to prevent rebleeding. Open surgical clipping of the neck of the aneurysm or intra-arterial filling of the aneurysm sack with platinum coils are major treatment strategies in an acute phase. About 40% of the patients suffering from aSAH die within a year of the bleeding despite the intensive treatment. After aSAH, the patient may develop a serious complication called vasospasm. Major risk for the vasospasm takes place at days 5–14 after the primary bleeding. In vasospasm, cerebral arteries contract uncontrollably causing brain ischemia that may lead to death. Nimodipine (NDP) is used to treat of vasospasm and it is administrated intravenously or orally every four hours for 21 days. NDP treatment has been scientifically proven to improve patients’ clinical outcome. The therapeutic effect of L-type calcium channel blocker NDP is due to the ability to dilate cerebral arteries. In addition to vasodilatation, recent research has shown the pleiotropic effect of NDP such as inhibition of neuronal apoptosis and inhibition of microthrombi formation. Indeed, NDP inhibits cortical spreading ischemia. Knowledge of the pathophysiology of the vasospasm has evolved in recent years to a complex entity of early brain injury, secondary injuries and cortical spreading ischemia, instead of being pure intracranial vessel spasm. High NDP levels are beneficial since they protect neurons and inhibit the cortical spreading ischemia. One of the drawbacks of the intravenous or oral administration of NPD is systemic hypotension, which is harmful particularly when the brain is injured. Maximizing the beneficial effects and avoiding systemic hypotension of NDP, we developed a sustained release biodegradable NDP implant that was surgically positioned in the basal cistern of animal models (dog and pig). Higher concentrations were achieved locally and lower concentrations systemically. Using this treatment approach in humans, it may be possible to reduce incidence of harmful hypotension and potentiate beneficial effects of NDP on neurons. Intracellular calcium regulation has a pivotal role in brain plasticity. NDP blocks L-type calcium channels in neurons, substantially decreasing intracellular calcium levels. Thus, we were interested in how NDP affects brain plasticity and tested the hypothesis in a mouse model. We found that NDP activates Brain-derived neurotrophic factor (BDNF) receptor TrkB and its downstream signaling in a reminiscent of antidepressant drugs. In contrast to antidepressant drugs, NDP activates Akt, a major survival-promoting factor. Our group’s previous findings demonstrate that long-term antidepressant treatment reactivates developmental-type of plasticity mechanisms in the adult brain, which allows the remodeling of neuronal networks if combined with appropriate rehabilitation. It seems that NDP has antidepressant-like properties and it is able to induce neuronal plasticity. In general, drug induced neuronal plasticity has a huge potential in neurorehabilitation and more studies are warranted.

Workplace Social Capital and Employee Health

Työyhteisön sosiaalinen pääoma ja työntekijöiden terveys Monien tutkimusten mukaan sosiaalinen pääoma vaikuttaa terveyteen. Vaikka työssä käyvä väestönosa on merkittävän osan valveillaoloajastaan työyhteisössä, siellä kertyvää sosiaalista pääomaa on toistaiseksi tutkittu vähän. Tässä tutkimuksessa selvitettiin työyhteisön sosiaalisen pääoman ja kuntatyöntekijöiden terveyden välistä yhteyttä pitkittäisasetelmassa hyödyntäen Kuntasektorin henkilöstön seurantatutkimuksen aineistoa vuosilta 2000–2005. Yhteensä 48592 kuntatyöntekijää vastasi kyselyyn vuosina 2000–02 (vastausprosentti 68 %). Heistä 35914 (77 %) osallistui myös seurantatutkimukseen vuosina 2004–05. Tutkimuksessa kehitettiin kyselyyn perustuva työyhteisön sosiaalisen pääoman mittausmenetelmä. Työntekijän omaan arvioon perustuvan sosiaalisen pääoman lisäksi mitattiin työyhteisön sosiaalista pääomaa käyttämällä samassa työyhteisössä työskentelevien muiden työntekijöiden keskimääräistä arviota sosiaalisesta pääomasta. Terveyttä mitattiin kysymyksellä koetusta terveydestä. Masennusta arvioitiin sekä kysymällä lääkärin toteamasta masennuksesta että masennuslääkeostoilla Kelan lääkerekistereistä. Analyyseihin otettiin mukaan vain ne kuntatyöntekijät, jotka olivat lähtötilanteissa terveitä eli kokivat terveytensä hyväksi tai heillä ei ollut aiempaa diagnosoitua tai lääkehoitoa vaatinutta masennusta. Tulosten analysointiin käytettiin monitasomallinnusta. Tulokset vakioitiin sosiodemografisten tekijöiden ja terveyskäyttäytymisen suhteen. Neljän vuoden seurannassa sekä jatkuvasti vähäinen että vähenevä yksilön sosiaalinen pääoma työssä lisäsi riskiä koetun terveyden heikkenemiseen niillä kuntatyöntekijöillä, jotka eivät vaihtaneet työpaikkaa seurannan aikana ja jotka seurannan alussa kokivat terveytensä hyväksi. Tulos ei selittynyt sosiodemografisilla tekijöillä tai terveyskäyttäytymisen eroilla. Tuloksen merkittävyyttä tuki havainto, että myös työtoverien arvioon perustuva sosiaalinen pääoma ennusti oman terveyden huononemista seuranta-aikana. Niillä työntekijöillä, jotka työskentelivät sellaisissa työyhteisöissä, joissa koko seurannan ajan oli vähiten sosiaalista pääomaa, oli lähes 1.3 -kertainen riski terveyden heikentymiseen. Vähäinen omaan arvioon perustuva sosiaalinen pääoma työssä ennusti myös masennuksen ilmaantuvuutta lähtötilanteessa ei-masentuneilla lähes neljän vuoden seurannassa. Matalaan sosiaaliseen pääomaan liittyi 20–50 % suurempi todennäköisyys sairastua masennukseen seurannan aikana niin itseraportoidun lääkärin totea-man masennuksen kuin masennuslääkeostojen perusteella. Tätä tulosta ei kuitenkaan pystytty toistamaan käyttämällä oman arvion sijasta työtoverien arviota työyhteisön sosiaalisesta pääomasta. Tutkimusta sosiaalisen pääoman vaikutusta masennuksen ilmaantumiseen jatkettiin selvittämällä miten sosiaalisen pääoman eri ulottuvuudet vaikuttivat masennuksen ilmaantumiseen. Tulosten mukaan sosiaalisen pääoman vertikaalinen komponentti (työntekijöiden ja esimiesten välinen luottamus, vastavuoroisuus ja jaetut arvot ja normit, jotka edesauttavat yhteistyötä) sekä horisontaalinen komponentti (työntekijöiden välisissä suhteissa yhteistyöstä, luottamuksesta ja vastavuoroisuudesta syntyvä sosiaalinen pääoma) vaikuttivat itsenäisesti masennusriskiin. Tutkimuksen perusteella korkea työyhteisön sosiaalinen pääoma saattaa vaikuttaa edullisesti työntekijöiden terveyteen. Jos näin on, olisi tärkeää edistää työyhteisöjen sosiaalista pääomaa ja kannustaa sellaiseen toimintaan, joka lisää suvaitsevaisuutta, luottamusta ja vastavuoroisuutta sekä työntekijöiden kesken että työntekijöiden ja esimiesten välillä.

Surgical treatment of hamstring injuries and disorders – the clinical spectrum from chronic tendinopathy to complete rupture

Hamstring muscle injuries and tendon disorders are common, especially in sports. They can be severe and difficult to treat, often resulting in impaired athletic performance and long rehabilitation times. Previous studies considering treatment of these problems are scarce. The current study was designed to investigate the effect of surgery on different types of hamstring muscle injuries and on proximal hamstring tendinopathy. In addition, we wanted to study the typical histopathological findings relating to proximal hamstring tendinopathy. In the study of complete (all three muscles torn) proximal hamstring avulsions (41 patients), our results showed that early operative treatment gives significantly better results than late surgery, and is therefore recommended. Despite this, considerable improvement of symptoms could also be achieved in chronic cases. In the study of partial (one or two muscles torn) proximal hamstring tears (47 patients), we observed that these injuries can cause significant functional deficit and impaired performance in athletes. The main finding was that after surgical repair most of the patients were able to return to their pre-injury level of sports. In the study of distal hamstring tears (18 patients), the results showed that surgical treatment had a good effect in the majority of these cases. In proximal hamstring tendinopathy, the main problem is pain which limits sports. In this study (90 patients), we found that after unsuccessful conservative treatment, surgery was a good treatment option resulting in full return to sports in most cases. In tendinopathic hamstring tendons, the morphological changes of tendinosis were largely identical to those previously described in other common (e.g. Achilles and patellar) tendinopathies. In chronic proximal hamstring avulsions, and also in reoperations, a large defect between distally retracted tendons and the ischial tuberosity may occasionally prevent anatomic reinsertion. We have described a reconstruction method using fascia lata autograft augmentation to be used in these most challenging repairs. This technique was utilized in the treatment of five patients, with encouraging results.

Borrelia burgdorferi evades the effects of ceftriaxone treatment in a mouse model of Lyme borreliosis

Borrelia burgdorferi infektoitujen hiirten antibioottihoidon jälkeinen oireilu Lymen borrelioosi on puutiaisten välittämä monimuotoinen infektiotauti, jonka tunnetuin oire on ns. vaeltava ihottuma eli erythema migrans. Muita tavallisia ilmentymiä ovat erityisesti nivel- ja hermosto-oireet sekä harvemmin sydän- ja silmäoireet. Suurin osa potilaista paranee täysin terveeksi antibioottihoidon avulla, mutta jopa 10 % borrelioosiin sairastuneista oireilee suositusten mukaisesta hoidosta huolimatta. Pitkittyneen oireilun on ajateltu johtuvan mm. infektion laukaisemasta autoimmuunitaudista tai kroonisesta infektiosta, mutta teorioiden tueksi ei ole kyetty esittämään kiistattomia todisteita. Onkin todennäköistä, että antibioottihoidon jälkeisen oireilun takana on useampia mekanismeja eikä yksi teoria selitä kaikkien potilaiden oireilua. Tässä väitöskirjatyössä on tutkittu hoidonjälkeistä borrelioosia hiirimallin avulla. Varhaisvaiheessa (2 viikkoa infektoinnin jälkeen) annettu antibiootti vähensi hiirten nivelturvotusta ja esti B. burgdorferi – bakteerin kasvun kudoksista otetuista näytteissä. Hoidettu¬jen hiirten B. burgdorferi -spesifiset IgG-luokan vasta-aineet pysyivät kuitenkin koholla ja osasta kudosnäytteistä löytyi B. burgdorferi:n DNA:ta PCR-tutkimuksen avulla. Mikäli hiiret hoidettiin myöhäisessä vaiheessa (yli 18 viikkoa infektoinnista) tulokset olivat muuten samanlaiset, mutta keftriaksoni ei vaikuttanut nivelturvotukseen. Näin hiirissä oli aikaansaatu tilanne, joka on hyvin samankaltainen ihmisen hoitoresistentin borrelia-artriitin kanssa: oireet jatkuvat, mutta taudinaiheuttajaa ei saada esiin. Inflammaatiota vaimentavaa anti-TNF-alphaa on käytetty nivelreuman hoidossa menestyksekkäästi huonosti muuhun hoitoon reagoivilla potilailla ja siitä syystä sen ajateltiin voivan vaikuttaa suotuisasti myös B. burgdorferi -infektoitujen hiirten hoidonjälkeiseen nivelturvotukseen. Sillä ei kuitenkaan ollut vaikutusta nivelturvotukseen, mutta yllättäen hoidon jälkeen osa hiirten kudosnäytteistä osoittautui viljelypositiivisiksi. On siis ilmeistä, että hiirimallissamme osa B. burgdorferi spirokeetoista pystyy välttämään keftriaksonihoidon vaikutuksen joko hakeutumalla elimistössä kudokseen, jossa antibiootin pitoisuus ei nouse riittävän korkeaksi, tai ne kykenevät muuntautumaan metabolisesti inaktiiviin tilaan eikä mikrobilääke yhdessä immuunipuolustuksen kanssa onnistu tappamaan niitä. Jatkotutkimuksissa selvitimme B. burgdorferi - spirokeetan mahdollista piilopaikkaa tutkimalla antibioottihoidon jälkeen useita eri kudoksia PCR-menetelmällä. Tulosten perusteella spirokeetta näyttää suosivan nivelkudosta tai soluja, joita esiintyy nivelessä runsaasti. On kuitenkin edelleen epäselvää, missä muodossa B. burgdorferi –spirokeetat säilyvät kudoksessa antibioottihoidon jälkeen.

Vascular Function in Chronic Kidney Disease and in Renovascular Disease

Cardiovascular mortality is 15 to 30 times higher in patients with chronic kidney disease than in the age-adjusted general population. Even minor renal dysfunction predicts cardiovascular events and death in the general population. In patients with atherosclerotic renovascular disease the annual cardiovascular event and death rate is even higher. The abnormalities in coronary and peripheral artery function in the different stages of chronic kidney disease and in renovascular disease are still poorly understood, nor have the cardiac effects of renal artery revascularization been well characterized, although considered to be beneficial. This study was conducted to characterize myocardial perfusion and peripheral endothelial function in patients with chronic kidney disease and in patients with atherosclerotic renovascular disease. Myocardial perfusion was measured with positron emission tomography (PET) and peripheral endothelial function with brachial artery flow-mediated dilatation. It has been suggested that the poor renal outcomes after the renal artery revascularization could be due to damage in the stenotic kidney parenchyma; especially the reduction in the microvascular density, changes mainly evident at the cortical level which controls almost 80% of the total renal blood flow. This study was also performed to measure the effect of renal artery stenosis revascularization on renal perfusion in patients with renovascular disease. In order to do that a PET-based method for quantification of renal perfusion was developed. The coronary flow reserve of patients with chronic kidney disease was similar to the coronary flow reserve of healthy controls. In renovascular disease the coronary flow reserve was, however, markedly reduced. Flow-mediated dilatation of brachial artery was decreased in patients with chronic kidney disease compared to healthy controls, and even more so in patients with renovascular disease. After renal artery stenosis revascularization, coronary vascular function and renal perfusion did not improve in patients with atherosclerotic renovascular disease, but in patients with bilateral renal artery stenosis, flow-mediated dilatation improved. Chronic kidney disease does not significantly affect coronary vascular function. On the contrary, coronary vascular function was severely deteriorated in patients with atherosclerotic renovascular disease, possibly because of diffuse coronary artery disease and/or diffuse microvascular disease. The peripheral endothelial function was disturbed in patients with chronic kidney disease and even more so in patient with atherosclerotic renovascular disease. Renal artery stenosis dilatation does not seem to offer any benefits over medical treatment in patients with renovascular disease, since revascularization does not improve coronary vascular function or renal perfusion.

A Comparative Study of the Effectiveness of a Prefabricated Appliance and a Stabilization Appliance in the Treatment of Myofascial pain and Headache

The aim of this thesis was to evaluate the short- and long-term effectiveness of a prefabricated occlusal appliance (R) on patients with myofascial pain and headache by comparing it with the treatment of the stabilization appliance (S). Another aim was to evaluate the effect of appliance treatment on stress-related salivary parameters like cortisol and IgA, as well as on flow rate values in these patients. Sixty-five patients diagnosed with myofascial temporomandibular disorder (TMD) pain, of whom 94% suffered concomitantly from headache, at two centres for Stomatognathic Physiology, one in Sweden and one in Finland, were included in this randomized controlled trial using Research Diagnostic Criteria for TMD (RDC/TMD), with history questionnaires and clinical examinations performed at baseline and at 6- and 10-weeks, and 6- and 12-month follow-ups. Patients were randomly assigned either to the R or the S group. Treatment outcome was measured according to IMMPACT (Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials), i.e. four chronic pain outcome domains: pain intensity, overall improvement, physical and emotional functioning. Changes in frequency and intensity of headache were recorded. Thirty-nine patients participated in the saliva study. Salivary analyses were performed at 6 and 10 weeks. The results revealed no differences between groups at baseline. At all follow-ups, all four outcome measures, as well as frequency and intensity of headache, showed statistically significant within-group improvement compared to baseline, without significant differences between groups. No treatment-induced changes in saliva parameters could be registered. In conclusion, the effectiveness of the prefabricated appliance seemed to be similar to that of the stabilization appliance in alleviating myofascial pain, and frequency and intensity of headache, in the short as well as the long term. However, no changes in salivary parameters were observed during treatment.

Starting Insulin Treatment in Type 2 Diabetes

Type 2 diabetes is a disorder of glucose metabolism characterized by chronic hyperglycemia. Initially type 2 diabetes is characterized by insulin resistance and impaired function of beta cells, leading progressively to insulin deficiency. Type 2 diabetes is treated with diet and other lifestyle changes, and with medication modulating e.g. insulin resistance, liver glucose production and insulin secretion. Injectable insulin is added to the treatment when lifestyle changes and other medication are insufficient to maintain adequate control of hyperglycemia. The aim of the treatment is to remove the symptoms of diabetes and to prevent late complications of diabetes. Insulin was traditionally started at hospital wards, but from the early 1990’s also in outpatient care. The first substudy of this thesis examined retrospectively initiation practices and how successfully insulin treatment was introduced in 1990 – 1996 in Southwestern Finland. This study aimed also at identifying the best methods of controlling plasma glucose. It showed that in the 1990’s the incidence of insulin treatment increased and was initiated more often in outpatient care than previously. The use of combination treatment also increased, first with sulfonylureas and later with metformin as the oral drug. In combination therapy the insulin dose was smaller than with insulin monotherapy. HbA1c improved similarly in middle-aged and older age groups. Weight increase associated with insulin initiation was smaller when combined with oral agents. A prospective insulin initiation study (1994 – 1998) tested the hypothesis that hyperglycemia (fasting and postprandial hyperglycemia) may affect the outcome of insulin initiation. The type of hyperglycemia was determined by the relation of fasting plasma glucose to HbA1c. Treatment was initiated with insulin Lente or human NPH insulin. In patients treated with insulin monotherapy twice daily the decline in HbA1c was markedly greater for postprandial than fasting hyperglycemia patients suggesting that hyperglycemia type has significance in the selection of the insulin regimen. Another insulin initiation study showed that patients with fasting hyperglycemia starting on insulin (2004-2005) were significantly more prone to overweight than patients with postprandial hyperglycemia. Irrespective of the insulin preparation (insulin NPH or insulin glargine), patients with fasting hyperglycemia had a greater weight increase compared to patients with postprandial hyperglycemia. Special attention should be paid to prevention of weight increase in these patients.

Novel word learning ability in chronic post-stroke aphasia : variability and modality effects

Novel word learning has been rarely studied in people with aphasia (PWA), although it can provide a relatively pure measure of their learning potential, and thereby contribute to the development of effective aphasia treatment methods. The main aim of the present thesis was to explore the capacity of PWA for associative learning of word–referent pairings and cognitive-linguistic factors related to it. More specifically, the thesis examined learning and long-term maintenance of the learned pairings, the role of lexical-semantic abilities in learning as well as acquisition of phonological versus semantic information in associative novel word learning. Furthermore, the effect of modality on associative novel word learning and the neural underpinnings of successful learning were explored. The learning experiments utilized the Ancient Farming Equipment (AFE) paradigm that employs drawings of unfamiliar referents and their unfamiliar names. Case studies of Finnishand English-speaking people with chronic aphasia (n = 6) were conducted in the investigation. The learning results of PWA were compared to those of healthy control participants, and active production of the novel words and their semantic definitions was used as learning outcome measures. PWA learned novel word–novel referent pairings, but the variation between individuals was very wide, from more modest outcomes (Studies I–II) up to levels on a par with healthy individuals (Studies III–IV). In incidental learning of semantic definitions, none of the PWA reached the performance level of the healthy control participants. Some PWA maintained part of the learning outcomes up to months post-training, and one individual showed full maintenance of the novel words at six months post-training (Study IV). Intact lexical-semantic processing skills promoted learning in PWA (Studies I–II) but poor phonological short-term memory capacities did not rule out novel word learning. In two PWA with successful learning and long-term maintenance of novel word–novel referent pairings, learning relied on orthographic input while auditory input led to significantly inferior learning outcomes (Studies III–IV). In one of these individuals, this previously undetected modalityspecific learning ability was successfully translated into training with familiar but inaccessible everyday words (Study IV). Functional magnetic resonance imaging revealed that this individual had a disconnected dorsal speech processing pathway in the left hemisphere, but a right-hemispheric neural network mediated successful novel word learning via reading. Finally, the results of Study III suggested that the cognitive-linguistic profile may not always predict the optimal learning channel for an individual with aphasia. Small-scale learning probes seem therefore useful in revealing functional learning channels in post-stroke aphasia.