Part I: Enzyme replacement versus neurotrophic factor viral vector-mediated gene therapy of Parkinson’s disease, Part II: The effects of orally dosed tolcapone and entacapone on dopamine metabolism in the dorsal striatum and nucleus accumbens in rats

Part I: Parkinson’s disease is a slowly progressive neurodegenerative disorder in which particularly the dopaminergic neurons of the substantia nigra pars compacta degenerate and die. Current conventional treatment is based on restraining symptoms but it has no effect on the progression of the disease. Gene therapy research has focused on the possibility of restoring the lost brain function by at least two means: substitution of critical enzymes needed for the synthesis of dopamine and slowing down the progression of the disease by supporting the functions of the remaining nigral dopaminergic neurons by neurotrophic factors. The striatal levels of enzymes such as tyrosine hydroxylase, dopadecarboxylase and GTP-CH1 are decreased as the disease progresses. By replacing one or all of the enzymes, dopamine levels in the striatum may be restored to normal and behavioral impairments caused by the disease may be ameliorated especially in the later stages of the disease. The neurotrophic factors glial cell derived neurotrophic factor (GDNF) and neurturin have shown to protect and restore functions of dopaminergic cell somas and terminals as well as improve behavior in animal lesion models. This therapy may be best suited at the early stages of the disease when there are more dopaminergic neurons for neurotrophic factors to reach. Viral vector-mediated gene transfer provides a tool to deliver proteins with complex structures into specific brain locations and provides long-term protein over-expression. Part II: The aim of our study was to investigate the effects of two orally dosed COMT inhibitors entacapone (10 and 30 mg/kg) and tolcapone (10 and 30 mg/kg) with a subsequent administration of a peripheral dopadecarboxylase inhibitor carbidopa (30 mg/kg) and L- dopa (30 mg/kg) on dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens of freely moving rats using dual-probe in vivo microdialysis. Earlier similarly designed studies have only been conducted in the dorsal striatum. We also confirmed the result of earlier ex vivo studies regarding the effects of intraperitoneally dosed tolcapone (30 mg/kg) and entacapone (30 mg/kg) on striatal and hepatic COMT activity. The results obtained from the dorsal striatum were generally in line with earlier studies, where tolcapone tended to increase dopamine and DOPAC levels and decrease HVA levels. Entacapone tended to keep striatal dopamine and HVA levels elevated longer than in controls and also tended to elevate the levels of DOPAC. Surprisingly in the nucleus accumbens, dopamine levels after either dose of entacapone or tolcapone were not elevated. Accumbal DOPAC levels, especially in the tolcapone 30 mg/kg group, were elevated nearly to the same extent as measured in the dorsal striatum. Entacapone 10 mg/kg elevated accumbal HVA levels more than the dose of 30 mg/kg and the effect was more pronounced in the nucleus accumbens than in the dorsal striatum. This suggests that entacapone 30 mg/kg has minor central effects. Also our ex vivo study results obtained from the dorsal striatum suggest that entacapone 30 mg/kg has minor and transient central effects, even though central HVA levels were not suppressed below those of the control group in either brain area in the microdialysis study. Both entacapone and tolcapone suppressed hepatic COMT activity more than striatal COMT activity. Tolcapone was more effective than entacapone in the dorsal striatum. The differences between dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens may be due to different properties of the two brain areas.

The Effects of Reduction Mammaplasty

Symptomatic hypertrophic breasts cause a health burden with physical and psychosocial morbidity. The value of reduction mammaplasty in the treatment of symptomatic breast hypertrophy has been consistently reported by patients and has been well recognised by plastic surgeons for a long time. However, the scientific evidence of the effects of reduction mammaplasty has been weak or lacking. During the design of this study most of the previous studies were retrospective and the few prospective studies had methodological limitations. Therefore, an obvious need for prospective randomised studies was present. Nevertheless, practical and ethical considerations seemed to make this study design impossible, because the waiting time for the operation was several years. The legislation and subsequent introduction of the uniform criteria for access to non-emergency treatment in Finland removed these obstacles, as all patients received their treatment within a reasonable time. As a result, a randomised controlled trial with a six-month follow-up time was designed and conducted. In addition, a follow-up study with two to five years follow-up was also carried out later. The effects of reduction mammaplasty on the patients breast-related symptoms, psychological symptoms, pain and quality of life was assessed. In addition, factors affecting the outcome were investigated. This study was carried out in the Hospital District of Helsinki and Uusimaa, Finland. Eighty-two out of the approximately 300 patients on the waiting list in 2004 agreed to participate in the study. Patients were randomised either to be operated (40 patients) on or to be followed up (42 patients). The follow-up time for both groups was six months. The patients were operated on by plastic surgeons or trainees at the Department of Plastic Surgery at Helsinki University Central Hospital or at the Department of Surgery at Hyvinkää Hospital. The patients completed five questionnaires: the SF-36 and the 15D quality of life questionnaires, the Finnish Breast-Associated Symptoms questionnaire (FBAS), a mood questionnaire (Raitasalo s modification of the short form of the Beck Depression Inventory, RBDI), and a pain questionnaire (The Finnish Pain Questionnaire, FPQ). Sixty-two out of the original 82 patients agreed to participate in the prospective follow-up study. In this study, patients completed the 15D quality of life questionnaire, the Finnish Breast-Associated Symptoms questionnaire, and the RBDI mood questionnaire. After six months follow-up, patients who had undergone reduction mammaplasty had a significantly better quality of life, fewer breast-associated symptoms and less pain, and they were less depressed or anxious when compared to patients who had not undergone surgery. The change in quality of life was more than two times the minimal clinically important difference. The patients preoperative quality of life was significantly inferior when compared to the age-standardised general population. This health burden was removed with reduction mammaplasty. The health loss related to symptomatic breast hypertrophy was comparable to that of patients with major joint arthrosis. In terms of change in quality of life, the intervention effect of reduction mammaplasty was comparable to that of hip joint replacement and more pronounced than that of knee joint replacement surgery. The outcome of reduction mammaplasty was affected more by preoperative psychosocial factors than by changes in breast dimensions. The effects of reduction mammaplasty remained stable at two to five years follow-up. In terms of quality of life, symptomatic breast hypertrophy causes a considerable health loss comparable to that of major joint arthrosis. Patients who undergo surgery have fewer breast-associated symptoms and less pain, and they are less depressed or anxious and have an improved quality of life. The intervention effect is comparable to that of major joint replacement surgery, and it remains stable at two to five years follow-up. The outcome of reduction mammaplasty is affected by preoperative psychosocial factors.

Making Music, Making Muslims : A Case Study of Islamic Hip Hop and the Discursive Construction of Muslim Identities on the Internet

Hip-hopin juuret juontavat 1970-luvulle Yhdysvaltoihin, mutta hip-hop-kulttuuri ja musiikkityyli ovat sen jälkeen levinneet ympäri maailmaa osana globalisaatiokehitystä. Myös monet nuoret muslimit tekevät nykyään hip-hop-musiikkia, ja yhä useampi tuo myös sanoituksiinsa vaikutteita Islamista ja elämästään muslimina. Musiikin asema on islamissa varsin kiistelty, eikä sitä ole selvästi sallittu (halal) tai kielletty (haram) muslimeilta. Muslimien tekemää hip-hoppia on toistaiseksi tutkittu hyvin vähän. Tutkielmassa tarkastellaan diskurssianalyysin keinoin, miten tapaustutkimuksena toimivalla muslimhiphop.com-internetsivustolla argumentoidaan ja konstruoidaan käsityksiä muslimi-identiteetistä. Teoreettisena ja analyyttisenä viitekehyksenä toimii sosiaalikonstruktivistinen näkemys identiteetistä kontekstisidonnaisena sekä puheessa ja teksteissä diskursiivisesti rakentuvana. Tutkielma kyseenalaistaa aiempien tutkimusten oletuksen hip-hopista vaikutuksiltaan yksinomaan positiivisena muslimi-identiteetille sekä muslimeja yhdentävänä tekijänä. Aineisto on kerätty edellä mainitulta sivustolta syksyn 2010 ja kevään 2011 aikana, josta analyysiin on rajattu vain itse sivusto ja sen hip-hoppia käsittelevät osiot. Sivusto ja sen perustaja ovat yhdysvaltalaisia, mutta sivustolla esiteltävien artistien tausta on hyvin monikulttuurinen. Moni on myös maahanmuuttajana nykyisessä kotimaassaan. Aineistossa esiintyviä teemoja ja diskursseja eritellään ja analysoidaan tutkielmassa lainauksien avulla. Sivuston periaatteissa ja artistien esillepääsyn kriteereissä määritellään tarkasti asennoituminen Islamin ja musiikin yhdistämiseen: mikäli sanoitukset ja artistit noudattavat Islamin oppeja, on muslimin sallittua tehdä ja kuunnella tällaista musiikkia. Islam-aiheisen hip-hopin perustellaan olevan ennen kaikkea vaihtoehto valtavirran hip-hopille, jota konstruoidaan aineistossa moraalisesti arveluttavaksi. Hip-hopille sekä muslimeille sallittuja ja kiellettyjä elementtejä erottelevan halal-haram-diskurssin ohella aineistosta nousee esiin opetusdiskurssi. Muslimien tekemän hip-hopin perustellaan edistävän Islamin opettamista erityisesti nuorille muslimeille ja siten vahvistavan positiivista muslimi-identiteettiä. Myös positiivisen muutoksen diskurssia käytetään aineistossa runsaasti liittyen mm. muslimiyhteisöihin sekä muslimeihin kohdistuviin taloudellisiin ja sosiaalipoliittisiin epäkohtiin ja stereotypioihin; musiikin sisältöä ja sen tekemistä perustellaan sen voimalla muuttaa asioita parempaan suuntaan. Monet muslimiartistit kamppailevat yhdistääkseen toisaalta Islamin ja taiteellisen luovuuden ja ilmaisuvapauden, toisaalta menestyäkseen kaupallisesti unohtamatta uskonnollista vakaumustaan. Monilla heistä hip-hop on ollut vahvasti läsnä kasvuympäristössä, mutta sen yhdistäminen Islamin periaatteisiin aiheuttaa kysymyksiä ja kyseenalaistuksia oman musiikillisen ja uskonnollisen identiteetin muodosta ja sisällöstä. Aineiston perusteella monet muslimiartistit ja Islam-aiheista hip-hoppia kuuntelevat muslimit joutuvat jatkuvasti puolustamaan musiikkia siihen kielteisesti suhtautuville muslimeille sekä ei-muslimeille, jotka vierastavat sen uskonnollisuutta. Muslimi-identiteettiä neuvotellaan jatkuvasti, ja se näyttäytyy aineistossa moniulotteisena ja tilanteisesti rakentuvana. Avainsanat: Muslimit, Islam, hip-hop, identiteetti, Internet, diskurssi, diskurssianalyysi