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Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it. We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology. Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis. Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis. We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups. In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.

<p>Research shows that phonological processing skill is the greatest single predictor for reading ability and it is agreed that phonological awareness specific tasks correlate positively with literacy acquisition in typically developing children. Children with Down’s syndrome are at risk for reading acquisition difficulties, primarily because of their reduced phonological awareness and a phonological awareness based approach to literacy has been shown to be beneficial for them. The aim of the present study was to investigate if the PhonicStick can be used to initiate interest in language play in children with Down’s syndrome, in order to stimulate their reduced phonological awareness. Six children with Down’s syndrome between five and 15 years of age, currently enrolled within the UK educational system, were recruited to participate in six sessions; two sessions of pre- and post testing of their phonological awareness, and four intervention sessions with the PhonicStick. During the intervention sessions, the ability to remember the six phonemes of the PhonicStick, to generate three-phoneme combinations, to produce given target real words or non-words and to perform in phoneme substitution tasks using the PhonicStick were investigated. The results of this study show that the PhonicStick, with advantage, can be used to introduce and enhance phonological awareness in children with Down’s syndrome and that an increase in phonological awareness is possible even during a short time of practise with the PhonicStick. Since children with Down’s syndrome benefit from a phonological awareness based approach to literacy, practising phonological awareness skills through language play with the PhonicStick might also have a future positive effect on their literacy acquisition.</p> / <p>Tidigare forskning visar att fonologisk medvetenhet är den främsta prediktorn för läs- och skrivkunnighet och att övning i fonologisk medvetenhet korrelerar positivt med läs- och skrivinlärning hos barn med typisk läs- och skrivutveckling. Barn med Downs syndrom riskerar att utveckla läs- och skrivsvårigheter framförallt till följd av nedsatt fonologisk medvetenhet och det har även visats att en metod för läs- och skrivinlärning baserad på fonologisk medvetenhet, kan gagna dem. Syftet med den här studien var att undersöka om the PhonicStick kan användas för att initiera intresse till språklek hos barn med Downs syndrom, med avsikt att stimulera deras fonologiska medvetenhet. Sex barn med Downs syndrom, i åldrarna fem till 15 år, inskrivna i det brittiska skolsystemet, medverkade i två sessioner bestående av pre- och post testning av fonologisk medvetenhet, och fyra interventionssessioner med the PhonicStick. Under interventionssessionerna undersöktes förmågan att komma ihåg placering av fonem hos the PhonicStick och med den generera kombinationer av fonem (dvs. ord), generera givna målord och substituera fonem i ord. Resultaten visar att the PhonicStick med fördel kan användas för att introducera och öka den fonologiska medvetenheten hos barn med Downs syndrom och att en ökning är möjlig även efter kort tids träning. Eftersom en metod för läs- och skrivinlärning baserat på fonologisk medvetenhet gagnar barn med Downs syndrom skulle övning av fonologisk medvetenhet genom språklekar med the PhonicStick även kunna ha en långsiktig positiv inverkan på deras läs- och skrivkunnighet.</p>

<p>α₁- and α₂-Adrenoceptors are involved in various physiological events in the eye: blood flow regulation, aqueous humor dynamics and pupil regulation. The α₁- and α₂-adrenoceptors can be further subdivided into six subtypes (α_1A, α_1B, α_1D, α_2A , α_2B, and α_2C ). Currently available α1- and α₂-adrenergic drugs are not selective for the different subtypes and some ocular adrenergics have undesirable side-effects, both local and systemic. A better understanding of the subtype distribution in the eye would be useful when designing new drugs with greater efficacy and fewer adverse effects; this applies especially to the treatment of glaucoma. The purpose of the thesis was therefore to identify and localize the different subtypes of α₁- and α₂-adrenoceptors in the eye. </p><p>The identities of the α₁-adrenoceptor subtypes were studied in various parts of pig and albino rabbit eyes by radioligand binding. In the pig retina and in the albino rabbit iris, ciliary body and retina, mixed populations of α_1A- and α_1B-adrenoceptors were localized. In the rabbit choroid only the α_1A-adrenoceptor subtype was detected. </p><p>The α₂-adrenoceptor subtypes were also characterized by radioligand binding, in different parts of the pig eye. In the iris, ciliary body and choroid, only α_2A-adrenoceptors were localized, while in the retina, mostly α_2A-adrenoceptors and a minor population of α_2C-adrenoceptors were identified. High densities of α_2A-adrenoceptors were found in the ciliary body and choroid.</p><p>The effect of α₂-adrenoceptor agonists on the porcine ciliary artery was studied on a small-vessel myograph. α₂-Adrenoceptor agonists proved to be potent vasoconstrictors in the porcine ciliary artery and it was found that the vasoconstriction induced by brimonidine was mediated by the α_A-adrenoceptor.</p>

<p>Apoptosis is a genetically regulated cell death program, which shows distinct morphological characteristics. It takes place during neuronal development and in some neurodegenerative diseases. During apoptosis, the intracellular proteins are degraded by various caspases, cysteine aspartases, which are regulated by pro- and anti-apoptotic signals. This thesis elucidates the role of anti-apoptotic proteins in nerve cell survival and neurodegeneration. Studies have focused on Bcl-2 family members and Inhibitor of Apoptosis Proteins (IAP).</p><p>XIAP and RIAP-2 are IAP proteins, which are expressed by neurons in the central nervous system. Kainic acid, a glutamate receptor agonist that induces seizures, increased XIAP immunoreactivity in rat hippocampus, whereas RIAP-2 expression in the same time decreased in degenerating neurons. Both XIAP and RIAP-2 were absent in dying neurons indicating that these proteins have a protective role in kainic acid induced neurodegeneration.</p><p>NAIP, another IAP family member, was shown to interact with the calcium binding protein Hippocalcin using the yeast two-hybrid system and immunoprecipitation experiments. Hippocalcin-NAIP interaction increased motoneuron survival in caspase-3 independent and dependent manners.</p><p>The anti-apoptotic Bcl-2 proteins, Bcl-2 and Bcl-x, were studied using cultured neurons and human neuronal progenitor cells. In the progenitor cells, Bcl-2 overexpression enhanced cell survival and induced downregulation of Caspase-2 (ICH-1) and caspase-3 (YAMA/CPP32). These results suggest a novel mechanism for the action of Bcl-2.</p><p>Estrogen was shown to inhibit death of cultured dorsal root ganglion neurons (DRG) after nerve growth factor withdrawal. The hormone increased the levels of Bcl-x, which may explain the known neuroprotective function of estrogen.</p>

<p>Delivery of drugs to the brain requires passage across the blood-brain barrier (BBB). Both for drugs already on the market and for new drugs under development, it is important to know to what extent a drug enters the CNS. Many drugs used clinically are racemic mixtures, <i>i.e.</i> equal parts of the (<i>S</i>)- and (<i>R</i>)-enantiomers. </p><p>The present studies focus on the enantiomers and racemates of a number of 5-HT_1A receptor agonists and antagonists (pindolol, propranolol, 8-OH-DPAT and other 8-substituted-2-(di-<i>n</i>-propylamino)tetralin derivatives) and BBB transport <i>in vitro</i> and distribution to the brain <i>in vivo.</i> Assays (HPLC-based) were set up or developed for determination of the racemates and the pure enantiomers (chiral column) of drugs in plasma and brain tissue. BBB transport was assessed <i>in vitro</i> using bovine brain endothelial cells cocultured with rat astrocytes. The physicochemical constants (log P, pKa) and plasma protein binding were determined. Pindolol, propranolol and several tetralines accumulated over time in brain tissue. For pindolol and propranolol, but not for most tetralins, the distribution to the brain was stereoselective, (<i>S</i>)>(<i>R</i>). Pretreatment with verapamil, an inhibitor of drug efflux <i>via</i> P-glycoprotein, differentially decreased the brain/plasma ratios of the enantiomers of pindolol and propranolol, indicating that verapamil may also inhibit an influx transport mechanism. <i>In vitro</i> results with racemic pindolol, propranolol and tetralins showed no differences in BBB transport between the enantiomers. A more rapid apical to basolateral transport (influx) <i>vs</i>. the basolateral to apical (efflux) transport of propranolol (not pindolol) and most tetralins <i>in vitro</i> indicated active transport across the BBB. </p><p>In conclusion, the combined <i>in vivo</i> and <i>in vitro</i> results are consistent with active transport of the studied compounds across the BBB rather than passive diffusion due to their lipophilicity. Some, but not all, chiral drugs are stereoselectively distributed to the brain. Stereoselective plasma protein binding or stereoselective transport across brain endothelial cells does not seem to explain the stereoselective accumulation of pindolol and propranolol. The stereochemical configuration of compounds contributes to their pharmacokinetic as well as their pharmacodynamic uniqueness. The characteristics of the enantiomers of chiral compounds need to be determined empirically rather than based on generalizations from structural or physicochemical information.</p>

<p>Individuals afflicted with childhood and adolescent mental disorders have an increased risk for poor outcome in adulthood. The progression of psychopathology from childhood to adult life may be influenced by a multitude of interacting variables, both biological and psychosocial. There is limited information on the relationships between child psychopathology and adult personality and personality disorders. The main aim of this thesis was therefore to gain better knowledge concerning adult personality outcome in patients with early onset of mental disorders. </p><p>Former child psychiatric patients as compared to controls had a significantly higher prevalence of all DSM-IV personality disorders (38.0 vs. 10.9 percent, p<0.001) and also a considerably higher personality disorder co-morbidity. They also had more psychosocial and environmental problems. This was exaggerated in those diagnosed with a personality disorder. Major depression, disruptive disorders and substance use disorders at a young age were strong predictors for adult personality disorder.</p><p>Patients with an early onset major depression had more personality disorders and more deviant personality traits than those with a late onset. </p><p>Forensic psychiatric male patients diagnosed with a previous conduct disorder as compared to those without had more cluster B personality disorders, and more repeated violent criminality and mixed abuse. They also exhibited more deviant personality traits and higher psychopathy scores.</p><p>The instrument "Child and Adolescent Psychiatric Screening Inventory-Retrospect" had acceptable sensitivity and specificity for assessment of child psychiatric disorders. Subscales demonstrated good internal reliability (Crohnbach´s alpha = 0.76-0.93).</p><p>The results suggest that adult personality disturbances are prevalent in individuals affected with mental problems at young ages. A better understanding of the transition of psychopathology from childhood to adulthood and a better identification of those at risk will be of help in attempts to prevent permanent impact on the adult personality.</p>

<p>Social phobia is a disabling, lifelong disorder characterised by fear in social settings.</p><p>The aim of the present study was to gain more knowledge about diagnostic, neurobiologic and epidemiologic aspects of social phobia.</p><p>Thirty-two individuals were assessed by the Structured Clinical Interview for DSM-IV Axis I and II psychiatric disorders, the Karolinska Scales of Personality and the Temperament and Character Inventory. Social phobia was accompanied by concurrent axis I disorders in about 28% of individuals, lifetime axis I disorders in 54%, personality disorders in 60%, and avoidant personality disorder (APD) in 47%. This suggests that there is a high comorbidity between social phobia and APD according to the DSM-IV criteria. The personality profiles associated with social phobia were dominated by anxiety-related traits that were primarily related to social phobia itself and not to the presence of concurrent personality disorders.</p><p>Eighteen subjects with social phobia and eighteen controls were investigated with positron emission tomography and the radiolabeled serotonin precursor, [3 -11C]–5-HTP (5-HTP). Individuals with social phobia demonstrated proportionally lower regional relative whole brain accumulation of 5-HTP in areas of the frontal and temporal cortices as well as the striatum, but higher accumulation in the cerebellum. This suggests that there are imbalances in presynaptic serotonin function in individuals with social phobia, although this could only be confirmed in men, and not in women.</p><p>By means of a postal survey, distributed to 2000 randomly selected individuals, social phobia in Sweden was found to be common, with a point prevalence of 15.6%.</p>

<p>Neuropeptide Y (NPY) is an abundant neurotransmitter in the nervous system and forms a family of evolutionarily related peptides together with peptide YY (PYY), pancreatic polypeptide (PP) and polypeptide Y (PY). These peptides are ligands to a family of receptors that mediate a wide range of physiological effects including stimulation of appetite. This work describes the molecular cloning of four novel NPY receptors.</p><p>In rat a receptor called PP1, later renamed Y₄, was cloned and characterized. It displays the highest amino acid sequence identity to the Y₁ receptor. Rat Y₄ differs extensively from human Y₄, cloned subsequently, in both pharmacological properties, tissue distribution, and amino acid sequence with only 75% identity. Rat and human Y₄are the most diverged orthologues in the NPY receptor family.</p><p>In guinea pig, the y₆ receptor gene was found to be a pseudogene with several frameshift mutations. The gene is a pseudogene in human and pig too, but seems to give rise to a functional receptor in mouse and rabbit. This unusual evolutionary situa- tion may be due to inactivation of the gene in a mammalian ancestor and then restoration of expression in mouse and rabbit, but perhaps more likely due to independent inactivations in guinea pig, human and pig.</p><p>In zebrafish, two new intronless receptor genes were cloned. Sequence comparisons suggest that both receptors are distinct from the mammalian receptors Y₁, Y₄ and y₆, hence they were named Ya and Yb. Chromosomal localization provides further support that Ya and Yb may be distinct subtypes. </p><p>The discoveries of the rat Y₄ and zebrafish Ya and Yb receptors were unexpected and show that the NPY receptor family is larger than previously thought.</p>

<p>Apoptosis is a type of cell death with a specific morphology and molecular program, which is essential for the development of the nervous system. However, inappropriate cell death has been implicated in several neurodegenerative diseases. The Bcl-2 protein family is a class of proteins, which can regulate the cell death program in either a positive (pro-apoptotic family members) or a negative (anti-apoptotic family members) way. </p><p> This thesis further elucidates the role of Bcl-2 family members in the nervous system. Special focus has been put on the anti-apoptotic family member Bcl-w, whose function in the nervous system was previously unknown, and the pro-apoptotic family member Bad which serves as a link between growth factor signalling and apoptosis.</p><p> Bcl-w mRNA was found to be upregulated during rat brain development suggesting increasing importance of Bcl-w with age in the nervous system. In contrast, mRNA levels encoding the anti-apoptotic protein Bcl-x were downregulated during development. Bcl-w was also found to have an anti-apoptotic function in neurons, rescuing sympathetic neurons from cell death after nerve growth factor deprivation.</p><p> To further elucidate the mechanism by which Bcl-w exerts its function, we screened a yeast two-hybrid library for proteins interacting with Bcl-w. Two of the isolated positive clones encoded the pro-apoptotic protein Bad and a novel splice variant of Bad with a different carboxyterminal sequence. Both isoforms of Bad induced cell death in sympathetic neurons, which could be counteracted by Bcl-w, indicating that Bcl-w and Bad can interact both physically and functionally.</p><p> Further studies on the genomic structure of the Bad gene suggested the presence of an additional splice variant, not expressing the first exon. Immunohistochemical analysis indicates that the isoform(s) not expressing the first exon is more widely expressed in adult rat brain than the known forms.</p><p> Finally, we show that high cell density can enhance survival of cerebellar granule neurons and that bcl-2 and bcl-x mRNA levels are upregulated in high density cultures.</p>