This thesis evaluates surgical correction in patients with paralytic scoliosis with emphasis on function and activity. The thesis includes four studies of 100 consecutive patients preoperatively evaluated and surgically corrected between 1992 and 1996 at Linköping University Hospital. Eighteen different diagnoses were represented. The postoperative follow-ups were at one year and in average seven years. Six patients dropped out during the first year and twelve during the long-term follow-up period. The assessments included general information, lung function, and measurements of radiographs, function and activity - seating posture, ADL, pain, care and need for rest. The patients or relatives view on the effects of surgery were evaluated in follow-up questionnaires. The preoperative results of the 100 patients described a heterogeneous group in terms of function and activity. Even when the patients were grouped into subgroups according to the Scoliosis Research Society classification, they remained heterogeneous. In patients who could understand verbal instructions assessments that needed co-operation could be used and in those who could not understand verbal instructions, assessments relied more heavily on measures of function and level of dependence. Preoperative results of weight distribution on the seating surface were explained by thoracolumbar/lumbar spinal imbalance and pelvic obliquity R2=0.45 (n=45). The one-year follow-up of 94 patients showed improvements in angle of scoliosis, sitting balance, weight distribution to the seating surface, seating supports in the wheelchair, time needed for rest. The results in subgroups were almost the same as in the whole group. The subjective results for patients or relatives in the follow-up questionnaire showed a positive outcome of surgery. In the comparison between the one-year follow-up and the long-term follow-up there were further improvements in sitting balance, ADL, and care given, but the angle of scoliosis was increased. These results were in line with patients’ and relatives’ assessments in the follow-up questionnaire and in the open-ended questions. Due to the heterogeneity of patients with paralytic scoliosis, irrespective of disorder, it is important to focus on different subgroups with regards to the patients’ total situation. The surgically corrected and stabilised spine resulted in the strength to keep the body upright with improvements in function, activity and possibilities to belong in social activities. Further improvements were shown between the one-year follow-up and the long-term follow-up. It is recommended that patients who have been surgically corrected for paralytic scoliosis are followed for more than one year.

This is a study of muscle function in Juvenile Idiopathic Arthritis (JIA). Rheumatoid arthritis (RA) is a disease that primarily affects the synovial membrane of joints. Muscle weakness, atrophy and pain occur in adult RA. This may be a consequence of joint pain, stiffness and immobility. Muscle inflammation and neuropathy occur as complications in adults. Muscle function in JIA has been much less studied. The aim of the study was to examine whether muscle weakness and atrophy also occur in children with JIA. This was a longitudinal study over a two-year period, where muscle strength and thickness were measured repeatedly in a group of 20 children and teenagers with JIA. Muscle strength was measured using different methods and in several muscle groups. Muscle biopsies were obtained and nerve conduction velocity studies performed. The study concludes that, compared to healthy people, children and teenagers with JIA have as a group reduced muscle strength and muscle thickness. For most of these children and teenagers, muscle strength is only slightly lower than expected, but a few have marked muscle weakness. This is most apparent in patients with severe polyarthritis where the weakness seems to be widespread. Patients with isolated arthritis may also have greatly reduced strength and thickness of muscles near the inflamed joint. There is a risk of decreasing strength in patients with polyarthritis and in muscles near an active arthritis. Minor changes are common in muscle biopsies, and findings may indicate immunological activity in the muscles. Atrophy of type II fibres, as in adult RA, was not found in JIA. No patient had signs of neuropathy. / On the day of the public defence the status of article IV was: Submitted.

In an unselected series of mentally retarded children in the county of Västerbotten, Sweden, the annual incidence of children with severe mental retardation (SMR) (IQ &lt; 50) and alive at the age of one year decreased from 5.3 per 1,000 in 1959 - 1963 to 3.1 per 1,000 in 1967 -1970. This was mainly due to a decrease in the incidence of Down's syndrome. In parallel the proportion of mothers 35 years of age or more at the birth of the child decreased significantly. The prevalence of children with SMR in 1976 was 3.5 per 1,000. The main cause of the SMR was prenatal in 70 percent, perinatal in 8 percent and postnatal in 1 percent. The cause of the SMR was untraceable in 20 percent of the cases. Associated CNS-handicaps occurred in 52 percent of the cases. The annual incidence of mildly mentally retarded children (IQ 50 - 69) registered at the Bureau for Provision and Services for Mentally Retarded was 4.2 per 1,000 and the prevalence in 1979 was 3.8 per 1,000. The cause of the mild mental retardation (MMR) was untraceable in 43 percent. Prenatal causes were identified in as many as 43 percent. Perinatal causes were found in 7 percent and postnatal causes in 5 percent of the cases. Associated CNS-handicaps occurred in 30 percent of the cases.A syndrome of mental retardation with X-linked inheritance not recognized previously in Sweden was characterized clinically (mainly in boys, machro-orchidism, verbal disabilities) and cytogenetically (a fragile site on the X-chromosomes seen after cui turing in special folic acid deficient media) and found to have a prevalence of 6 percent in the population of severely mentally retarded boys. This makes this syndrome the next most common cause of SMR in boys after Down's syndrome. The chromosomal fragility was also identified in female carriers, which has implications for genetic counselling.Through identification of an untreated Phenylketonurie mother giving birth to five severely mentally retarded children, attention was focused on the risks for the fetus of the growing number of Phenylketonurie women identified neonatally and treated di etarily but untreated after the age of 10 - 15 years.Great improvement in intellectual and social ability was seen in a boy with phenylketonuria although the dietary treatment was not introduced until the age of eight years.Heavy irradiation of a fetus late in gestation caused mental retardation, microcephaly, stunted growth, and eye and teeth abnormalities, although such abnormalities are thought not to result from irradiation after 20 weeks of pregnancy. / <p>Endast s.1-71: sammanfattningen (kappan) i fulltexten.</p><p>Ej med i fulltexten s.72-145: 7 delar.</p> / digitalisering@umu

Panikattacken sind mit einer Lebenszeitprävalenz von ungefähr 15% ein relativ häufiges Phänomen im Gegensatz zu einer vollen Panikstörung, die eine Prävalenz von 2,3–3% aufweist. In der vorliegenden epidemiologischen Untersuchung (n = 481) einer bundesweiten repräsentativen Stichprobe wurde geprüft, ob früh (vor dem 25. Lebensjahr) und spat auftretende Panikattacken sich hinsichtlich Symptomatik, Verlaufs- und Komorbiditätsmustern unterscheiden. Neben einer erhöhten Angstsymptomatik, insbesondere bezüglich respiratorischer Beschwerden und der Angst zu sterben, zeigte sich bei Panikattacken mit spätem Beginn ein erhöhtes Risiko für Multimorbidität. Auch entwickelten sich bei dieser Gruppe komorbide Bedingungen schneller. Dagegen waren Panikattacken mit frühem Beginn und einem erhöhten Risiko für Agoraphobie sowie phobische Störungen verbunden. Die Ergebnisse werden im Hinblick auf pathogenetische Mechanismen und Implikationen für die Planung therapeutischer Interventionen diskutiert.

Η προγεννητική έκθεση στον καπνό του τσιγάρου προκαλεί χρόνια εμβρυϊκή υποξία, απορρύθμιση της ομαλής λειτρουγίας του ενδοκρινικού συστήματος, και διαταραχή της νευροανάπτυξης του εμβρύου, η οποία σχετίζεται με εγκεφαλική δυσλειτουργία, τα οποία δυνητικά θα μπορούσαν να προκαλέσουν ευαλωτότητα για σχιζοφρένεια.. Συνολικά 212 ασθενείς με σχιζοφρένεια ηλικίας 14-30 ετών, και 212 αντίστοιχοι μάρτυρες μελετήθηκαν. Η προγεννητική έκθεση στον καπνό του τσιγάρου των ασθενών με σχιζοφρένεια συγκρίθηκε με εκείνη των μαρτύρων εφαρμόζοντας ανάλυση λογιστικής παλινδρόμησης και έλεγχο για διάφορους παράγοντες που αλληλεπιδρούν και συμβάλλουν στην έκβαση της επίδρασης. Εστίες ενδιαφέροντος ήταν η σύγκριση της συχνότητας καπνίσματος της μητέρας και του πατέρα μεταξύ ασθενών και μαρτύρων, καθώς επίσης και η σοβαρότητα των θετικών και αρνητικών συμπτωμάτων μεταξύ των απογόνων καπνιζόντων και μη καπνιζόντων γονέων. Επιπλέον, διερευνήθηκε η σχετική συχνότητα των υποτύπων σχιζοφρένειας μεταξύ των ασθενών καπνιστών και μη καπνιστών γονέων. Μεταξύ των μητέρων των ασθενών με σχιζοφρένεια και των μαρτύρων, 92 (43,4%) και 46 (21,7%) κάπνιζαν, αντίστοιχα. Το κάπνισμα της μητέρας κατά την εγκυμοσύνη είχε μια σημαντικά μοναδική συνεισφορά στην αύξηση του κινδύνου για την ανάπτυξη της σχιζοφρένειας (p = 0,001), καθώς και μεγαλύτερη σοβαρότητα των αρνητικών συμπτωμάτων (p = 0,023). Ταυτόχρονα, λογιστική ανάλυση παλινδρόμησης έδειξε ότι το κάπνισμα της μητέρας κατά την εγκυμοσύνη είχε σημαντικά μοναδική συνεισφορά στην αύξηση κινδύνου για την ανάπτυξη της σχιζοφρένειας με πιθανή αναλογία=2.32, 95%CI=1.41-3.81, p=0.001 και τη συχνότητα των μη-παρανοϊκών υποτύπων με πιθανή αναλογία= 2.94,95%CI=1.50-5.76, p=0.002. Το κάπνισμα του πατέρα δεν είχε σημαντική επίδραση στον κίνδυνο εκδήλωσης σχιζοφρένειας, ούτε στη σοβαρότητα των αρνητικών συμπτωμάτων. Τα ευρήματα υποδεικνύουν ότι το κάπνισμα της μητέρας κατά τη διάρκεια της εγκυμοσύνης θέτει τους απογόνους σε αυξημένο κίνδυνο για σχιζοφρένεια μετέπειτα στη ζωη τους, με αυξημένη σοβαρότητα των αρνητικών συμπτωμάτων. Λαμβάνοντας υπόψη την ευρεία πρακτική του καπνίσματος κατά την εγκυμοσύνη, η έκθεση του εμβρύου στον καπνό θα μπορούσε να είναι ένας σημαντικός αποτρέψιμος τροποποιήσιμος νευροαναπτυξιακός παράγοντας που αυξάνει την ευαλωτότητα για την εκδήλωση σχιζοφρένειας. / Prenatal exposure to cigarette smoke causes chronic fetal hypoxia, dysregulation of endocrine equilibrium, and disruption of fetal neurodevelopment associated with brain malfunction, all of which potentially could induce vulnerability to schizophrenia. A total of 212 schizophrenia patients aged 14-30 years, and 212 matched controls were studied. Prenatal tobacco smoke exposure of the schizophrenia patients was compared to that of the normal controls by applying logistic regression analysis and controlling for several confounding factors The outcomes of interest were comparison of the frequency of maternal and paternal smoking between patients and controls as well as the severity of positive and negative symptoms between the offspring of smoking and nonsmoking parents. Furthermore, we investigated the relative frequency of subtypes of schizophrenia among offspring of smoking and non-smoking parent. Among the mothers of schizophrenia patients and controls, 92 (43.4%) and 46 (21.7%) smoked, respectively. Maternal smoking during pregnancy had a significant unique contribution on increasing the risk for development of schizophrenia (p=0.001), and a greater severity of negative symptoms (p=0.023). Simultaneously, logistic regression analysis showed that maternal smoking during pregnancy had significantly unique contribution to increased risk for the development of schizophrenia with possible ratio = 2.32, 95% CI = 1.41-3.81, p = 0.001 and frequency of non-paranoid subtypes as potential ratio = 2.94,95% CI = 1.50-5.76, p = 0.002. Paternal smoking did not have a significant effect on the risk of schizophrenia, or severity of negative symptoms. The findings suggest that maternal smoking during pregnancy puts offspring at an increased risk for later schizophrenia, with increased severity of negative symptoms. Given the wide practice of smoking during pregnancy, fetal exposure to tobacco smoke could be a major preventable neurodevelopmental factor that increases vulnerability to schizophrenia.

Objective. Most biomarker studies of maternal smoking have been based on a single blood or urinary cotinine value, which is inadequate in capturing maternal tobacco exposure over the entire pregnancy. This thesis used maternal hair biomarkers to investigate the association between maternal active and passive smoking, and birthweight for gestational age (BW for GA). / Methods. Subjects were 444 term controls drawn from 5,337 participants of a multi-centre nested case-control study of preterm birth in Montreal. Maternal hair, collected after delivery, was measured for average nicotine and cotinine concentration across the pregnancy, assuming hair growth of 1 cm/month. The BW for GA z-score used Canadian population-based standards. Multiple linear regression was used to assess effects on the z-score, after controlling for potential confounders. / Results. In regression models for maternal active smoking analysis, the addition of hair nicotine to models containing either self-report or hair cotinine or both self-report and cotinine explained significantly more variance in the BW for GA z-score (p=0.009, p=0.017, and p=0.033, respectively). In maternal passive smoking analysis, no significant effect of ETS on BW for GA was found using hair biomarkers. / Conclusion. These results indicate that hair biomarkers are sensitive tools capable of predicting reductions in birthweight for maternal active smoking. The stronger results obtained for nicotine are reflective of the fact that hair nicotine is a better measure of maternal smoking, but it could also suggest that nicotine plays an aetiologic role in affecting foetal growth.

Disruptions in folate metabolism are known to increase the risk for neural tube defects (NTD) and this is preventable by folic acid supplementation. However, the relationship between folate metabolism and cardiac development remains unclear. The interaction between other folate pathway nutrients, choline and riboflavin, and folate metabolism was studied in a murine model of methylenetetrahydrofolate reductase (MTHFR) deficiency. Maternal choline deficiency, riboflavin deficiency and MTHFR deficiency adversely affected embryonic or heart development. The promoters of MTHFR were also examined for interactions with GATA-4, TBX5, MEF2A and NKX-2.5, known transcription factors of cardiac development. Upstream promoter activity was increased in the presence of GATA-4 and this interaction was further enhanced upon the addition of MEF2A. TBX5 appeared to decrease upstream promoter activity. GATA-4 modestly increased downstream promoter activity. These results highlight the importance of adequate nutrient intake during pregnancy and provide a link between folate metabolism and cardiac development.

Environmental and genetic factors contribute to the development of schizophrenia. For example, epidemiological evidence has linked infections during pregnancy with increased incidence of schizophrenia in the adult offspring. At the same time mutation to DISC1, a protein involved in neurone migration and synaptic plasticity, is an important genetic risk for the disorder. Accordingly, the aim of this project was to determine if these environmental and genetic influences converge along a common pathogenic pathway leading to schizophrenia. Using a model of prenatal infection by bacterial endotoxin in rodents, we demonstrated a 50% reduction in DISC1 protein expression in the hippocampus and cortex of juvenile offspring. In addition, we found a significant induction of prostaglandins (final mediators of the inflammatory process) in the fetal brain while many cytokines remained unaltered. Taken together our results identify prostaglandins as potential mediators of the teratogenic effects of prenatal infection and show that prenatal infection itself can affect systems related to genetic risk factors for schizophrenia, in this case DISC1.

Folate deficiency, a prevalent vitamin deficiency in America, can stem from environmental and/or genetic causes. The most common inborn error of folate metabolism is deficiency of methylenetetrahydrofolate reductase (MTHFR), which catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Severe MTHFR deficiency results in hyperhomocysteinemia and homocystinuria; patients present with developmental delay, and various neurological and vascular disorders. This thesis describes three mutations identified in the MTHFR locus in patients with severe deficiency: 1025T&rarr;C (M&rarr;T), 1027T&rarr;G (W&rarr;G), and 1768G&rarr;A (E&rarr;K). Genotype-phenotype correlations are described, along with biochemical characterization of three mutations (983A&rarr;G (N&rarr;S), 1025T&rarr;C, 1027T&rarr;G). All three mutations exert their effect by decreasing Vmax without changing the enzyme's affinity for its substrate, 5-methyltetrahydrofolate. The 983A&rarr;G variant also conferred decreased affinity for FAD, a cofactor. / The more common and mild deficiency observed in the general healthy population is probably due in part to insufficient dietary intake of folate. Folate deficiency has been associated with increased risk for colon cancer. In a pilot study presented here, the impact of altered folate intake on tumor multiplicity in the Min mouse, a model for multiple intestinal neoplasia, was assessed. Folate deficient diets did not produce a consistent change in tumor numbers. However, a linear correlation between S-adenosylmethionine and S-adenosylhomocysteine content of preneoplastic tissue and tumor multiplicity was identified. / This thesis contributes to our understanding of the impact of genetic- and/or dietary-induced folate deficiency on cellular and organismal functions.

Thesis (PhD)--Stellenbosch University, 2012. / Bibliography / ENGLISH ABSTRACT: Most individuals latently infected with Mycobacterium tuberculosis (Mtb) contain the infection by a balance of effector and regulatory immune responses. However, this balance can be influenced by steroid hormones such as glucocorticoids (GCs), which are known to increase the risk of reactivation of TB. The contraceptive medroxyprogesterone acetate (MPA), which also possesses selective glucocorticoid activity, is widely used in developing countries with approximately 60% of women on contraceptives using MPA in our study cohort. Therefore, our aim was to investigate the effect of this hormone on protective immune responses to BCG in HIV negative household contacts of active TB patients. When PBMCs of TB household contacts were stimulated with BCG in the presence of 10 μM MPA; this hormone displayed both glucocorticoid as well as progestogenic properties. Similarly to cortisol, MPA suppressed antigen specific expression of a range of cytokines including IL-1α, IL-1ra, IL- 17, TNFα, IL-5 and IFNγ. Dose response curves showed that MPA can also alter expression of some cytokines at lower contraceptive doses (in the nano molar range). To assess whether this effect of MPA in vitro also occurs in women using this hormone as contraceptive the PBMCs of MPA users and controls were stimulated with BCG and the levels of up to 29 different cytokines measured by luminex analysis. PBMCs of MPA users produced significantly lower levels of cytokines involved in immune responses against Mtb such as IL-12p40, IL-1α, IL-10, IL-13 and G-CSF, which corresponds with lower numbers of circulating monocytes observed in these women. These findings warrant further investigation and clinical trials should investigate the risk of progression from latent to active TB disease in women using this contraceptive. These trials, however, require a large number of participants and are prohibitively expensive; therefore it was decided to setup an Mtb/MPA mouse model to determine the effect of MPA on the disease outcome. BALB/c and C57BL/6 mice were injected with a weekly dose of one mg MPA or PBS and infected with 30 colony forming units of Mtb H37Rv one week after commencing the hormonal treatment. Both strains were included to establish which strain best represents the human model. Three and eight weeks post infection the MPA treated C57BL/6 mice had a significantly higher bacterial load in their lungs compared to untreated mice, whereas no difference was found in the bacterial loads of the BALB/c mice. MPA treated C57BL/6 mice had significantly lower serum levels of IL-10 and G-CSF and MPA treated BALB/c mice lower serum levels of IFNγ, when compared to untreated mice. Furthermore, cells isolated from the MLNs of MPA treated C57BL/6 mice, produced significantly less TNFα, significantly more IP-10 and less IL-10 in response to PPD, while MLN cells of MPA treated BALB/c mice produced significantly less IFNγ, IL-2, IL-17, GM-CSF and MCP-1. Data of the C57BL/6 mouse strain correlated with our human data and can it therefore be said that the C57BL/6 mouse strain, together with the serum concentration of MPA used in these experiments, is a good model to determine the effect of MPA in the context of a low dose Mtb infection. To conclude MPA use could therefore alter susceptibility to TB, TB disease severity as well as change the efficacy of new BCG-based vaccines, especially prime-boost vaccine strategies which may be administered to adult of adolescent women in the future. / AFRIKAANSE OPSOMMING: Die meeste mense wat latent met Mycobacterium tuberculosis (Mtb) geïnfekteer is, hou die infeksie onder beheer deur ʼn balans te handhaaf tussen effektor en regulatoriese immuunresponse. Hierdie balans kan egter beïnvloed word deur steroïedhormone soos glukokortikoïede (GCs), wat bewys is om die risiko van die heraktivering van TB te verhoog. Die voorbehoedmiddel medroksiprogesteroon-asetaat (MPA), wat ook selektiewe glukokortikoïed-aktiwiteit toon, word wyd gebruik in ontwikkelende lande en omtrent 60% van die vrouens in ons studie-bevolking wat voorbehoedmiddels gebruik, gebruik MPA. Om dié rede wou ons die effek van hierdie hormoon op die beskermende immuun-response teenoor M.bovis Bacilli Calmette-Guérin (BCG) in HIV negatiewe huishoudelike kontakte (HHKe) van pasiënte met aktiewe TB ondersoek. Ons het gevind dat wanneer perifere bloed mononukleêre selle (PBMSe) met BCG gestimuleer word in die teenwoordigheid van 10 μM MPA, hierdie hormoon beide glukokortikoïede en progesterogeniese eienskappe toon. Soos kortisol het MPA die antigeenspesifieke-uitdrukking van ʼn reeks sitokiene, insluitend IL-1α, IL-1ra, IL-17, TNFα, IL-5 en IFNγ, onderdruk. Respons kurwes wat verskillende konsentrasies van hormoon insluit, het getoon dat MPA ook by laer (nano-molare) dosisse die uitdrukking van sommige sitokiene kon verander. Om te bepaal of hierdie in vitro effek van MPA ook in vrouens wat MPA as voorbehoedmiddel gebruik voorkom, het ons PBMSe van MPA-gebruikers and kontroles met BCG gestimuleer en die vlakke van tot 29 verskillende sitokiene met behulp van Luminexanalise gemeet. PBMSe van MPA-gebruikers produseer beduidende laer vlakke van IL-12p40, IL-1α, IL- 10, IL-13 en G-CSF, wat elk in imuunafweerreaksies teen Mtb betrokke is. Die afname in dié sitokiene het gepaard gegaan met laer hoeveelhede sirkulerende monosiete. Ons resultate regverdig verdere ondersoeke en kliniese proewe behoort die risiko van progressie vanaf latente tot aktiewe TB in vrouens wat hierdie voorbehoedmiddel gebruik te bepaal. Sulke proewe vereis egter groot getalle deelnemers en is skrikwekkend duur, om die rede het ons besluit om ʼn Mtb/MPA muis-model op te stel om sodoende die algehele effek van MPA op die uitkoms van die siekte te bepaal. BALB/c en C57BL/6 muise is met ʼn weeklikse dosis van een mg MPA of sout oplossing ingespuit en een week na die aanvang van die hormoon behandeling met 30 kolonie-vormende eenhede Mtb H37Rv geïnfekteer. Beide muis tipes was ingesluit om sodoende te bepaal watter tipe die mens data die beste verteenwoordig. Drie en agt weke na die infeksie het die MPA-behandelde C57BL/6 muise ‘n beduidende hoër bakteriële lading in hul longe gehad as die onbehandelde muise, maar was daar geen verskil in die bakteriële ladings in die longe van die BALB/c muise nie. MPA-behandelde C57BL/6 muise het beduidende laer serumvlakke van IL-10 en G-CSF gehad, terwyl MPA-behandelde BALB/c muise laer serumvlakke van IFNγ gehad het. Verder het ons gevind dat die geisoleerde limfosiete van MPA-behandelde C57BL/6 muise beduidend minder TNFα, beduidend meer IP-10 en minder IL-10 geproduseer het na stimulasie met PPD, terwyl die limfosiete van MPA-behandelde BALB/c muise beduidend minder IFNγ, IL-2, IL-17, GM-CSF en MCP-1 geproduseer het. Data van die C57BL/6 muise stem ooreen met die van ons mens studie en ons kan dus vermeld dat die C57BL/6 muise, tesame met die spesifieke serumkonsentrasie van MPA wat gebruik is, ʼn goeie model is om die effek van MPA in die konteks van ʼn lae-dosis Mtb-infeksie te bestudeer. MPA gebruik kan dus die vatbaarheid vir TB, asook die erns van die siekte verander en kan ook die effektiwiteit van nuwe BCG-gebaseerde entstowwe, veral prima-hupstoot enstowwe, wat moontlik in die nabye toekoms vir volwasse en adolessente vroue toegedien kan word, verander.