Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping, swallowing difficulties, and proximal limb weakness. The autosomal dominant form of this disease is caused by the expansion of a polyalanine stretch from 10 to 12--17 alanines in the N-terminus of PABPN1. Mutated PABPN1 (mPABPN1) is able to induce the formation of filamentous intranuclear inclusions that are the pathological hallmark of OPMD. PABPN1 is predominantly localized to the nucleus, binds RNA poly(A) tail, forms oliogmers, and is involved in polyadenylation. In this study we first demonstrated that oligomerization of PABPN1 is mediated by two potential oligomerization domains (OD), while inactivating oligomerization of mPABPN1 by deletions of 6--8 residues in either of the ODs prevents intranuclear protein aggregation. Expression of mPABPN1 in COS-7 cells is associated with cell death, whereas preventing nuclear protein aggregation by inactivating oligomerization of mPABPN1 significantly reduces cell death. We then identified two PABPN1 interacting proteins, hnRNP A1 and A/B, using a yeast two-hybrid library screen. The interaction between PABPN1 and hnRNP A1 or A/B was confirmed by GST pull-down and co-immunoprecipitation assays. When coexpressed with mPABPN1 in COS-7 cells, predominantly nuclear localized hnRNP A1 and A/B co-localize with mPABPN1 to the insoluble intranuclear aggregates. Patient studies showed that hnRNP A1 is sequestered in OPMD nuclear inclusions. We finally found a nuclear localization signal (NLS) in PABPN1 that is not homologous to any known NLSs. The 18 amino acids 289RGRVYRGRARATSWYSPY 306 in PABPN1 are necessary and sufficient for nuclear translocation. Attaching this sequence to cytoplasmic protein PKM2 completely re-localizes it to the nucleus. Alanine-scanning mutagenesis analysis showed that the last 9 residues 298RATSWYSPY306 are crucial to the function as an NLS. Our studies showed that mPABPN1 induced intran

Thyroid cancer constitutes about 1% of all malignant tumours and the incidence is increasing in Sweden. It is rare in children before the age of 10. During puberty the female to male ratio increases to be two to three times more common in females. The ratio remains constant until menopause and thereafter declines. The etiology of this gender-dependent incidence difference is unclear. Ionizing radiation is the only well-established risk factor for the disease, while the impact of other etiological factors is not clear. A retrospective study based upon medical records of 218 females and 91 males with papillary, mixed or follicular types of thyroid cancer was conducted. Prognostic factors were compared by multivariate analysis using Cox's semiparametric hazard model. Differences in prognosis between women and men were found. There was a higher relapse rate and mortality risk among men. Distant metastasis, age &gt;50 years, regional lymph node metastasis, low or moderate differentiation, and tumour related symptoms at diagnosis were also independent factors related to increased tumour mortality risk. A population-based case-control study including 180 cases and 360 controls was carried out to identify risk factors for thyroid cancer. Information on exposure was obtained by mailed questionnaires. The first part of the study investigated connections between medical ionizing radiation and thyroid cancer. The results showed that diagnostic X rays were a significant risk factor for papillary thyroid cancer in women between 20 and 50 years at diagnosis. Exposure to iodine-131 caused no increased risk for thyroid cancer. The result supports that external radiotherapy is a risk factor for thyroid cancer in women. The second part of the case-control study dealt with occupation and different exposures. Work with diagnostic X-ray investigations and work as a lineman was associated with thyroid cancer. Exposure to impregnating agents increased the risk. The third part of this study showed that one pregnancy increased the risk for papillary thyroid cancer. A medical history of asthma or allergy decreased the risk. Another case-control study using medical records as the source for assessment of exposure gave a non significantly increased risk for thyroid cancer in patients who had been treated with external radiotherapy including the thyroid gland. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1994, härtill 5 uppsatser.</p> / digitalisering@umu

A retrospective study of invasive pneumococcal disease in patients from Greater Göteborg in 1964- 1980 identified 125 cases of meningitis, 305 of pneumonia, 61 of septicemia with unknown focus, and 17 with other manifestations, all verified by cultures from normally sterile body fluids. The incidence was several times higher in infants and in the elderly than in any other age-group. A wide variety of underlying conditions were present in 23% of the infants, 34% of the children, and 81% of the adults. In adults alcoholism was known in one third of the cases. The case fatality rate was 24% among patients with underlying conditions and 9% among previously healthy individuals. The case fatality rate was 50% in patients with hospital-acquired infection. Twohundred-fifteen pneumococcal strains, isolated from blood or CSF from 1971 to 1983 at the laboratories of clinical bacteriology of Göteborg, Malmö, and Umeå were serotyped by coagglutination (COA). Of all isolates, 89% belonged to serotypes represented in the 23-valent vaccine. In a separate study COA was compared with counterimmunoelectrophoresis (CIE). COA was found to have several advantages; rapidity, lower cost, and ability to disclose serotypes with neutral charge, which constituted 19% of all strains. In a prospective study the etiology was determined in 196 hospitalized patients with pneumonia, most of them community-acquired. Culture of specimens from blood, transtracheal aspirate (TTA), sputum, and nasopharynx, assays of antigen in sputum, urine, and TTA, and assays of pneumococcal antibodies to capsular polysaccharide, C-polysaccharide, and pneumolysin in paired sera were performed. The etiology was established in 64% of the patients. Streptococcus pneumoniae was the most common agent (32%). In a serological study of patients with pneumococcal infection, diagnosed by culture of CSF, TTA, or blood, IgG antibodies against C-polysaccharide and pneumolysin were determined by ELISA. The diagnostic sensitivity was only 51% and 60%, respectively. In conclusion, invasive pneumococcal disease is strongly overrepresented at tender and high age and in patients with concomitant conditions, notably alcoholism. S. pneumoniae remains a predominant causative agent of community-acquired pneumonia in adults needing hospitalization. Due to the low sensitivity and/or specificity of individual microbiological techniques, a combined use of several techniques is necessary when trying to assess the relative importance of pneumococci and other agents in pneumonia. Extended use of the currently available pneumococcal vaccine and development of improved pneumococcal vaccines seem highly warranted. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 5 uppsatser.</p> / digitalisering@umu.se

Chemical dependency as it pertains to African-American males is examined through the theoretical perspectives of critical medical anthropology and clinically applied anthropology, the synthesis of the two referred to as critical clinically applied anthropology. The major etiological models and theories of chemical dependency are reviewed as are the contemporary chemical dependency treatment services.The critical clinically applied anthropological perspective examines chemical dependency and its treatment at four levels: 1) the macrosocial, 2) intermediate, 3) the microsocial, and 4) the individual. Additional variables concerning chemical dependency such as societal or large scale, institutional, local/environmental, organizational, and small scale factors are addressed as well. The above levels of analysis and independent variables indicate that racism, in the form of economic, political, and cultural oppression is a significant etiological factor concerning AfricanAmerican male chemical dependency. It is suggested that in order to provide more effective chemical dependency treatment, racial oppression must be addressed in the treatment setting. / Department of Anthropology

Soft tissue sarcomas account for about 1% of all malignancies. The increase in incidence of soft tissue sarcomas during the recent decades may predominantly be attributed to AIDS-related Kaposi’s sarcoma; when this tumor is excluded, conclusive evidence for an age-adjusted increase is lacking. Beside the well investigated role of the human immunodeficiency virus 1 (HIV-1) and the human herpesvirus 8 (HHV-8) in the tumorigenesis of AIDS-related Kaposi’s sarcoma and several inherited disorders, considerable evidence support a relationship between occupational chemicals as vinyl chloride, phenoxyacetic acid herbicides, chlorphenols, dioxin, medicinal measures as Thorotrast exposure and therapeutic irradiation, and the development of soft tissue sarcoma. Hormones and chronic repair processes are further probably sarcoma-promoting factors. Considering the rarity of soft tissue sarcomas despite the vast portion that soft tissues comprise in the human body, additional knowledge on the tumorigenesis of soft tissue sarcomas might considerably contribute to the understanding of the etiologic pathways of malignant tumors in humans. / Weichteilsarkome stellen etwa 1% aller bösartigen Neubildungen. Der in den vergangenen Jahrzehnten beobachtete Inzidenzanstieg geht fast ausschließlich auf die rasante Zunahme an AIDS-assoziierten Kaposi-Sarkomen zurück. Bei Außerachtlassung dieses Tumors gibt es bisher keinen schlüssigen Beweis für eine wirkliche alterskorrigierte Häufigkeitszunahme der Weichteilsarkome. Neben der gut untersuchten Rolle des HIV-1-Virus und des humanen Herpes-Virus 8 bei der Entstehung des AIDS-assoziierten Kaposi-Sarkoms und einigen prädisponierenden genetischen Erkrankungen existieren starke Hinweise für einen Zusammenhang zwischen Industriegiften wie Vinylchlorid, Phenoxyessigsäure-Herbiziden, Chlorphenolen, Dioxinen, medizinischen Maßnahmen wie therapeutischer Bestrahlung oder dem Einsatz von Thorotrast, und der Entwicklung von Weichteilsarkomen. Hormone und chronische Reparaturprozesse sind weitere wahrscheinlich fördernde Einflüsse auf die Entstehung von Weichteilsarkomen. Die Tatsache, daß trotz des großen Anteils, den die Binde- und Stützgewebe an der Körpermasse stellen, nur selten maligne Tumoren von diesen Strukturen ausgehen, läßt hoffen, daß ein besseres Verständnis der an der Kanzerogenese von Weichteilsarkomen beteiligten Mechanismen in der Zukunft wichtige Erkenntnisse über die Entstehung menschlicher Tumoren liefern kann. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Karvių slaptojo mastito etiologija, gydymas ir prevencija Raktiniai žodžiai: Slaptas mastitas, karvių, etiologija, gydymas, prevencija Darbą atliko: Darbo vadovas: Darbo apimtis: 45 puslapiai, 5 lentelės, 17 paveikslėlių, 34 naudotos literatūros šaltiniai. Darbo tikslas: Įvertinti mikroorganizmų paplitimą karvių mastito etiologijoje ir nustatyti jų atsparumą antimikrobinėms medžiagoms Darbo uždaviniai: 5. Nustatyti mikroorganizmų, sukėlusių karvėms slaptąjį mastitą paplitimą; 6. Nustatyti mikroorganizmų atsparumą antimikrobinėms medžiagoms; 7. Išanalizuoti ryšį tarp mikroorganizmų rūšių ir somatinių ląstelių skaičiumi 8. Įvertinti preparatų gydomąjį efektyvumą slaptuoju mastitu sergančioms karvėms; Mokslinis - tiriamasis darbas buvo atliekamas 2012 – 2014 metais Lazdijų raj. esančiame X ūkyje. Šiuo metu ūkyje kiekviena dieną melžiama ~ 500 karvių. X ūkyje melžiamos karvės yra laikomos šaltojo tipo tvarte naudojant palaidą sistemą. Tyrimams buvo atrinktos 62 karvės sergančios subklinikiniu mastitu, kurios suskirstytos į 2 grupes po 31 karvę. Grupėms buvo skirtas skirtingas gydymas, 1 –oji grupė gydyta kombinuotu gydymu- „SYNULOX RTU“ injekcinė suspensija kartu su „SYNULOX LC“ intramaminė suspensija galvijams laktacijos metu, o 2 – jai grupei skirtas paprastas gydymas „SYNULOX LC“ intramaminė suspensija. Prieš gydymą ir po gydymo buvo stebėtas SLS kitimas piene, sukėlėjų diagnozavimas, primilžio kitimas, ketvirčių užkrėstumas. X ūkyje nustatėme, kad subklinikiniu... [toliau žr. visą tekstą] / Key Words: latent mastitis, cows, etiology, treatment, prevention Work done by: Supervisor: Volume: 45 pages, 5 tables, 17 images, 34 sources of used literature Aim and goals: Aim: To evaluate spreading of microorganisms in the etiology of cow mastitis and to establish antimicrobal drug resistance Goals: 1. To establish spreading of microorganisms causing latent mastitis of cows; 2. To establish antimicrobal microorganisms resistance; 3. To analyse the relation between the types of microorganisms and number of somatic cells; 4. To evaluate the effectiveness of preparations applied to treat the cows on latent mastitis; The scientific research was carried out in the years 2012 – 2014 in the farm X located in Lazdijai district. Currently, ~ 500 of cows are milked every day in this farm. The milch - cows in the farm X are being kept in the cold type of cow - shed applying a loose system. 62 cows with subclinical mastitis were selected for research. 2 groups were formed, each consisting of 31 cow. Special treatments were applied for both groups. A combined treatment was delivered to the Ist group of cows - injection suspension „SYNULOX RTU“ together with Intramammary suspension „SYNULOX LC“ to cattles during lacation period. Meanwhile, a simple treatment was delivered to the IInd group of cows - Intramammary suspension „SYNULOX LC“. SLS change in milk, diagnosis of agents of desease, change of milk yield, infection of the quarters has been observed before and... [to full text]

Methylmalonic aciduria results from defects in the enzyme methylmalonyl-CoA mutase and from defects in the synthesis of the enzyme's cofactor adenosylcobalamin. Two patients who excrete methylmalonic acid have been shown to have a homozygous nonsense mutation in the methylmalonyl-CoA epimerase gene (MCEE). To further understand the causes of methylmalonic acid excretion, the MCEE gene was sequenced in 229 patients who excreted methylmalonic acid for which no cause was known. Mutations were detected in five patients. Fusion of fibroblast lines from two patients with a homozygous nonsense mutation in MCEE did not result in correction of [14C]propionate incorporation toward control values while the defect in these fibroblasts was complemented by mut, cblA, and cblB fibroblasts. Transfection with wild-type MCEE cDNA resulted in correction of the biochemical phenotype in cells from both patients. These experiments support the hypothesis that a defective epimerase enzyme can be a cause of elevated methylmalonic acid excretion.

[Truncated abstract] The dramatic increase in the expression of allergic diseases such as asthma and allergy over the last 20-30 years has highlighted the urgent need to identify causative factors. It was hypothesised that direct immune interactions between mother and fetus contribute to the cytokine milieu of pregnancy, thus influencing immune maturation after birth. Further it was speculated that the cytokine responses produced as a result of maternalfetal interactions are Th-2 skewed in women allergic disease, which programmes their offspring towards developing an allergic phenotype after birth. To test this hypothesis a cohort of 169 pregnant women were recruited at 20 weeks gestation and defined as allergic or non-allergic based on both clinical history and skin prick test sensitisation. These women and their infants were followed up throughout pregnancy (20 weeks, 30 weeks, 36 weeks gestation and 6 weeks post-partum) and up to 2.5 years of age. Mixed lymphocyte reactions (MLR) were used to measure maternal cytokine (IL-6, IL-10, IL-13 and IFN-) and lymphoproliferative responses to fetal alloantigens at each pregnancy time-point. Human leukocyte antigen (HLA) typing of mothers and infants were performed to assess the effect of HLA mismatch on maternal MLR responses to their fetus. After delivery, mononuclear cells (MNC) were isolated from cord blood (CB) and stimulated with allergens, mitogen and toll-like receptor (TLR) ligands. .... As IL-6 also participates in adaptive immunity by promoting Th-2 differentiation it is proposed that the production of IL-6 as a results of maternal encounters with paternal antigens during pregnancy, contribute to the Th-2 skewed responses observed universally in most infants at birth. Associations between maternal-fetal interaction and clinical outcomes in infancy: Although clinical signs of allergy in infancy were not the main outcome measure of this thesis, there were interesting, yet complex relationships between the production of these maternal cytokines towards the fetus and allergic disease at infant follow-ups. Increased maternal IFN-¿ to fetal alloantigen was associated with asthma at 2.5 years and a trend towards recurrent wheeze at 12 months. In contrast decreased maternal IL-13 production was associated with IgE mediated food allergy at 12 months. Adjusting for maternal allergy and other potential confounders including infant gender, method of delivery, HLA mismatch, and paternal allergy did not account for these relationships. Further follow-ups of these infants are required to determine if these relationship last in to early childhood. In conclusion, the findings of this thesis provides further support for the hypothesis that immune responses at birth are programmed prenatally, and that this programming has implications later in life. Importantly, the placenta is the immunologically active interface between mother and fetus during pregnancy. Therefore it is emphasised that there is a crucial need for future research to focus on early immune programming at the placental level before the aetiological pathways of immune mediated diseases can be fully elucidated.

Master of Public Health / OBJECTIVES: In Australia, diabetes causes significant morbidity and mortality. Whilst the need to prevent diabetes and its complications has been widely recognised, the capacity of health care systems - which organise diabetes care - to facilitate prevention has not been fully established. METHODS: A series of seven population-based case-control studies were used to examine the effectiveness of the Australian health care system and its capacity to manage diabetes. Six of the studies compared the patterns of care of patients who had developed advanced diabetes complications in 2000 (cases), to similar patients who remained free of the condition (controls) across Australia and for various risk groups. A secondary study investigated the role of treating GPs in the development of the outcome. RESULTS: A strong relationship between the patterns of care and the development of advanced diabetes complications was found and is described in Chapter 4. In Chapter 5, this same relationship was investigated for each Australian state and territory, and similar findings were made. The study in Chapter 6 investigated whether late diagnosis or the patterns of care was the stronger risk factor for advanced diabetes complications, finding that the greatest risk was associated with the latter. In Chapter 7 the influence of medical care during the pre-diagnosis period was explored, and a strong relationship between care obtained in this period and the development of advanced complications was found. In Chapter 8, which investigated the role of socio-economic status in the development of advanced complications, found that the risk of advanced diabetes complications was higher in low socio-economic groups. Chapter 9 investigated geographic isolation and the development of advanced diabetes complications and found that the risk of advanced complications was higher in geographically isolated populations. Finally, Chapter 10, which utilised a provider database, found that some GP characteristics were associated with the development of advanced diabetes complications in patients. CONCLUSION: A number of major risk factors for the development of advanced complications in Australia was found. These related to poorer diabetes management, later diagnosis, low socioeconomic status and geographic isolation. Strategies must be devised to promote effective diabetes management and the early diagnosis of diabetes across the Australian population.

Impairments in both theory of mind (ToM; the ability to attribute mental states to oneself and others) and executive function (EF; a group of high-level cognitive functions which help guide and control goal-directed behaviour) have been demonstrated in individuals with autism spectrum disorders (ASDs). Both deficits have been proposed by different groups of researchers as being the single primary cognitive deficit of autism, which can subsume the other deficit as secondary or artefactual. However, few studies have examined the nature of the relationship between ToM and EF in ASDs or conducted a systematic investigation of their relative primacy. This research principally sought to establish the primacy and independence of impairments in ToM and EF in ASDs and thereby evaluate the validity of single versus multiple primary deficit models of autism. These aims were addressed in two studies, both broad in scope. The first study was an investigation of the profile, primacy, and independence of ToM and EF impairments in individuals with ASDs. The sample included 46 participants with ASDs and 48 control participants matched on age and non-verbal ability. The profile of impairments was examined by measuring ToM and a range of EF components using tasks employing, wherever possible, process-pure indices of performance. Primacy was measured by focussing on i) whether or not the deficits observed were universal among individuals with ASDs; ii) whether the deficits were able to discriminate individuals with ASDs from matched controls (i.e., predict group membership); and iii) the ability of ToM and EF deficits to explain the full range of autistic symptomatology, as measured by correlating cognitive performances with behavioural indices. The relationship between ToM and EF impairments was investigated by conducting correlations between ToM and EF variables as well as analysing the incidence of dissociations between impairments in the two domains. The ASD group was found to demonstrate significant impairments in ToM and several components of EF including planning, verbal inhibition, working memory (in a context where inhibitory control was required), and both verbal and non-verbal generativity. However, neither ToM nor EF impairments were able to meet all of the criteria for a primary deficit in ASDs. EF deficits were found to be more primary, but could not account for ToM as a secondary deficit, as ToM and EF were found to be independent (i.e., uncorrelated and dissociable) deficits in the ASD group. This pattern of results suggested that a multiple deficits model involving at least two independent impairments appeared to best characterise ASDs, but the data were compatible with several variants of such a model (e.g., involving distinct subtypes versus a multidimensional spectrum). The second study was an investigation of ToM and EF impairments in siblings of individuals with ASDs, who have previously been found to demonstrate a subclinical “broad autism phenotype”. The main aims of this study were i) to identify whether ToM or EF deficits could meet criteria for an “endophenotype” or vulnerability marker for the autism genotype in unaffected relatives, which would have further implications about the primacy of ToM and EF in ASDs; and ii) to further investigate the validity of various multiple deficits models of ASDs by examining the pattern of ToM and EF performance in those showing the broad phenotype. Participants were 108 siblings of individuals with ASDs and 67 siblings of controls, tested on the same ToM and EF tasks used in the first study. Confirming the superior primacy of EF deficits found in Study One, there was no significant difference in ToM performance between ASD and control siblings, but ASD siblings showed weaknesses on two measures of EF. Furthermore, there appeared to be different subgroups of siblings demonstrating different cognitive profiles, consistent with the heterogeneity evident in the first study. This research indicated that ASDs cannot be explained by a single primary cognitive deficit. These findings hold important theoretical and empirical implications and highlight further questions about which type of multiple deficits model might best explain ASDs.