No description available.

The Positive Predictive Value (PPV) of the Modified Checklist for Autism in Toddlers (M-CHAT), a parent report autism screening tool, is higher for males than for females (Ludwig et al., IMFAR 2011). Given the long waitlists and high costs for ASD evaluations, there is a need to reduce the number of false positive females on the M-CHAT. The current study examined the sex specific clinical profiles of toddlers who received an ASD evaluation based on M-CHAT screen positive status in order to explore potential differences that may contribute to the differential PPV of the M-CHAT in boys and girls. The sample included 250 males and 106 females (mean age=25.3 months, SD=4.6) who were evaluated based on screen positive status on the M-CHAT. Although children with ASD demonstrated greater ASD symptoms, lower IQ and weaker language and motor skills, minimal sex differences were discovered.

Glycolytic enzymes have been indicated as potential drug targets in trypanosomatid parasites such as Trypanosoma brucei (T. brucei), Trypanosoma cruzi (T. cruzi) and Leishmania spp. Pyruvate kinase (PYK) catalyses the final reaction in the glycolytic pathway to produce ATP and pyruvate from ADP and phosphoenolpyruvate (PEP), and has been validated by RNAi experiments as a suitable drug target in T. brucei. This thesis describes biochemical and structural studies of PYKs from T. cruzi (TcPYK) and T. brucei (TbPYK), providing not only a foundation but also new clues for PYK-specific inhibitor screening and structure-based drug design. Soluble TcPYK and TbPYK (81% sequence identity) have been expressed and purified from E. coli, and their kinetics have been fully characterised. X-ray crystal structures of apoenzyme TcPYK (apo TcPYK), and of TbPYK in complex with fructose 2,6-bisphosphate (F26BP) (TbPYK/F26BP/Mg) have been determined, and each possesses a tetrameric architecture composed of four identical protein chains. Each chain contains four domains which are A-domain, B-domain, C-domain and N-terminal domain. The active site is located in the cleft between the A- and B-domains, while the F26BP-bound effector site is within the C-domain. The conformational transition between inactive T-state and active R-state for both enzymes requires a concerted 8o rigid-body rotation of each of the four AC-cores (Aand C-domains) in the tetramer. During the T- to R-state transition induced by F26BP binding, the side chain of Arg311 is re-orientated to stabilise the short Aα6′ helix at the active site, and the flexible loop at the effector site is stabilised by F26BP. In this active conformation additional salt bridges form across the C-C interface to lock the enzyme in a more stable R-state. TbPYK/F26BP/Mg is the first ‘effector only’ PYK structure and identifies a third Mg2+ binding site (Mg-3) which is distinct from the two canonical Mg2+ binding sites. The substrate PEP was soaked into crystals of TbPYK/F26BP/Mg resulting in an ‘in crystallo’ 23° B-domain rotation forming a partially closed active site. This is accompanied by active site side-chain reorientations, and the movement of Mg2+ from its ‘priming’ position Mg-3 to its canonical position Mg-1. It is plausible that Mg2+ is retained in its ‘priming’ position after product release to act as a co-activator with F26BP to maintain the enzyme in its R-state conformation, as long as F26BP is present. The inherent oxaloacetate decarboxylase activity of PYK was reported over 30 years ago and has been further characterised by 1H NMR studies in this thesis. In addition, a series of TbPYK structures in complex with product (pyruvate), with analogues of the decarboxylase substrate oxaloacetate (D-malate and α-ketoglutarate), or with the competitive inhibitor oxalate have been determined by crystal soaking, and indicate that both decarboxylase activity and kinase activity share a common active site. A proposed mechanism explains the conserved decarboxylase activity of PYK where the active-site Mg2+ and Lys239 in TbPYK (which is conserved between species) play essential roles in the decarboxylation reaction. Three strategies for designing novel inhibitors against trypanosomatid PYKs have been proposed in this thesis. (1) Develop selective modulators to increase the binding affinity of inhibitors. As an example, F16BP has been shown to regulate the inhibitory effect of PEP analogues (oxalate, D-malate, α-ketoglutarate, malonate and L-tartrate) on TbPYK activity. (2) Develop allosteric inhibitors in order to lock trypanosomatid PYKs in an inactive state where the enzyme has low affinity for substrate binding. (3) A third strategy is to combine multiple modulators and inhibitors to increase the inhibition efficiency and selectivity.

No description available.

Three hundred and four women with mild dyskaryosis were recruited into this study. They were examined using cervical cytology, HPV 16 & HPV 18 detection and colposcopic assessment, and the histological outcome was diagnosed by Large Loop Excision of the Transformation Zone. The resulting statistical analysis of this data showed that a secondary screening programme that combines HPV 16 & HPV 18 level with repeat cytology would not be a very efficient screening programme for the management of women with a mildly dyskaryotic smear. The study women were also examined for the presence of a specific P4501A1 polymorphism. When considering the women who had high grade disease, it was discovered that the mean age of the women with the normal genotype was 29 years, whereas the mean age of the women with the 'high' risk genotype was 25 years. This difference was significant and could not be accounted for by years the women with the 'high' risk genotype have smoked, or how many cigarettes these women smoked a day. CIN is commonly treated by excisional surgical procedures. Chemotherapy, however, would represent a new, less invasive and potentially less expensive alternative for the prevention of cervical cancer. There are a number of anticancer drugs available, daunorubicin and doxorubicin being the 2 most commonly used antracyclines. However, the use of such drugs is strongly limited by their lack of selectivity for cancer cells. A method has thus been adapted to test whether DaunoXomes (daunorubicin encapsulated liposomes) could be used to kill cervical cancer cells. The long term aim of this is to achieve specific targeting of DaunoXomes to cancer cells using antibody-enzyme conjugates. Preliminary results appear promising as death of cancer cells was achieved by release of the DaunoXomes contents in the close proximity of the cancer cells.

New microscopy techniques are continuously developed, resulting in more rapid acquisition of large amounts of data. Manual analysis of such data is extremely time-consuming and many features are difficult to quantify without the aid of a computer. But with automated image analysis biologists can extract quantitative measurements and increases throughput significantly, which becomes particularly important in high-throughput screening (HTS). This thesis addresses automation of traditional analysis of cell data as well as automation of both image capture and analysis in zebrafish high-throughput screening.  It is common in microscopy images to stain the nuclei in the cells, and to label the DNA and proteins in different ways. Padlock-probing and proximity ligation are highly specific detection methods that  produce point-like signals within the cells. Accurate signal detection and segmentation is often a key step in analysis of these types of images. Cells in a sample will always show some degree of variation in DNA and protein expression and to quantify these variations each cell has to be analyzed individually. This thesis presents development and evaluation of single cell analysis on a range of different types of image data. In addition, we present a novel method for signal detection in three dimensions.  HTS systems often use a combination of microscopy and image analysis to analyze cell-based samples. However, many diseases and biological pathways can be better studied in whole animals, particularly those that involve organ systems and multi-cellular interactions. The zebrafish is a widely-used vertebrate model of human organ function and development. Our collaborators have developed a high-throughput platform for cellular-resolution in vivo chemical and genetic screens on zebrafish larvae. This thesis presents improvements to the system, including accurate positioning of the fish which incorporates methods for detecting regions of interest, making the system fully automatic. Furthermore, the thesis describes a novel high-throughput tomography system for screening live zebrafish in both fluorescence and bright field microscopy. This 3D imaging approach combined with automatic quantification of morphological changes enables previously intractable high-throughput screening of vertebrate model organisms.

Hensikt: Hensikten med studien er å fordype kunnskapen om hvordan gravide kvinner opplever en tidlig ultralydundersøkelse med risikovurdering for kromosomavvik, og hvordan de resonnerer omkring resultatet. Nytteverdien blir å løfte frem denne kunnskapen, og ta den med i den videre debatten omkring dette tema. Metode: Det ble gjort en kvalitativ intervjuundersøkelse med ti gravide kvinner som skulle få utført en risikovurdering for kromosomavvik. Kvinnene ble intervjuet både før og etter undersøkelsen. Grounded theory ble benyttet som analysemetode. Resultater: I studien ble det ble generert en kjernekategori; Jeg vil ha valget, men ikke ta det, og fem hovedkategorier: Eksistensielle valg, Trygghetsfølelse, Engstelse, Skyldfølelse og Veiledning / Ivaretakelse. Kjernekategorien beskriver kvinnenes konflikt mellom å ville ha muligheten til denne undersøkelsen, og samtidig ha vanskeligheter med å ta de påfølgende valgene. Noen av faktorene som gjorde valgene så vanskelige var engstelse, tap av kontroll / mestring, tilknytning til fosteret, skyldfølelse og sosialt press. Siden kvinnene ønsket selvstendige valg uten påvirkning fra andre, følte de også en større ansvarlighet for de valg som ble tatt. Forståelsen av den kalkulerte risikoen varierte mellom kvinnene, og de benyttet ulike metoder for å lette vurderingen og valget. Gravide kvinner har et stort informasjonsbehov når det gjelder prenatal diagnostikk, og de ønsker en lett tilgjengelighet til spesialisthelsetjenesten. For å få tid til refleksjon over egne verdier og holdninger, er det viktig at informasjonen blir gitt på et så tidlig tidspunkt i svangerskapet som mulig. Konklusjon: Studien viser kompleksiteten av følelser som gravide kvinner kan oppleve i forbindelse med en tidlig ultralydundersøkelse og risikovurdering for kromosomavvik. Disse stressrelaterte følelsene kan sammen med beslutninger på komplisert risikoinformasjon, og på et sterkt ansvarlig og moralsk område vanskeliggjøre beslutningsprosessen. En bedre informasjonsformidling og kontakt med helsevesenet er nødvendig for at kvinnene skal ta informerte valg, som er i tråd med deres verdier og holdninger. / Purpose: This qualitative study aimed to increase understanding of how pregnant women experience early ultrasound examination that includes risk assessment for chromosomal anomalies. Moreover, this study examined how such women rationalize test results. Method: I conducted pre- and post-examination interviews of ten pregnant women undergoing risk assessment for chromosomal anomolies, and used grounded theory to analyze the results. Results: The study generated a core category (I want a choice, but I don’t want to decide) and five main categories (existential choices, feeling of safety, anxiety, guilt, and counselling and care). Factors contributing to choice difficulty included anxiety, loss of control or coping, emotional connection to the fetus, feelings of guilt, and social pressures. The core category describes the conflict between choice and decision. Since the women sought independent choices without external influence, they also felt greater responsibility. The women’s understanding of actual risk varied, and they used different logic and methods to evaluate risk and reach a decision. Conclusion: Pregnant women need for prenatal diagnostic information and want easy access to specialty services. This study shows the complex feelings pregnant women experience regarding early ultrasound examination that includes risk assessment for chromosomal defects. Stress, non-transparent information about actual and perceived risks, and personal moral judgments further complicate the decision-making process. Therefore, improved distribution of information and frequent contact with health professionals will help women to make informed choices in accordance with their values and beliefs. / <p>ISBN 978-91-5-85721-47-4</p>

The present research concerned the validation of a neuropsychological screening measure. In a series of investigations the reliability, predictive validity and factor structure of the Ball Neuropsychological Screening Measure (BNSM) were examined.Such procedures were considered essential to investigate the utility of the BNSM.In a two part study, the reliability of the BNSM was investigated (Study 1). First, an attempt was made to determine BNSM test-retest reliability with the finding that subtest means on test and retest were too similar to permit interpretation. In the second portion of Study 1 the internal consistency of the BNSM was examined by computing Cronbach's alphas. The BNSM was found to have high internal consistency, producing an overall alpha coefficient of .951.A discriminant analysis was performed in study 2 to examine the utility of the BNSM in discriminating between normal and impaired adults.The BNSM was found to be highly accurate in this regard, achieving an overall correct placement prediction rate of 96%. Study 3 looked at the utility of the BNSM in correctly predicting lateralization of brain Impairment.The BNSM successfully predicted placement into three groups (Normals, Right-Hemispheric Impairment, LeftHemispheric Impairment) with 95% overall accuracy. Finally, the factor structure of the BNSM was examined in Study 4. Utilizing a varimax rotation, a two factor solution was found to account for 66.8% of the total variance. / Department of Educational Psychology

The purpose of the study was to evaluate the construct validity of the Substance Abuse Subtle Screening Inventory (SASSI) as a screening test for alcoholism. The study sample consisted of 238 participants. These included 50 alcoholics, 50 normals, 50 psychiatric outpatients, 50 co-dependent family members and 38 drug addicts, so classified by clinician diagnosis.All participants were administered the SASSI and also the Michigan Alcoholism Screening Test (MAST) and the MacAndrew Alcoholism-Screening Scale (AMAC). Correct classification rates for all three tests were determined using both a five-group criterion of classifying as an alcoholic, normal, psychiatric outpatient, co-dependent or drug addict, and a simpler two-group criterion of classifying as a substance abuser or non-abuser. Five null hypotheses were tested using Chi-square (alpha = .01) tests for equal proportions of classification accuracy. A sixth null hypothesis was tested using linear discriminant function analyses.Results Five-group criterion:1. The three tests differed in correctly classifying alcoholics, with the MAST statistically significantly superior to the AMAC and the SASSI.2. The three tests differed in correctly classifying normals, with the MAST and the AMAC statistically significantly superior to the SASSI.3. The three tests differed in correctly classifying psychiatric outpatients, with the AMAC statistically significantly superior to the SASSI.4. The three tests differed in correctly classifying drug addicts, with the AMAC and the SASSI statistically significantly superior to the MAST.5. The three tests did not differ to a statistically significant degree in classifying codependents.Two-group criterion (abuser/non-abuser):1. The three tests differed in correctly classifying alcoholics, with the MAST statitically significantly superior to the AMAC and the SASSI.2. The three tests differed in correctly classifying normals, with the SASSI statistically significantly superior to the AMAC and the MAST.3. The three tests differed in correctly classifying psychiatric outpatients, with the SASSI and the AMAC statistically significantly superior to the MAST.4. The three tests differed in correctly classifying drug addicts, with the MAST statistically significantly superior to the AMAC and the SASSI.5. The three tests differed in correctly classifying co-dependents, with the SASSI statistically significantly superior to the AMAC and the MAST.Employing the two-group criterion, all tests vastly improved their performance with the SASSI significantly superior to the MAST and the AMAC at author-recommended cutting scores. Increasing the cutting score for the MAST improved classification accuracy even further. Employing the linear discriminant function, the three tests differed significantly, with the MAST statistically significantly superior to all other scales.ConclusionsNone of the three scales performed adequately with the five-group criterion. The simpler two-group criterion produced an 87% classification accuracy rate for the SASSI with the study sample at author-recommended cutting scores, which was statistically significantly superior to the MAST and the AMAC. The highest classification accuracy rates of 90.3% and 91.2% respectively were produced by the MAST at elevated cutting scores of 10 and 12 in the two-group criterion. These parallelled linear discriminant function results for the MAST. / Department of Counseling Psychology and Guidance Services

Thesis (M. Environmental Management)--North-West University, Potchefstroom Campus, 2009.