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Thesis (M.Med. (Radiation Oncology)) -- University of Limpopo, 2022 / Background Breast cancer is known to be a heterogeneous disease that demands patient centered care. Establishing the clinicopathological characteristics of breast cancer patients is a vital step in an effort to individualize their treatment. Aim The aim is to evaluate the clinicopathologic features of the different subtypes of breast cancer when classified according to immunohistochemistry markers in women attending Pietersburg hospital. Methods A retrospective review of medical records of women treated at Pietersburg hospital between 2010 and 2011 was done. Data collection was extracted on a customized data collection sheet. Chi square was used to determine association between clinicopathologic features and molecular subtypes. Analysis of variants was used to assess association between molecular types and age. Results The mean age of the population was 55.3 years (+/-14 standard deviation). The majority of patients were in stage III (46.9%) and IV (33.5%). The ER, PR, HER2/neu positive rate was 50.6%, 30% and 14,3 % respectively with a negative rate of 13,4%, 19,5% and 23,4% respectively. ER, PR and HER2/neu was unknown in 18%, 19, 5% and 23,4% respectively. The most common molecular subtype was luminal A (53,6%) followed by triple negative (27.2%), HER2/neu (11, 4%) and luminal B (7. 9%).There was no association between the subtypes and tumour stage (p=0.578).The rate of distant metastasis was similar across the subtypes being 37,9%,35%, 32,4% and 31,9% in HER2/neu, luminal B ,luminal A and TNBC, respectively. All four molecular subtypes had high rate of axillary lymph node involvement (p=0.886) Luminal A had the least percentage of high grade tumours with TNBC having the highest. Five-year overall survival for the cohort was 25, 6% with luminal A and B having a better 5 year overall survival of 27,2% and 25% respectively, whereas HER2/neu and TNBC had lower 5 year OS of 24% and 23,3%. Conclusion The findings of this study suggest that luminal A subtype is the most predominant and the majority might benefit from hormonal therapy. However, some patients could not be classified due to missing IHC marker test results. The outcome across all four subtypes is poor and more effort should be put towards improving the diagnosis and treatment individualization and follow-up in these patients.

Thesis (M. Sc. (Medical Sciences)) -- University of Limpopo, 2021 / Background: This study was designed to determine the relationship of immunohistochemical subtypes of breast cancer and clinicopathological features and demographic information in Limpopo since there has been no data published on the association of immunohistochemical subtypes, clinicopathological features and demographic characteristics in recent years. Methods: Data was obtained from records of patients diagnosed with breast cancer between 2015 and 2020. Chi-Square and ANOVA tests were performed, and results considered significant at p ≤ 0.05. Results: The mean age was 50.32 ± 11.40, estrogen receptor positive(ER+), progesterone receptor positive(PR+) and human epidermal growth receptor 2 positive(HER2+) prevalence were 73.5%, 62.3% and 26.5% respectively. More than half of the patients (54.3%) had a Ki-67 level >15%. Grade II tumors were the predominant type of tumors in this study (51.7%). 43.7% of the cases showed lymph node involvement. Luminal B subtype was the most predominant immunohistochemical subtype in the study (46.4%), followed by Luminal A (24.5 %), TNBC (19.9%) and HER2- enriched (6.6%). 2.6 % of the cases were classified as undetermined. Conclusion: A significant association was observed between immunohistochemical subtypes and tumor grade

Two main theories of neural atypicality have been postulated in autism. One theory proposes that autism can be explained as the result of atypical patterns of hypo and hyper functional connectivity (FC) within and between brain areas. A complementary theory suggests that atypical functional communication in autism could result from an altered ratio between excitatory and inhibitory input (E:I imbalance). These theories have been previously explored as they might apply to all individuals with a behavioral diagnosis. However, given the multiscale heterogeneity characterizing autism, different subsets of individuals with autism may display different patterns of functional connectivity atypicalities and E:I imbalance. This thesis sets out to explore how neural atypicalities in connectivity and E:I imbalance might be differentially expressed in subsets of the autistic population. To this end, two empirical investigations were conducted. First, the connectivity hypothesis was explored by investigating whether behaviorally-defined subtypes were associated with different patterns of FC atypicalities. Behaviorally-defined subtypes were obtained by stratifying autistic individuals based on their relative balance between social communication (SC) and restricted and repetitive behaviors (RRBs) core symptom domains. This approach yielded three behaviorally-based subtypes: SC>RRB, SCRRB displayed hypoconnectivity between somatomotor and perisylvian circuitry, while subtypes SC=RRB showed hypoconnectivity between somatomotor and visual association areas and hyperconnectivity between medial motor and anterior salience networks. Finally, these subtype-specific FC alterations were shown to be enriched for partially distinct genetic mechanisms, some of which related to excitatory-inhibitory neurons and astrocytes. In a second study, the EI imbalance hypothesis was explored by investigating whether autism subtypes could be identified based on an E:I-sensitive metric computed from electroencephalographic (EEG) data. Specifically, the Hurst exponent (H) – a metric that has been shown to be affected by changes in excitatory input – was computed on EEG time-series data, obtained in two resting state conditions of eyes open and closed. H-based clustering revealed two E:I-based neurosubtypes across conditions with opposing patterns of E:I imbalance compared to neurotypical controls. Autism neurosubtype 1 showed on-average higher H values, while neurosubtype 2 displayed on-average lower H. These opposing E:I balance patterns were present globally across the brain, with the limited exception of an orthogonal larger decrease in H in non-frontal electrodes in neurosubtype 2. Finally, investigation at the behavioral level identified distinct multivariate brain-behavior relationships between age, intelligence, autistic traits and H. Taken together, these empirical findings demonstrate that the two major theories of neural atypicality in autism – FC alteration and E:I imbalance – do not apply equally to all individuals with a behavioral diagnosis. Rather, different subtypes of autism exist that display contrasting patterns of neural atypicality compared to typically-developing individuals. These contrasting patterns might be driven by differentially altered primary or compensatory E:I mechanisms shaping distinct atypical cortical organizations within the subtypes. Interestingly, the relationship between specific neural atypicalities and variability at the behavioral and genetic level is, however, subtle across the subtypes. This limited multiscale association could suggest that heterogeneity in autism might be due to the presence, within the larger population, of subtype-specific mosaic-like patterns of atypicalities at the behavioral and biological level. Further research is required to thoroughly characterize how these levels map onto one another within the subtypes and determine the pathophysiological mechanisms driving their development.

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Den aktuella studien syftade till att applicera Johnsons typologier om två subtyper av förövare av partnervåld, intimate terrorism och situational couple violence, i en kontext av digitalt dejtingvåld bland unga universitetsstudenter. En kvantitativ metod med tvärsnittsdesign användes. Studien identifierade 185 förövare av digitalt dejtingvåld från ett urval på 512 studenter mellan 19-29 år. De 185 förövarna kategoriserades som intimate terrorism (n=46) eller situational couple violence (n=139) beroende på om respondenten endast hade utövat digitalt dejtingvåld eller om respondenten både utövat och själv blivit utsatt för digitalt dejtingvåld. Resultatet visade att kvinnor som ingick i subtypen situational couple violence utövade digitalt dejtingvåld med en signifikant högre allvarlighetsgrad än män. Flera resultat från studien visade inga signifikanta könsskillnader i en av subtyperna eller mellan de två subtyperna i grad av kontrollerande beteenden och allvarlighetsgrad. Med stöd i studiens resultat bör framtida forskning vidare utforska digitalt dejtingvåld bland unga för att få en fördjupad kunskap inom digitalt dejtingvåld och för att stärka det brottspreventiva arbetet. / This study examined Johnson's typology of two different subtypes of perpetrators of intimate partner violence, intimate terrorism and situational couple violence, on digital dating violence among young college students. A quantitative cross-sectional design was used. The study identified 185 perpetrators of digital dating violence from a sample of 512 students, ages 19 to 29 years. The 185 perpetrators were categorized as intimate terrorism (n=46) or situational couple violence (n=139) based on whether the person was only a perpetrator of digital dating violence or if the person was both a perpetrator and a victim of digital dating violence. The current study found that women included in the subtype situational couple violence committed digital dating violence with a significantly higher degree of severity than men. Results from the study showed no significant differences between genders in one of the subtypes or between perpetrator subtypes in controlling behavior or severity. In light of these findings, future research should investigate digital dating violence among young adults to gain a deeper understanding of digital dating violence in order to strengthen crime prevention.

<p>Social phobia is a disabling anxiety disorder characterized by an excessive fear of negative evaluation in social situations. The present thesis explored the epidemiology and neurobiology of the disorder. By means of a mailed questionnaire, the point prevalence of social phobia in the Swedish general population was estimated at 15.6%. However, prevalence rates varied between 1.9 and 20.4% across the different levels of distress and impairment used to define cases. Thus, although social anxiety is widespread within the community, the precise diagnostic boundaries for social phobia are difficult to determine. Social phobia was associated with female gender, low educational attainment, psychoactive medication use, and lack of social support. A cluster analysis revealed that subtypes of social phobia mainly differed dimensionally on a mild-moderate-severe continuum, with number of cases declining with increasing severity. Public speaking was the most common social fear in all groups of social phobics and in the population at large.</p><p>In the neurobiological studies, positron emission tomography was used to examine brain serotonin metabolism and changes in the regional cerebral blood flow (rCBF) response to public speaking stress following treatment with a selective serotonin reuptake inhibitor (SSRI) or cognitive-behavioral group therapy. Social phobics exhibited lowered serotonin turnover, relative to non-phobics, mainly in the medial temporal cortex including the bilateral rhinal and periamygdaloid regions. Symptom improvement with cognitive-behavioral- as well as SSRI-treatment was accompanied by a reduced rCBF-response to public speaking in the amygdala, hippocampus and adjacent temporal cortex, i.e. regions that serve important functions in anxiety. Thorough suppression of rCBF in limbic brain regions was associated with favorable long-term treatment outcome. These results provide neuroimaging evidence for a presynaptic serotonergic dysfunction in social phobia and for a common neural mechanism whereby psychological and pharmacological anti-anxiety treatments act.</p>

Social phobia is a disabling anxiety disorder characterized by an excessive fear of negative evaluation in social situations. The present thesis explored the epidemiology and neurobiology of the disorder. By means of a mailed questionnaire, the point prevalence of social phobia in the Swedish general population was estimated at 15.6%. However, prevalence rates varied between 1.9 and 20.4% across the different levels of distress and impairment used to define cases. Thus, although social anxiety is widespread within the community, the precise diagnostic boundaries for social phobia are difficult to determine. Social phobia was associated with female gender, low educational attainment, psychoactive medication use, and lack of social support. A cluster analysis revealed that subtypes of social phobia mainly differed dimensionally on a mild-moderate-severe continuum, with number of cases declining with increasing severity. Public speaking was the most common social fear in all groups of social phobics and in the population at large. In the neurobiological studies, positron emission tomography was used to examine brain serotonin metabolism and changes in the regional cerebral blood flow (rCBF) response to public speaking stress following treatment with a selective serotonin reuptake inhibitor (SSRI) or cognitive-behavioral group therapy. Social phobics exhibited lowered serotonin turnover, relative to non-phobics, mainly in the medial temporal cortex including the bilateral rhinal and periamygdaloid regions. Symptom improvement with cognitive-behavioral- as well as SSRI-treatment was accompanied by a reduced rCBF-response to public speaking in the amygdala, hippocampus and adjacent temporal cortex, i.e. regions that serve important functions in anxiety. Thorough suppression of rCBF in limbic brain regions was associated with favorable long-term treatment outcome. These results provide neuroimaging evidence for a presynaptic serotonergic dysfunction in social phobia and for a common neural mechanism whereby psychological and pharmacological anti-anxiety treatments act.

Neuronal networks are the central functional units of the nervous system. Knowledge about the identity of participating neurons and the assembly of these during development is crucial for the understanding of CNS function. A promising system to dissect the development and functionalities of a neuronal network is the central pattern generator (CPG) for locomotion. We used screening approaches to identify spinal neuronal subpopulations by their specific gene expression, potentially involved in CPG function. Amongst others we found paired-like homeodomain transcription factor 2 (Pitx2) as a cholinergic interneuron marker for partition cells, with a possible role in the spinal network for locomotion. In addition, we present two genes, Chondrolectin (Chodl) and Estrogen-related receptor beta (ERRβ) as novel markers for fast and slow motor neurons, respectively. The neuronal components of the CPG integrate three key functions; rhythm generation, ipsilateral flexors/extensors coordination and bilateral coordination over the midline. Commissural interneurons (CINs) are considered to participate in the latter. During development axons are guided to their targets by the help of axon guidance molecules. Netrin-1 and its receptor DCC (Deleted in Colorectal Cancer) have been shown to play an important role for spinal cord neurons in axon-pathfinding and migration towards the midline. We show that loss of netrin-1 functionally results in a switch from alternating to synchronous left-right locomotor activity and deletion of DCC surprisingly leads to a different phenotype, best described as uncoordination. Thus, during development, netrin-1 and DCC play a critical role for the establishment of a functional balanced CPG. Further we show a selective loss of CINs, predominantly from dorsally originating subtypes, not affecting the ventral-most V3 subtype in netrin-1 mutant mice, but a loss of CINs from all progenitor domains in Dcc mutant mice. Together, our data suggest a netrin-1-independent mechanism for DCC in axon guidance and a role of the most ventral originating CINs as part of the neuronal network controlling synchronous activities over the midline. Another pair of axon guidance molecules, EphA4 and ephrinB3, has been shown to cooperate in preventing ipsilateral interneurons from crossing the spinal midline and if either molecule is deleted in mice, this will result in a defect in left-right coordination of locomotion. We provide in vivo and in vitro evidence that the GTPase-activating protein α2-chimerin, as a downstream molecule of EphA4 signaling, is essential in axon guidance decisions involved in the correct formation of the spinal circuitry for locomotion.