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Fructose-2, 6-bisphosphate (fru-2, 6P2), synthesized by 6-phosphofructo-2-kinase (PFK2), regulates glucose metabolism via modulating phosphofructokinase-1 (PFK1) and fructose-1, 6-bisphosphatase (FBPase1) reciprocally in mammalian tissues. How this control system develops in brain is poorly understood. This article presents the postnatal comparative profiles of fru-2, 6P2 and PFK2 & fru-2, 6P2 dependent regulation of PFK1 and FBPase1 in mice brain. Fru-2, 6P2 and PFK2 activity both attained their adult levels in concordance from day1 to 1wk age. Western blot analysis of mice liver and brain & rat liver PFK2 using anti rat liver PFK2/FBPase2 confirmed that both, mice liver and brain isoforms cross- react efficiently with this antibody. In addition, DEAE-eluted brain fractions from different postnatal ages revealed that 1day mice brain expresses a liver type enzyme (∼55 kDa) that is replaced by an adult brain type protein (∼110 kDa) from 1wk onward ages. As compared to 1day mice, significantly decreased Km values of PFK2 at 1wk-10wk ages also suggest the existence of a kinetically different isoform of this enzyme from 1wk onward ages. In vitro effects of fru-2, 6P2 on partially enriched brain PFK1 and FBPase1 suggest that fru-2, 6P2 dependent respective stimulatory and inhibitory responses of both these enzymes increase progressively from day1 to 3wk age. This is well corroborated with the postnatal age-dependent linear increase in PFK1 and decrease in FBPase1 activities in mice brain. The results suggest that fru-2, 6P2 associated regulatory components develop in concordance in mice brain during early postnatal life.

The prefrontal cortices, in particular lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC), have been implicated in top-down control of attention switching and behavioral flexibility. These cortices and their networks are disrupted in autism, a condition in which diverse behaviors such as social communication and attention control are dysregulated. However, little is known about the typical development of these cortical areas or the ways in which this process is altered in neurodevelopmental disorders. In order to identify changes that could affect the local processing of signals transmitted by the short-range pathways connecting the ACC and LPFC I assessed developmental changes in the distinct cortical layers, which send and receive different pathways and have unique inhibitory microenvironments that dictate excitatory-inhibitory balance. Normative developmental trends were compared with those seen in individuals with autism to identify changes that may contribute to symptoms of attention dysfunction. Unbiased quantitative methods were used to study overall neuron density, the density of inhibitory neurons labeled by the calcium-binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV), and the density, size, and trajectory of myelinated axons in the individual cortical layers in children and adults with and without a diagnosis of autism. There was a reduction in neuron density and an increase in the density of myelinated axons in both areas during neurotypical development. Axons in layers 1-3 of LPFC were disorganized in autism, with increased variability in the trajectory of axons in children and a decrease in the proportion of thin axons in adults. These findings were most significant in layer 1, the ultimate feedback-receiving layer in the cortex. While there were no differences in neuron populations between cohorts in children, in adults with autism there was a significant reduction in the density of CR-expressing neurons in LPFC layers 2-6 and a significant increase in the density of PV-expressing neurons in ACC layers 5-6. In autism, these findings suggest that dysregulation of the normal development of axonal networks, seen in children, may induce compensatory developmental changes in cell and axon populations in adults that could be connected to attention dysregulation. / 2021-10-07T00:00:00Z

Masters of Public Health - see Magister Public Health / Introduction: Mother-to-child transmission (MTCT) is the cause of most HIV acquisition among children. Prevention of mother-to-child transmission (PMTCT) of HIV programs aim to enable pregnant women to attain viral suppression so that they are unlikely to pass HIV to the foetus in utero or during birth, and to the neonate during breastfeeding. The Option B+ treatment regimen - initiating pregnant and breastfeeding women, diagnosed with HIV, on lifelong triple antiretroviral therapy (ART) regardless of their WHO clinical stage – was introduced in 2013 in Zambia but to date, no evaluation of this program has been done. Study Aim: The current study described factors associated with adherence and retention in care(RIC) among postnatal women initiated on ART during the antenatal and postnatal period at five PMTCT centres in Lusaka District, Zambia in 2017 and 2018. Methodology: A quantitative, retrospective cohort analysis of 311 postnatal women who were initiated on option B+ regimen at five PMTCT centres in Lusaka District between 1 January 2017 and 30 April 2018 was done. Adherence to treatment was measured by analysing data on patients’ missed clinic appointments and self-reported missed medication doses. Kaplan-Meier survival analysis was used to calculate RIC at 6, 12, 18, and 24 months. Bivariate analysis was conducted to determine the significance of associations between adherence and RIC, and sociodemographic and clinical characteristics, respectively. Results: Retention in care decreased over time, from 92% at the time of delivery to 81%, 77%, 74% and 70% at 6, 12, 18 and 24 months postnatal, respectively. Higher retention in care was observed amongst married women (p=0.012); who stayed within one kilometer from the health facility (p=0.018); whose spouses were on ART (p=0.027); who knew their HIV status before pregnancy (p=0.005); who were commenced on ART in the first trimester (p=<0.001); and the postnatal period (p=<0.001); who were on other medication, in addition to ART (p=0.001); who did not miss a dose of medication in the week before the last appointment (p=<0.001); and who did not miss any clinic appointment since commencing ART (p=<0.001). Half of the study participants (50.2%; n=155) reported optimal adherence (did not miss a scheduled clinic appointment since commencing ART). Optimal adherence to ART was significantly associated with women who lived within 1 km from the health facility (p=0.012) and who had a treatment supporter (p=0.030). Conclusion: Half of the study participants had optimal adherence to their scheduled clinic visits since enrolment into the Option B+ program, and 30% were lost to follow up over the first two years. Staying closer to the health facility where the woman received ART, knowing one’s HIV status before pregnancy or earlier in pregnancy, and initiating ART earlier in pregnancy, increased the likelihood of optimal adherence to ART and RIC at 24 months postnatal. Additionally, having a treatment supporter increased the likelihood of optimal adherence.

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Geschwisterkinder aus der LIFE-Child-Studie, des Leipziger Forschungszentrums für Zivilisationskrankheiten (LIFE), wurden hinsichtlich des Einflusses bekannter prä- und postnataler Risikofaktoren für die Entwicklung von Übergewicht und Adipositas verglichen. Analysiert wurden der Einfluss verschiedener Geschwisterkonstellationen (mit und ohne Geschwister, Zwillinge), der Altersabstand zwischen den Geschwistern, die Geburtsreihenfolge und die Entwicklung des BMI über den gesamten Zeitraum bis zum Erwachsenenalter. Die Forschungshypothese besagt, dass Geschwister einen signifikanten Einfluss auf den BMI-SDS haben und dass Erstgeborene das geringste Risiko haben, Übergewicht zu entwickeln. Zusammenfassend zeigen die Ergebnisse der vorliegenden Arbeit einen starken positiven Zusammenhang zwischen zunehmender Geburtsreihenfolge und Geburtsgewicht, unabhängig von bekannten pränatalen Risikofaktoren. Postnatal zeigte sich, dass das Vorhandensein von Geschwistern einen positiven Einfluss auf den jeweiligen BMI hat, womit sich die aufgestellte Hypothese bis zum Alter von 11 Jahren bestätigt. Ebenfalls wurde die Hypothese bestätigt, dass erstgeborene Kinder das geringste Risiko hatten, Übergewicht zu bekommen. Mehr Bewegung und eine längere Stilldauer könnten dazu beigetragen haben, dass sich bei Dritt- oder spätergeborenen Kindern, trotz des hohen Geburtsgewichts, der BMI an den der weiteren Geschwisterkinder angenährt hat. Bei Einzelkindern scheinen die familiären und postnatalen Faktoren mit einem starken Anstieg des BMI verbunden zu sein. Basierend auf den Daten der vorliegenden Arbeit könnte die Geburtsreihenfolge als ein neuer Risikofaktor für ein höheres Geburtsgewicht angesehen werden. Ebenso wurde erstmals gezeigt, dass das Aufwachsen als Einzelkind zu einem erhöhten BMI im jugendlichen Alter beitragen kann.:Abkürzungsverzeichnis Abbildungsverzeichnis 1 Einführung und Hintergrund 1.1. Prävalenz von Übergewicht und Adipositas 1.1.1. Pränatale Faktoren 1.1.2. Postnatale Faktoren 1.1.3. Sozioökonomische Status 1.2. Geschwisterstudien 1.3. Ableitung der Rationalen 2 Publikationsmanuskripte 3 Zusammenfassung der Arbeit Literaturverzeichnis Darstellung des eigenen wissenschaftlichen Beitrags Erklärung über die eigenständige Abfassung der Arbeit

Treatments for skeletal tissue injuries include surgery and rehabilitation but in adult patients, the healing process is slow and incomplete, and the underlying biological mechanisms are largely unknown. Skeletal tissues contain stem cells responsible for their maintenance and repair, but the identity and location of these stem cells, and what molecular mechanisms regulate their fate decisions remain unclear. To design more effective regenerative therapies for skeletal conditions, understanding the fundamental biology of skeletal stem cells (SSC) in postnatal organisms is required. Our project aims at identifying and characterizing these SSC populations in postnatal murine and human tissues using lineage tracing techniques, combined with multicolor 3D confocal microscopy and computational image analysis, in vitro assays, and single cell transcriptomics. We hypothesized that the postnatal skeleton contains self-renewing and multipotent Sox9+ SSCs that persist in adulthood. We showed that the adult mouse skeleton contains Sox9+ cells self-renewing, multipotent skeletal stem cells (SSCs) with osteogenic and chondrogenic potential. They are located adjacent to the growth plates and in periosteum and persist in adulthood. Transcriptome analysis revealed that these cells express other putative SSCs markers, as well as genes involved in skeletal development, stem cell self-renewal, and fate decision. This data provides testable drug targets to pharmacologically manipulate SSCs fate decisions in situ. In addition, we showed that human tissues contain SSCs similar to murine tissues. This is the first experimental proof of self-renewal in postnatal Sox9+ SSCs in vivo. These findings provide actionable insights for the use of culture-expanded stem cell product for regenerative medicine product or pharmacological targeting of these stem cells in situ. We believe our data will help improve stem-cell based and tissue engineering therapies, increasing success rate of regenerative orthopaedic surgeries while reducing reoccurrence of injuries.

Following decades of research on stress and its impact on behaviour, it is now widely accepted that selective psycho-pathologies, in particular clinical depression are more prevalent in humans with prior history of life-stress events. Interest in stress has led to questions about how it might affect the physiology and behaviour of animals exposed indirectly during gestational development. Not unexpectedly gestational stress has been shown to affect the offspring in several ways: endocrine responses to stress are elevated, fear, arousal and affective disturbances are all subject to vary if the pregnant animal is subjected to periods of aversive stimulation. Beginning in 1997, Michael Meaney of McGill University produced a series of publications suggesting that peri-natal events influence offspring and infant development, not via physical discomfort or physiological disturbance, but does so through modifications of maternal behaviour. Highly nurturant mothers (those who engage in active arched-back nursing (ABN), and spend more time licking and grooming (L/G) their pups), programme their offspring with improved cognitive abilities, decreased anxiety and fear, and reduced HPA axis hormone secretion. Low-nurturant mothers, who engage in less ABN and less L/G, tend to programme the opposite responses in their offspring. Our initial foray into this field was to investigate if gestational stress might also produce responses in the offspring via changes in maternal behaviour, and indeed ABN and L/G were reduced in dams which were subjected to gestational stress. We queried why stressed Dams would be less maternal towards their infants, and tested gestationally-stressed Dams in the Porsolt test for depressive-like behaviour. Our results suggested that these stressed Dams were actually depressed and this resulted in less maternal behaviour. Human mothers with depression are also less maternal and have been shown to divest themselves of infant care much like our prenatally-stressed Dams. On this basis we have proposed that gestational stress induced decrements in maternal behaviour represent a novel rat model for postnatal depression with face and construct validities. In the present work we have attempted to replicate the findings of Smythe¿s group (Smith et al., 2004), and have investigated the potential for antidepressants to alter the influence of gestational stress on maternal behaviours and depressive-like response, and whether or not the offspring¿ are modified by maternal treatment with ant-depressants. Approximately 140 time-mated, lister hooded rats were generated in house, and subjected to gestational stress on days 10-20 (1hr restraint/day) or remained undisturbed in their home cages. Following birth, cohorts of control and stressed Dams were administered vehicle or an antidepressant (imipramine 15mg/kg; or sertraline 10mg/kg) once daily until postnatal day 10. We assessed maternal Porsolt activity, nurturance (ABN, L/G, nest building) and anxiety-like behaviour in the elevated plus maze (EPM). Representative offspring of each Dam¿s treatment conditions were maintained post weaning and assessed in the Porsolt and EPM to determine if any changes in maternal behaviour elicited by the antidepressants altered their behavioural programming. Our findings confirm that Dams show depressive-like symptoms following gestational stress, and that administration of antidepressants to the Dams reduces depressive-like behaviour and increased maternal care. We propose that rat gestational stress is a putative model for human postnatal depression. Prenatal stress effects on maternal behaviour in the rat Dam represent a novel, and innovative model for human postnatal depression. / Ministry of Defence, Prince Sultan Military College of Health Sciences and the Saudi Culture Bureau

Background: Given that 43-97% of preterm infants face postnatal growth restriction by hospital discharge, monitoring of growth is challenging but critical for clinical management of preterm infants. Currently, serial anthropometric measurements of weight and height are used to monitor growth but lack sensitivity. Thus, by the time significant deviations in growth trajectory are identified, an infant has already reached sub-optimal growth. A biomarker that is predictive of sub-optimal growth can serve as a preventative tool in clinical decision making. Blood urea nitrogen (BUN) may be one such potential metabolic biomarker, as it has been used as a measure of protein adequacy and thus, may additionally indicate quality of growth. While protein intake has a well-established correlation with growth, it is currently unknown if BUN is correlated with postnatal growth and if it can be used as a biomarker for growth. Objectives: 1) to examine the relationship between BUN and macronutrient intake factors such as protein intake, protein-to-energy (P:E) ratios, and carbohydrate to non-protein energy (CHO:NPE %) to better understand BUN response; 2) to examine the potential of using BUN as a predictive metabolic biomarker of growth status in a multiple linear regression. We hypothesize that BUN will positively correlate with protein intake, P:E and negatively with CHO:NPE ratio. It will also be positively correlated with growth parameters: growth velocity, length gain, head circumference gain and fat free mass. Methods: Very low birth weight preterm infants (n=101) born ≤30 weeks of gestation at McMaster Children’s Hospital’s level III NICU were included. BUN was assessed at three time points: baseline (SDay1), study day 14 (SDay14) and study day 21 (SDay21). Intake of protein and energy were collected for the 24-hour period prior to the BUN measure, their averages computed over SDay14 and SDay21 and included as confounding predictor variables. Other confounding variables such as maternal characteristics and baseline study group characteristics were also considered. Growth velocity, length gain and head circumference gain at SDay14 and SDay21, and body composition (FFM%, FFMI) between 36-40 weeks were examined as dependent growth variables. After an initial univariate analysis of baseline and maternal confounders, multiple linear regression models were then developed in a block design as follows: for the analysis of BUN vs macronutrient factors- block 1: 24-hour macronutrient intake factors + relevant baseline and/or maternal confounders; block 2: average macronutrient factors; for the analysis of BUN vs growth- block 3: BUN. Results: In the analysis of BUN and macronutrient intake, BUN was found to have a significant positive correlation with P:E ratio at all time points. Protein intake was positively correlated with BUN only at SDay1 and SDay21. CHO:NPE ratio did not correlated with BUN at any time point. The R2 for the multiple regression of BUN and macronutrient factor analysis at SDay1, SDay14 and SDay21 was 0.19, 0.42 and 0.44 respectively. In the analysis of BUN vs growth, SDay1 BUN had a significant negative correlation with SDay21 growth velocity (p=0.02). The addition of SDay1 BUN to the model of SDay21 growth velocity was significant (p<0.01 of F change statistic, R2= 0.17). SDay21 BUN also had a significant negative correlation with SDay21 growth velocity (p<0.01) and its addition was significant to the model (p<0.01 of F change statistic, R2 =0.22). BUN was not related to SDay 14 growth velocity, or to length gain, head circumference gain or any body composition estimates at any time point. Additionally, P:E was found to be significantly negatively correlated with growth. Conclusion: BUN is a statistically and clinically significant marker of nutritional adequacy, both of protein intake and energy in relation to protein intake. Addition of BUN adds to the explanation of variation in growth, and this is statistically significant, however, the additional variation explained may be too small to be clinically significant. Additionally, we observed that P:E ratio was significantly negatively correlated with growth. Thus, it may be more clinically pertinent to use high BUN values as a marker of inadequate energy to protein intake to prevent future sub-optimal growth. / Thesis / Master of Science (MSc)