Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter

Although the promoters of both the Bax and p21 genes are activated by p53, they differ in the effect on this activation of the POU family transcription factor Brn-3a. Thus, Brn-3a inhibits activation of the Bax promoter by p53 but enhances the ability of p53 to activate the p21 promoter. We demonstrate that repression of p53-mediated activation of the Bax promoter involves a complex upstream sequence in which two Brn-3a response elements flank the p53 response element. In contrast, a minimal p21 promoter is activated by Brn-3a and such activation cannot be abolished without abolishing basal promoter activity. Moreover, synergistic activation by Brn-3a and p53 continues to be observed when the p53-binding sites in the p21 promoter are substituted by the Bax p53 site or by the region of the Bax promoter essential for Brn-3a-mediated repression, indicating that the p21 core promoter plays a central role in this response. The significance of these effects is discussed in terms of the different responses of the Bax and p21 promoters and the overlapping but distinct roles of Brn-3a and p53 in neuronal growth arrest and apoptosis

Characterization of wild-type and laboratory attenuated “Brachyspira hampsonii”

This thesis aimed to characterize Western Canadian “Brachyspira hampsonii” clinical isolates and to develop and characterize an attenuated “B. hampsonii” vaccine candidate. Clinical “B. hampsonii” isolates selected from different Western Canadian barns were described biochemically and by sequencing the NADH-oxidase (nox) gene to improve the information available about clinical isolates present in Western Canada. The biochemical profiles of two clade I and eight clade II isolates were compared and variability in some diagnostic biochemical markers (β-glucosidase and hippurate hydrolysis) was detected. Representative isolates of clade I and II “B. hampsonii” were also compared to other swine-associated Brachyspira spp. based on biochemical profiles and morphometric data. Cell dimensions, number of flagella, and select biochemical markers (hippurate hydrolysis, α-glucosidase, and β-glucosidase) were not sufficient to discern “B. hampsonii” from other Brachyspira species. The data highlighted that consistent biochemical characteristics (indole and α-galactosidase negative) of “B. hampsonii” and morphology were not sufficient to differentiate them from other Brachyspira spp. and that nox gene sequencing is a more reliable tool for identification and differentiation of Brachyspira species. Development of a potential vaccine strain was also carried out by serial passage of a virulent “B. hampsonii” clade II strain (passage 13 (P13)) for 100 passages, resulting in strain P113. The virulent P13 and serially passaged P113 strains were phenotypically and genotypically compared to identify any changes in P113. Phenotypes of P13 and P113, including the biochemical profile, β-haemolysis, growth profile, and virulence in a murine model, were compared to identify changes. More extensive β-haemolysis and more rapid growth of P113 over P13 was observed suggesting laboratory adaptation after serial passage. Two experiments were performed to assess the virulence of P113 and P13 in a murine model, which both demonstrated a decrease of P113 virulence, suggesting that partial attenuation was achieved. No difference between the virulent and attenuated strains was detected based on genomic profiling by random amplified polymorphic DNA (RAPD) or whole genome sequence comparison. The results of this thesis demonstrate the complexity of phenotypic identification and discrimination of “B. hampsonii” and other swine-associated Brachyspira species. Serial passage of a virulent “B. hampsonii” resulted in a laboratory adapted, partially attenuated strain that will be attenuated further and used as a potential vaccine. This serially passaged strain also provides opportunities for further studies to identify virulence determinants, which can aid immensely with prevention and treatment of “B. hampsonii”

Malnutrition secondary to gastrojejunal stricture after biliopancreatic diversion

Context: Bariatric surgery has beneficial effects on obesity and associated comorbidities such as glycaemic control in type 2 diabetes, dyslipidaemia, hypertension, and renal and hepatic function. Nevertheless, this surgery is not free of complications and possible side effects due to restrictive and/or malabsorptive related components. Case description: We report the case of a 60-year-old woman whose past medical history included morbid obesity, hypertension and Scopinaro biliopancreatic diversion (BPD) with duodenal switch in 1998. In 2015, she attended the emergency department hypotensive with bad general condition and reporting chronic constitutional symptoms. A wide variety of tests were performed including endoscopic studies as her symptoms were not immediately correlated with the BPD surgery. Finally, she was diagnosed from gastrojejunal stricture which caused her severe malnutrition. The patient underwent successful surgical management. Discussion: BPD is one of the most effective surgical procedures for obesity, with an overall 5-year loss of excess body weight higher than 72%. Nonetheless, it is associated with long-term complications such as protein malnutrition and vitamin deficiencies due to malabsorption. Being surgically challenging, with high risk of nutritional complications and lifelong needed for the follow-up, BPD is rarely performed nowadays. Conclusions: Bariatric Surgery is a well-known effective therapeutic measure to improve obesity and cardiovascular related disease. However, this case highlights the importance of robust multidisciplinary lifelong surgical and medical follow-up in all BPD patients. BPD complications can be minimised and recognised early with patient and healthcare staff education on the importance of lifetime follow-up and adherence to dietary and supplement regimes

The multidisciplinary management of rectal cancer

Rectal cancer treatment has evolved during the past 40 years with the use of a standardized surgical technique for tumour resection: total mesorectal excision. A dramatic reduction in local recurrence rates and improved survival outcomes have been achieved as consequences of a better understanding of the surgical oncology of rectal cancer, and the advent of adjuvant and neoadjuvant treatments to compliment surgery have paved the way for a multidisciplinary approach to disease management. Further improvements in imaging techniques and the ability to identify prognostic factors such as tumour regression, extramural venous invasion and threatened margins have introduced the concept of decision-making based on preoperative staging information. Modern treatment strategies are underpinned by accurate high-resolution imaging guiding both neoadjuvant therapy and precision surgery, followed by meticulous pathological scrutiny identifying the important prognostic factors for adjuvant chemotherapy. Included in these strategies are organ-sparing approaches and watch-and-wait strategies in selected patients. These pathways rely on the close working of interlinked disciplines within a multidisciplinary team. Such multidisciplinary forums are becoming standard in the treatment of rectal cancer across the UK, Europe and, more recently, the USA. This Review examines the essential components of modern-day management of rectal cancer through a multidisciplinary team approach, providing information that is essential for any practising colorectal surgeon to guide the best patient care

Evolution of transanal total mesorectal excision for rectal cancer: From top to bottom

The gold standard for curative treatment of locally advanced rectal cancer involves radical resection with a total mesorectal excision (TME). TME is the most effective treatment strategy to reduce local recurrence and improve survival outcomes regardless of the surgical platform used. However, there are associated morbidities, functional consequences, and quality of life (QoL) issues associated with TME; these risks must be considered during the modern-day multidisciplinary treatment for rectal cancer. This has led to the development of new surgical techniques to improve patient, oncologic, and QoL outcomes. In this work, we review the evolution of TME to the transanal total mesorectal excision (TaTME) through more traditional minimally invasive platforms. The review the development, safety and feasibility, proposed benefits and risks of the procedure, implementation and education models, and future direction for research and implementation of the TaTME in colorectal surgery. While satisfactory short-term results have been reported, the procedure is in its infancy, and long term outcomes and definitive results from controlled trials are pending. As evidence for safety and feasibility accumulates, structured training programs to standardize teaching, training, and safe expansion will aid the safe spread of the TaTME

Fluoxetine: a case history of its discovery and preclinical development

Introduction: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine. Areas covered: The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment. Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetine’s effects on depressive-like behaviour, anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine. Expert opinion: Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved

Prediction of electric consumption using multiple linear regression methods

In the new global and local scenario, the advent of intelligent distribution networks, or Smart Grids, allows the collection of data about the operational state of the electric network in real time. Based on this data availability, the consumption prediction becomes feasible and convenient in the short term, from a few hours to a week (temporary variables). The research proposes that the method used to present the temporary variables for a system to predict electrical consumption affects the results. To verify this hypothesis, different methods for representing these variables are considered, applied to the problem of predicting daily values of electricity consumption in the city of Bogota, Colombia

Online Sexual Partner Seeking as a Social Practice: Qualitative Evidence from the 4(th) British National Survey of Sexual Attitudes and Lifestyles (Natsal-4)

Once perceived as a means for those unsuccessful at traditional dating, online dating has become normalized as a way to seek sexual or romantic partners. In 2019, we interviewed 40 British adults on the role of digital technologies in their sexual lives; this paper draws on the accounts of 22 who had used such technologies for seeking partners. We analyzed qualitative accounts of online partner seeking as a social practice, drawing on a sample diverse in age, gender and sexual orientation, and informed by sexual script and social practice theory. Our theoretically informed analysis emphasized the multiple meanings and goals involved, the affordances of the technology and individuals’ skills. Our study provided several novel contributions. Young heterosexual people commonly used general social media, rather than dating apps, to meet partners; meeting partners often involved complex interplays between online and offline networks and encounters. Risks were defined not merely in relation to “risky others” but in terms of one’s own actions or attitudes. Participants deployed various skills in minimizing harms such as non-consensual sharing of intimate images, and used self-care skills such as setting limits to engagement

Comparative study of Selva and Camarosa strawberries for the commercial market

Selva and Camarosa strawberry varieties were characterized chemically and physically. The importance of keeping the stem until processing, the influence of different transport periods under refrigerated conditions, the effects of freezing and exposure to air of damaged surfaces were evaluated. During freezing, losses of ascorbic acid, sucrose, fructose and glucose were reported for both varieties. However, keeping the stem intact minimizes the losses of ascorbic acid in frozen fruits. The exposure to air of cut surfaces affects ascorbic acid content of fresh fruits, with the highest losses reported in Camarosa. Selva showed properties important for commercial use, as compared to Camarosa, with regard to a higher resistance to thawing and higher contents of total phenolics, total protein, and ascorbic acid