Molecular Aspects of Mitochondrial Dysfunction in Diabetes, Pearson and Kearns-Sayre Syndromes, and Neurodegenerative Disorders

Amirmohammad Shafiee,1,2 Amir Ali Akhlaghi,3 Abigail Ellstrom,1,2 Seyed Omid Mohammadi,2 Alimohammad Shafiee,4 Mohanakrishnan Sathyamoorthy1,2 1Sathyamoorthy Laboratory in Department of Internal Medicine, Burnett School of Medicine at Texas Christian University, Fort Worth, TX, USA; 2Burnett School of Medicine at Texas Christian University, Fort Worth, TX, USA; 3School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada; 4Department of Family Medicine, Kelvington Hospital, Kelvington, SK, CanadaCorrespondence: Mohanakrishnan Sathyamoorthy, Email [email protected]: Mitochondrial dysfunction results in complex pathophysiological alterations associated with clinical disease states including cancer, cardiovascular diseases, diabetes mellitus, and anxiety disorders. As a key organelle within mammalian cells, the mitochondrion serves as the energetic source of cellular function which are crucial to cellular homeostasis, and cell death. In this report, we review key molecular causes of mitochondrial dysfunction and discuss how it influences insulin resistance, Pearson Syndrome and Kearns-Sayre syndrome, the latter of which occur due to pathogenic variants in mitochondrial DNA that lead to direct cellular pathology. We discuss the molecular and cellular pathophysiological mechanisms, disease interplays, and clinical considerations related to these diseases influenced by mitochondrial dysfunction.Keywords: mitochondrial dysfunction, insulin resistance, Kearns-Sayre syndrome, Pearson syndrom

HPV type-specific prevalence using a urine assay in unvaccinated male and female 11- to 18-year olds in Scotland

We conducted a baseline prevalence survey of unvaccinated 11- to 18-year olds to inform effectiveness studies for the new human papillomavirus (HPV) immunisation programme in Scotland

Designing and Supporting Extraordinary Work Experience

“There is a big difference between a lesson that is about the practice and takes place outside of it, and explanations and stories that are part of the practice and take place within it” (Wenger, Communities of practice. Learning, meaning and identity. Cambridge University Press, New York, 1998, p. 100).The real world learning experienced by students on placement is highly significant (Morley, Enhancing employability in higher education through work based learning. Palgrave Macmillan, 2018). This chapter focuses on how these experiences can be accelerated from being part of courses to a pivotal event towards students’ future development.The chapter explores emerging areas of practice pedagogy and how innovative design can bridge the theory-practice divide and support structures between university and work. The chapter is contextualised in the higher education landscape where students ‘work readiness’ is gaining greater traction and how attributes for employability are developed during university

The “ebb and flow” of student learning on placement

There is a rise in interest in work based learning as part of student choice at subject level in the UK (DOE 2017) but there remains an absence of specific guidance on how to best support higher education students learning on placement. An alternative HE experience in England, the degree apprenticeship, underlies the continued focus by policy in securing placement experiences for students without stipulating the type of support that is required at the ‘coal face’ of work based learning. Policy documents (UUK 2016), that urge universities to enter into partnership agreements with both employers and FE colleges to plug skills shortages, are noticeably lacking in their appreciation of the unique qualities of work based learning and how best to support students in this setting (Morley 2017a). Unfortunately, this is not unusual as placements have predominantly been an enriching ‘add on’ to the real business of academic learning in more traditional university programmes. Support initiatives, such as that described in chapter 9, are a rare appreciation of the importance of this role. Undergraduate nursing programmes currently support a 50:50 split between practice learning in clinical placements and the theory delivered at universities. Vocational degrees, such as this, provide an interesting case study as to how students can be supported in the practice environment by an appreciation of how students really learn on placement and how hidden resources can be utilised more explicitly for practice learning. During 2013 – 2015 a professional doctorate research study (Morley 2015) conducted a grounded theory study of 21 first year student nurses on their first placement to discover how they learnt ‘at work’ and the strategies they enlisted to be successful work based learners

Costs and Effects of Abdominal versus Laparoscopic Hysterectomy: Systematic Review of Controlled Trials

Objective: Comparative evaluation of costs and effects of laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH). Data sources: Controlled trials from Cochrane Central register of controlled trials, Medline, Embase and prospective trial registers. Selection of studies: Twelve (randomized) controlled studies including the search terms costs, laparoscopy, laparotomy and hysterectomy were identified. Methods: The type of cost analysis, perspective of cost analyses and separate cost components were assessed. The direct and indirect costs were extracted from the original studies. For the cost estimation, hospital stay and procedure costs were selected as most important cost drivers. As main outcome the major complication rate was taken. Findings: Analysis was performed on 2226 patients, of which 1013 (45.5%) in the LH group and 1213 (54.5%) in the AH group. Five studies scored >= 10 points (out of 19) for methodological quality. The reported total direct costs in the LH group ($63,997) were 6.1$60,114). The reported total indirect costs of the LH group ($1,609) were half of the total indirect in the AH group ($3,139). The estimated mean major complication rate in the LH group (14.3%) was lower than in the AH group (15.9%). The estimated total costs in the LH group were $3,884 versus$3,312 in the AH group. The incremental costs for reducing one patient with major complication(s) in the LH group compared to the AH group was $35,750. Conclusions: The shorter hospital stay in the LH group compensates for the increased procedure costs, with less morbidity. LH points in the direction of cost effectiveness, however further research is warranted with a broader costs perspective including long term effects as societal benefit, quality of life and survival

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16–23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrolment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy=100%; 95% CI:12–100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts

Maternal Programming of Sexual Behavior and Hypothalamic-Pituitary-Gonadal Function in the Female Rat

Variations in parental care predict the age of puberty, sexual activity in adolescence and the age at first pregnancy in humans. These findings parallel descriptions of maternal effects on phenotypic variation in reproductive function in other species. Despite the prevalence of such reports, little is known about potential biological mechanisms and this especially true for effects on female reproductive development. We examined the hypothesis that parental care might alter hypothalamic-pituitary-ovarian function and thus reproductive function in the female offspring of rat mothers that vary pup licking/grooming (LG) over the first week postpartum. As adults, the female offspring of Low LG mothers showed 1) increased sexual receptivity; 2) increased plasma levels of luteinizing hormone (LH) and progesterone at proestrus; 3) an increased positive-feedback effect of estradiol on both plasma LH levels and gonadotropin releasing-hormone (GnRH) expression in the medial preoptic region; and 4) increased estrogen receptor α (ERα) expression in the anterioventral paraventricular nucleus, a system that regulates GnRH. The results of a cross-fostering study provide evidence for a direct effect of postnatal maternal care as well as a possible prenatal influence. Indeed, we found evidence for increased fetal testosterone levels at embryonic day 20 in the female fetuses of High compared to Low LG mothers. Finally, the female offspring of Low LG mothers showed accelerated puberty compared to those of High LG mothers. These data suggest maternal effects in the rat on the development of neuroendocrine systems that regulate female sexual behaviour. Together with studies revealing a maternal effect on the maternal behavior of the female offspring, these findings suggest that maternal care can program alternative reproductive phenotypes in the rat through regionally-specific effects on ERα expression