289 research outputs found
MicroRNA modulation of caenorhadbitis elegans dietary restriction and longevity
No full textAging is a universal biological phenomenon involving a complex decline in the ability of the organism to respond adequately to intrinsic and extrinsic stresses, leading to age-related diseases and pathologies. All organisms age, but the larger questions of how and why aging occurs are still being deciphered despite decades of research and experimentation . We present evidence identifying microRNAs, small non-coding RNAs that regulate gene expression by repressing target mRNAs through partially complementary binding, significantly impact Caenorhabditis elegans longevity. We have identified several mir mutants that impact not only lifespan but also specific aspects of aging like metabolic aging vs muscle aging. Excitingly we have also identified that the mir-80 mutant animal is under chronic dietary restriction – a conserved pathway that extends life- and healthspan in many diverse organisms. The mir-80(Δ) mutant exhibits multiple parameters of healthy aging, reduced fecundity and expression of molecular reporters associated with dietary restriction. Using a targeted RNAi approach we have identified several stress response transcription factors (daf-16, hsf-1 and skn-1), the metabolic energy sensor (AMPK) and the transcriptional co-factor cbp-1 as important requirements for mir-80(Δ) longevity and the DR-state. Finally we show that mir-80 longevity is also partially regulated by the conserved insulin/IGF-1 signaling pathway. In summary, we identify the first metazoan microRNA that regulates longevity through conserved dietary restriction and suggest a model whereby mir-80 may regulate a network of stress response and metabolic genes to impact C. elegans longevity. In conclusion, we identify novel miRNAs that modulate C. elegans longevity and the first microRNA that modulates longevity through dietary restriction.Ph. D.Includes bibliographical referencesby Mehul M Vor
An Investigation of Multidisciplinary Pathways in Paediatric DSD: Evaluation in Tertiary Centres in the United Kingdom and Hong Kong
No full textDifferences/Disorders of Sex Development (DSD) represent a diverse spectrum of conditions that are often present at birth when a baby’s sex cannot be immediately determined based on the appearance of their genitalia. This affects approximately 1 in 4500 newborns, although the exact incidence is unknown. These conditions can present at various other stages of life too. Having a child with potential DSD creates anxiety and considerable uncertainty among families. A multidisciplinary approach to provide early support and guiding investigations to a specific diagnosis and management plan are pivotal to holistic DSD care. The four aims of this work are to: (1) map out the 25- year clinical landscape of DSD referrals and changes over time in Great Ormond Street Hospital, London; (2) evaluate the prevalence of primary adrenal insufficiency (PAI) among 46,XY children and the role of biochemical testing in 46,XY children presenting with atypical genitalia in the newborn period; (3) explore the application of targeted gene panel multiplexed sequencing as an example of state-of-the-art research genetic technology for reaching a molecular diagnosis in DSD; and (4) analyse parents’ experiences of current pathways during the early days, including the source of information, and the psychological consequences of early experiences in Queen Mary Hospital (Hong Kong). In this study, we present clinical, biochemical and genetic data from what is, to our knowledge, the largest single-centre cohort of DSD conditions in newborns, children and young people reported, over a 25-year period. We also describe a collection of early parental experiences from recent DSD families. Our data highlight the range of presentations, associated features and approximate point prevalence of these diverse conditions, as well as the imperative roles of timely clinical assessment, biochemical analysis, genetics and psychosocial support in an integrated DSD care model. This work should help to inform service commissioning going forward and initiate quality improvement exercises that would potentially impact on patients’ outcomes in the long run, as well as other aspects of DSD service improvement
Advances in differential diagnosis and management of growth hormone deficiency in children
No full textGrowth hormone (GH) deficiency (GHD) in children is defined as impaired production of GH by the pituitary gland that results in growth failure. This disease might be congenital or acquired, and occurs in isolation or in the setting of multiple pituitary hormone deficiency. Isolated GHD has an estimated prevalence of 1 patient per 4000–10,000 live births and can be due to multiple causes, some of which are yet to be determined. Establishing the correct diagnosis remains key in children with short stature, as initiating treatment with recombinant human GH can help them attain their genetically determined adult height. During the past two decades, our understanding of the benefits of continuing GH therapy throughout the transition period from childhood to adulthood has increased. Improvements in transitional care will help alleviate the consequent physical and psychological problems that can arise from adult GHD, although the consequences of a lack of hormone replacement are less severe in adults than in children. In this Review, we discuss the differential diagnosis in children with GHD, including details of clinical presentation, neuroimaging and genetic testing. Furthermore, we highlight advances and issues in the management of GHD, including details of transitional care
Use of combined liothyronine and thyroxine therapy for consumptive hypothyroidism associated with hepatic haemangiomas in infancy
No full textHepatic haemiangiomas in infancy are rare. An association with hypothyroidism has been previously reported and is believed to be secondary to the conversion of thyroxine (fT4) to biologically inactive reverse triiodothyronine (rT3) by type 3 iodothyronine deiodinase (D3). We report a case that responded well to the combined use of liothyronine and thyroxine therapy
Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD)
No full textThe definitive version is available at www.blackwell-synergy.comObjective Mutations within the pituitary-specific paired-like homeobox gene PROP1 have been described in 50–100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1. Design and patients Patients with congenital hypopituitarism were recruited from the London Centre for Paediatric Endocrinology as well as several national and international centres. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to panhypopituitarism. Clinical data, including endocrine and neuro-radiological studies were obtained from patient records, and DNA was collected and screened for mutations within PROP1 using PCR and single-stranded conformation polymorphism (SSCP) analysis. Positive results on SSCP were sequenced directly. Results The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1·1%) than in familial cases (29·5%). PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia. We describe the waxing and waning of a pituitary mass over 20 months in association with a PROP1 mutation that is predicted to lead to complete loss of function. Additionally, we have identified a possible founder mutation in CPHD patients from the Indian subcontinent. Conclusions PROP1 mutations are rare in sporadic cases of CPHD, although the prevalence rises if there is a positive family history or if the patients are carefully selected with respect to the endocrine and neuroradiological phenotype. There is considerable phenotypic variability in families with the same mutation, indicating the role of other genetic or environmental factors on phenotypic expression. Finally, the pituitary enlargement that is observed in patients with PROP1 mutations can wax and wane in size before eventual involution.James P. G. Turton, Ameeta Mehta, Jamal Raza, Kathryn S. Woods, Tiulpakov, Anatoly,Joseph Cassar, Paul Q. Thomas, Marumudi Eunice, Ariachery C Ammini, Pierre M. Bouloux, Jerzy Starzyk, Peter C. Hindmarsh and Mehul T. Dattan
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