Thyroid Related Quality of Life in Elderly with Subclinical Hypothyroidism and Improvement on Levothyroxine is Distinct from that in Young Patients (TSAGE).

The aim of this study was to investigate in a longitudinal approach whether levothyroxine (LT4) substitution has a different impact on quality of life (QoL) and thyroid related QoL in younger (<40 years) and older subjects (>60 years) with elevated thyroid-stimulating hormone (TSH) concentrations. The study included male and female patients with newly diagnosed, untreated subclinical hypothyroidism defined by TSH>8 mU/l. Patients were recruited throughout Germany from 2013-2016 and evaluated by clinical assessment, blood sampling and questionnaires for health related QoL and thyroid-disease thyroid-related QoL (ThyPRO) at time of diagnosis and six months after initiation of LT4 treatment. We found significantly lower QoL in both young and old patients with subclinical hypothyroidism compared to age-matched healthy individuals. Higher scores on follow-up were found in all patients irrespective of age, indicating better QoL on LT4 therapy. Analysis of the ThyPRO questionnaire showed that old patients experienced less Emotional Susceptibility, Tiredness, and Impaired Day Life on LT4, while young patients reported less Cognitive Complaints, Emotional Susceptibility, and Impaired Day Life compared to baseline assessment. Hypothyroidism with TSH concentrations>8 mU/l is associated with impairment in general and ThyPRO QoL in young and old age. Older patients benefited from LT4 therapy and remarkably show similar degree of improvement as younger patients, albeit with some thematic variation in ThyPRO QoL. Our data confirm current recommendations on initiation of LT4 substitution and suggest that this should not be withheld in elderly with TSH concentration above 8-10 mU/l.

[Subclinical hypothyroidism - laboratory finding or disease?]. / Latente Hypothyreose - Laborkonstellation oder Krankheit?

Subclinical hypothyroidism first of all is a laboratory finding, defined by elevated TSH and normal peripheral thyroxine concentrations. The first steps are to verify the condition and to clarify whether the patient has underlying thyroid disease or other comorbidities. Results of recent studies on subclinical hypothyroidism are reassuring. No consistent association has been demonstrated between mildly elevated TSH levels (5-10 mIU / l) and cardiovascular events, mortality, fracture risk or cognitive impairment. In contrast TSH levels between 5-10 mIU / l may even confer lower mortality in the elderly and may hence be protective. These data strongly suggest that the long-time controversy on definition of normal upper TSH levels should take a more conservative turn. Thus, diagnosis of subclinical hypothyroidism should be handled cautiously. Individualized treatment decision is recommended if TSH levels are only mildly elevated and less than 8-10 mIU / l. In case of autoimmune thyroiditis or previous thyroid therapy (surgery, radioiodine treatment) the risk of progression to overt hypothyroidism has to be considered and there is no doubt that the latter should be avoided.

A Novel Adenoviral Hybrid-vector System Carrying a Plasmid Replicon for Safe and Efficient Cell and Gene Therapeutic Applications.

In dividing cells, the two aims a gene therapeutic approach should accomplish are efficient nuclear delivery and retention of therapeutic DNA. For stable transgene expression, therapeutic DNA can either be maintained by somatic integration or episomal persistence of which the latter approach would diminish the risk of insertional mutagenesis. As most monosystems fail to fulfill both tasks with equal efficiency, hybrid-vector systems represent promising alternatives. Our hybrid-vector system synergizes high-capacity adenoviral vectors (HCAdV) for efficient delivery and the scaffold/matrix attachment region (S/MAR)-based pEPito plasmid replicon for episomal persistence. After proving that this plasmid replicon can be excised from adenovirus in vitro, colony forming assays were performed. We found an increased number of colonies of up to sevenfold in cells that received the functional plasmid replicon proving that the hybrid-vector system is functional. Transgene expression could be maintained for 6 weeks and the extrachromosomal plasmid replicon was rescued. To show efficacy in vivo, the adenoviral hybrid-vector system was injected into C57Bl/6 mice. We found that the plasmid replicon can be released from adenoviral DNA in murine liver resulting in long-term transgene expression. In conclusion, we demonstrate the efficacy of our novel HCAdV-pEPito hybrid-vector system in vitro and in vivo.Molecular Therapy-Nucleic Acids (2013) 2, e83; doi:10.1038/mtna.2013.11; published online 2 April 2013.

Development of adenovirus hybrid vectors for Sleeping Beauty transposition in large mammals.

The Sleeping Beauty (SB) transposase system for somatic integration offers great potential for in vivo gene therapeutic applications and genome engineering. Until recently, however, efficacy of SB transposase as a gene transfer vector especially in large animals was lacking. Herein, we report about the newest viral vector development for delivery of the SB transposase system into large mammals. Over the past decade various hyperactive versions of SB transposase and advanced adenovirus vectors enabling efficient and safe delivery of transgenes in vivo were developed. Already several years ago it was demonstrated that adenovirus vectors can be used for delivery of the SB transposase system into murine liver. Our newest study showed for the first time that a hyperactive transposase system delivered by high-capacity adenoviral vectors can result in somatic integration of exogenous DNA in canine liver, facilitating stabilized transgene expression and phenotypic correction for up to three years in a canine model of human disease. In this review we discuss safety issues and further improvements of this adenovirus based hybrid vector system for somatic integration. In the future this approach paves new paths towards the possible cure of human genetic diseases and novel strategies for in vivo genome engineering in large mammals.