Cell Therapy for Type 1 Diabetes

Acknowledgements The work described in this review was supported by a grant from the MRC. K.R.M. is supported by a fellowship from the Scottish Translational Medicines and Therapeutics Initiative through the Wellcome Trust.Peer reviewedPublisher PD

Lin28A induces energetic switching to glycolytic metabolism in human embryonic kidney cells

Background: Loss of a cell’s capacity to generate sufficient energy for cellular functions is a key hallmark of the ageing process and ultimately leads to a variety of important age-related pathologies such as cancer, Parkinson’s disease and atherosclerosis. Regenerative medicine has sought to reverse these pathologies by reprogramming somatic cells to a more juvenile energetic state using a variety of stem cell factors. One of these factors, Lin28, is considered a candidate for modification in the reprogramming of cellular energetics to ameliorate the ageing process while retaining cell phenotype. Results: Over-expression of Lin28A resulted in key changes to cellular metabolism not observed in wild-type controls. Extracellular pH flux analysis indicated that Lin28A over expression significantly increased the rate of glycolysis, whilst high resolution oxygen respirometry demonstrated a reduced oxygen consumption. Western blot and real-time PCR analysis identified Hexokinase II as one of the key modulators of glycolysis in these cells which was further confirmed by increased glucose transport. A metabolic switching effect was further emphasised by Western blot analysis where the oxygen consuming mitochondrial complex IV was significantly reduced after Lin28A over expression. Conclusions: Results from this study confirm that Lin28A expression promotes metabolic switching to a phenotype that relies predominantly on glycolysis as an energy source, while compromising oxidative phosphorylation. Mechanisms to augment regulated Lin28A in age related pathologies that are characterised by mitochondria dysfunction or in differentiated and aged post-mitotic cells is the future goal of this work

Transport strategy in Scotland since devolution

This article critically reviews how the Scottish Executive's approach to transport has developed since devolution. Although there is much to commend, a number of concerns can be identified, including the possibility that a number of strategic infrastructure schemes appear to have been approved on political rather than on technical grounds. It is difficult to know whether the current set of transport infrastructure investment plans represents good value for public money

Anhedonia and deficits in positive emotional experience in individuals with genetic liability for schizophrenia

There is growing evidence that anhedonia--the extent to which an individual reports pleasure or interest in social and physical stimuli--is important to the pathophysiology of schizophrenia. At the same time, some research has suggested that there are different facets of pleasure and positive affect (PA), such as liking vs. wanting (Berridge & Robinson, 1998). Previous research has not directly examined the relationship between anhedonia symptoms and measures of positive affect in relation to genetic liability to schizophrenia. This research examined people with schizophrenia and schizoaffective disorder, their first-degree relatives, and nonpsychiatric controls to assess emotion traits as potential phenotypes for anhedonia in genetic liability for schizophrenia. Multiple methods and measures were used to assess anhedonia and affective traits. There was a general lack of association between interview anhedonia and many facets of PA, coupled with a lack of group differences across PA variables. However, there was general evidence of association of self-reported anhedonia (in both probands and relatives) with many PA variables, suggesting the presence of confounding methodological variance. Significant group differences on a novel behavioral measure of effort for reward were detected. Last, results suggested that ambivalence, long considered relevant to psychosis, is more associated with affect than with liability to schizophrenia

The temporary anatomical structures prominent in the first trimester may be fulfilling exchange functions assigned to the placenta in the second and third trimester

The extra-embryonic coelom (EEC) and secondary yolk sac are prominent structures in the gestational sac during the first trimester of human pregnancy, at a time before the definitive placental circulation becomes established. We propose that the EEC and yolk sac play a critical role in the nutrition of early pregnancy, fulfilling exchange functions which are assumed by the placenta at a later stage

Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy.

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects.FundingGalderma International S.A.S., Paris, France

Young and Older Adults Differ in Integration of Sensory Cues for Vertical Perception.

Introduction: The subjective visual vertical (SVV) measures the perception of a person's spatial orientation relative to gravity. Weighted central integration of vestibular, visual, and proprioceptive inputs is essential for SVV perception. Without any visual references and minimal proprioceptive contribution, the static SVV reflects balance of the otolith organs. Normal aging is associated with bilateral and progressive decline in otolith organ function, but age-dependent effects on SVV are inconclusive. Studies on sensory reweighting for visual vertical and multisensory integration strategies reveal age-dependent differences, but most studies have included elderly participants in comparison to younger adults. The aim of this study was to compare young adults with older adults, an age group younger than the elderly. Methods: Thirty-three young and 28 older adults (50-65 years old) adjusted a tilted line accurately to their perceived vertical. The rod's final position from true vertical was recorded as tilt error in degrees. For otolithic balance, visual vertical was recorded in the dark without any visual references. The rod and frame task (RFT) with tilted disorienting visual frames was used for creating visuovestibular conflict. We adopted Nyborg's analysis method to derive the rod and frame effect (RFE) and trial-to-trial variability measures. Rod alignment times were also analyzed. Results: There was no age difference in signed tilts of SVV without visual reference. There was an age effect on RFE and on overall trial-to-trial variability of rod tilt, with older adults displaying larger frame effects and greater variability in rod tilts. Alignment times were longer in the tilted-frame conditions for both groups and in the older adults compared to their younger counterparts. The association between tilt accuracy and tilt precision was significant for older adults only during visuovestibular conflict, revealing an increase in RFE with an increase in tilt variability. Correlation of σSVV, which represents vestibular input precision, with RFE yielded exactly the same contribution of σSVV to the variance in RFE for both age groups. Conclusions: Older adults have balanced otolithic input in an upright position. Increased reliance on visual cues may begin at ages younger than what is considered elderly. Increased alignment times for older adults may create a broader time window for integration of relevant and irrelevant sensory information, thus enhancing their multisensory integration. In parallel with the elderly, older adults may differ from young adults in their integration of sensory cues for visual vertical perception

Role of the aryl hydrocarbon receptor in Sugen 5416-induced experimental pulmonary hypertension

Rationale: Rats dosed with the vascular endothelial growth factor (VEGF) inhibitor Sugen 5416 (Su), placed in hypoxia then restored to normoxia has become a widely used model of pulmonary arterial hypertension (PAH). The mechanism by which Su exaccerbates pulmonary hypertension is, however, unclear. Objectives: We investigated Su-activation of the aryl hydrocarbon receptor (AhR) in patient human pulmonary arterial smooth muscle cells (hPASMCs) and patient blood outgrowth endothelial cells (BOECs). We also examined the effect of AhR on aromatase and estrogen levels in the lung. Methods, Measurements and Main Results: Protein and mRNA analysis demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191 as was AhR nuclear translocator (ARNT [HIF-1β]) which is shared by HIF-1α and AhR. Su reduced HIF1α expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular endothelial cells (hPMECs) and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs do not proliferate to Su. However when grown in hypoxia (1%) Su induced hPASMC proliferation. Conclusion: In combination with hypoxia, Su is proliferative in patient hPASMCs and patient BOECs and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT and aromatase. Inhibition of the AhR receptor may be a novel approach to the treatment of pulmonary hypertension

Influence of 2-methoxyestradiol and sex on hypoxia-induced pulmonary hypertension and hypoxia-inducible factor‐1‐α

Background: Women are at greater risk of developing pulmonary arterial hypertension, with estrogen and its downstream metabolites playing a potential role in the pathogenesis of the disease. Hypoxia‐inducible factor‐1‐α (HIF1α) is a pro‐proliferative mediator and may be involved in the development of human pulmonary arterial hypertension. The estrogen metabolite 2‐methoxyestradiol (2ME2) has antiproliferative properties and is also an inhibitor of HIF1α. Here, we examine sex differences in HIF1α signaling in the rat and human pulmonary circulation and determine if 2ME2 can inhibit HIF1α in vivo and in vitro. Methods and Results: HIF1α signaling was assessed in male and female distal human pulmonary artery smooth muscle cells (hPASMCs), and the effects of 2ME2 were also studied in female hPASMCs. The in vivo effects of 2ME2 in the chronic hypoxic rat (male and female) model of pulmonary hypertension were also determined. Basal HIF1α protein expression was higher in female hPASMCs compared with male. Both factor‐inhibiting HIF and prolyl hydroxylase‐2 (hydroxylates HIF leading to proteosomal degradation) protein levels were significantly lower in female hPASMCs when compared with males. In vivo, 2ME2 ablated hypoxia‐induced pulmonary hypertension in male and female rats while decreasing protein expression of HIF1α. 2ME2 reduced proliferation in hPASMCs and reduced basal protein expression of HIF1α. Furthermore, 2ME2 caused apoptosis and significant disruption to the microtubule network. Conclusions: Higher basal HIF1α in female hPASMCs may increase susceptibility to developing pulmonary arterial hypertension. These data also demonstrate that the antiproliferative and therapeutic effects of 2ME2 in pulmonary hypertension may involve inhibition of HIF1α and/or microtubular disruption in PASMCs