Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging

BACKGROUND: Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARgamma) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer\u27s disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Abeta accumulation. While TZD\u27s actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions. METHODS AND FINDINGS: We used the F344 rat model of aging, and monitored behavioral, electrophysiological, and molecular variables to assess the effects of pioglitazone (PIO-Actos® a TZD) on several peripheral (blood and liver) and central (hippocampal) biomarkers of aging. Starting at 3 months or 17 months of age, male rats were treated for 4-5 months with either a control or a PIO-containing diet (final dose approximately 2.3 mg/kg body weight/day). A significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals, with no significant change in long-term potentiation maintenance or learning and memory performance. Blood insulin levels were unchanged with age, but significantly reduced by PIO. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory increases were not reversed by PIO. CONCLUSIONS: While current research efforts continue to identify the underlying processes responsible for the progressive decline in cognitive function seen during normal aging, available medical treatments are still very limited. Because TZDs have been shown to have benefits in age-related conditions such as T2DM and AD, our study was aimed at elucidating PIO\u27s potentially beneficial actions in normal aging. Using a clinically-relevant dose and delivery method, long-term PIO treatment was able to blunt several indices of aging but apparently affected neither age-related cognitive decline nor peripheral/central age-related increases in inflammatory signaling

Mental Health of Parents and Life Satisfaction of Children: A Within-Family Analysis of Intergenerational Transmission of Well-Being

This paper addresses the extent to which there is an intergenerational transmission of mental health and subjective well-being within families. Specifically it asks whether parents’ own mental distress influences their child’s life satisfaction, and vice versa. Whilst the evidence on daily contagion of stress and strain between members of the same family is substantial, the evidence on the transmission between parental distress and children’s well-being over a longer period of time is sparse. We tested this idea by examining the within-family transmission of mental distress from parent to child’s life satisfaction, and vice versa, using rich longitudinal data on 1,175 British youths. Results show that parental distress at year t-1 is an important determinant of child’s life satisfaction in the current year. This is true for boys and girls, although boys do not appear to be affected by maternal distress levels. The results also indicated that the child’s own life satisfaction is related with their father’s distress levels in the following year, regardless of the gender of the child. Finally, we examined whether the underlying transmission correlation is due to shared social environment, empathic reactions, or transmission via parent-child interaction

A mediation approach to understanding socio-economic inequalities in maternal health-seeking behaviours in Egypt.

BACKGROUND: The levels and origins of socio-economic inequalities in health-seeking behaviours in Egypt are poorly understood. This paper assesses the levels of health-seeking behaviours related to maternal care (antenatal care [ANC] and facility delivery) and their accumulation during pregnancy and childbirth. Secondly, it explores the mechanisms underlying the association between socio-economic position (SEP) and maternal health-seeking behaviours. Thirdly, it examines the effectiveness of targeting of free public ANC and delivery care. METHODS: Data from the 2008 Demographic and Health Survey were used to capture two latent constructs of SEP: individual socio-cultural capital and household-level economic capital. These variables were entered into an adjusted mediation model, predicting twelve dimensions of maternal health-seeking; including any ANC, private ANC, first ANC visit in first trimester, regular ANC (four or more visits during pregnancy), facility delivery, and private delivery. ANC and delivery care costs were examined separately by provider type (public or private). RESULTS: While 74.2% of women with a birth in the 5-year recall period obtained any ANC and 72.4% delivered in a facility, only 48.8% obtained the complete maternal care package (timely and regular facility-based ANC as well as facility delivery) for their most recent live birth. Both socio-cultural capital and economic capital were independently positively associated with receiving any ANC and delivering in a facility. The strongest direct effect of socio-cultural capital was seen in models predicting private provider use of both ANC and delivery. Despite substantial proportions of women using public providers reporting receipt of free care (ANC: 38%, delivery: 24%), this free-of-charge public care was not effectively targeted to women with lowest economic resources. CONCLUSIONS: Socio-cultural capital is the primary mechanism leading to inequalities in maternal health-seeking in Egypt. Future studies should therefore examine the objective and perceived quality of care from different types of providers. Improvements in the targeting of free public care could help reduce the existing SEP-based inequalities in maternal care coverage in the short term

Update on a pilot study: Flumeltbi peripheral blood HLAhaploidentical stem cell transplantation with post-transplant cyclophosphamide and bortezomib (Cy2Bor3)

Background: Bortezomib (Bor) can inhibit the proliferation of dendritic cells (DCs) and block the expression of co-receptors CD80, CD86 and secretion of cytokines IL-12 and TNF-α and hence the ability of DCs to activate T cells. We started a pilot study incorporating the addition of bortezomib to post-transplant cyclophosphamide (PTCY) in the setting of peripheral blood (PB) HLA-haploidentical stem cell transplantation (Haplo-SCT). Methods: This is a single center open label pilot study. Eligible patients received Fludarabine Melphalan TBI 200 cGy as conditioning followed by haplo-SCT and PTCY. Bor was administered at 1.3mg/m2 on day+1, 4 and 7. Tacrolimus and MMF were started at day+5. Results: Seven patients were enrolled so far, five males and 2 females. Median age was 58 years (26-60). Donors were 3 brothers, 3 sons and 1 mother. Disease risk index was high in 3, intermediate in 3 and low in 1. Three patients had AML, two had ALL and MM, one had ALL and one had CML. CMV recipient status was negative in one and positive in 6. Median HCT-CI was 3(1-4). Median CD34 and CD3 infused were 4.13 x10-6 and 1.7x10-8/ kg recipient respectively, all were cryopreserved except 2. Four patients had CRS before Cy infusion with ASTCT grade of 1. Six patients had grade 3 hypokalemia around day+ 4-5. Five patients had grade 3 mucositis and 2 had grade 1. Four patients had neutropenic fever and one patient had engraftment fever. Median neutrophils and platelets engraftment were 16 and 26 days respectively. Chimerism post SCT was \u3e =99% donor at day 30 for all patients. Six patients are off tacrolimus with median time to be off it was 187.5 days. Five pts had aGVHD with maximum grade of I in 3 patients, II in one patient and III in one patient at a median 50days post SCT. None developed early hematuria, four had late hematuria with highest grade of 4. Two patients were positive for BK virus. One patient had reactivation of CMV, 2 had EBV and one had adenovirus, all resolved. Three pts had HHV6 that resolved. Of the 5 patients who were evaluable, one developed moderate chronic GVHD. So far the median time to follow up is 455 days (70-1239) with relapse and subsequently death in one patient who had high risk AML with 3 different inductions prior to SCT. . At 1 year for 4 evaluable patients IgG were \u3e400 mg/dl and CD4 \u3e 350 cells/ul. Conclusions: Cy2Bor3 post PB Haplo-SCT was well tolerated. Although small number of patients and limited but encouraging results so far. The trial is ongoing

Making Room for Zoom in Focus Group Methods: Opportunities and Challenges for Novice Researchers (During and Beyond COVID-19)

Als die COVID-19-Pandemie über die Welt hereinbrach, waren viele Menschen gezwungen, sich auf online-basierte Routinen einzustellen, darunter auch qualitative Forscher*innen, die nach alternativen Möglichkeiten zur Erhebung aussagekräftiger Daten suchten. Während Fokusgruppen traditionell Face to Face durchgeführt werden, bieten Fortschritte bei Online-Videokonferenzanwendungen neue Methoden zur Datenerhebung, die jedoch bisher nur selten untersucht wurden. In diesem Artikel berichten wir über die Erfahrungen von 12 Doktorand*innen mit der Durchführung von Fokusgruppen unter Verwendung von Zoom im Rahmen eines Kurses zu qualitativen Interviewmethoden. Wir reflektieren Chancen und Herausforderungen, die wir als Moderator*innen und Teilnehmer*innen bei der Nutzung von Zoom erlebten z.B. bei der Vorbereitung oder in Bezug auf Rapport, die Einbindung anderer digitaler Tools und von Internetverbindungen. Zusammenfassend lässt sich sagen, dass die Durchführung von Online-Fokusgruppen unter Verwendung von Zoom insgesamt eine positive Erfahrung war und mit Face-to-Face-Fokusgruppen vergleichbar ist. Möglichkeiten der Teilnehmer*innenrekrutierung, die Sicherheitsmerkmale von Zoom und die Nutzung von Zoom und allgemeiner neuen Technologien sollten auch jenseits der Pandemie weiter erforscht werden.As the COVID-19 pandemic swept through the world, it forced many people to adapt to an online-based routine, including qualitative researchers looking for alternative ways to collect meaningful data. While focus groups are traditionally conducted in-person, advances with online videoconferencing applications present a new method to collect data, however, few studies have explored this. In this article we present 12 doctoral students' experiences with conducting focus groups using the videoconferencing application Zoom during a qualitative methods course on interviewing methods. Through this self-study qualitative analysis, participants reflected on the opportunities and challenges experienced as both moderators and participants using Zoom including: preparation, rapport, incorporating other digital tools, and internet connectivity. In conclusion, doing focus groups online using Zoom was a positive experience overall and comparable to in-person focus groups for collecting qualitative data, despite the introduction of technology. More research on participant recruitment, new technology, Zoom's security features, and Zoom's use outside of a pandemic should be further explored

Preclinical evaluation of EpCAM-binding designed ankyrin repeat proteins (DARPins) as targeting moieties for bimodal near-infrared fluorescence and photoacoustic imaging of cancer

PURPOSE Fluorescence-guided surgery (FGS) can play a key role in improving radical resection rates by assisting surgeons to gain adequate visualization of malignant tissue intraoperatively. Designed ankyrin repeat proteins (DARPins) possess optimal pharmacokinetic and other properties for in vivo imaging. This study aims to evaluate the preclinical potential of epithelial cell adhesion molecule (EpCAM)-binding DARPins as targeting moieties for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of cancer. METHODS EpCAM-binding DARPins Ac2, Ec4.1, and non-binding control DARPin Off7 were conjugated to IRDye 800CW and their binding efficacy was evaluated on EpCAM-positive HT-29 and EpCAM-negative COLO-320 human colon cancer cell lines. Thereafter, NIRF and PA imaging of all three conjugates were performed in HT-29_luc2 tumor-bearing mice. At 24 h post-injection, tumors and organs were resected and tracer biodistributions were analyzed. RESULTS Ac2-800CW and Ec4.1-800CW specifically bound to HT-29 cells, but not to COLO-320 cells. Next, 6 nmol and 24 h were established as the optimal in vivo dose and imaging time point for both DARPin tracers. At 24 h post-injection, mean tumor-to-background ratios of 2.60 ± 0.3 and 3.1 ± 0.3 were observed for Ac2-800CW and Ec4.1-800CW, respectively, allowing clear tumor delineation using the clinical Artemis NIRF imager. Biodistribution analyses in non-neoplastic tissue solely showed high fluorescence signal in the liver and kidney, which reflects the clearance of the DARPin tracers. CONCLUSION Our encouraging results show that EpCAM-binding DARPins are a promising class of targeting moieties for pan-carcinoma targeting, providing clear tumor delineation at 24 h post-injection. The work described provides the preclinical foundation for DARPin-based bimodal NIRF/PA imaging of cancer

Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation

Alternative (M2) macrophage activation driven through interleukin 4 receptor α (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of fatty acids to support this metabolic program has not been clear. We show that the uptake of triacylglycerol substrates via CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation (OXPHOS), enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth, and blocked protective responses against this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation

Detection of solar-like oscillations from Kepler photometry of the open cluster NGC 6819

Asteroseismology of stars in clusters has been a long-sought goal because the assumption of a common age, distance and initial chemical composition allows strong tests of the theory of stellar evolution. We report results from the first 34 days of science data from the Kepler Mission for the open cluster NGC 6819 -- one of four clusters in the field of view. We obtain the first clear detections of solar-like oscillations in the cluster red giants and are able to measure the large frequency separation and the frequency of maximum oscillation power. We find that the asteroseismic parameters allow us to test cluster-membership of the stars, and even with the limited seismic data in hand, we can already identify four possible non-members despite their having a better than 80% membership probability from radial velocity measurements. We are also able to determine the oscillation amplitudes for stars that span about two orders of magnitude in luminosity and find good agreement with the prediction that oscillation amplitudes scale as the luminosity to the power of 0.7. These early results demonstrate the unique potential of asteroseismology of the stellar clusters observed by Kepler.Comment: 5 pages, 4 figures, accepted by ApJ (Lett.

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials