Effects of Probiotics on Inflammatory Responses in Neuronal Tissue

Alzheimer’s disease (AD) is a neurodegenerative disease that affects more than 40 million people. While the pathophysiology has yet to be fully elucidated, some studies suggest AD associated chronic inflammation is caused by hyperactive microglia that produce pro-inflammatory factors. Probiotics have been shown to have anti-inflammatory properties and may influence neurochemistry via the gut-brain-axis, which controls communication between the intestines and brain, crossing over the blood brain barrier (BBB). A model of the BBB was constructed with a double transwell system to clarify the effects of probiotics on cerebral inflammation. Microglia cells grown in the basolateral chamber were co-cultured with endothelial cells in the upper compartment while an astrocyte monolayer separated the two compartments. Once the system was exposed to human peripheral blood T-cells and combined with histamine (probiotic anti-inflammatory product), formic acid (probiotic inflammatory product), both, or neither, the microglial medium was collected and analyzed for tumor necrosis factor α (TNFα) and interleukin-10 using ELISA. ANOVA and T-Tests were run and showed no significant results, except for the histamine and formic acid combination. In the combination treatment, levels of TNFα were slightly different than the control (p = 0.00006), contrary to what was expected. Under these conditions, probiotics do not reduce inflammation in the brain and thus cannot effectively treat AD patients. However, in the future, more experiments should be conducted with multiple inflammatory and anti-inflammatory molecules as there could be overlapping interactions between several probiotic products that produce advantageous metabolic effects and mitigate elevations in inflammatory responses

Infrared Emission from the Nearby Cool Core Cluster Abell 2597

We observed the brightest central galaxy (BCG) in the nearby (z=0.0821) cool core galaxy cluster Abell 2597 with the IRAC and MIPS instruments on board the Spitzer Space Telescope. The BCG was clearly detected in all Spitzer bandpasses, including the 70 and 160 micron wavebands. We report aperture photometry of the BCG. The spectral energy distribution exhibits a clear excess in the FIR over a Rayleigh-Jeans stellar tail, indicating a star formation rate of ~4-5 solar masses per year, consistent with the estimates from the UV and its H-alpha luminosity. This large FIR luminosity is consistent with that of a starburst or a Luminous Infrared Galaxy (LIRG), but together with a very massive and old population of stars that dominate the energy output of the galaxy. If the dust is at one temperature, the ratio of 70 to 160 micron fluxes indicate that the dust emitting mid-IR in this source is somewhat hotter than the dust emitting mid-IR in two BCGs at higher-redshift (z~0.2-0.3) and higher FIR luminosities observed earlier by Spitzer, in clusters Abell 1835 and Zwicky 3146.Comment: Accepted at Ap

Hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival

Chronic myeloid leukemia (CML) stem/progenitor cells (SPC) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPC maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase dependent pathway mediated by the up-regulation of hsa-mir183, the down-regulation of its direct target EGR1 and, as a consequence, up-regulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPC. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPC, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Introduction: AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients. Methods/design: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire. Conclusion: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN

Roles and experiences of informal caregivers of older adults in community and healthcare system navigation: a scoping review

Objective Informal caregivers are playing a vital role in improving the degree to which older adults access community and healthcare systems in a more seamless and timely manner, thereby fulfilling their complex needs. It is critical to understand their experiences and perspectives while navigating these systems. This review aimed to identify and organise the research findings on the roles and experiences of informal caregivers of older adults while navigating community and healthcare systems.Design This scoping review was undertaken according to the Joanna Briggs Institute’s Reviewer manual. Four databases were used: AgeLine, PsycINFO, CINAHL and Medline to capture literature with a focus on informal caregivers whose care recipients are aged 55 years or older. Articles were included if they focused on examining the experience, perspective and/or role of informal caregivers in providing care for their older care recipients, while articles were excluded if they only focused on healthcare professionals or older adults.Results A total of 24 studies were identified that met the study inclusion criteria. This review elucidated the roles of caregivers as a primary system navigator and as an advocate for older adults. Numerous challenges/barriers in system navigation were uncovered, such as lack of consistency in fragmented systems, as well as facilitators, including interface/coordination roles. Finally, recommendations for better system navigation such as caregiver engagement and integration of continuity of care services were identified.Conclusion The need to raise the visibility of the roles and experiences of informal caregivers in system navigation was highlighted. Further research needs to focus on implementing interventions for informal caregivers incorporating a care coordinator to fill the care gap within community and healthcare systems. This review has the potential to foster greater integration of community and healthcare systems

The response of the innate immune and cardiovascular systems to LPS in pregnant and nonpregnant mice

Sepsis is the leading cause of direct maternal mortality, but there are no data directly comparing the response to sepsis in pregnant and nonpregnant (NP) individuals. This study uses a mouse model of sepsis to test the hypothesis that the cardiovascular response to sepsis is more marked during pregnancy. Female CD1 mice had radiotelemetry probes implanted and were time mated. NP and day 16 pregnant CD-1 mice received intraperitoneal lipopolysaccharide (LPS; 10 μg, serotype 0111: B4). In a separate study, tissue and serum (for RNA, protein and flow cytometry studies), aorta and uterine vessels (for wire myography) were collected after LPS or vehicle control administration. Administration of LPS resulted in a greater fall in blood pressure in pregnant mice compared to NP mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors, and circulating leukocytes, but with a greater monocyte and lesser neutrophil margination in the lungs of pregnant mice. Baseline markers of cardiac dysfunction and apoptosis as well as cytokine expression were higher in pregnant mice, but the response to LPS was similar in both groups as was the ex vivo assessment of vascular function. In pregnant mice, nonfatal sepsis is associated with a more marked hypotensive response but not a greater immune response. We conclude that endotoxemia induces a more marked hypotensive response in pregnant compared to NP mice. These changes were not associated with a more marked systemic inflammatory response in pregnant mice, although monocyte lung margination was greater. The more marked hypotensive response to LPS may explain the greater vulnerability to some infections exhibited by pregnant women

Self-esteem mediates the relationship between connectedness to nature and body appreciation in women, but not men

Connectedness to nature (i.e., an affective and experiential connection to nature) is known to have a positive effect on psychological well-being, but its specific associations with body image have not been fully examined. To attend to this oversight, we conducted a preliminary investigation of associations between connectedness to nature and body appreciation. A total of 380 British adults completed measures of connectedness to nature, body appreciation, and self-esteem. Bivariate correlations revealed significant positive associations between all variables in women. In men, body appreciation was significantly correlated with self-esteem, but not connectedness to nature. Mediation analysis showed that, in women, self-esteem fully mediated the relationship between connectedness to nature and body appreciation. In men, body appreciation was significantly associated with self-esteem, but not connectedness to nature. These results point to a potential route for improving body image among women through connectedness to nature and self-esteem, but further research is necessary