Corticosterone alters materno-fetal glucose partitioning and insulin signalling in pregnant mice.

Glucocorticoids affect glucose metabolism in adults and fetuses, although their effects on materno-fetal glucose partitioning remain unknown. The present study measured maternal hepatic glucose handling and placental glucose transport together with insulin signalling in these tissues in mice drinking corticosterone either from day (D) 11 to D16 or D14 to D19 of pregnancy (term = D21). On the final day of administration, corticosterone-treated mice were hyperinsulinaemic (P 0.05). Insulin receptor and insulin-like growth factor type I receptor abundance did not differ with treatment in either tissue. Corticosterone upregulated the stress-inducible mechanistic target of rapamycin (mTOR) suppressor, Redd1, in liver (D16 and D19) and placenta (D19), in ad libitum fed animals (P < 0.05). Concomitantly, hepatic protein content and placental weight were reduced on D19 (P < 0.05), in association with altered abundance and/or phosphorylation of signalling proteins downstream of mTOR. Taken together, the data indicate that maternal glucocorticoid excess reduces fetal growth partially by altering placental glucose transport and mTOR signalling.The studies described in this manuscript were supported by a graduate studentship to ORV from the Centre for Trophoblast Research in Cambridge.This is the accepted manuscript of a paper published in The Journal of Physiology Volume 593, Issue 5, pages 1307–1321, 1 March 2015, DOI: 10.1113/jphysiol.2014.28717

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r.Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping

Neighbourhood environments and cognitive health in the longitudinal Personality and Total Health (PATH) through life study: A 12-year follow-up of older Australians

Background: Urban neighbourhood environments may impact older adults’ cognitive health. However, longitudinal studies examining key environmental correlates of cognitive health are lacking. We estimated cross-sectional and longitudinal associations of neighbourhood built and natural environments and ambient air pollution with multiple cognitive health outcomes in Australian urban dwellers aged 60+ years. Methods: The study included 1160 participants of the PATH Through Life study (60+ cohort) who were followed up for 12 years (four assessments; 2001/02 to 2013/15) and with data on socio-demographics, health, cognitive functions and diagnoses, and full residential address. Neighbourhood environmental features encompassed population and street-intersection densities, non-commercial land use mix, transit points, presence of blue space, percentages of commercial land, parkland and tree cover, and annual average PM2.5 and NO2 concentrations. All exposures except for tree cover were assessed at two time points. Generalised additive mixed models estimated associations of person-level average, and within-person changes in, exposures with cognitive functions. Multi-state hidden Markov models estimated the associations of neighbourhood attributes with transitions to/from mild cognitive impairment (MCI). Results: Dense, destination-rich neighbourhoods were associated with a lower likelihood of transition to MCI and reversal to no MCI. Positive cross-sectional and longitudinal associations of non-commercial land use mix, street intersection density and percentage of commercial land were observed especially with global cognition and processing speed. While access to parkland and blue spaces were associated with a lower risk of transition to MCI, the findings related to cognitive functions were mixed and supportive of an effect of parkland on verbal memory only. Higher levels of PM2.5 and NO2 were consistently associated with steeper declines and/or decreases in cognitive functions and worse cognitive states across time. Conclusion: To support cognitive health in ageing populations, neighbourhoods need to provide an optimal mix of environmental complexity, destinations and access to the natural environment and, at the same time, minimise ambient air pollution

Activation of Type 1 Cannabinoid Receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures

The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor (CB1R) activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ) stem/progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells (Nestin-positive), neurons and astrocytes. Stimulation of the CB1R by (R)-(+)-Methanandamide (R-m-AEA) increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+/+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation (without affecting glial differentiation), at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations ([Ca2+](i)) in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.Fundacao para a Ciencia e a Tecnologia - Portugal [POCTI/SAU-NEU/68465/2006, PTDC/SAU-NEU/104415/2008, PTDC/SAU-NEU/101783/2008, POCTI/SAU-NEU/110838/2009]; Fundacao Calouste Gulbenkian [96542]; Fundacao para a Ciencia e Tecnologiainfo:eu-repo/semantics/publishedVersio

Association between Use of HMG CoA Reductase Inhibitors and Mortality in HIV-Infected Patients

HIV infection is a disease associated with chronic inflammation and immune activation. Antiretroviral therapy reduces inflammation, but not to levels in comparable HIV-negative individuals. The HMG-coenzyme A reductase inhibitors (statins) inhibit several pro-inflammatory processes and suppress immune activation, and are a logical therapy to assess for a possible salutary effect on HIV disease progression and outcomes.Eligible patients were patients enrolled in the Johns Hopkins HIV Clinical Cohort who achieved virologic suppression within 180 days of starting a new highly active antiretroviral therapy (HAART) regimen after January 1, 1998. Assessment was continued until death in patients who maintained a virologic suppression, with right-censoring of their follow-up time if they had an HIV RNA > 500 copies/ml. Cox proportional hazards regression was used to assess statin use as a time-varying covariate, as well as other demographic and clinical factors.A total of 1538 HIV-infected patients fulfilled eligibility criteria, of whom 238 (15.5%) received a statin while taking HAART. There were 85 deaths (7 in statin users, 78 in non-users). By multivariate Cox regression, statin use was associated with a relative hazard of 0.33 (95% CI: 0.14, 0.76; P =  0.009) after adjusting for CD4, HIV-1 RNA, hemoglobin and cholesterol levels at the start of HAART, age, race, HIV risk group, prior use of ART, year of HAART start, NNRTI vs. PI-based ART, prior AIDS-defining illness, and viral hepatitis coinfection. Malignancy, non-AIDS-defining infection and liver failure were particularly prominent causes of death.Statin use was associated with significantly lower hazard of dying in these HIV-infected patients who were being effectively treated with HAART as determined by virologic suppression. Our results suggest the need for confirmation in other observational cohorts, and if confirmed, the need for a clinical trial of statin use in HIV infection

A modified Trastuzumab antibody for the immunohistochemical detection of HER-2 overexpression in breast cancer

The immunohistochemical determination of HER-2 to identify patients with advanced breast cancer candidates for Trastuzumab treatment proved neither accurate nor fully reliable, possibly because none of the current reagents detects the specific antigenic site target of Trastuzumab. To circumvent this problem, we conjugated the NH2 groups of Trastuzumab with biotin, and the compound obtained, designated BiotHER, was added directly to tissue sections. Biotin-labelling was revealed with horseradish peroxidase-conjugated streptavidin. Specificity and sensitivity of BiotHER immunostaining with respect to HER-2 amplification were tested on 164 breast carcinoma samples. BiotHER staining was detected on the tumour cell membrane of 12% of all specimens and in 49% specimens with gene amplification, while absent in nonamplified tumours. Predictivity of BiotHER status with respect to the clinical outcome was analysed in 54 patients with HER-2 amplified advanced breast cancer treated with Trastuzumab plus chemotherapy. BiotHER staining, detected in 50% of tumours with HER-2 amplification, was an independent predictor of clinical outcome. In fact, BiotHER positivity was independently associated with increased likelihood of tumour response and reduced risk of tumour progression and death. Biotinylated Trastuzumab can thus be used for immunohistochemical detection of HER-2 overexpression in breast cancer, and has the potential to identify patients likely to benefit from Trastuzumab treatment

Failure of dual radius hydroxyapatite-coated acetabular cups

<p>Abstract</p> <p>Introduction</p> <p>Many kind of hydroxyapatite-coated cups were used, with favorable results in short term studies; it was supposed that its use could improve osteointegration of the cup, enhancing thus stability and survivorship. The purpose of this study is to analyze the long term behavior of the hemispheric HA coated, Dual Radius Osteonics cup and to discuss the way of failure through the exam of the revised components and of both periacetabular and osteolysis tissue.</p> <p>Materials and Methods</p> <p>Between 1994 and 1997, at the Department of Orthopedic Sciences of the Insubria University, using the posterolateral approach, were implanted 276 Dual Radius Osteonics^®in 256 patients, with mean age of 63 years.</p> <p>Results</p> <p>At a mean follow-up of 10 years (range 8–12 years), 183 cups in 165 patients, were available for clinical and radiographical evaluation. 22 Cups among the 183 were revised (11%). The cause of revision was aseptic loosening in 17 cases, septic loosening in one case, periprosthetic fracture in another case, osteolysis and polyethylene wear in two cases and, finally, recurrent dislocations in the last one. In the remaining patients, mean HHS increased from a preoperative value of 50,15 to a postoperative value of 92,69. The mean polyethylene wear was 1,25 mm (min. 0,08, max. 3,9 mm), with a mean annual wear of 0,17 mm. The mean acetabular migration on the two axis was 1,6 mm and 1,8 mm. Peri-acetabular osteolysis were recorded in 89% of the implants (163 cases). The cumulative survivorship (revision as endpoint) at the time was 88,9%.</p> <p>Conclusion</p> <p>Our study confirms the bad behavior of this type of cup probably related to the design, to the method of HA fixation. The observations carried out on the revised cup confirm these hypotheses but did not clarify if the third body wear could be a further problem. Another interesting aspect is the high incidence of osteolysis, which are often asymptomatic becoming a problem for the surgeon as the patient refuses the possibility of a revision.</p

A Potassium Metal-Organic Framework based on Perylene- 3,4,9,10-tetracarboxylate as Sensing Layer for Humidity Actuators

We have synthesized a novel three-dimensional metal-organic-framework (MOF) based on the perylene-3,4,9,10-tetracarboxylate linker and potassium as metallic centre. We report the formation of this K-based MOF using conventional routes with water as solvent. This material displays intense green photoluminescence at room temperature, and displays an aggregation dependent quenching. Correlation of the optical properties with the crystalline packing was confirmed by DFT calculations. We also demonstrate its potential to build humidity actuators with a reversible and reproducible response, with a change of 5 orders of magnitudes in its impedance at about 40% relative humidity (RH). This 3D-MOF is based on an interesting perylene derivative octadentate ligand, a moiety with interesting fluorescent properties and known component in organic semiconductors. To the best of our knowledge, this is the first time to build such a printed and flexible actuator towards humidity with a reversible response, enabling precise humidity threshold monitoring.This work was supported by the Junta de Andalucía (FQM-1484, and FQM-195). Red Guipuzcoana de Ciencia, Tecnología e Innovación (OF188/2017) and University of the Basque Country (GIU14/01, EHUA16/32). BB acknowledges funding by RyC-2012–10381 contract and computational resources provided by the RES and Alhambra supercomputing facilities. This work was also supported by the German Research Foundation (DFG) and the Technical University of Munich within the Open Access Publishing Funding Programme