Optical coherence tomography in Alzheimer's disease. A meta-analysis

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies. METHODS AND FINDINGS: Data sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls. RESULTS: 11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p<0.0001) patients compared to HC. RNFL in the 4 quadrants were all significantly thinner in AD superior (superior WMD = -24.0, 95% CI: -34.9 to -13.1, p<0.0001; inferior WMD = -20.8, 95% CI: -32.0 to -9.7, p<0.0001; nasal WMD = -14.7, 95% CI: -23.9 to -5.5, p<0.0001; and temporal WMD = -10.7, 95% CI: -19.9 to -1.4, p<0.0001); the same significant reduction in quadrant RNFL was observed in MCI patients compared with HC (Inferior WMD = -20.22, 95% CI: -30.41 to -10.03, p = 0.0001; nasal WMD = -7.4, 95% CI: -10.08 to -4.7, p = 0.0000; and temporal WMD = -6.88, 95% CI: -12.62 to -1.13, p = 0.01), with the exception of superior quadrant (WMD = -19.45, 95% CI: -40.23 to 1.32, p = 0.06). CONCLUSION: Results from the meta-analysis support the important role of OCT for RNFL analysis in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments

architectural and energy refurbishment of the headquarter of the university of teramo

Abstract The recent seismic events, which distressed the population of the Central Italy, have caused the incompliance with national safety standards of several historical buildings. In particular, the headquarter of the University of Teramo revealed some structural damages which make necessary to operate a restoration of the buildings. It represents a rare opportunity for investigating possible applications of a cluster of technologies and approaches largely recognized as efficient and high-performing to such particular buildings in order to achieve an upgrading in terms of energy efficiency. The proposal includes the improvement of the exploitation of renewable energy sources through adequate systems, which do not modify the visual perception of the pavilions. In that regards, the required electricity could be produced by a PV roofing installed on the parking area, while a biomass boiler and an absorption chiller could allow supplying the thermal and cooling needs. Furthermore, the rain water recovery system permits to reduce the exploitation of potable water for uses which do not require a high quality, such as irrigation. On the other hand, the envelope energy efficiency could be enhanced by applying passive strategies for reducing the heat losses ( winter conditions ) and gains ( summer conditions ) through facades and roof. The results confirmed the reliability of those interventions and the consequent advantages from an economical and energy point of view

Evaluating the effect of pupil dilation on spectral-domain optical coherence tomography measurements and their quality score

BACKGROUND: Spectral-domain optical coherence tomography (SD-OCT) provides fast scan speed and high scan resolution improving its diagnostic accuracy. The purpose of this study was to evaluate if SD-OCT measurements and their quality score are influenced by pupil dilation. METHODS: Retinal nerve fiber layer thickness (RNFL), ganglion cell complex (GCC) and optic nerve head (ONH) were measured in one eye of 57 glaucoma patients and 36 healthy subjects using spectral domain optical coherence tomography (SD-OCT) before and after pupil dilation. Comparisons were made between measurements and their quality score pre- and post dilation (Signal Strength Index, SSI). Overall RNFL, average GCC and ONH rim volume were considered in the analysis. RESULTS: No statistically significant differences were found between pre- and post-dilation measurements in both groups (glaucoma: RNFL 80 ± 15 μm vs 80 ± 16 μm, p = 0.87; GCC 81.35 ± 13.4 μm vs 81.10 ± 13.14 μm, p = 0.92; ONH 0.05 ± 0.11 mm(3) vs 0.04 ± 0.07 mm(3), p = 0.74; controls RNFL 99 ± 12 μm vs 98 ± 14 μm, p = 0.70; GCC 92.12 ± 6.7 μm vs 91.54 ± 7.05 μm, p = 0.72; ONH 0.11 ± 0.1 mm(3) vs 0.04 ± 0.07 mm(3), p = 0.36) nor between pre- and post-dilation quality score (glaucoma SSI RNFL 54.3 ± 10.3 vs 51.7 ± 18.1, p = 0.12; SSI GCC 58 ± 9.5 vs 57 ± 8.09, p = 0.55; SSI ONH 48.5 ± 7.6 vs 46.6 ± 7.2, p = 0.16; controls SSI RNFL 57 ± 10.3 vs 54 ± 9.31, p = 0.2; SSI GCC 60.9 ± 8.1 vs 58.8 ± 7.3, p = 0.3; SSI ONH 51.5 ± 8.9 vs 50.4 ± 8.3, p = 0.59). CONCLUSION: Pupil dilation doesn’t affect SD-OCT measurements and their quality score

Levels of plasma homocysteine in pseudoexfoliation glaucoma.

BACKGROUND: To examine levels of serum homocysteine (Hcy), vitamin B12 and folic acid in patients with pseudoexfoliation glaucoma (PEXG), primary open-angle glaucoma (POAG), and healthy control subjects. METHODS: This study included 36 patients with PEXG, 40 with POAG, and 40 age-matched healthy subjects. Fasting plasma Hcy concentrations and levels of serum vitamin B12 and folic acid were measured using competitive chemiluminescent enzyme immunoassay; values exceeding 14 μm/l were considered elevated. RESULTS: Mean plasma Hcy was significantly higher in PEXG (16.55 ± 7.23 μm/l) compared with POAG (13.91 ± 3.61 μm/l) and controls (13.12 ± 5.13 μm/l) (p = 0.03 and p = 0.0007 respectively). There were no statistical differences in serum vitamin B12 and folic acid levels among PEXG, POAG and control subjects (p > 0.05). A moderate, although statistically significant, relationship between Hcy and folic acid levels was found in the PEXG group (R(2) = 0.23, p = 0.003). Hcy levels were found not to be related with folic acid or vitamin B12 in either POAG or control subjects. CONCLUSIONS: In this study, plasma Hcy is significantly higher in PEXG group than the POAG and control groups. Hyper-Hcy might play a role in the pathogenesis of PEXG. Hyper-Hcy may be an independent factor stressing vasculopathy in addition to pseudoexfoliation, so might be a modifiable risk factor for PEXG

The energy sensor AMPK regulates Hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint

Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of Medulloblastoma, the most frequent pediatric brain tumor. We show here that the energy sensor AMPK inhibits Hh signaling by phosphorylating a single residue of human Gli1 that is not conserved in other species.Studies with selective agonists and genetic deletion have revealed that AMPK activation inhibits canonical Hh signaling in human, but not in mouse cells. Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. Notably, we show that selective AMPK activation inhibits Gli1-driven proliferation and that this effect is linked to Ser408 phosphorylation, which represents a key metabolic checkpoint for Hh signaling.Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors

Retinal functional changes measured by frequency-doubling technology in patients treated with hydroxychloroquine.

BACKGROUND: Antimalarial drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) are mainly used in the treatment of rheumatologic diseases, and their use may be associated with irreversible retinal toxicity. Previous studies indicate early paracentral visual field loss (Humphrey 10-2) in patients taking HCQ". These paracentral defects appear before changes in other clinical parameters as visual acuity and fundoscopy. The mechanism of CQ toxicity remains unclear. It was reported that toxic doses of CQ administered for as long as 4.5 years to Rhesus monkeys caused an initial dramatic effect on ganglion cells, followed later by photoreceptors and RPE degeneration. The purpose of this study is to explore early retinal functional changes measured by frequency-doubling technology (FDT) in patients treated with hydroxychloroquine (HCQ). METHODS: Forty-eight eyes of 48 subjects treated with hydroxychloroquine (HCQ), with no signs of retinal toxicity, and 36 eyes of 36 age and sex-matched healthy subjects were enrolled in this cross-sectional, prospective, observational, case control study. Functional testing included frequency-doubling Humphrey-matrix perimetry (FDP), white-on-white Humphrey visual field perimetry (HFA), using the 24-2 and 10-2 threshold programs, multifocal electroretinogram (mfERG, Veris 4.9) and low contrast sensitivity (CS) measurement. RESULTS: FDP mean deviation (MD) was found to be significantly reduced in HCQ-treated patients compared to controls both in the 24-2 (-1.38 ± 2.41 dB vs 0.21 ± 1.83 dB, p < 0.01) and in the 10-2 program (-0.97 ± 2.88 dB vs 0.15 ± 1.72 dB, p < 0.01). FDP pattern standard deviation (PSD) was found to be significantly worse in HCQ-treated patients compared to controls both in the 24-2 (2.70 ± 0.65 dB vs 2.41 ± 0.31 dB, p < 0.01 and in the 10-2 program (2.86 ± 0.48 dB vs 2.48 ± 0.39 dB, p < 0.01). HFA PSD and CS was also significantly reduced in HCQ patients, while response amplitude densities (RAD) were similar between patients and controls. A statistically significant difference in the ratio of the 5°-10° RAD and the 0°-2.5° RAD (0.31 ± 0.08 vs 0.36 ± 0.07 respectively, p < 0.05) was found between groups. CONCLUSION: Frequency doubling perimetry could be useful to detect early retinal impairment in patients treated with hydroxychloroquine

Differential Protein Expression Profiles in Glaucomatous Trabecular Meshwork: An Evaluation Study on a Small Primary Open Angle Glaucoma Population

INTRODUCTION: Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis. METHODS: TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls. Forty POAG TMs were collected at the time of surgery and 23 post-mortem specimens were from non-glaucomatous donor sclerocorneal tissues. Protein profiles were evaluated using a chip-based array consisting of 60 literature-selected antibodies. RESULTS: A different expression of some factors was observed in POAG TMs with respect to post-mortem specimens, either in abundance (interleukin [IL]10, IL6, IL5, IL7, IL12, IL3, macrophage inflammatory protein [MIP]1δ/α, vascular endothelial growth factor [VEGF], transforming growth factor beta 1 [TGFβ1], soluble tumor necrosis factor receptor I [sTNFRI]) or in scarcity (IL16, IL18, intercellular adhesion molecule 3 [ICAM3], matrix metalloproteinase-7 [MMP7], tissue inhibitor of metalloproteinase 1 [TIMP1]). MMP2, MMP7, TGFβ1, and VEGF expressions were confirmed by Western blot, zymography, and polymerase chain reaction. No difference in protein profile expression was detected between glaucomatous subtypes. CONCLUSION: The analysis of this small TM population highlighted some proteins linked to POAG, some previously reported and others of new detection (IL7, MIPs, sTNFαRI). A larger POAG population is required to select promising disease-associated biomarker candidates. FUNDING: This study was partially supported by the Fondazione Roma, the Italian Ministry of Health and the “National 5xMille 2010 tax donation to IRCCS-G.B. Bietti Foundation”. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-016-0285-x) contains supplementary material, which is available to authorized users

Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review

Cytidine 5'-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials)

Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.

SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB