Do Biometric Readings Change Significantly over Time in Phakic Eyes? A Cohort Study.

Background: Precise biometric assessment is crucial in achieving desirable refractive outcomes following cataract surgery. The current evidence for longitudinal biometric changes is lacking. We have performed a cohort study of phakic patients undergoing cataract surgery to help demonstrate whether biometric parameters change over time. Methods: We performed a single-centre, historic cohort study of patients who attended a "two-stop" pre-assessment clinic for consideration of cataract surgery between November 2002 and March 2015. Data were collected retrospectively. Four biometric measurements were recorded: axial length, horizontal (K1) readings, vertical (K2) readings and dioptric power of lens (AR40). Patients were allocated to three groups according to the time interval between initial and latest biometric assessment: Group 1: up to 12 months; Group 2: 12-24 months; Group 3: over 24 months. Results: Data were obtained for 109 eyes from 62 patients. Mean patient age at first biometry was 78 (range: 49-95; S.D.:10). Thirty-eight patients (61.3%) were female. Paired t-tests were performed per biometric measurement per group. No statistically significant changes were observed in Group 1 (n = 9). In Group 2, a statistically significant change was observed in K1 readings (median change: -0.12 mm, range: -0.65 mm to 0.64 mm; P = .002). In Group 3, statistically significant changes were observed in K1 readings (median change: 0.06 mm, range: -0.59 mm to 1.29 mm, P = .03), K2 readings: (median change: 0.33 mm, range: -0.50 mm to 1.09 mm, P < .001) and no change in AR40 readings (median change: 0.00, range -2.00 to 3.00, P = .02). Conclusion: Statistically significant biometric changes were observed over time in this cohort. We recommend considering repeat biometric assessment in patients who have had an interval of longer than 24 months between initial biometric assessment and surgery for optimal refractive outcomes. Further research is required to identify more precisely when to expect changes in the various biometric parameters and which patient characteristics may contribute.

Resveratrol reduces albuminuria in diabetic nephropathy: A randomized double-blind placebo-controlled clinical trial.

AIM: Albuminuria is the most important indicator of diabetic nephropathy (DN). Resveratrol, a natural compound found in grape skins and red wine, has antioxidant effects. This study aimed to evaluate the effects of resveratrol on DN. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 60 patients with type 2 diabetes and albuminuria were randomly assigned to receive either resveratrol (500mg/day) or placebo for 90 days. Losartan (12.5mg/day) was also administered to all participants. Primary outcomes were urinary albumin/creatinine ratio, estimated glomerular filtration rate (eGFR) and serum creatinine levels. Secondary outcomes were oxidative stress markers, and anthropometric and biochemical measures. RESULTS: Mean urine albumin/creatinine ratio was significantly reduced in the resveratrol group vs placebo (-46.4mg/g, 95% CI: -64.5 to -28.3 vs 29.9mg/g, 95% CI: 4.9 to 54.9; P<0.001), whereas eGFR (1.7mL/min/1.73m2, 95% CI: -3.4 to 6.8 vs -4.0, 95% CI: -8.2 to 0.2; P=0.08) and serum creatinine (-0.3mg/dL, 95% CI: -0.1 to 0.1 vs 0.1mg/dL, 95% CI: -0.0 to 0.1; P=0.13) were unchanged. Serum antioxidant enzymes were significantly increased with resveratrol. After adjusting for confounding variables, the effect of resveratrol in reducing urinary albumin excretion was still significant (P<0.001). Regression analysis revealed that every 1-cm decrease in waist circumference and 1-µmol/L increase in nitric oxide (NO) was associated with 9.4mg/g and 4.0mg/g reductions, respectively, of urine albumin/creatinine ratio. CONCLUSION: This clinical trial has shown that resveratrol may be an effective adjunct to angiotensin receptor blockers (ARBs) for reducing urinary albumin excretion in patients with DN (ClinicalTrials.gov: NCT02704494).

Autophagy activation is required for influenza A virus-induced apoptosis and replication.

Autophagy and apoptosis are two major interconnected host cell responses to viral infection, including influenza A virus (IAV). Thus, delineating these events could facilitate the development of better treatment options and provide an effective anti-viral strategy for controlling IAV infection. We used A549 cells and mouse embryonic fibroblasts (MEF) to study the role of virus-induced autophagy and apoptosis, the cross-talk between both pathways, and their relation to IAV infection [ATCC strain A/Puerto Rico/8/34(H1N1) (hereafter; PR8)]. PR8-infected and mock-infected cells were analyzed by immunoblotting, immunofluorescence confocal microscopy, electron microscopy and flow cytometry (FACS). We found that PR8 infection simultaneously induced autophagy and apoptosis in A549 cells. Autophagy was associated with Bax and Bak activation, intrinsic caspase cleavage and subsequent PARP-1 and BID cleavage. Both Bax knockout (KO) and Bax/Bak double knockout MEFs displayed inhibition of virus-induced cytopathology and cell death and diminished virus-mediated caspase activation, suggesting that virus-induced apoptosis is Bax/Bak-dependent. Biochemical inhibition of autophagy induction with 3-methyladenine blocked both virus replication and apoptosis pathways. These effects were replicated using autophagy-refractory Atg3 KO and Atg5 KO cells. Taken together, our data indicate that PR8 infection simultaneously induces autophagy and Bax/caspase-dependent apoptosis, with autophagy playing a role to support PR8 replication, in part, by modulating virus-induced apoptosis.

Lysosomal Acid Phosphatase Biosynthesis and Dysfunction: A Mini Review Focused on Lysosomal Enzyme Dysfunction in Brain.

Lysosomes are membrane-bound organelles that are responsible for degrading and recycling macromolecules. Lysosomal dysfunction occurs in enzymatic and non-enzymatic deficiencies, which result in abnormal accumulation of materials. Although lysosomal storage disorders affect different organs, the central nervous system is the most vulnerable. Evidence shows the role of lysosomal dysfunction in different neurodegenerative diseases, such as Niemann-Pick Type C disease, juvenile neuronal ceroid lipofuscinosis, Alzheimer's disease and Parkinson's disease. Lysosomal enzymes such as lysosomal acid phosphatase 2 (Acp2) play a critical role in mannose-6-phosphate removal and Acp2 controls molecular and cellular functions in the brain during development and adulthood. Acp2 is essential in cerebellar development, and mutations in this gene cause severe cerebellar neurodevelopmental and neurodegenerative disorders. In this mini-review, we highlight lysosomal dysfunctions in the pathogenesis of neurodevelopmental and/or neurodegenerative diseases with special attention to Acp2 dysfunction.

Autophagy in airway diseases: a new frontier in human asthma?

The study of autophagy ('self-eating'), a fundamental cell fate pathway involved in physiological and pathological subcellular processes, opens a new frontier in the continuous search for novel therapies for human asthma. Asthma is a complex syndrome with different disease phenotypes. Autophagy plays a central role in cell physiology, energy and metabolism, and cell survival. Autophagy's hallmark is the formation of double-membrane autophagic autophagosomes, and this process is operational in airway epithelial and mesenchymal cells in asthma. Genetic associations between autophagy genes and asthma have been observed including single nucleotide polymorphisms in Atg5 which correlate with reduced lung function. Immune mechanisms important in asthma such as Th2 cells and eosinophils also manifest autophagy. Lastly, we address the role of autophagy in extracellular matrix deposition and fibrosis in asthmatic airways remodeling, a pathologic process still without effective therapy, and discuss potential pharmacologic inhibitors. We end by offering two opposing but plausible hypotheses as to how autophagy may be directly involved in airway fibrosis.

Autophagy is a regulator of TGF-ß1-induced fibrogenesis in primary human atrial myofibroblasts.

Transforming growth factor-ß(1) (TGF-ß(1)) is an important regulator of fibrogenesis in heart disease. In many other cellular systems, TGF-ß(1) may also induce autophagy, but a link between its fibrogenic and autophagic effects is unknown. Thus we tested whether or not TGF-ß(1)-induced autophagy has a regulatory function on fibrosis in human atrial myofibroblasts (hATMyofbs). Primary hATMyofbs were treated with TGF-ß(1) to assess for fibrogenic and autophagic responses. Using immunoblotting, immunofluorescence and transmission electron microscopic analyses, we found that TGF-ß(1) promoted collagen type Iα2 and fibronectin synthesis in hATMyofbs and that this was paralleled by an increase in autophagic activation in these cells. Pharmacological inhibition of autophagy by bafilomycin-A1 and 3-methyladenine decreased the fibrotic response in hATMyofb cells. ATG7 knockdown in hATMyofbs and ATG5 knockout (mouse embryonic fibroblast) fibroblasts decreased the fibrotic effect of TGF-ß(1) in experimental versus control cells. Furthermore, using a coronary artery ligation model of myocardial infarction in rats, we observed increases in the levels of protein markers of fibrosis, autophagy and Smad2 phosphorylation in whole scar tissue lysates. Immunohistochemistry for LC3ß indicated the localization of punctate LC3ß with vimentin (a mesenchymal-derived cell marker), ED-A fibronectin and phosphorylated Smad2. These results support the hypothesis that TGF-ß(1)-induced autophagy is required for the fibrogenic response in hATMyofbs.

Properties of a-SiGe Thin Films on Glass by Co-Sputtering for Photovoltaic Absorber Application.

Non-hydrogenated amorphous Silicon-Germanium (a-SiGe) thin films were deposited at two different base pressures by RF magnetron co-sputtering. Moreover, an ex-situ thermal annealing was carried out to investigate the material properties to be suitable as the bottom cell of multi-junction solar cells. Compositional study of the films using EDX showed Ge-rich thin films with 75 atomic% of Ge. XRD reflection study implied that all samples were entirely amorphous in nature. However, a significant improvement of morphology possibly due to low base pressure was observed while thermal annealing caused peening and reduction of surface inhomogeneity in both as-sputtered films. UV-VIS-IR analysis confirmed the FESEM results. The highest transmittance was observed in the as-deposited sample grown at 4 x 10(-5) Torr, which however reduced after thermal annealing. Tauc's model was implied for band gap determination and band gap energy as low as 1.07 eV was found in the annealed sample grown at lower base pressure (4 x 10(-6) Torr). Electrical properties of films were investigated by Hall effect measurement system and results found the reduction of resistivity with the same trend of optical band gap energy.

Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts.

3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are cholesterol-lowering drugs that exert other cellular effects and underlie their beneficial health effects, including those associated with myocardial remodeling. We recently demonstrated that statins induces apoptosis and autophagy in human lung mesenchymal cells. Here, we extend our knowledge showing that statins simultaneously induces activation of the apoptosis, autophagy and the unfolded protein response (UPR) in primary human atrial fibroblasts (hATF). Thus we tested the degree to which coordination exists between signaling from mitochondria, endoplasmic reticulum and lysosomes during response to simvastatin exposure. Pharmacologic blockade of the activation of ER-dependent cysteine-dependent aspartate-directed protease (caspase)-4 and lysosomal cathepsin-B and -L significantly decreased simvastatin-induced cell death. Simvastatin altered total abundance and the mitochondrial fraction of proapoptotic and antiapoptotic proteins, while c-Jun N-terminal kinase/stress-activated protein kinase mediated effects on B-cell lymphoma 2 expression. Chemical inhibition of autophagy flux with bafilomycin-A1 augmented simvastatin-induced caspase activation, UPR and cell death. In mouse embryonic fibroblasts that are deficient in autophagy protein 5 and refractory to autophagy induction, caspase-7 and UPR were hyper-induced upon treatment with simvastatin. These data demonstrate that mevalonate cascade inhibition-induced death of hATF manifests from a complex mechanism involving co-regulation of apoptosis, autophagy and UPR. Furthermore, autophagy has a crucial role in determining the extent of ER stress, UPR and permissiveness of hATF to cell death induced by statins.

Virus-triggered autophagy in viral hepatitis - possible novel strategies for drug development.

Autophagy is a very tightly regulated process that is important in many cellular processes including development, differentiation, survival and homoeostasis. The importance of this process has already been proven in numerous common diseases such as cancer and neurodegenerative disorders. Emerging data indicate that autophagy plays an important role in some liver diseases including liver injury induced by ischaemia reperfusion and alpha-1 antitrypsin Z allele-dependent liver disease. Autophagy may also occur in viral infection, and it may play a crucial role in antimicrobial host defence against pathogens, while supporting cellular homoeostasis processes. Here, the latest findings on the role of autophagy in viral hepatitis B and C infection, which are both serious health threats, will be reviewed.

Apoptosis and cancer: mutations within caspase genes.

The inactivation of programmed cell death has profound effects not only on the development but also on the overall integrity of multicellular organisms. Beside developmental abnormalities, it may lead to tumorigenesis, autoimmunity, and other serious health problems. Deregulated apoptosis may also be the leading cause of cancer therapy chemoresistance. Caspase family of cysteinyl-proteases plays the key role in the initiation and execution of programmed cell death. This review gives an overview of the role of caspases, their natural modulators like IAPs, FLIPs, and Smac/Diablo in apoptosis and upon inactivation, and also in cancer development. Besides describing the basic mechanisms governing programmed cell death, a large part of this review is dedicated to previous studies that were focused on screening tumours for mutations within caspase genes as well as their regulators. The last part of this review discusses several emerging treatments that involve modulation of caspases and their regulators. Thus, we also highlight caspase cascade modulating experimental anticancer drugs like cFLIP-antagonist CDDO-Me; cIAP1 antagonists OSU-03012 and ME-BS; and XIAP small molecule antagonists 1396-11, 1396-12, 1396-28, triptolide, AEG35156, survivin/Hsp90 antagonist shephedrin, and some of the direct activators of procaspase-3.