Astigmatism of the ex vivo human lens: Surface and gradient refractive index age-dependent contributions

7 págs.; 5 figs.© 2015 The Association for Research in Vision and Ophthalmology, Inc. PURPOSE. We estimated the contribution of the gradient refractive index (GRIN) and lens surfaces to lens astigmatism and lens astigmatic angle as a function of age in human donor lenses. METHODS. Human lenses were imaged, ex vivo, with 3D-spectral optical coherence tomography (OCT) and their back focal length was measured using laser ray tracing. The contribution of lens surfaces and GRIN to lens astigmatism were evaluated by computational ray tracing on the GRIN lens and a homogenous equivalent index lens. Astigmatism magnitude and relative astigmatic angle of and between lens surfaces, GRIN lens, and lens with homogeneous refractive index were evaluated, and all results were correlated with age. RESULTS. The magnitude of astigmatism in the anterior lens surface decreased with age (slope = -0.005 diopters [D]/y; r = 0.397, P =0.018). Posterior surface astigmatism and lens astigmatism were not age-dependent. Presence of GRIN did not alter significantly the magnitude or axis of the lens astigmatism. The astigmatism of GRIN lens and lens with homogeneous refractive index correlated with anterior lens surface astigmatism (GRIN, P = 3.9E - 6, r = 0.693; equivalent refractive index lens, P = 4.1E - 4, r = 0.565). The astigmatic angle of posterior surface, GRIN lens, and homogeneous refractive index lens did not change significantly with age. CONCLUSIONS. The axis of lens astigmatism is close to the astigmatic axis of the anterior lens surface. Age-related changes in lens astigmatism appear to be related to changes in the anterior lens astigmatism. The influence of the GRIN on lens astigmatism and the astigmatic axis is minor.Supported by Spanish Government Grant FIS2011-25637 (SM), Consejo Superior de Investigaciones Científicas Junta de Ampliacion de Estudios (CSIC JAE)-Pre Program (JB), CSIC i-LINKþ 2012, iLINKþ0609 (SM). The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement 294099 (SM).Peer Reviewe

In situ fluorescence analysis demonstrates active siRNA exclusion from the nucleus by Exportin 5

Two types of short double-stranded RNA molecules, namely microRNAs (miRNAs) and short interfering RNAs (siRNAs), have emerged recently as important regulators of gene expression. Although these molecules show similar sizes and structural features, the mechanisms of action underlying their respective target silencing activities appear to differ: siRNAs act primarily through mRNA degradation, whereas most miRNAs appear to act primarily through translational inhibition. Our understanding of how these overlapping pathways are differentially regulated within the cell remains incomplete. In the present work, quantitative fluorescence microscopy was used to study how siRNAs are processed within human cells. We found that siRNAs are excluded from non-nucleolar areas of the nucleus in an Exportin-5 dependent process that specifically recognizes key structural features shared by these and other small RNAs such as miRNAs. We further established that the Exportin-5-based exclusion of siRNAs from the nucleus can, when Exp5 itself is inhibited, become a rate-limiting step for siRNA-induced silencing activity. Exportin 5 therefore represents a key point of intersection between the siRNA and miRNA pathways, and, as such, is of fundamental importance for the design and interpretation of RNA interference experimentation

Knockdown of Indy/CeNac2 extends Caenorhabditis elegans life span by inducing AMPK/aak-2

Reducing the expression of the Indy (Acronym for 'I'm Not Dead, Yet') gene in lower organisms promotes longevity and leads to a phenotype that resembles various aspects of caloric restriction. In C. elegans, the available data on life span extension is controversial. Therefore, the aim of this study was to determine the role of the C. elegans INDY homolog CeNAC2 in life span regulation and to delineate possible molecular mechanisms. siRNA against Indy/CeNAC2 was used to reduce expression of Indy/CeNAC2. Mean life span was assessed in four independent experiments, as well as whole body fat content and AMPK activation. Moreover, the effect of Indy/CeNAC2 knockdown in C. elegans with inactivating variants of AMPK (TG38) was studied. Knockdown of Indy/CeNAC2 increased life span by 22±3 % compared to control siRNA treated C. elegans, together with a decrease in whole body fat content by ~50%. Indy/CeNAC2 reduction also increased the activation of the intracellular energy sensor AMPK/aak2. In worms without functional AMPK/aak2, life span was not extended when Indy/CeNAC2 was reduced. Inhibition of glycolysis with deoxyglucose, an intervention known to increase AMPK/aak2 activity and life span, did not promote longevity when Indy/CeNAC2 was knocked down. Together, these data indicate that reducing the expression of Indy/CeNAC2 increases life span in C. elegans, an effect mediated at least in part by AMPK/aak2

Atrial natriuretic Peptide and adiponectin interactions in man

Reduced circulating natriuretic peptide concentrations are independently associated with insulin resistance and type 2 diabetes, while increased natriuretic peptide levels appear to be protective. Observations in vitro and in heart failure patients suggest that atrial natriuretic peptide (ANP) promotes adiponectin release, an adipokine with insulin sensitizing properties. We tested the hypothesis that ANP acutely raises adiponectin levels in 12 healthy men. We infused ANP intravenously over 135 minutes while collecting venous blood and adipose tissue microdialysates at baseline and at the end of ANP-infusion. We obtained blood samples at identical time-points without ANP infusion in 7 age and BMI matched men. With infusion, venous ANP concentrations increased ∼10 fold. Systemic and adipose tissue glycerol concentrations increased 70% and 80%, respectively (P<0.01). ANP infusion increased total adiponectin 14±5% and high molecular-weight (HMW)-adiponectin 13±5% (P<0.05). Adiponectin did not change in the control group (P<0.05 vs. infusion). ANP-induced changes in HMW adiponectin and adipose tissue lipolysis were directly correlated with each other, possibly suggesting a common mechanism. Our data show that ANP acutely increases systemic total and HMW-adiponectin concentrations in healthy subjects. Our study could have implications for the physiological regulation of adiponectin and for disease states associated with altered natriuretic peptide availability

Comparison of the Effects of Iodine and Iodide on Thyroid Function in Humans

The present experiment in humans failed to confirm the differential effect of I(sub 2) on maintenance of serum T(sub 4) concentrations relative to the effects of I(-) that was observed in prior experiments in rats. The reaction of I(sub 2) with metabolites of thyroid hormones in the intestine that appears responsible for this effect in rats probably also exists at some level in humans. The present results suggest that the concentrations of such metabolites in the human intestinal tract are too small to significantly affect circulating concentration of T(sub 4). However, based on the elevations in TSH, there should be some concern over the potential impacts of chronic consumption of iodine in drinking water

Plasma exchange for primary autoimmune autonomic failure

We report on a patient with long-standing severe autonomic failure that affected his sympathetic and parasympathetic nervous systems. Antibodies against the ganglionic acetylcholine receptors were detected in the serum. Removal of the antibodies by means of plasma exchange resulted in a dramatic clinical improvement

Full OCT anterior segment biometry: An application in cataract surgery

In vivo three-dimensional (3-D) anterior segment biometry before and after cataract surgery was analyzed by using custom highresolution high-speed anterior segment spectral domain Optical Coherence Tomography (OCT). The system was provided with custom algorithms for denoising, segmentation, full distortion correction (fan and optical) and merging of the anterior segment volumes (cornea, iris, and crystalline lens or IOL), to provide fully quantitative data of the anterior segment of the eye. The method was tested on an in vitro artificial eye with known surfaces geometry at different orientations and demonstrated on an aging cataract patient in vivo. Biometric parameters CCT, ACD/ILP, CLT/ILT Tilt and decentration are retrieved with a very high degree of accuracy. IOL was placed 400 οm behind the natural crystalline lens, The IOL was aligned with a similar orientation of the natural lens (2.47 deg superiorly), but slightly lower amounts (0.77 deg superiorly). The IOL was decentered superiorly (0.39 mm) and nasally (0.26 mm). © 2013 Optical Society of America.This study has been funded by Spanish Government Grant FIS2011-25637 and European Research Council Grant ERC-2011-AdG-294099 to S. Marcos.Peer Reviewe

Normalized indices derived from visceral adipose mass assessed by MRI and their correlation with markers for insulin resistance and prediabetes

Visceral adipose tissue (VAT) plays an important role in the pathogenesis of insulin resistance (IR), prediabetes and type 2 diabetes. However, VAT volume alone might not be the best marker for insulin resistance and prediabetes or diabetes, as a given VAT volume may differently impact on these metabolic traits based on body height, gender, age and ethnicity. In a cohort of 1295 subjects from the Tübingen Diabetes Family Study (TDFS) and in 9978 subjects from the UK Biobank (UKBB), undergoing magnetic resonance imaging for quantification of VAT volume, total adipose tissue (TAT, in the TDFS), total abdominal adipose tissue (TAAT) in the UKBB, and total lean tissue (TLT), VAT volume and several VAT-indices were investigated for their relationships with insulin resistance and glycemic traits. VAT-related indices were calculated by correcting for body height (VAT/m: VAT/body height; VAT/m²: VAT/(body height)², and VAT/m³: VAT/(body height)³), TAT (%VAT), TLT (VAT/TLT) and weight (VAT/WEI), with closest equivalents used within the UKBB dataset. Prognostic values of VAT and VAT-related indices for insulin sensitivity, HbA1c levels and prediabetes/diabetes were analyzed for males and females. Males had higher VAT volume and VAT-related indices than females in both cohorts (p < 0.0001) and VAT volume has shown to be a stronger determinant for insulin sensitivity than anthropometric variables. Among the parameters uncorrected VAT and derived indices, VAT/m³ most strongly correlated negatively with insulin sensitivity and positively with HbA1c levels and prediabetes/diabetes in the TDFS (R² = 0.375/0.305 for females/males for insulin sensitivity, 0.178/0.148 for HbA1c levels vs. – e.g. – 0.355/0.293 and 0.144/0.133 for VAT, respectively) and positively with HbA1c (R² = 0.046/0.042) in the UKBB for females and males. Furthermore, VAT/m³ was found to be a significantly better determinant of insulin resistance or prediabetes than uncorrected VAT volume (p < 0.001/0.019 for females/males regarding insulin sensitivity, p < 0.001/< 0.001 for females/males regarding HbA1c). Evaluation of several indices derived from VAT volume identified VAT/m³ to most strongly correlate with insulin sensitivity and glucose metabolism. Thus, VAT/m³ appears to provide better indications of metabolic characteristics (insulin sensitivity and pre-diabetes/diabetes) than VAT volume alone

Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections.

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 &lt;sup&gt;+&lt;/sup&gt; and CD8 &lt;sup&gt;+&lt;/sup&gt; T cells. Co-culturing CD4 &lt;sup&gt;+&lt;/sup&gt; with autologous CD8 &lt;sup&gt;+&lt;/sup&gt; T cells from ART-suppressed HIV &lt;sup&gt;+&lt;/sup&gt; donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 &lt;sup&gt;+&lt;/sup&gt; T cells. This trispecific antibody mediates CD4 &lt;sup&gt;+&lt;/sup&gt; and CD8 &lt;sup&gt;+&lt;/sup&gt; T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection

Practical recommendations for the management of diabetes in patients with COVID-19

Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20-50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups