Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort

Aims/hypothesis: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. Methods: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as ‘high ACR’ or ‘low ACR’ (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. Results: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. Conclusions/interpretation: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies

Vascular Effects of ACE (Angiotensin-Converting Enzyme) Inhibitors and Statins in Adolescents With Type 1 Diabetes

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0-7.2] versus 5.3% [4.7-5.9]; P=0.005), whereas no effect was observed following statin use (6.2% [5.5-6.8] versus 5.8% [5.1-6.4]; P=0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8-5.9] versus 6.3% [5.8-6.7] for high-risk versus low-risk groups; P=0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment (P>0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03-0.12]; P=0.001 and 0.5 m/s [0.4-0.6]; P<0.001 for reactive hyperemia index and pulse wave velocity, respectively). ACE inhibitors improve endothelial function in high-risk adolescents as they transition through puberty. The longer-term protective effects of this intervention at this early age remain to be determined. Registration- URL: https://www.clinicaltrials.gov; Unique identifier NCT01581476

Clustering of cardio-metabolic risk factors in parents of adolescents with type 1 diabetes and microalbuminuria

Objective To evaluate the association between a clustering of cardio-metabolic risk factors in parents and the development of microalbuminuria (MA) in their offspring with childhood-onset type 1 diabetes (T1D). Methods The study population comprised 53 parents (mean age [±SD]: 56.7±6.2 years) of 35 T1D young people with MA (MA+) and 86 parents (age: 56.1±6.3 years) of 50 matched offspring with normoalbuminuria (MA–), who underwent clinical, biochemical and cardiovascular imaging assessments. The primary study endpoint was the difference between parents from the MA+ and MA− groups in a cardio-metabolic risk score, calculated as the average value of the standardized measures (z-scores) for waist circumference, blood pressure, fasting glucose, insulin, HDL-cholesterol and triglycerides levels. Cardiovascular parameters, including carotid intima-media thickness (cIMT), flow-mediated dilatation (FMD) and pulse wave velocity (PWV), were also assessed. A DXA scan was performed to assess body composition. Results The cardio-metabolic risk score was significantly higher in parents of MA+ compared to parents of MA− offspring (mean [95% CI]: 1.066[0.076; 2.056] vs −0.268[−0.997; 0.460], P = .03). Parents of MA+ offspring had slightly higher values of waist circumference, lipids, insulin and blood pressure, although only diastolic blood pressure was statistically different between the 2 groups (P = .0085). FMD, cIMT, PWV (all P > .3), and DXA parameters (all P > .2) were not significantly different between the 2 groups. Conclusions Parents of young offspring with childhood-onset T1D and MA showed an abnormal metabolic profile, reflected by a calculated risk score. The finding supports the role of a familial predisposition to risk of developing diabetic nephropathy.The study was supported by a grant from Diabetes UK (09/0003859). P.H.T. was financially supported by Academy of Finland (decision 130171); The Diabetes Research Foundation, Finland; Foundation for Pediatric Research, Finland; The Alma and K. A. Snellman Foundation, Oulu, Finland; and The Finnish Medical Foundation

Clustering of cardio-metabolic risk factors in parents of adolescents with type 1 diabetes and microalbuminuria

OBJECTIVE: To evaluate the association between a clustering of cardio‐metabolic risk factors in parents and the development of microalbuminuria (MA) in their offspring with childhood‐onset type 1 diabetes (T1D). METHODS: The study population comprised 53 parents (mean age [±SD]: 56.7±6.2 years) of 35 T1D young people with MA (MA+) and 86 parents (age: 56.1±6.3 years) of 50 matched offspring with normoalbuminuria (MA–), who underwent clinical, biochemical and cardiovascular imaging assessments. The primary study endpoint was the difference between parents from the MA+ and MA− groups in a cardio‐metabolic risk score, calculated as the average value of the standardized measures (z‐scores) for waist circumference, blood pressure, fasting glucose, insulin, HDL‐cholesterol and triglycerides levels. Cardiovascular parameters, including carotid intima‐media thickness (cIMT), flow‐mediated dilatation (FMD) and pulse wave velocity (PWV), were also assessed. A DXA scan was performed to assess body composition. RESULTS: The cardio‐metabolic risk score was significantly higher in parents of MA+ compared to parents of MA− offspring (mean [95% CI]: 1.066[0.076; 2.056] vs −0.268[−0.997; 0.460], P = .03). Parents of MA+ offspring had slightly higher values of waist circumference, lipids, insulin and blood pressure, although only diastolic blood pressure was statistically different between the 2 groups (P = .0085). FMD, cIMT, PWV (all P > .3), and DXA parameters (all P > .2) were not significantly different between the 2 groups. CONCLUSIONS: Parents of young offspring with childhood‐onset T1D and MA showed an abnormal metabolic profile, reflected by a calculated risk score. The finding supports the role of a familial predisposition to risk of developing diabetic nephropathy

High-fidelity multimode fibre-based endoscopy for deep brain in vivo imaging

Progress in neuroscience constantly relies on the development of new techniques to investigate the complex dynamics of neuronal networks. An ongoing challenge is to achieve minimally-invasive and high-resolution observations of neuronal activity in vivo inside deep brain areas. A perspective strategy is to utilise holographic control of light propagation in complex media, which allows converting a hair-thin multimode optical fibre into an ultra-narrow imaging tool. Compared to current endoscopes based on GRIN lenses or fibre bundles, this concept offers a footprint reduction exceeding an order of magnitude, together with a significant enhancement in resolution. We designed a compact and high-speed system for fluorescent imaging at the tip of a fibre, achieving micron-scale resolution across a 50 um field of view, and yielding 7-kilopixel images at a rate of 3.5 frames/s. Furthermore, we demonstrate in vivo observations of cell bodies and processes of inhibitory neurons within deep layers of the visual cortex and hippocampus of anesthetised mice. This study forms the basis for several perspective techniques of modern microscopy to be delivered deep inside the tissue of living animal models while causing minimal impact on its structural and functional properties.Comment: 10 pages, 2 figures, Supplementary movie: https://drive.google.com/file/d/1Fm0G3TAIC49LVX6FaEiAtlefkWx1T2a5/vie

Quantum Gravity in Everyday Life: General Relativity as an Effective Field Theory

This article is meant as a summary and introduction to the ideas of effective field theory as applied to gravitational systems. Contents: 1. Introduction 2. Effective Field Theories 3. Low-Energy Quantum Gravity 4. Explicit Quantum Calculations 5. ConclusionsComment: 56 pages, 2 figures, JHEP style, Invited review to appear in Living Reviews of Relativit

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

BACKGROUND: The urokinase plasminogen activator (uPA) and its receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions. The uPA/uPAR system has been of great interest in cancer research because it is involved in the development of most invasive cancer phenotypes and is a strong predictor of poor patient survival. However, little is known about the role of uPA/uPAR in small cell lung cancer (SCLC), the most aggressive type of lung cancer. We therefore determined whether uPA and uPAR are involved in generation of drug resistant SCLC cell phenotype. METHODS AND FINDINGS: We screened six human SCLC cell lines for surface markers for putative stem and cancer cells. We used fluorescence-activated cell sorting (FACS), fluorescence microscopy and clonogenic assays to demonstrate uPAR expression in a subpopulation of cells derived from primary and metastatic SCLC cell lines. Cytotoxic assays were used to determine the sensitivity of uPAR-positive and uPAR-negative cells to chemotherapeutic agents. The uPAR-positive cells in all SCLC lines demonstrated multi-drug resistance, high clonogenic activity and co-expression of CD44 and MDR1, putative cancer stem cell markers. CONCLUSIONS: These data suggest that uPAR-positive cells may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies, and could serve as critical targets for more effective therapeutic interventions in SCLC

Tracking Down Abstract Linguistic Meaning: Neural Correlates of Spatial Frame of Reference Ambiguities in Language

This functional magnetic resonance imaging (fMRI) study investigates a crucial parameter in spatial description, namely variants in the frame of reference chosen. Two frames of reference are available in European languages for the description of small-scale assemblages, namely the intrinsic (or object-oriented) frame and the relative (or egocentric) frame. We showed participants a sentence such as “the ball is in front of the man”, ambiguous between the two frames, and then a picture of a scene with a ball and a man – participants had to respond by indicating whether the picture did or did not match the sentence. There were two blocks, in which we induced each frame of reference by feedback. Thus for the crucial test items, participants saw exactly the same sentence and the same picture but now from one perspective, now the other. Using this method, we were able to precisely pinpoint the pattern of neural activation associated with each linguistic interpretation of the ambiguity, while holding the perceptual stimuli constant. Increased brain activity in bilateral parahippocampal gyrus was associated with the intrinsic frame of reference whereas increased activity in the right superior frontal gyrus and in the parietal lobe was observed for the relative frame of reference. The study is among the few to show a distinctive pattern of neural activation for an abstract yet specific semantic parameter in language. It shows with special clarity the nature of the neural substrate supporting each frame of spatial reference

Relationship between tobacco, cagA and vacA i1 virulence factors and bacterial load in patients infected by Helicobacter pylori

Background and Aim Several biological and epidemiological studies support a relationship between smoking and Helicobacter pylori (H. pylori) to increase the risk of pathology. However, there have been few studies on the potential synergistic association between specific cagA and vacA virulence factors and smoking in patients infected by Helicobacter pylori. We studied the relationship between smoking and cagA, vacA i1 virulence factors and bacterial load in H. pylori infected patients. Methods Biopsies of the gastric corpus and antrum from 155 consecutive patients in whom there was clinical suspicion of infection by H. pylori were processed. In 106 patients H. pylori infection was detected. Molecular methods were used to quantify the number of microorganisms and presence of cagA and vacA i1 genes. A standardized questionnaire was used to obtain patients’ clinical data and lifestyle variables, including tobacco and alcohol consumption. Adjusted Odds Ratios (ORadjusted) were estimated by unconditional logistic regression. Results cagA was significantly associated with active-smoking at endoscope: ORadjusted 4.52. Evidence of association was found for vacA i1 (ORadjusted 3.15). Bacterial load was higher in active-smokers, although these differences did not yield statistical significance (median of 262.2 versus 79.4 copies of H. pylori per cell). Conclusions The association between smoking and a higher risk of being infected by a virulent bacterial population and with higher bacterial load, support a complex interaction between H. pylori infection and environmental factors

Large-scale patterns of turnover and basal area change in Andean forests

General patterns of forest dynamics and productivity in the Andes Mountains are poorly characterized. Here we present the first large-scale study of Andean forest dynamics using a set of 63 permanent forest plots assembled over the past two decades. In the North-Central Andes tree turnover (mortality and recruitment) and tree growth declined with increasing elevation and decreasing temperature. In addition, basal area increased in Lower Montane Moist Forests but did not change in Higher Montane Humid Forests. However, at higher elevations the lack of net basal area change and excess of mortality over recruitment suggests negative environmental impacts. In North-Western Argentina, forest dynamics appear to be influenced by land use history in addition to environmental variation. Taken together, our results indicate that combinations of abiotic and biotic factors that vary across elevation gradients are important determinants of tree turnover and productivity in the Andes. More extensive and longer-term monitoring and analyses of forest dynamics in permanent plots will be necessary to understand how demographic processes and woody biomass are responding to changing environmental conditions along elevation gradients through this century