Prolonged Adaptation to a Low or High Protein Diet Does Not Modulate Basal Muscle Protein Synthesis Rates – A Substudy

Background

Based on controlled 36 h experiments a higher dietary protein intake causes a positive protein balance and a negative fat balance. A positive net protein balance may support fat free mass accrual. However, few data are available on the impact of more prolonged changes in habitual protein intake on whole-body protein metabolism and basal muscle protein synthesis rates.

Objective

To assess changes in whole-body protein turnover and basal muscle protein synthesis rates following 12 weeks of adaptation to a low versus high dietary protein intake.

Methods

A randomized parallel study was performed in 40 subjects who followed either a high protein (2.4 g protein/kg/d) or low protein (0.4 g protein/kg/d) energy-balanced diet (30/35/35% or 5/60/35% energy from protein/carbohydrate/fat) for a period of 12 weeks. A subgroup of 7 men and 8 women (body mass index: 22.8±2.3 kg/m², age: 24.3±4.9 y) were selected to evaluate the impact of prolonged adaptation to either a high or low protein intake on whole body protein metabolism and basal muscle protein synthesis rates. After the diet, subjects received continuous infusions with L-[ring-²H₅]phenylalanine and L-[ring-²H₂]tyrosine in an overnight fasted state, with blood samples and muscle biopsies being collected to assess post-absorptive whole-body protein turnover and muscle protein synthesis rates in vivo in humans.

Results

After 12 weeks of intervention, whole-body protein balance in the fasted state was more negative in the high protein treatment when compared with the low protein treatment (-4.1±0.5 vs -2.7±0.6 μmol phenylalanine/kg/h;P<0.001). Whole-body protein breakdown (43.0±4.4 vs 37.8±3.8 μmol phenylalanine/kg/h;P<0.03), synthesis (38.9±4.2 vs 35.1±3.6 μmol phenylalanine/kg/h;P<0.01) and phenylalanine hydroxylation rates (4.1±0.6 vs 2.7±0.6 μmol phenylalanine/kg/h;P<0.001) were significantly higher in the high vs low protein group. Basal muscle protein synthesis rates were maintained on a low vs high protein diet (0.042±0.01 vs 0.045±0.01%/h;P = 0.620).

Conclusions

In the overnight fasted state, adaptation to a low-protein intake (0.4 g/kg/d) does not result in a more negative whole-body protein balance and does not lower basal muscle protein synthesis rates when compared to a high-protein intake.

Trial Registration

Clinicaltrials.gov NCT01551238.     

Ocular Dominance Is Associated with the Ganglion Cell-Inner Plexiform Layer Thickness Profile in the Macula

Purpose

To investigate the characteristics of macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles associated with ocular dominance.

Setting

Private practice, Seoul, Republic of Korea.

Design

Comparative case-control study.

Methods

Both eyes of 199 participants with no ophthalmic abnormalities were included. Participants were imaged by spectral-domain optical coherence tomography, and underwent dominant eye testing using a hole-in-a-card test (sighting dominance) at the same visit. Macular GCIPL, as well as circumpapillary retinal nerve fiber layer (RNFL) thickness were compared for individual patients, according to ocular dominance.

Results

Ocular dominance occurred predominantly in the right eye (right vs. left: 72.36 vs. 27.60%; P < 0.001). In the comparison of macular GCIPL thickness, the average (81.27±5.01 μm vs. 80.66±6.31 μm in dominant vs. non-dominant eyes), inferonasal (81.39±5.47μm vs. 80.33±6.82μm, and inferior sectors (77.95±6.05μm vs. 76.97±8.15μm) were significantly different between dominant and non-dominant eyes (P = 0.040, 0.005, and 0.032, respectively). Significant predictors of average GCIPL thickness were spherical equivalent (β = 1.37, P<0.001), astigmatic power (β = 1.44, P = 0.009), disc area (β = 3.90, P < 0.001), average RNFL thickness (β = 0.22, P<0.001), average cup-to-disc ratio (β = 5.74, P = 0.002), difference between the inferior and superior quadrant RNFL thicknesses (β = 0.08, P = 0.024), and ocular dominance (β = 2.10, P = 0.020). On multivariate regression analysis, ocular dominance was correlated with average GCIPL thickness after adjusting for potential confounders (β = 1.63, P = 0.048).

Conclusions

Dominant eyes accompanied significantly thicker average macular GCIPL. This information suggests that macular GCIPL thickness may provide an indicator of the relative dominance of an eye.     

Polymorphic Variants of SCN1A and EPHX1 Influence Plasma Carbamazepine Concentration,Metabolism and Pharmacoresistance in a Population of Kosovar Albanian Epileptic Patients

Aim

The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy.

Materials & Methods

Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A (sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight.

Results

The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71±0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76±0.16 vs 0.94±0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; P<0.05 for both). Carriers of the EPHX1 c.416A>G showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13±0.08 to 0.26±0.17, p<0.05) also of CBZD to CBZE (1.74±1.06 to 3.08±2.90; P<0.05) and CDR_CBZD (0.13±0.08 vs 0.24±0.19 μg/mL per mg/Kg; P<0.05). ABCB1 3455C>T SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657±285 vs 489±231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84±4.37 vs 7.41±3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated.

Conclusions

The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy.     

First-Trimester Maternal Serum Levels of sFLT1, PGF and ADMA Predict Preeclampsia

Background

Placental growth factor (PGF), soluble fms-like tyrosine kinase 1 (sFLT1) and asymmetric dimethylarginine (ADMA) are involved in the pathogenesis of preeclampsia. Abnormal maternal sFLT1, PGF and ADMA levels are detectable weeks before the onset of preeclampsia.

Objective

To investigate sFLT1, PGF and ADMA in the first trimester of pregnancy as predictors of preeclampsia.

Methods

In this prospective nested case-control study, 740 pregnant women enrolled at 12–16 weeks of gestation and followed up until 6 weeks after delivery at the Shanghai First Maternity and Infant Health Hospital of Tongji University between January 2010 and December 2012. Forty-four women developed preeclampsia. Urinary proteins were measured using 24-hour collection or dipsticks. sFLT1, PGF and ADMA were measured by ELISA in the first trimester. Pulsatility index (PI) was measured by Doppler ultrasound in the second trimester.

Results

First-trimester serum sFLT1 and ADMA levels of women who developed preeclampsia were significantly higher compared with women with normal pregnancies (sFLT1: 0.321±0.023 vs. 0.308±0.019 ng/ml, P = 0.001; ADMA: 0.86±0.16 vs. 0.68±0.20 μM, P<0.001). First-trimester serum PGF levels of women who developed preeclampsia were significantly lower than in women with normal pregnancies (115.72±32.55 vs. 217.30±74.48 pg/ml, P<0.001). Multiple logistic regression and receiver-operating characteristic curves identified first-trimester PGF and ADMA to be sensitive and selective predictors of preeclampsia (area under the curve [AUC]: 0.902), as well as second-trimester uterine artery pulse index (AUC: 0.836).

Conclusion

In the first trimester, maternal serum sFLT1, PGF and ADMA levels, as well as second-trimester uterine artery PI, could predict preeclampsia.     

Ethnic Variations in Central Corneal Thickness in a Rural Population in China: The Yunnan Minority Eye Studies

Purpose

To describe the ethnic differences in central corneal thickness (CCT) in population-based samples of ethnic Bai, Yi and Han people living in rural China.

Methods

6504 adults (2119 ethnic Bai, 2202 ethnic Yi and 2183 ethnic Han) aged 50 years or older participated in the study. Each subject underwent standardized ocular examinations and interviewer-administered questionnaires for risk factor assessment. CCT was measured for both eyes using an ultrasound pachymeter. Regression and principal component analysis were performed to examine the relationship of ethnicity and other factors with CCT.

Results

The mean CCT readings were 536.4 ± 34.2 μm in ethnic Bai, 532.1 ± 32.1 μm in ethnic Yi and 529.6 ± 32.7 μm in ethnic Han adults (P<0.001), respectively. There was a decreasing trend of mean CCT with increasing age across all ethnic groups. In multivariate linear regression models, increasing CCT was associated with younger age (P<0.001), male gender (P<0.001), Bai (P<0.001) or Yi (P<0.001) ethnicity, greater body mass index (P<0.001), higher systolic blood pressure (P<0.001), greater corneal curvature (P<0.001), deeper anterior chamber (P < 0.001), and thicker lens (P<0.001). Ethnicity contributed significantly to presence of thin cornea (60%; P< 0.001) compared with other factors. CCT had similar impact on intraocular pressure readings across all ethnic groups.

Conclusions

This study of more than 6500 multiethnic participants demonstrates significant ethnic variations in CCT, with Han ethnicity having the thinnest cornea compared with ethnic minorities. These data are essential to guide future multiethnic clinical trials on CCT-related ocular conditions such as glaucoma.     

Liver Fat Content Is Associated with Elevated Serum Uric Acid in the Chinese Middle-Aged and Elderly Populations: Shanghai Changfeng Study

Background and Aims

Although many studies have indicated a relationship between nonalcoholic fatty liver disease (NAFLD) and hyperuricemia, a few studies specifically examining the effects of the severity of liver fat content (LFC) on serum uric acid (SUA) and the presence of hyperuricemia because of the limitation of the examination methods for NAFLD. In this study, we investigate the relationship between the NAFLD and SUA levels in the Chinese population using standardized quantitative ultrasound.

Methods

A community-based study was conducted from May 2010 to December 2012. A total of 4,305 people aged 45 years and above without excessive drinking were enrolled. A standard interview and anthropometric and laboratory blood parameters were collected for each person. The standardized ultrasound hepatic/renal ratio and hepatic attenuation rate was used to quantify LFC.

Results

The prevalence of NAFLD and hyperuricemia was 33.1% and 17.1%, respectively. A total of 23.5% of the NAFLD subjects had hyperuricemia, and their SUA was higher than that of non-NAFLD subjects (327.2±76.8 vs 301.9±77.4 μmol/L, P<0.001). The LFC was positively correlated with SUA (r = 0.130, P<0.001) and an independent factor for SUA (standardized β = 0.054, P<0.001). The OR for the presence of hypreuricemia was 1.175 (95% CI 1.048–1.318; P<0.001) with a 1 SD increase in the log LFC. LFC greater than 10% was related to elevated SUA and an increased presence of hyperuricemia.

Conclusions

LFC accumulation was associated with an increase in the prevalence of hyperuricemia and elevated SUA in our community-based population. LFC greater than 10% is related to the risk for hyperuricemia.     

Effect of Misalignment between Successive Corneal Videokeratography Maps on the Repeatability of Topography Data

Purpose

To improve the reliability of corneal topographic data through the development of a method to estimate the magnitude of misalignment between successive corneal videokeratography (VK) maps and eliminate the effect of misalignment on the repeatability of topography data.

Methods

Anterior and posterior topography maps were recorded twice for 124 healthy eyes of 124 participants using a Pentacam, and the repeatability of measurements was assessed by calculating the differences in elevation between each two sets of data. The repeatability of measurements was re-assessed following the determination of the magnitude of misalignment components (translational displacements: x₀, y₀ and z₀, and rotational displacements: α, β and γ) between each two data sets and using them to modify the second data set within each pair based on an Iterative Closest Point (ICP) algorithm. The method simultaneously considered the anterior and posterior maps taken for the same eye since they were assumed to have the same set of misalignment components. A new parameter, named Combined Misalignment parameter (CM), has been developed to combine the effect of all six misalignment components on topography data and so enable study of the association between misalignment and the data repeatability test results.

Results

The repeatability tests resulted in average root mean square (RMS) differences in elevation data of 8.46±2.75 μm before ICP map matching when simultaneously considering anterior and posterior surfaces. With map matching and misalignment correction, the differences decreased to 7.28±2.58 μm (P = 0.00). When applied to only the anterior maps, misalignment correction led to a more pronounced reduction in elevation data differences from 4.58±1.84 μm to 2.97±1.29 μm (P = 0.00). CM was found to be associated with the repeatability error (P = 0.00), with posterior maps being responsible for most of the error due to their relatively lower accuracy compared to anterior maps.

Conclusions

The ICP algorithm can be used to estimate, and effectively correct for, the potential misalignment between successive corneal videokeratography maps.     

Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats

Background

Mitochondrial large-conductance Ca²⁺-sensitive potassium (mBK_Ca) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBK_Ca channels in the rat heart in vitro.

Methods

Male Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBK_Ca channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate.

Results

In control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P<0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P<0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups.

Conclusion

This study shows that in male rats protein kinase G-dependent opening of mBK_Ca channels plays a pivotal role in sildenafil-induced cardioprotection.     

TGF-β1-Mediated Differentiation of Fibroblasts Is Associated with Increased Mitochondrial Content and Cellular Respiration

Objectivs

Cytokine-dependent activation of fibroblasts to myofibroblasts, a key event in fibrosis, is accompanied by phenotypic changes with increased secretory and contractile properties dependent on increased energy utilization, yet changes in the energetic profile of these cells are not fully described. We hypothesize that the TGF-β1-mediated transformation of myofibroblasts is associated with an increase in mitochondrial content and function when compared to naive fibroblasts.

Methods

Cultured NIH/3T3 mouse fibroblasts treated with TGF-β1, a profibrotic cytokine, or vehicle were assessed for transformation to myofibroblasts (appearance of α-smooth muscle actin [α-SMA] stress fibers) and associated changes in mitochondrial content and functions using laser confocal microscopy, Seahorse respirometry, multi-well plate reader and biochemical protocols. Expression of mitochondrial-specific proteins was determined using western blotting, and the mitochondrial DNA quantified using Mitochondrial DNA isolation kit.

Results

Treatment with TGF-β1 (5 ng/mL) induced transformation of naive fibroblasts into myofibroblasts with a threefold increase in the expression of α-SMA (6.85 ± 0.27 RU) compared to cells not treated with TGF-β1 (2.52 ± 0.11 RU). TGF-β1 exposure increased the number of mitochondria in the cells, as monitored by membrane potential sensitive dye tetramethylrhodamine, and expression of mitochondria-specific proteins; voltage-dependent anion channels (0.54 ± 0.05 vs. 0.23 ± 0.05 RU) and adenine nucleotide transporter (0.61 ± 0.11 vs. 0.22 ± 0.05 RU), as well as mitochondrial DNA content (530 ± 12 μg DNA/10⁶ cells vs. 307 ± 9 μg DNA/10⁶ cells in control). TGF-β1 treatment was associated with an increase in mitochondrial function with a twofold increase in baseline oxygen consumption rate (2.25 ± 0.03 vs. 1.13 ± 0.1 nmol O₂/min/10⁶ cells) and FCCP-induced mitochondrial respiration (2.87 ± 0.03 vs. 1.46 ± 0.15 nmol O₂/min/10⁶ cells).

Conclusions

TGF-β1 induced differentiation of fibroblasts is accompanied by energetic remodeling of myofibroblasts with an increase in mitochondrial respiration and mitochondrial content.     

Relationship between Inflammatory Cytokines and Indices of Cardiac Dysfunction following Intense Endurance Exercise

Objectives

Pro-inflammatory cytokines have been noted to increase following exercise but their relationship to exercise-induced cardiac dysfunction has not previously been investigated. We sought to evaluate whether exercise-induced cardiac dysfunction was associated with increases in cytokines, particularly the pro-inflammatory cytokines IL-1β, IL-12p70 and TNFα, which have been most implicated in cardiac pathology.

Methods

40 well-trained endurance athletes underwent evaluation prior to and immediately following one of four endurance sporting events ranging from 3 to 11 hours duration. Cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were analyzed by flow cytometry from serum samples collected within 50 minutes of race completion. Cardiac troponin (cTnI) and B-type natriuretic peptide were combined with an echocardiographic assessment of cardiac function, and a composite of cTnI > 0.04 μg/L, BNP increase > 10 ng/L and a decrease in right ventricular ejection (RVEF) > 10% were prospectively defined as evidence of myocardial dysfunction.

Results

Relative to baseline, IL-6 IL-8 and IL-10 increased 8.5-, 2.9-, and 7.1-fold, respectively, P<0.0001. Thirty-one (78%), 19 (48%) and 18 (45%) of the athletes met the pre-specified criteria for significant cTnI, BNP and RVEF changes, respectively. TNFα, IL-12p70 were univariate predictors of ΔRVEF and ΔBNP whilst none of the anti-inflammatory cytokines were significantly associated with these measures. Ten athletes (25%, all athletes competing in the endurance event of longest duration) met criteria for exercise-induced myocardial dysfunction. In these 10 athletes with myocardial dysfunction, as compared to those without, there was significantly greater post-race expression of the pro-inflammatory cytokines IL-12p70 (8.1±3.8pg/ml vs. 2.5±2.6pg/ml, P<0.0001) and TNFα (6.5±3.1pg/ml vs. 2.0±2.5pg/ml, P<0.0001).

Conclusion

Cardiac dysfunction following intense endurance exercise was associated with increased expression of pro-inflammatory cytokines. This does not prove a causal relationship but provides rationale for further investigations into whether inflammation mediates exercise-induced myocardial dysfunction.     

Macular Microcysts in Mitochondrial Optic Neuropathies: Prevalence and Retinal Layer Thickness Measurements

Purpose

To investigate the thickness of the retinal layers and to assess the prevalence of macular microcysts (MM) in the inner nuclear layer (INL) of patients with mitochondrial optic neuropathies (MON).

Methods

All patients with molecularly confirmed MON, i.e. Leber’s Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), referred between 2010 and 2012 were enrolled. Eight patients with MM were compared with two control groups: MON patients without MM matched by age, peripapillary retinal nerve fiber layer (RNFL) thickness, and visual acuity, as well as age-matched controls. Retinal segmentation was performed using specific Optical coherence tomography (OCT) software (Carl Zeiss Meditec). Macular segmentation thickness values of the three groups were compared by one-way analysis of variance with Bonferroni post hoc corrections.

Results

MM were identified in 5/90 (5.6%) patients with LHON and 3/58 (5.2%) with DOA. The INL was thicker in patients with MON compared to controls regardless of the presence of MM [133.1±7μm vs 122.3±9μm in MM patients (p<0.01) and 128.5±8μm vs. 122.3±9μm in no-MM patients (p<0.05)], however the outer nuclear layer (ONL) was thicker in patients with MM (101.4±1mμ) compared to patients without MM [77.5±8mμ (p<0.001)] and controls [78.4±7mμ (p<0.001)]. ONL thickness did not significantly differ between patients without MM and controls.

Conclusion

The prevalence of MM in MON is low (5-6%), but associated with ONL thickening. We speculate that in MON patients with MM, vitreo-retinal traction contributes to the thickening of ONL as well as to the production of cystic spaces.     

Age-Related Vitamin D Deficiency Is Associated with Reduced Macular Ganglion Cell Complex: A Cross-Sectional High-Definition Optical Coherence Tomography Study

Background

Vitamin D deficiency is associated with smaller volume of optic chiasm in older adults, indicating a possible loss of the visual axons and their cellular bodies. Our objective was to determine whether vitamin D deficiency in older adults is associated with reduced thickness of the ganglion cell complex(GCC) and of the retinal nerve fibre layer(RNFL), as measured with high-definition optical coherence tomography(HD-OCT).

Methods

Eighty-five French older community-dwellers without open-angle glaucoma and patent age-related macular degeneration(mean, 71.1±4.7years; 45.9%female) from the GAIT study were separated into 2 groups according to serum 25OHD level(i.e., deficient≤25nmol/L or sufficient>25nmol/L). Measurements of GCC and RNFL thickness were performed using HD-OCT. Age, gender, body mass index, number of comorbidities, dementia, functional autonomy, intracranial volume, visual acuity, serum calcium concentration and season of testing were considered as potential confounders.

Results

Mean serum 25OHD concentration was 58.4±26.8nmol/L. Mean logMAR visual acuity was 0.03±0.06. Mean visual field mean deviation was -1.25±2.29dB. Patients with vitamin D deficiency(n=11) had a reduced mean GCC thickness compared to those without vitamin D deficiency(72.1±7.4μm versus 77.5±7.5μm, P=0.028). There was no difference of the mean RNFL thickness in these two groups(P=0.133). After adjustment for potential confounders, vitamin D deficiency was associated with reduced GCC thickness(ß=-5.12, P=0.048) but not RNFL thickness(ß=-9.98, P=0.061). Specifically, vitamin D deficiency correlated with the superior medial GCC area(P=0.017) and superior temporal GCC area(P=0.010).

Conclusions

Vitamin D deficiency in older patients is associated with reduced mean GCC thickness, which can represent an early stage of optic nerve damage, prior to RNFL loss.     

HbA1c Levels Are Associated with Chronic Kidney Disease in a Non-Diabetic Adult Population: A Nationwide Survey (KNHANES 2011–2013)

Background

Many studies have reported an association between glycated hemoglobin A1c (HbA1c) and metabolic syndrome (MetS) in non-diabetes patients. Each component of MetS is in fact related to chronic kidney disease (CKD) incidence and progression. Therefore, HbA1c in non-diabetic mellitus (DM) may be intrinsically associated with the prevalence of CKD. The hypothesis of the present study was that high HbA1c in non-DM patients is associated with CKD.

Patients and Methods

The total number of participants in this study was 24,594. The participants were divided into three groups according to their HbA1c levels: a Low group (<5.7% or <39 mmol/mol), a Middle group (5.7–6.0% or 39–42 mmol/mol), and a High group (>6.0% or >42 mmol/mol). The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

Results

The number of participants allocated to the Low, Middle, and High groups was 8,651, 4,634, and 1,387, respectively. Linear regression analyses were performed to evaluate the association between variables. Standardized β ± standard error was 0.25 ± 0.22 for waist circumference, 0.44 ± 0.20 for fasting glucose, –0.14 ± 0.30 for high-density lipoprotein cholesterol levels, 0.15 ± 2.31 for triglyceride levels, 0.21 ± 0.00 for systolic blood pressure, 0.10 ± 0.00 for diastolic blood pressure, and –0.22 ± 0.42 for eGFR (P < 0.001 for all variables). eGFR in non-diabetes participants was inversely associated with the HbA1c level, where eGFR decreased as HbA1c levels increased. Standardized βs were –0.04 ± 0.42 in multivariable analysis (P < 0.001). The proportion of participants with only MetS, only CKD, or both MetS and CKD was higher in the High group than in the Low and Middle groups.

Conclusion

High HbA1c in non-DM patients may be associated with CKD. Renal function in patients with high HbA1c levels may need to be monitored.     

Repeatability of Foveal Measurements Using Spectralis Optical Coherence Tomography Segmentation Software

Purpose

To investigate repeatability and reproducibility of thickness of eight individual retinal layers at axial and lateral foveal locations, as well as foveal width, measured from Spectralis spectral domain optical coherence tomography (SD-OCT) scans using newly available retinal layer segmentation software.

Methods

High-resolution SD-OCT scans were acquired for 40 eyes of 40 young healthy volunteers. Two scans were obtained in a single visit for each participant. Using new Spectralis segmentation software, two investigators independently obtained thickness of each of eight individual retinal layers at 0°, 2° and 5° eccentricities nasal and temporal to foveal centre, as well as foveal width measurements. Bland-Altman Coefficient of Repeatability (CoR) was calculated for inter-investigator and inter-scan agreement of all retinal measurements. Spearman''s ρ indicated correlation of manually located central retinal thickness (RT₀) with automated minimum foveal thickness (MFT) measurements. In addition, we investigated nasal-temporal symmetry of individual retinal layer thickness within the foveal pit.

Results

Inter-scan CoR values ranged from 3.1μm for axial retinal nerve fibre layer thickness to 15.0μm for the ganglion cell layer at 5° eccentricity. Mean foveal width was 2550μm ± 322μm with a CoR of 13μm for inter-investigator and 40μm for inter-scan agreement. Correlation of RT₀ and MFT was very good (ρ = 0.97, P < 0.0005). There were no significant differences in thickness of any individual retinal layers at 2° nasal compared to temporal to fovea (P > 0.05); however this symmetry could not be found at 5° eccentricity.

Conclusions

We demonstrate excellent repeatability and reproducibility of each of eight individual retinal layer thickness measurements within the fovea as well as foveal width using Spectralis SD-OCT segmentation software in a young, healthy cohort. Thickness of all individual retinal layers were symmetrical at 2°, but not at 5° eccentricity away from the fovea.     

Heart Rate Variability Analysis in an Experimental Model of Hemorrhagic Shock and Resuscitation in Pigs

Background

The analysis of heart rate variability (HRV) has been shown as a promising non-invasive technique for assessing the cardiac autonomic modulation in trauma. The aim of this study was to evaluate HRV during hemorrhagic shock and fluid resuscitation, comparing to traditional hemodynamic and metabolic parameters.

Methods

Twenty anesthetized and mechanically ventilated pigs were submitted to hemorrhagic shock (60% of estimated blood volume) and evaluated for 60 minutes without fluid replacement. Surviving animals were treated with Ringer solution and evaluated for an additional period of 180 minutes. HRV metrics (time and frequency domain) as well as hemodynamic and metabolic parameters were evaluated in survivors and non-survivors animals.

Results

Seven of the 20 animals died during hemorrhage and initial fluid resuscitation. All animals presented an increase in time-domain HRV measures during haemorrhage and fluid resuscitation restored baseline values. Although not significantly, normalized low-frequency and LF/HF ratio decreased during early stages of haemorrhage, recovering baseline values later during hemorrhagic shock, and increased after fluid resuscitation. Non-surviving animals presented significantly lower mean arterial pressure (43±7vs57±9 mmHg, P<0.05) and cardiac index (1.7±0.2vs2.6±0.5 L/min/m², P<0.05), and higher levels of plasma lactate (7.2±2.4vs3.7±1.4 mmol/L, P<0.05), base excess (-6.8±3.3vs-2.3±2.8 mmol/L, P<0.05) and potassium (5.3±0.6vs4.2±0.3 mmol/L, P<0.05) at 30 minutes after hemorrhagic shock compared with surviving animals.

Conclusions

The HRV increased early during hemorrhage but none of the evaluated HRV metrics was able to discriminate survivors from non-survivors during hemorrhagic shock. Moreover, metabolic and hemodynamic variables were more reliable to reflect hemorrhagic shock severity than HRV metrics.     

RGD-Targeted Ultrasound Contrast Agent for Longitudinal Assessment of Hep-2 Tumor Angiogenesis In Vivo

Objective

To prepare arginine-glycine-aspartate (RGD)-targeted ultrasound contrast microbubbles (MBs) and explore the feasibility of their use in assessing dynamic changes in αvβ3 integrin expression in a murine model of tumor angiogenesis.

Methods

RGD peptides were conjugated to the surfaces of microbubbles via biotin-avidin linkage. Microbubbles bearing RADfK peptides were prepared as controls. The RGD-MBs were characterized using an Accusizer 780 and optical microscopy. The binding specificity of the RGD-MBs for ανβ3-expressing endothelial cells (bEnd.3) was demonstrated in vitro by a competitive inhibition experiment. In an in vivo study, mice bearing tumors of three different stages were intravenously injected with RGD-MBs and subjected to targeted, contrast-enhanced, high-frequency ultrasound. Subsequently, tumors were harvested and sectioned for immunofluorescence analysis of ανβ3 expression.

Results

The mean size of the RGD-MBs was 2.36 ± 1.7 μm. The RGD-MBs showed significantly higher adhesion levels to bEnd.3 cells compared to control MBs (P < 0.01). There was rarely binding of RGD-MBs to αvβ3-negative MCF-7 cells. Adhesion of the RGD-MBs to the bEnd.3 cells was significantly inhibited following treatment with anti-alpha(v) antibodies. The quantitative acoustic video intensity for high-frequency, contrast-enhanced ultrasound imaging of subcutaneous human laryngeal carcinoma (Hep-2) tumor xenografts was significantly higher in small tumors (19.89 ± 2.49) than in medium tumors (11.25 ± 2.23) and large tumors (3.38 ± 0.67) (P < 0.01).

Conclusions

RGD-MBs enable noninvasive in vivo visualization of changes in tumor angiogenesis during tumor growth in subcutaneous cancer xenografts.     

Effect of Intraocular Forward Scattering and Corneal Higher-Order Aberrations on Visual Acuity after Descemet’s Stripping Automated Endothelial Keratoplasty

Purpose

To assess the relationship of intraocular forward scattering and corneal higher-order aberrations (HOAs) with best spectacle corrected visual acuity (BSCVA) after Descemet’s stripping automated endothelial keratoplasty (DSAEK), and to compare these parameters between DSAEK and non-Descemet’s stripping automated endothelial keratoplasty (n-DSAEK) groups.

Methods

This retrospective study enrolled thirty eyes of 30 consecutive patients who underwent standard DSAEK, and who underwent successful phacoemulsification with intraocular lens implantation before DSAEK. The mean age at the time of surgery was 71.7 ± 10.4 years. We quantitatively evaluated the objective scattering index (OSI) using the double-pass instrument (OQAS II, Visiometrics) and corneal HOAs using Hartmann-Shack aberrometry (KR-9000PW, Topcon) 3 months postoperatively.

Results

The mean OSI, corneal HOAs, and logMAR BSCVA 3 months after DSAEK were 7.91 ± 3.58, 0.43 ± 0.27 μm, and 0.32 ± 0.25, respectively. We found a significant correlation between the OSI and logMAR BSCVA (Spearman correlation coefficient r=0.714, p<0.001), but no significant association between corneal HOAs and logMAR BSCVA 3 months postoperatively (r=0.209, p=0.267). We found no significant differences in any postoperative parameters between the DSAEK and n-DSAEK groups (p>0.05).

Conclusions

Our pilot study demonstrated that the postoperative corrected visual acuity was significantly correlated with intraocular forward scattering, but not with corneal HOAs in post-DSAEK eyes, suggesting that intraocular forward scattering plays a more essential role in postoperative visual performance than corneal aberrations after DSAEK. The detailed visual performance, such as HOAs and intraocular scattering, after n-DSAEK appears to be essentially equivalent to that after DSAEK.     

Importance of Central Retinal Sensitivity for Prediction of Visual Acuity after Intravitreal Bevacizumb in Eyes with Macular Edema Associated with Branch Retinal Vein Occlusion

Objective

To determine whether the baseline retinal sensitivity can predict the best-corrected visual acuity (BCVA) at 1 month after intravitreal bevacizumab (IVB) in eyes with macular edema (ME) associated with a branch retinal vein occlusion (BRVO).

Subjects and Methods

We evaluated 16 eyes of 16 patients who had ME associated with a BRVO. The mean ± standard deviation age was 69.1 ± 8.9 years, and all had a single IVB injection. The BCVA, central macular thickness (CMT), integrity of the ellipsoid zone (EZ) of the photoreceptors, and retinal sensitivity were determined before (baseline) and at 1 day, 1 week, and 1 month following the IVB. The average threshold retinal sensitivity (AT) within the central 10° was determined by Macular Integrity Assessment. The correlations between the BCVA at 1 month and the CMT, integrity of the EZ, and AT at each visit were determined.

Results

One month after IVB, the BCVA improved significantly from 0.56 ± 0.27 logMAR units to 0.32 ± 0.28 logMAR units, and the CMT from 611.4 ± 209.3 μm to 258.7 ± 64.0 μm (P <0.05). The AT improved significantly from 17.9 ± 5.3 dB to 21.2 ± 5.0 dB (P <0.05). At 1 day after the treatment, both the integrity of the EZ (r = 0.59) and the retinal sensitivity (r = 0.76) were moderately correlated with the BCVA at 1 month.

Conclusion

These results indicate that both the integrity of the EZ and the AT at 1 day after the IVB can predict the BCVA after treatment for ME associated with BRVO. There is a possibility that these parameters will predict the effectiveness of IVB for each case.     

Long-Term Once-Daily Tiotropium Respimat? Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised,Placebo-Controlled Study

Background

This study assessed the long-term safety and efficacy of tiotropium Respimat, a long-acting inhaled anticholinergic bronchodilator, in asthma, added on to inhaled corticosteroids (ICS) with or without long-acting β₂-agonist (LABA).

Methods

285 patients with symptomatic asthma, despite treatment with ICS±LABA, were randomised 2:2:1 to once-daily tiotropium 5 μg, tiotropium 2.5 μg or placebo for 52 weeks (via the Respimat SoftMist inhaler) added on to ICS±LABA, in a double-blind, placebo-controlled, parallel-group study (NCT01340209). Primary objective: to describe the long-term safety profile of tiotropium. Secondary end points included: trough forced expiratory volume in 1 second (FEV₁) response; peak expiratory flow rate (PEFR) response; seven-question Asthma Control Questionnaire (ACQ-7) score.

Results

At Week 52, adverse-event (AE) rates with tiotropium 5 μg, 2.5 μg and placebo were 88.6%, 86.8% and 89.5%, respectively. Commonly reported AEs with tiotropium 5 μg, 2.5 μg and placebo were nasopharyngitis (48.2%, 44.7%, 42.1%), asthma (28.9%, 29.8%, 38.6%), decreased PEFR (15.8%, 7.9%, 21.1%), bronchitis (9.6%, 13.2%, 7.0%), pharyngitis (7.9%, 13.2%, 3.5%) and gastroenteritis (10.5%, 3.5%, 5.3%). In the tiotropium 5 μg, 2.5 μg and placebo groups, 8.8%, 5.3% and 5.3% of patients reported drug-related AEs; 3.5%, 3.5% and 15.8% reported serious AEs. Asthma worsening was the only serious AE reported in more than one patient. At Week 52, adjusted mean trough FEV₁ and trough PEFR responses were significantly higher with tiotropium 5 μg (but not 2.5 μg) versus placebo. ACQ-7 responder rates were higher with tiotropium 5 μg and 2.5 μg versus placebo at Week 24.

Conclusions

The long-term tiotropium Respimat safety profile was comparable with that of placebo Respimat, and associated with mild to moderate, non-serious AEs in patients with symptomatic asthma despite ICS±LABA therapy. Compared with placebo, tiotropium 5 μg, but not 2.5 μg, significantly improved lung function and symptoms, supporting the long-term efficacy of the 5 μg dose.

Trial Registration

ClinicalTrials.gov NCT01340209     

Impacts of Co-Existing Chronic Rhinosinusitis on Disease Severity and Risks of Exacerbations in Chinese Adults with Bronchiectasis

Background

Mounting evidence supports the notion of “one airway, one disease.”

Objective

To determine whether chronic rhinosinusitis (CRS) poses adverse impacts on Chinese adults with bronchiectasis.

Methods

We enrolled 148 consecutive adults with clinically stable bronchiectasis. CRS diagnosed based on the 2012 EP³OS criteria. We systematically evaluated the bronchiectasis etiology, radiology, lung function, sputum bacteriology, airway inflammatory biomarkers, Bronchiectasis Severity Index, cough sensitivity and healthcare resource utilization. All patients were prospectively followed-up for 1 year to examine the frequency of bronchiectasis exacerbations (BEs).

Results

Forty-seven patients (31.8%) were diagnosed as having CRS. Bronchiectasis etiologies did not vary statistically between CRS and no-CRS group. There was a trend towards non-statistically higher Bronchiectasis Severity Index [6.4±3.4 vs. 5.0(6.0), P = 0.19], a higher proportion of patients with BEs needing hospitalization before enrollment (48.9% vs. 29.7%, P = 0.13), poorer FVC [78.2±19.8% vs. 82.2(16.8)%, P = 0.54] and FEV₁ [68.2±24.8% vs. 74.8(21.2)%, P = 0.29], a higher prevalence of Pseudomonas aeruginosa isolated (36.2% vs. 26.7%, P = 0.27) or colonized in sputum (36.2% vs. 21.8%, P = 0.12) and greater capsaicin cough sensitivity [C2: 3.9(123.0) μmol/L vs. 11.7(123.0) μmol/L, P = 0.81; C5: 62.5(996.0) μmol/L vs. 250.0(973.0) μmol/L, P = 0.32]. Patients with CRS had significantly greater risks of experiencing BEs during follow-up (P = 0.02 for negative binominal regression test).

Conclusion

Chinese adults with bronchiectasis appear to have a lower prevalence of CRS than that in western countries. There was a trend towards greater adverse impacts on bronchiectasis in patients with CRS. Studies with greater sample sizes might help to resolve this issue. In future clinical practice, physicians should be vigilant to the screening of concomitant CRS in bronchiectasis so as to better improve patient’s healthcare. Our findings may be of clinical significance in that proper treatment of upper airway symptoms due to CRS will be the prevention of infection or re-infection of the tracheobronchial tree, which should be addressed for the future management of bronchiectasis.