Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes

Objective Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. Setting Antenatal clinics. Population Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). Methods Maternal serum levels of sRAGE (total circulating pool), N -(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. Main outcome measures Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-). Results In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P <0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P <0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P <0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. Conclusions In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM. © 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.

Highly Sensitive, Uniform, and Reproducible Surface-Enhanced Raman Spectroscopy from Hollow Au-Ag Alloy Nanourchins

A hierarchical nanoparticle strategy to simultaneously gain super Raman signal amplification, high uniformity, and reproducibility is presented. Using hollow Au-Ag alloy nanourchins, an ultrahigh sensitivity, e.g., down to 1 fM concentrations for DEHP molecule is obtained. A small standard deviation of <10% is achieved by simply dropping and evaporating sub-100 nm nanourchins onto a substrate.

Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia

Deficits in sensitivity to visual stimuli of low spatial frequency and high temporal frequency (so-called frequency-doubled gratings) have been demonstrated both in schizophrenia and in autism spectrum disorder (ASD). Such basic perceptual functions are ideal candidates for molecular genetic study, because the underlying neural mechanisms are well characterized; but they have sometimes been overlooked in favor of cognitive and neurophysiological endophenotypes, for which neural substrates are often unknown. Here, we report a genome-wide association study of a basic visual endophenotype associated with psychological disorder. Sensitivity to frequency-doubled gratings was measured in 1060 healthy young adults, and analyzed for association with genotype using linear regression at 642758 single nucleotide polymorphism (SNP) markers. A significant association (P=7.9×10) was found with the SNP marker rs1797052, situated in the 5′-untranslated region of PDZK1; each additional copy of the minor allele was associated with an increase in sensitivity equivalent to more than half a standard deviation. A permutation procedure, which accounts for multiple testing, showed that the association was significant at the α=0.005 level. The region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for ASD, mirroring the common association of the visual endophenotype with the two disorders. PDZK1 interacts with N-methyl-d-aspartate receptors and neuroligins, which have been implicated in the etiologies of schizophrenia and ASD. These findings suggest that perceptual abnormalities observed in two different disorders may be linked by common genetic elements. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Evaluation of sources of uncertainties in microtensile bond strength of dental adhesive system for different specimen geometries

Objective: The aim of this research is to use finite element analysis (FEA) to quantify the effect of the sample shape and the imperfections induced during the manufacturing process of samples on the bond strength and modes of failure of dental adhesive systems through microtensile test. Using the FEA prediction for individual parameters effect, estimation of expected variation and spread of the microtensile bond strength results for different sample geometries is made. Methods: The estimated stress distributions for three different sample shapes, hourglass, stick and dumbbell predicted by FEA are used to predict the strength for different fracture modes. Parameters such as the adhesive thickness, uneven interface of the adhesive and composite and dentin, misalignment of axis of loading, the existence of flaws such as induced cracks during shaping the samples or bubbles created during application of the adhesive are considered. Microtensile experiments are performed simultaneously to measure bond strength and modes of failure. These are compared with the FEA results. Results: The relative bonding strength and its standard deviation for the specimens with different geometries measured through the microtensile tests confirm the findings of the FEA. The hourglass shape samples show lower tensile bond strength and standard deviation compared to the stick and dumbbell shape samples. ANOVA analysis confirms no significant difference between dumbbell and stick geometry results, and major differences of these two geometries compared to hourglass shape measured values. Induced flaws in the adhesive and misalignment of the angle of application of load have significant effect on the microtensile bond strength. Using adhesive with higher modulus the differences between the bond strength of the three sample geometries increase. Significance: The result of the research clarifies the importance of the sample geometry chosen in measuring the bond strength. It quantifies the effect of the imperfections on the bond strength for each of the sample geometries through a systematic and all embracing study. The results explain the reasons of the large spread of the microtensile test results reported by various researchers working in different labs and the need for standardization of the test method and sample shape used in evaluation of the dentin-adhesive bonding system. © 2007 Academy of Dental Materials.

Monitoring daily MLC positional errors using trajectory log files and EPID measurements for IMRT and VMAT deliveries

This work investigated the differences between multileaf collimator (MLC) positioning accuracy determined using either log files or electronic portal imaging devices (EPID) and then assessed the possibility of reducing patient specific quality control (QC) via phantom-less methodologies. In-house software was developed, and validated, to track MLC positional accuracy with the rotational and static gantry picket fence tests using an integrated electronic portal image. This software was used to monitor MLC daily performance over a 1 year period for two Varian TrueBeam linear accelerators, with the results directly compared with MLC positions determined using leaf trajectory log files. This software was validated by introducing known shifts and collimator errors. Skewness of the MLCs was found to be 0.03 ± 0.06° (mean ±1 standard deviation (SD)) and was dependent on whether the collimator was rotated manually or automatically. Trajectory log files, analysed using in-house software, showed average MLC positioning errors with a magnitude of 0.004 ± 0.003 mm (rotational) and 0.004 ± 0.011 mm (static) across two TrueBeam units over 1 year (mean ±1 SD). These ranges, as indicated by the SD, were lower than the related average MLC positioning errors of 0.000 ± 0.025 mm (rotational) and 0.000 ± 0.039 mm (static) that were obtained using the in-house EPID based software. The range of EPID measured MLC positional errors was larger due to the inherent uncertainties of the procedure. Over the duration of the study, multiple MLC positional errors were detected using the EPID based software but these same errors were not detected using the trajectory log files. This work shows the importance of increasing linac specific QC when phantom-less methodologies, such as the use of log files, are used to reduce patient specific QC. Tolerances of 0.25 mm have been created for the MLC positional errors using the EPID-based automated picket fence test. The software allows diagnosis of any specific leaf that needs repair and gives an indication as to the course of action that is required.

Physical activity, sedentary behaviour and fetal macrosomia in uncomplicated pregnancies: A prospective cohort study

Objective: to explore maternal energy balance, incorporating free living physical activity and sedentary behaviour, in uncomplicated pregnancies at risk of macrosomia.

Methods: a parallel-group cross-sectional analysis was conducted in healthy pregnant women predicted to deliver infants weighing Z4000 g (study group) or o4000 g (control group). Women were recruited in a 1:1 ratio from antenatal clinics in Northern Ireland. Women wore a SenseWears Body Media Pro3 physical activity armband and completed a food diary for four consecutive days in the third trimester. Physical activity was measured in Metabolic Equivalent of Tasks (METs) where 1 MET¼1 kcal per kilogram of body weight per hour. Analysis of covariance (ANCOVA) was employed using the General Linear Model to adjust for potential confounders.

Findings: of the 112 women recruited, 100 complete datasets were available for analysis. There was no significant difference in energy balance between the two groups. Intensity of free living physical activity (average METs) of women predicted to deliver macrosomic infants (n¼50) was significantly lower than that of women in the control group (n¼50) (1.3 (0.2) METs (mean, standard deviation) versus 1.2 (0.2) METs; difference in means 0.1 METs (95% confidence interval: 0.19, 0.01); p¼0.021). Women predicted to deliver macrosomic infants also spent significantly more time in sedentary behaviour (r1 MET) than the control group (16.1 (2.8) hours versus 13.8 (4.3) hours; 2.0 hours (0.3, 3.7), p¼0.020).

Key conclusions and implications for practice: although there was no association between predicted fetal macrosomia and energy balance, those women predicted to deliver a macrosomic infant exhibited increased sedentary behaviour and reduced physical activity in the third trimester of pregnancy. Professionals caring for women during pregnancy have an important role in promoting and supporting more active lifestyles amongst women who are predicted to deliver a macrosomic infant given the known associated risks.

Clinical Characteristics of Reticular Pseudodrusen in the Fellow Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration

Purpose: To describe associations between reticular pseudodrusen, individual characteristics, and retinal function.

Design: Cohort study.

Participants: We recruited 105 patients (age range, 52–93 years) who had advanced neovascular age-related macular degeneration (AMD) in only 1 eye from 3 clinical centers in Europe.

Methods: Minimum follow-up was 12 months. The eye selected for study was the fellow eye without advanced disease. Clinical measures of vision were distance visual acuity, near visual acuity, and results of the Smith-Kettlewell low-luminance acuity test (SKILL). Fundus imaging included color photography, red-free imaging, blue autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and optical coherence tomography using standardized protocols. These were used to detect progression to neovascular AMD in the study eye during follow-up. All imaging outputs were graded for the presence or absence of reticular pseudodrusen (RPD) using a multimodal approach. Choroidal thickness was measured at the foveal center and at 2 other equidistant locations from the fovea (1500 μm) nasally and temporally. Metrics on retinal thickness and volume were obtained from the manufacturer-supplied automated segmentation readouts.

Main Outcome Measures: Presence of RPD, distance visual acuity, near visual acuity, SKILL score, choroidal thickness, retinal thickness, and retinal volume.

Results: Reticular pseudodrusen was found in 43 participants (41%) on 1 or more imaging method. The SKILL score was significantly worse in those with reticular drusen (mean score ± standard deviation [SD, 38±12) versus those without (mean score ± SD, 33±9) (P = 0.034). Parafoveal retinal thickness, parafoveal retinal volume, and all of the choroidal thickness parameters measured were significantly lower in those with reticular drusen than in those without. The presence of RPD was associated with development of neovascular AMD when corrected for age and sex (odds ratio, 5.5; 95% confidence interval, 1.1–28.8; P = 0.042). All participants in whom geographic atrophy developed during follow-up had visible RPD at baseline.

Conclusions: Significant differences in retinal and choroidal anatomic features, visual function, and risk factor profile exist in unilateral neovascular AMD patients with RPD compared with those without; therefore, such patients should be monitored carefully because of the risk of developing bilateral disease.

Distribution of terminal nerve entry points to the flexor and extensor groups of forearm muscles:An anatomical study

The motor points of the skeletal muscles, mainly of interest to anatomists and physiologists, have recently attracted much attention from researchers in the field of functional electrical stimulation. The muscle motor point has been defined as the entry point of the motor nerve branch into the epimysium of the muscle belly. Anatomists have pointed out that many muscles in the limbs have multiple motor points. Knowledge of the location of nerve branches and terminal nerve entry points facilitates the exact insertion and the suitable selection of the number of electrodes required for each muscle for functional electrical stimulation. The present work therefore aimed to describe the number, location, and distribution of motor points in the human forearm muscles to obtain optimal hand function in many clinical situations. Twenty three adult human cadaveric forearms were dissected. The numbers of primary nerves and motor points for each muscle were tabulated. The mean numbers and the standard deviation were calculated and grouped in tables. Data analyses were performed with the use of a statistical analysis package (SPSS 13.0). The proximal third of the muscle was the usual part of the muscle that received the motor points. Most of the forearm muscles were innervated from the lateral side and deep surface of the muscle. The information in this study may also be usefully applied in selective denervation procedures to balance muscles in spastic upper limbs. Copyright © 2007 Via Medica.

A Comparison of Support Needs Between Rural and Urban Family Caregivers Providing Palliative Care

The present study examined the support needs for urban and rural family caregivers of a palliative family member using a cross-sectional telephone survey in northeastern Ontario, Canada (n = 140; 70 urban, 70 rural). Support needs identified as most important by both the groups were informational. Rural caregivers reported greater unmet needs in tangible support (P =.01). No differences were observed between the groups for emotional or informational support needs (P =.25 and P =.35, respectively). Rural and urban caregivers perceived care for care recipients as accessible (mean accessibility score 1.9, standard deviation [SD] = 0.09 and 1.7, SD = 0.7, respectively, P =.20); the majority indicated that when needed, services were easily and quickly obtained. Although there are similarities in the formal care experiences, rural caregivers experience greater unmet needs in receiving support for instrumental activities. © The Author(s) 2013.

Barrier characteristics of PtSi/p-Si schottky diodes as determined from I-V-T measurements

The current-voltage-temperature characteristics of PtSi/p-Si Schottky barrier diodes were measured in the temperature range 60-115 K. Deviation of the ideality factor from unity below 80 K may be modelled using the so-called T-0 parameter with T-0 = 18 K. It is also shown that the curvature in the Richardson plots may be remedied by using the flatband rather than the zero-bias saturation current density. Physically, the departure from ideality is interpreted in terms of an inhomogeneous Schottky contact. Here we determine a mean barrier height at T = 0 K, phi(b)(-0) = 223 mV, with an (assumed) Gaussian distribution of standard deviation sigma(phi) = 12.5 mV. These data are correlated with the zero-bias barrier height, phi(j)(0) = 192 mV (at T = 90 K), the photoresponse barrier height, phi(ph) = 205 mV, and the flatband barrier height, phi(fb) = 214 mV. Finally, the temperature coefficient of the flatband barrier was found to be -0.121 mV K-1, which is approximately equal to 1/2(dE(g)(i)/dT), thus suggesting that the Fermi level at the interface is pinned to the middle of the band gap.

Preaggregated Ag Nanoparticles in Dry Swellable Gel Films for Off-the-Shelf Surface-Enhanced Raman Spectroscopy

Large, thin (50 mu m) dry polymer sheets containing numerous surface-enhanced Raman spectroscopy (SERS) active Ag nanopartide aggregates have been prepared by drying aqueous mixtures of hydroxyethylcelloulose (HEC) and preaggregated Ag colloid in 10 x 10 cm molds. In these dry films, the particle aggregates are protected from the environment during storage and are easy to handle; for example, they can be cut to size with scissors. When in use, the highly swellable HEC polymer allowed the films to rapidly absorb aqueous analyte solutions while simultaneously releasing the Ag nanoparticle aggregates to interact with the analyte and generate large SERS signals. Either the films could be immersed in the analyte solution or 5 mu L droplets were applied to the surface; in the latter method, the local swelling caused the active area to dome upward, but the swollen film remained physically robust and could be handled as required. Importantly, encapsulation and release did not significantly compromise the SERS performance of the colloid; the signals given by the swollen films were similar to the very high signals obtained from the parent citrate-reduced colloid and were an order of magnitude larger than a commercially available nanoparticle substrate. These "Poly-SERS" films retained 70% of their SERS activity after being stored for 1 year in air. The films were sufficiently homogeneous to give a standard deviation of 3.2% in the absolute signal levels obtained from a test analyte, primarily due to the films' ability to suppress "coffee ring" drying marks, which meant that quantitative analysis without an internal standard was possible. The majority of the work used aqueous thiophenol as the test analyte; however, preliminary studies showed that the Poly-SERS films could also be used with nonaqueous solvents and for a range of other analytes including theophylline, a therapeutic drug, at a concentration as low as 1.0 x 10(-5) mol dm(-3) (1.8 mg/dm(3)), well below the sensitivity required for theophylline monitoring where the target range is 10-20 mg/dm(3).

Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection

Nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA) to patients with cystic fibrosis (CF) frequently results in chronic respiratory tract carriage. This is an increasing problem, adds to the burden of glycopeptide antibiotic use in hospitals, and represents a relative contraindication to lung transplantation. The aim of this study was to determine whether it is possible to eradicate MRSA with prolonged oral combination antibiotics, and whether this treatment is associated with improved clinical status. Adult CF patients (six male, one female) with chronic MRSA infection were treated for six months with rifampicin and sodium fusidate. Outcome data were examined for six months before treatment, on treatment and after treatment. The patients had a mean age of 29.3 (standard deviation=6.3) years and FEV(1) of 36.1% (standard deviation=12.7) predicted. The mean duration of MRSA isolation was 31 months. MRSA isolates identified in these patients was of the same lineage as the known endemic strain at the hospital when assessed by pulsed-field gel electrophoresis. Five of the seven had no evidence of MRSA during and for at least six months after rifampicin and sodium fusidate. The proportion of sputum samples positive for MRSA was lower during the six months of treatment (0.13) and after treatment (0.19) compared with before treatment (0.85) (P<0.0001). There was a reduction in the number of days of intravenous antibiotics per six months with 20.3+/-17.6 on treatment compared with 50.7 before treatment and 33.0 after treatment (P=0.02). There was no change in lung function. Gastrointestinal side effects occurred in three, but led to therapy cessation in only one patient. Despite the use of antibiotics with anti-staphylococcal activity for treatment of respiratory exacerbation, MRSA infection persists. MRSA can be eradicated from the sputum of patients with CF and chronic MRSA carriage by using rifampicin and sodium fusidate for six months. This finding was associated with a significant reduction in the duration of intravenous antibiotic treatment during therapy.

IMRT for image-guided single vocal cord irradiation

PURPOSE: We have been developing an image-guided single vocal cord irradiation technique to treat patients with stage T1a glottic carcinoma. In the present study, we compared the dose coverage to the affected vocal cord and the dose delivered to the organs at risk using conventional, intensity-modulated radiotherapy (IMRT) coplanar, and IMRT non-coplanar techniques.

METHODS AND MATERIALS: For 10 patients, conventional treatment plans using two laterally opposed wedged 6-MV photon beams were calculated in XiO (Elekta-CMS treatment planning system). An in-house IMRT/beam angle optimization algorithm was used to obtain the coplanar and non-coplanar optimized beam angles. Using these angles, the IMRT plans were generated in Monaco (IMRT treatment planning system, Elekta-CMS) with the implemented Monte Carlo dose calculation algorithm. The organs at risk included the contralateral vocal cord, arytenoids, swallowing muscles, carotid arteries, and spinal cord. The prescription dose was 66 Gy in 33 fractions.

RESULTS: For the conventional plans and coplanar and non-coplanar IMRT plans, the population-averaged mean dose ± standard deviation to the planning target volume was 67 ± 1 Gy. The contralateral vocal cord dose was reduced from 66 ± 1 Gy in the conventional plans to 39 ± 8 Gy and 36 ± 6 Gy in the coplanar and non-coplanar IMRT plans, respectively. IMRT consistently reduced the doses to the other organs at risk.

CONCLUSIONS: Single vocal cord irradiation with IMRT resulted in good target coverage and provided significant sparing of the critical structures. This has the potential to improve the quality-of-life outcomes after RT and maintain the same local control rates.

Four-dimensional CT analysis of vocal cords mobility for highly focused single vocal cord irradiation

Background and Purpose: To quantify respiratory motion of the vocal cords during normal respiration using 4D-CT. The final goal is to develop a technique for single vocal cord irradiation (SVCI) in early glottic carcinoma. Sparing the non-involved cord and surrounding structures has the potential to preserve voice quality and allow re-irradiation of recurrent and second primary tumors. Material and methods: Four-dimensional CTs of 1 mm slice thickness from 10 early glottic carcinoma patients were acquired. The lateral dimensions of the air gap separating the vocal cords were measured anteriorly, at mid-level and posteriorly at each phase of the 4D-CTs. The corresponding anterior-posterior gaps were similarly measured. Cranio-caudal vocal cords movements during breathing were derived from the shifts of the arythenoids. Results: The population-averaged mean gap size ± the corresponding standard deviation due to breathing (SD_B) for the lateral gaps was 5.8 ± 0.7 mm anteriorly, 8.7 ± 0.9 mm at mid-level, and 11.0 ± 1.3 mm posteriorly. Anterior-posterior gap values were 21.7 ± 0.7 mm, while cranio-caudal shift SD_B was 0.8 mm. Conclusion: Vocal cords breathing motions were found to be small relative to their separation. Hence, breathing motion does not seem to be a limiting factor for SVCI. © 2008 Elsevier Ireland Ltd. All rights reserved.

Retinal microvascular network attenuation in Alzheimer's disease

INTRODUCTION:Cerebral small-vessel disease has been implicated in the development of Alzheimer’sdisease (AD). The retinal microvasculature enables non-invasive visualization andevaluation of the systemic microcirculation. We evaluated retinal microvascular parametersin a case-control study of AD patients and cognitively-normal controls. 

METHODS:Retinal images were computationally analyzed and quantitative retinal parameters (caliber,fractal dimension, tortuosity, and bifurcation) measured. Regression models were used tocompute odds ratios (OR) and confidence intervals (CI) for AD with adjustment forconfounders. 

RESULTS:Retinal images were available in 213 AD participants and 294 cognitively-normal controls.Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77[CI: 0.62–0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63–0.97])were more likely to have AD following appropriate adjustment. 
DISCUSSION:Patients with AD have a sparser retinal microvascular network and retinal microvascularvariation may represent similar pathophysiological events within the cerebralmicrovasculature of patients with AD.