Risk factors associated with corneal nerve alteration in type 1 diabetes in the absence of neuropathy: A longitudinal in vivo corneal confocal microscopy study

Purpose The aim of this study was to determine alterations to the corneal subbasal nerve plexus (SNP) over four years using in vivo corneal confocal microscopy (IVCM) in participants with type 1 diabetes and to identify significant risk factors associated with these alterations. Methods A cohort of 108 individuals with type 1 diabetes and no evidence of peripheral neuropathy at enrollment underwent laser-scanning IVCM, ocular screening, and health and metabolic assessment at baseline and the examinations continued for four subsequent annual visits. At each annual visit, eight central corneal images of the SNP were selected and analyzed to quantify corneal nerve fiber density (CNFD), branch density (CNBD) and fiber length (CNFL). Linear mixed model approaches were fitted to examine the relationship between risk factors and corneal nerve parameters. Results A total of 96 participants completed the final visit and 91 participants completed all visits. No significant relationships were found between corneal nerve parameters and time, sex, duration of diabetes, smoking, alcohol consumption, blood pressure or BMI. However, CNFD was negatively associated with HbA1c (β=-0.76, P<0.01) and age (β=-0.13, P<0.01) and positively related to high density lipids (HDL) (β=2.01, P=0.03). Higher HbA1c (β=-1.58, P=0.04) and age (β=-0.23, P<0.01) also negatively impacted CNBD. CNFL was only affected by higher age (β=-0.06, P<0.01). Conclusions Glycemic control, HDL and age have significant effects on SNP structure. These findings highlight the importance of diabetic management to prevent corneal nerve damage as well as the capability of IVCM for monitoring subclinical alterations in the corneal SNP in diabetes.

Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: Comparing corneal confocal microscopy with intraepidermal nerve fiber density

OBJECTIVE Quantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard. RESEARCH DESIGN AND METHODS Eighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy. RESULTS Manual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14). CONCLUSIONS This study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN.

Biosynthesis of Long-Chain Alcohols by Developing and Regenerating Rat Sciatic Nerve

Cell-free preparations of rat sciatic nerve were found to catalyze the reduction of fatty acid to alcohol in the presence of NADPH as reducing cofactor. The reductase was membrane-bound and associated primarily with the microsomal fraction. When fatty acid was the substrate, ATP, coenzyme A (CoA), and Mg2+ were required, indicating the formation of acyl CoA prior to reduction. When acyl CoA was used as substrate, the presence of albumin was required to inhibit acyl CoA hydro-lase activity. Fatty acid reductase activity was highest with palmitic and stearic acids, and somewhat lower with lauric and myristic acids. It was inhibited by sulfhydryl reagents, indicating the participation of thiol groups in the reduction. Only traces of long-chain aldehyde could be detected or trapped as semicarbazone. Fatty acid reductase activity in rat sciatic nerve was highest between the second and tenth days after birth and decreased substantially thereafter. Microsomal preparations of sciatic nerve from 10-day-old rats exhibited about four times higher fatty acid reductase activity than brain or spinal cord microsomes from the same animals. Wallerian degeneration and regeneration of adult rat sciatic nerve resulted in enhanced fatty acid reductase activity, which reached a maximum at about 12 days after crush injury.

A Framework for Detecting Glaucomatous Progression in the Optic Nerve Head of an Eye Using Proper Orthogonal Decomposition

Glaucoma is the second leading cause of blindness worldwide. Often, the optic nerve head (ONH) glaucomatous damage and ONH changes occur prior to visual field loss and are observable in vivo. Thus, digital image analysis is a promising choice for detecting the onset and/or progression of glaucoma. In this paper, we present a new framework for detecting glaucomatous changes in the ONH of an eye using the method of proper orthogonal decomposition (POD). A baseline topograph subspace was constructed for each eye to describe the structure of the ONH of the eye at a reference/baseline condition using POD. Any glaucomatous changes in the ONH of the eye present during a follow-up exam were estimated by comparing the follow-up ONH topography with its baseline topograph subspace representation. Image correspondence measures of L-1-norm and L-2-norm, correlation, and image Euclidean distance (IMED) were used to quantify the ONH changes. An ONH topographic library built from the Louisiana State University Experimental Glaucoma study was used to evaluate the performance of the proposed method. The area under the receiver operating characteristic curves (AUCs) was used to compare the diagnostic performance of the POD-induced parameters with the parameters of the topographic change analysis (TCA) method. The IMED and L-2-norm parameters in the POD framework provided the highest AUC of 0.94 at 10 degrees. field of imaging and 0.91 at 15 degrees. field of imaging compared to the TCA parameters with an AUC of 0.86 and 0.88, respectively. The proposed POD framework captures the instrument measurement variability and inherent structure variability and shows promise for improving our ability to detect glaucomatous change over time in glaucoma management.

Does the addition of Clonidine to lumbar nerve root blocks improve outcome? A randomised, prospective, single-blinded controlled pilot study

Purpose To evaluate if adding clonidine to a standard nerve root block containing local anaesthetic and steroid improved the outcome of patients with severe lumbar nerve root pain secondary to MRI proven lumbar disc prolapse. Methods We undertook a single blind, prospective, randomised controlled trial evaluating 100 consecutive patients with nerve root pain secondary to lumbar disc prolapse undergoing trans-foraminal epidural steroid injection either with or without the addition of clonidine. 50 patients were allocated to each arm of the study. The primary outcome measure was the avoidance of a second procedure- repeat injection or micro-discectomy surgery. Secondary outcome measures were also studied: pain scores for leg and back pain using a visual analogue scale (VAS), the Roland Morris Disability Questionnaire (RMDQ) and the Measure Your Own Medical Outcome Profile (MYMOP). Follow up was carried out at 6 weeks, 6 months and 1 year. Results No serious complications occurred. Of the 50 patients who received the addition of clonidine, 56% were classified as successful injections, with no further intervention required, as opposed to 40% who received the standard injection. This difference did not reach statistical significance (p=0.109, chi-squared test). All secondary measures showed no statistically significant differences between the groups except curiously, the standard group who had been classified as successful had better leg pain relief than the clonidine group (p=0.026) at 1 year. Conclusions This pilot study has shown a 16% treatment effect with adding clonidine to lumbar nerve root blocks and that it is a safe injectate for this purpose.

Planar pursuit-evasion with variable speeds, part 1, extremal trajectory maps

Pursuit evasion in a plane is formulated with both players allowed to vary their speeds between fixed limits. A suitable choice of real-space coordinates confers open-loop optimality on the game. The solution in the small is described in terms of the individual players'' extremal trajectory maps (ETM). Each map is independent of role, adversary, and capture radius. An ETM depicts the actual real-space trajectories. A template method of generating constant control arcs is described. Examples of ETM for an aircraft flying at a constant altitude with fixed and varying speeds are presented.

Co2 emissions and income trajectory in Australia: The role of technological change

This study investigates the relationship between per capita carbon dioxide (CO2) emissions and per capita GDP in Australia, while controlling for technological state as measured by multifactor productivity and export of black coal. Although technological progress seems to play a critical role in achieving long term goals of CO2 reduction and economic growth, empirical studies have often considered time trend to proxy technological change. However, as discoveries and diffusion of new technologies may not progress smoothly with time, the assumption of a deterministic technological progress may be incorrect in the long run. The use of multifactor productivity as a measure of technological state, therefore, overcomes the limitations and provides practical policy directions. This study uses recently developed bound-testing approach, which is complemented by Johansen- Juselius maximum likelihood approach and a reasonably large sample size to investigate the cointegration relationship. Both of the techniques suggest that cointegration relationship exists among the variables. The long-run and short-run coefficients of CO2 emissions function is estimated using ARDL approach. The empirical findings in the study show evidence of the existence of Environmental Kuznets Curve type relationship for per capita CO2 emissions in the Australian context. The technology as measured by the multifactor productivity, however, is not found as an influencing variable in emissionsincome trajectory.

Determination of optimal trajectory under design constraints for a satellite launch vehicle

An optimal pitch steering programme of a solid-fuel satellite launch vehicle to maximize either (1) the injection velocity at a given altitude, or (2) the size of circular orbit, for a given payload is presented. The two-dimensional model includes the rotation of atmosphere with the Earth, the vehicle's lift and drag, variation of thrust with time and altitude, inverse-square gravitational field, and the specified initial vertical take-off. The inequality constraints on the aerodynamic load, control force, and turning rates are also imposed. Using the properties of the central force motion the terminal constraint conditions at coast apogee are transferred to the penultimate stage burnout. Such a transformation converts a time-free problem into a time-fixed one, reduces the number of terminal constraints, improves accuracy, besides demanding less computer memory and time. The adjoint equations are developed in a compact matrix form. The problem is solved on an IBM 360/44 computer using a steepest ascent algorithm. An illustrative analysis of a typical launch vehicle establishes the speed of convergence, and accuracy and applicability of the algorithm.

Trajectory sensitivity modification in optimal linear systems

A new procedure for reducing trajectory sensitivity for the optimal linear regulator is described. The design is achieved without increase in the order of optimization and without the feedback of trajectory sensitivity. The procedure is also used in the input signal design problem for linear system identification by interpreting it as increasing trajectory sensitivity with respect to parameters to be estimated.

Microneurovascular free muscle transfer with cross-over nerve grafts in facial reanimation

Microneurovascular free muscle transfer with cross-over nerve grafts in facial reanimation Loss of facial symmetry and mimetic function as seen in facial paralysis has an enormous impact on the psychosocial conditions of the patients. Patients with severe long-term facial paralysis are often reanimated with a two-stage procedure combining cross-facial nerve grafting, and 6 to 8 months later with microneurovascular (MNV) muscle transfer. In this thesis, we recorded the long-term results of MNV surgery in facial paralysis and observed the possible contributing factors to final functional and aesthetic outcome after this procedure. Twenty-seven out of forty patients operated on were interviewed, and the functional outcome was graded. Magnetic resonance imaging (MRI) of MNV muscle flaps was done, and nerve graft samples (n=37) were obtained in second stage of the operation and muscle biopsies (n=18) were taken during secondary operations.. The structure of MNV muscles and nerve grafts was evaluated using histological and immunohistochemical methods ( Ki-67, anti-myosin fast, S-100, NF-200, CD-31, p75NGFR, VEGF, Flt-1, Flk-1). Statistical analysis was performed. In our studies, we found that almost two-thirds of the patients achieved good result in facial reanimation. The longer the follow-up time after muscle transfer the weaker was the muscle function. A majority of the patients (78%) defined their quality of life improved after surgery. In MRI study, the free MNV flaps were significantly smaller than originally. A correlation was found between good functional outcome and normal muscle structure in MRI. In muscle biopsies, the mean muscle fiber diameter was diminished to 40% compared to control values. Proliferative activity of satellite cells was seen in 60% of the samples and it tended to decline with an increase of follow-up time. All samples showed intramuscular innervation. Severe muscle atrophy correlated with prolonged intraoperative ischaemia. The good long-term functional outcome correlated with dominance of fast fibers in muscle grafts. In nerve grafts, the mean number of viable axons amounted to 38% of that in control samples. The grafted nerves characterized by fibrosis and regenerated axons were thinner than in control samples although they were well vascularized. A longer time between cross facial nerve grafting and biopsy sampling correlated with a higher number of viable axons. P75Nerve Growth Factor Receptor (p75NGFR) was expressed in every nerve graft sample. The expression of p75NGFR was lower in older than in younger patients. A high expression of p75NGFR was often seen with better function of the transplanted muscle. In grafted nerve Vascular Endothelial Growth Factor (VEGF) and its receptors were expressed in nervous tissue. In conclusion, most of the patients achieved good result in facial reanimation and were satisfied with the functional outcome. The mimic function was poorer in patients with longer follow-up time. MRI can be used to evaluate the structure of the microneurovascular muscle flaps. Regeneration of the muscle flaps was still going on many years after the transplantation and reinnervation was seen in all muscle samples. Grafted nerves were characterized by fibrosis and fewer, thinner axons compared to control nerves although they were well vascularized. P75NGFR and VEGF were expressed in human nerve grafts with higher intensity than in control nerves which is described for the first time.

Aircraft trajectory clustering techniques using circular statistics

This paper presents a statistical aircraft trajectory clustering approach aimed at discriminating between typical manned and expected unmanned traffic patterns. First, a resampled version of each trajectory is modelled using a mixture of Von Mises distributions (circular statistics). Second, the remodelled trajectories are globally aligned using tools from bioinformatics. Third, the alignment scores are used to cluster the trajectories using an iterative k-medoids approach and an appropriate distance function. The approach is then evaluated using synthetically generated unmanned aircraft flights combined with real air traffic position reports taken over a sector of Northern Queensland, Australia. Results suggest that the technique is useful in distinguishing between expected unmanned and manned aircraft traffic behaviour, as well as identifying some common conventional air traffic patterns.

Trajectory controllability of nonlinear integro-differential system

A stronger concept of complete (exact) controllability which we call Trajectory Controllability is introduced in this paper. We study the Trajectory Controllability of an abstract nonlinear integro-differential system in the finite and infinite dimensional space setting. (C) 2010 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.

Experimental approach for studying structural changes in axonal membrane upon nerve excitation

The Hodgkin and Huxley (HH) model of action potential has become a central paradigm of neuroscience. Despite its ability to predict action potentials with remarkable accuracy, it fails to explain several biophysical findings related to the initiation and propagation of the nerve impulse. The isentropic heat release and optical phenomena demonstrated by various experiments suggest that action potential is accompanied by a transient phase change in the axonal membrane. In this study a method was developed for preparing a giant axon from the crayfish abdominal cord for studying the molecular mechanisms of action potential simultaneously by electrophysiological and optical methods. Also an alternative setup using a single-cell culture of an Aplysia sensory neuron is presented. In addition to the description of the method, the preliminary results on the effect of phloretin, a dipole potential lowering compound, on the excitability of a crayfish giant axon are presented.