Subjective and objective performance of the Lenstec KH-3500 "accommodative" intraocular lens

Aim: To determine whether eyes implanted with the Lenstec KH-3500 "accommodative" intraocular lenses (IOLs) have improved subjective and objective focusing performance compared to a standard monofocal IOLs. Methods: 28 participants were implanted monocularly with a KH-3500 " accommodative" IOL and 20 controls with a Softec1 IOL. Outcome measures of refraction, visual acuity, subjective amplitude of accommodation, objective accommodative stimulus response curve, aberrometry, and Scheimpflug imaging were taken at ∼3 weeks and repeated after 6 months. Results: Best corrected acuity with the KH-3500 was 0.06 (SD 0.13) logMAR at distance and 0.58 (0.20) logMAR at near. Accommodation was 0.39 (0.53) D measured objectively and 3.1 (1.6) D subjectively. Higher order aberrations were 0.87 (0.85) μm and lower order were 0.24 (0.39) μm. Posterior subcapsular light scatter was 0.95% (1.37%) greater than IOL clarity. In comparison, all control group measures were similar except objective (0.17 (0.13) D; p = 0.032) and subjective (2.0 (0.9) D; p = 0.009) amplitude of accommodation. Six months following surgery, posterior subcapsular scatter had increased (p<0.01) in the KH-3500 implanted subjects and near word acuity had decreased (p<0.05). Conclusions: The objective accommodating effects of the KH-3500 IOL appear to be limited, although the subjective and objective accommodative range is significantly increased compared to control subjects implanted with conventional IOLs. However, this "accommodative" ability of the lens appears to have decreased by 6 months post-surgery.

Beta barrel trans-membrane proteins:enhanced prediction using a Bayesian approach

Membrane proteins, which constitute approximately 20% of most genomes, form two main classes: alpha helical and beta barrel transmembrane proteins. Using methods based on Bayesian Networks, a powerful approach for statistical inference, we have sought to address beta-barrel topology prediction. The beta-barrel topology predictor reports individual strand accuracies of 88.6%. The method outlined here represents a potentially important advance in the computational determination of membrane protein topology.

Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia

Weight loss in advanced cancer patients is refractory to conventional nutritional support. This may be due to metabolic changes mediated by proinflammatory cytokines, hormones, and tumor-derived products. We previously showed that a nutritional supplement enriched with fish oil will reverse weight loss in patients with pancreatic cancer cachexia. The present study examines the effect of this supplement on a number of mediators thought to play a role in cancer cachexia. Twenty weight-losing patients with pancreatic cancer were asked to consume a nutritional supplement providing 600 kcal and 2 g of eicosapentaenoic acid per day. At baseline and after 3 wk, patients were weighed and samples were collected to measure serum concentrations of interleukin (IL)-6 and its soluble receptor tumor necrosis factor receptors I and II, cortisol, insulin, and leptin, peripheral blood mononuclear cell production of IL-1 beta, IL-6, and tumor necrosis factor, and urinary excretion of proteolysis inducing factor. After 3 wk of consumption of the fish oil-enriched nutritional supplement, there was a significant fall in production of IL-6 (from median 16.5 to 13.7 ng/ml, P = 0.015), a rise in serum insulin concentration (from 3.3 to 5.0 mU/l, P = 0.0064), a fall in the cortisol-to-insulin ratio (P = 0.0084), and a fall in the proportion of patients excreting proteolysis inducing factor (from 88% to 40%, P = 0.008). These changes occurred in association with weight gain (median 1 kg, P = 0.024). Various mediators of catabolism in cachexia are modulated by administration of a fish oil-enriched nutritional supplement in pancreatic cancer patients. This may account for the reversal of weight loss in patients consuming this supplement.

Alpha helical trans-membrane proteins:enhanced prediction using a Bayesian approach

Membrane proteins, which constitute approximately 20% of most genomes, are poorly tractable targets for experimental structure determination, thus analysis by prediction and modelling makes an important contribution to their on-going study. Membrane proteins form two main classes: alpha helical and beta barrel trans-membrane proteins. By using a method based on Bayesian Networks, which provides a flexible and powerful framework for statistical inference, we addressed alpha-helical topology prediction. This method has accuracies of 77.4% for prokaryotic proteins and 61.4% for eukaryotic proteins. The method described here represents an important advance in the computational determination of membrane protein topology and offers a useful, and complementary, tool for the analysis of membrane proteins for a range of applications.

Novel glucagon-like peptide-1 (GLP-1) analog (Val8)GLP-1 results in significant improvements of glucose tolerance and pancreatic β-cell function after 3-week daily administration in obese diabetic (ob/ob) mice

This study evaluates the antidiabetic potential of an enzyme-resistant analog, (Val8)GLP-1. The effects of daily administration of a novel dipeptidyl peptidase IV-resistant glucagon-like peptide-1 (GLP-1) analog, (Val8)GLP-1, on glucose tolerance and pancreatic β-cell function were examined in obese-diabetic (ob/ob) mice. Acute intraperitoneal administration of (Val8)GLP-1 (6.25-25 nmol/kg) with glucose increased the insulin response and reduced the glycemic excursion in a dose-dependent manner. The effects of (Val8)GLP-1 were greater and longer lasting than native GLP-1. Once-daily subcutaneous administration of (Val8)GLP-1 (25 nmol/kg) for 21 days reduced plasma glucose concentrations, increased plasma insulin, and reduced body weight more than native GLP-1 without a significant change in daily food intake. Furthermore, (Val8)GLP-1 improved glucose tolerance, reduced the glycemic excursion after feeding, increased the plasma insulin response to glucose and feeding, and improved insulin sensitivity. These effects were consistently greater with (Val8)GLP-1 than with native GLP-1, and both peptides retained or increased their acute efficacy compared with initial administration. (Val8)GLP-1 treatment increased average islet area 1.2-fold without changing the number of islets, resulting in an increased number of larger islets. These data demonstrate that (Val8)GLP-1 is more effective and longer acting than native GLP-1 in obese-diabetic ob/ob mice.

Amyloid β 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks

Alzheimer's disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide. Brain hypometabolism is a major feature of AD, appearing decades before cognitive decline and pathologic lesions. To date, the majority of studies on hypometabolism in AD have used transgenic animal models or imaging studies of the human brain. As it is almost impossible to validate these findings using human tissue, alternative models are required. In this study, we show that human stem cell-derived neuron and astrocyte cultures treated with oligomers of amyloid beta 1-42 (Aβ1-42) also display a clear hypometabolism, particularly with regard to utilization of substrates such as glucose, pyruvate, lactate, and glutamate. In addition, a significant increase in the glycogen content of cells was also observed. These changes were accompanied by changes in NAD+ /NADH, ATP, and glutathione levels, suggesting a disruption in the energy-redox axis within these cultures. The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aβ-induced hypometabolism. Further research using this model may elucidate the mechanisms associated with Aβ-induced hypometabolism.

Oxidised LDL-lipids alter redox ratio, lipid raft formation and increase amyloid beta production by SHSY-5Y cells

Elevated cholesterol in mid-life has been associated with increased risk of dementia in later life. We have previously shown that low density lipoprotein (LDL) is more oxidised in the plasma of dementia patients although total cholesterol levels remained unchanged [1]. We have investigated the hypothesis that amyloid beta production and neurodegeneration can be driven by oxidised lipids derived from LDL following the loss of blood brain barrier integrity with ageing. Therefore, we have investigated amyloid beta formation in SHSY5Y cells treated with LDL, minimally modified (ox) LDL, and lipids extracted from both forms of LDL. LDL-treated SHSY-5Y cell viability was not significantly decreased with up to 8 μg LDL/2 × 104 cells compared to untreated cells. However, 8 μg oxLDL protein/2 × 104 cells decreased the cell viability significantly by 33.7% (P < 0.05). A more significant decrease in cell viability was observed when treating cells with extracted lipids from 8 μg of LDL (by 32.7%; P < 0.01) and oxLDL (by 41%; P < 0.01). In parallel, the ratio of reduced to oxidised GSH was decreased; GSH concentrations were significantly decreased following treatment with 0.8 μg/ml oxLD-L (7.35 ± 0.58;P < 0.01), 1.6 μg/ml (5.27 ± 0.23; P < 0.001) and 4 μg/ml (5.31 ± 0.31; P < 0.001). This decrease in redox potential was associated with an increase acid sphingomyelinase activity and lipid raft formation which could be inhibited by desipramine; SHSY5Y cells treated with oxLDL, and lipids from LDL and oxLDL for 16 h showed significantly increased acid sphingomyelinase activity (5.32 ± 0.35; P < 0.05, 5.21 ± 0.6; P < 0.05, and 5.58 ± 0.44; P < 0.01, respectively) compared to control cells (2.96 ± 0.34). As amyloid beta production is driven by the activity of beta secretase and its association with lipid rafts, we investigated whether lipids from ox-LDL can influence amyloid beta by SHSY-5Y cells in the presence of oxLDL. Using ELISA and Western blot, we confirmed that secretion of amyloid beta oligomers is increased by SHSY-5Y cells in the presence of oxLDL lipids. These data suggest a mechanism whereby LDL, and more significantly oxLDL lipids, can drive amyloid beta production and cytotoxicity in neuronal cells. [1] Li L, Willets RS, Polidori MC, Stahl W, Nelles G, Sies H, Griffiths HR. Oxidative LDL modification is increased in vascular dementia and is inversely associated with cognitive performance. Free Radic Res. 2010 Mar; 44(3): 241–8.