Ocular compatibility of hydrogel contact lenses:deposition and clinical performance

Currently over 50 million people worldwide wear contact lenses, of which over 75% wear hydrogel lenses. Significant deposition occurs in approximately 80% of hydrogel lenses and many contact lens wearers cease wearing lenses due to problems associated with deposition. The contact lens field is not alone in encountering complications associated with interactions between the body and artificial devices. The widespread use of man-made materials to replace structures in the body has emphasised the importance of studies that examine the interactions between implantation materials and body tissues.This project used carefully controlled, randomized clinical studies to study the interactive effects of contact lens materials, care systems, replacement periods and patient differences. Of principal interest was the influence of these factors on material deposition and their subsequent impact on subjective performance. A range of novel and established analytical techniques were used to examine hydrogel lenses following carefully controlled clinical studies in which clinical performance was meticulously monitored. These studies established the inter-relationship between clinical performance and deposition to be evaluated. This project showed that significant differences exist between individuals in their ability to deposit hydrogel lenses, with approximately 20% of subjects displaying significant deposition irrespective of the lens material. Additionally, materials traditionally categorised together show markedly different spoilation characteristics, which are wholly attributable to their detailed chemical structure. For the first time the in vivo deposition kinetics of both protein and lipid in charged and uncharged polymers was demonstrated. In addition the importance of care systems in the deposition process was shown, clearly demonstrating the significance of the quality rather than the quantity of deposition in influencing subjective performance.

Somatic cell gene therapy for diabetes mellitus: engineering a surrogate B-cell

Improved methods of insulin delivery are required for the treatment of insulin-dependent diabetes mellitus (IDDM) to achieve a more physiological profile of glucose homeostasis. Somatic cell gene therapy offers the prospect that insulin could be delivered by an autologous cell implant, engineered to secrete insulin in response to glucose. This study explores the feasibility of manipulating somatic cells to behave as a surrogate insulin-secreting β-cells. Initial studies were conducted using mouse pituitary AtT20 cells as a model, since these cells possess an endogenous complement of enzymes capable of processing proinsulin to mature insulin. Glucose sensitive insulin secretion was conferred to these cells by transfection with plasmids containing the human preproinsulin gene (hppI-1) and the GLUT2 gene for the glucose transporter isoform 2. Insulin secretion was responsive to changes in the glucose concentration up to about 50μM. Further studies to up-rate this glucose sensitivity into the mM range will require manipulation of the hexokinase and glucokinase enzymes. Intraperitoneal implantation of the manipulated AtT20 cells into athymic nude mice with streptozotocin-induced diabetes resulted in decreased plasma glucose concentrations. The cells formed vascularised tumours in vivo which were shown to contain insulin-secreting cells. To achieve proinsulin processing in non-endocrine cells, co-transfection with a suitable enzyme, or mutagenesis of the proinsulin itself are necessary. The mutation of the human preproinsulin gene to the consensus sequence for cleavage by the subtilisin-like serine protease, furin, was carried out. Co-transfection of human fibroblasts with wild-type proinsulin and furin resulted in 58% conversion to mature insulin by these cells. Intraperitoneal implantation of the mature-insulin secreting human fibroblasts into the diabetic nude mouse animal model gave less encouraging results than the AtT20 cells, apparently due to poor vascularisation. Cell aggregations removed from the mice at autopsy were shown to contain insulin secreting cells only at the periphery. This thesis provides evidence that it is possible to construct, by cellular engineering, a glucose-sensitive insulin-secreting surrogate β-cell. Therefore, somatic cell gene therapy offers a feasible alternative for insulin delivery in IDDM patients.

A decade of silicone hydrogel development:surface properties, mechanical properties, and ocular compatibility

Since the initial launch of silicone hydrogel lenses, there has been a considerable broadening in the range of available commercial material properties. The very mobile silicon–oxygen bonds convey distinctive surface and mechanical properties on silicone hydrogels, in which advantages of enhanced oxygen permeability, reduced protein deposition, and modest frictional interaction are balanced by increased lipid and elastic response. There are now some 15 silicone hydrogel material variants available to practitioners; arguably, the changes that have taken place have been strongly influenced by feedback based on clinical experience. Water content is one of the most influential properties, and the decade has seen a progressive rise from lotrafilcon-A (24%) to efrofilcon-A (74%). Moduli have decreased over the same period from 1.4 to 0.3 MPa, but not solely as a result of changes in water content. Surface properties do not correlate directly with water content, and ingenious approaches have been used to achieve desirable improvements (e.g., greater lubricity and lower contact angle hysteresis). This is demonstrated by comparing the hysteresis value of the earliest (lotrafilcon-A, >40°) and most recent (delefilcon-A, <10°) coated silicone hydrogels. Although wettability is important, it is not of itself a good predictor of ocular response because this involves a much wider range of physicochemical and biochemical factors. The interference of the lens with ocular dynamics is complex leading separately to tissue–material interactions involving anterior and posterior lens surfaces. The biochemical consequences of these interactions may hold the key to a greater understanding of ocular incompatibility and end of day discomfort.

Clonal composition of human adamantinomatous craniopharyngiomas and somatic mutation analyses of the patched (PTCH), Gsα and Gi2α genes

Craniopharyngioma is the most common childhood tumor and thought to arise from embryonic remnants of Rathke's pouch. The paucity of published data on the molecular basis of these tumors prompted us to examine 22 adamantinomatous craniopharyngiomas looking for genetic abnormalities. Using the X-linked polymorphic androgen receptor gene as a tool for X-chromosome inactivating analysis, we found that a subset of craniopharyngiomas are monoclonal and therefore are probably due to acquired somatic genetic defects. Thus, we investigated these tumours for mutations within three candidate genes, Gsα, Gi2α and patched (PTCH). Using single stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis and direct sequencing, the presence of somatic mutations in these genes could not be demonstrated in any tumor. Our data indicate that a subset of craniopharyngiomas are monoclonal and the mutations in the PTCH, Gsα, and Gi2α contribute little if any to cranipharyngioma development.

Psychophysiological responses to visceral and somatic pain in functional chest pain identify clinically relevant pain clusters

Background: Despite chronic pain being a feature of functional chest pain (FCP) its experience is variable. The factors responsible for this variability remain unresolved. We aimed to address these knowledge gaps, hypothesizing that the psychophysiological profiles of FCP patients will be distinct from healthy subjects. Methods: 20 Rome III defined FCP patients (nine males, mean age 38.7 years, range 28-59 years) and 20 healthy age-, sex-, and ethnicity-matched controls (nine males, mean 38.2 years, range 24-49) had anxiety, depression, and personality traits measured. Subjects had sympathetic and parasympathetic nervous system parameters measured at baseline and continuously thereafter. Subjects received standardized somatic (nail bed pressure) and visceral (esophageal balloon distension) stimuli to pain tolerance. Venous blood was sampled for cortisol at baseline, post somatic pain and post visceral pain. Key Results: Patients had higher neuroticism, state and trait anxiety, and depression scores but lower extroversion scores vs controls (all p < 0.005). Patients tolerated less somatic (p < 0.0001) and visceral stimulus (p = 0.009) and had a higher cortisol at baseline, and following pain (all p < 0.001). At baseline, patients had a higher sympathetic tone (p = 0.04), whereas in response to pain they increased their parasympathetic tone (p ≤ 0.008). The amalgamating the data, we identified two psychophysiologically distinct 'pain clusters'. Patients were overrepresented in the cluster characterized by high neuroticism, trait anxiety, baseline cortisol, pain hypersensitivity, and parasympathetic response to pain (all p < 0.03). Conclusions & Inferences: In future, such delineations in FCP populations may facilitate individualization of treatment based on psychophysiological profiling. © 2013 John Wiley & Sons Ltd.

A road safety performance indicator for vehicle fleet compatibility

This paper discusses the development and the application of a safety performance indicator which measures the intrinsic safety of a country's vehicle fleet related to fleet composition. The indicator takes into account both the ‘relative severity’ of individual collisions between different vehicle types, and the share of those vehicle types within a country's fleet. The relative severity is a measure for the personal damage that can be expected from a collision between two vehicles of any type, relative to that of a collision between passenger cars. It is shown how this number can be calculated using vehicle mass only. A sensitivity analysis is performed to study the dependence of the indicator on parameter values and basic assumptions made. The indicator is easy to apply and satisfies the requirements for appropriate safety performance indicators. It was developed in such a way that it specifically scores the intrinsic safety of a fleet due to its composition, without being influenced by other factors, like helmet wearing. For the sake of simplicity, and since the required data is available throughout Europe, the indicator was applied to the relative share of three of the main vehicle types: passenger cars, heavy goods vehicles and motorcycles. Using the vehicle fleet data from 13 EU Member States and Norway, the indicator was used to rank the countries’ safety performance. The UK was found to perform best in terms of its fleet composition (value is 1.07), while Greece has the worst performance with the highest indicator value (1.41).

On the compatibility of benevolence and self-interest:philanthropy and entrepreneurial orientation

This article explores the philanthropy of owner–managers of small- and medium-sized enterprises (SMEs) investigating whether and why more entrepreneurially oriented SMEs are also more likely to engage in philanthropic activities. We find support for a positive link between entrepreneurial orientation (EO) and philanthropy in a representative sample of 270 Lithuanian SMEs controlling for alternative explanations. We highlight that philanthropy is relatively common among SME owner–managers and thus complement existing research which views philanthropy as sequentially following wealth generation. In line with our theorizing, further qualitative findings point to drivers of philanthropy beyond those considered in the dominant strategic-instrumental perspective. Building on social-psychological theories of motivation, we argue and confirm that philanthropy can also be an expression of owner–managers’ altruistic values; these values can be compatible and even mutually reinforcing with entrepreneurship. Our study is set in a transition economy, Lithuania, facilitating the analysis of heterogeneity in attitudes toward philanthropy.

Medical conditions and depressive, anxiety, and somatic symptoms in older adults with and without generalized anxiety disorder

OBJECTIVE: The objective of this study was to examine medical illness and anxiety, depressive, and somatic symptoms in older medical patients with generalized anxiety disorder (GAD). METHOD: A case-control study was designed and conducted in the University of California, San Diego (UCSD) Geriatrics Clinics. A total of fifty-four older medical patients with GAD and 54 matched controls participated. MEASUREMENTS: The measurements used for this study include: Brief Symptom Inventory-18, Mini International Neuropsychiatric Interview, and the Anxiety Disorders Interview Schedule. RESULTS: Older medical patients with GAD reported higher levels of somatic symptoms, anxiety, and depression than other older adults, as well as higher rates of diabetes and gastrointestinal conditions. In a multivariate model that included somatic symptoms, medical conditions, and depressive and anxiety symptoms, anxiety symptoms were the only significant predictors of GAD. CONCLUSION: These results suggest first, that older medical patients with GAD do not primarily express distress as somatic symptoms; second, that anxiety symptoms in geriatric patients should not be discounted as a byproduct of medical illness or depression; and third, that older adults with diabetes and gastrointestinal conditions may benefit from screening for anxiety.