The role of advanced glycation end products in retinal ageing and disease

The retina is exposed to a lifetime of potentially damaging environmental and physiological factors that make the component cells exquisitely sensitive to age-related processes. Retinal ageing is complex and a raft of abnormalities can accumulate in all layers of the retina. Some of this pathology serves as a sinister preamble to serious conditions such as age-related macular degeneration (AMD) which remains the leading cause of irreversible blindness in the Western world.

The formation of advanced glycation end products (AGEs) is a natural function of ageing but accumulation of these adducts also represents a key pathophysiological event in a range of important human diseases. AGEs act as mediators of neurodegeneration, induce irreversible changes in the extracellular matrix, vascular dysfunction and pro-inflammatory signalling. Since many cells and tissues of the eye are profoundly influenced by such processes, it is fitting that advanced glycation is now receiving considerable attention as a possible pathogenic factor in visual disorders.

This review presents the current evidence for a pathogenic role for AGEs and activation of the receptor for AGEs (RAGE) in initiation and progression of retinal disease. It draws upon the clinical and experimental literature and highlights the opportunities for further research that would definitively establish these adducts as important instigators of retinal disease. The therapeutic potential for novel agents that can ameliorate AGE formation of attenuate RAGE signalling in the retina is also discussed.

Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

Objective: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs).

Breast cancer genetics: Unsolved questions and open perspectives in an expanding clinical practice

Breast cancer is the most common cause of cancer death in the United Kingdom, with a lifetime risk of one in nine in women. Only 5-10% of all cancers is thought to be due to strongly penetrant inherited predisposing genes, such as BRCA1 and BRCA2. However, other less penetrant genes, including some autosomal recessive genes, are likely to be of etiological importance in other families. This review addresses the current knowledge of breast cancer susceptibility genes and explores the possibilities for future developments. Features of tumor pathology, prognosis, and the scope for targeted treatments in mutation carriers are discussed, and the management of known carriers and those at increased risk for developing breast cancer are evaluated. Genetic testing for cancer susceptibility may become widely available in the future, and has important ethical and management implications. (C) 2004 Wiley-Liss, Inc.

Myocardial infarction in the C57BL/6J mouse - A quantifiable and highly reproducible experimental model

Introduction: The laboratory mouse is a powerful tool in cardiovascular research. In this report, we describe a method for a reproducible mouse myocardial infarction model that would allow subsequent comparative and quantitative studies on molecular and pathophysiological variables. Methods: (A) The distribution of the major coronary arteries including the septal artery in the left ventricle of the C57BL/6J mice (n=20) was mapped by perfusion of latex dye or fluorescent beads through the aorta. (B) The territory of myocardial infarction after the ligation of the most proximal aspect of the left anterior descending (LAD) coronary artery was quantified. (C) The consistency in the histological changes parallel to the infarction at different time points was analyzed. Results: (A) The coronary artery tree of the mouse is different from human and, particularly, in regard to the blood supply of the septum. (B) Contrary to previous belief, the septal coronary artery in the mouse is variable in origin. (C) A constant ligation of the LAD immediately below the left auricular level ensures a statistically significant reproducible infarct size. (D) The ischemic changes can be monitored at a histological level in a way similar to what is described in the human. Conclusion: We illustrate a method for maximal reproducibility of experimental acute myocardial infarction in the mouse model, due to a consistent loss of perfusion in the lower half of the left ventricle. This will allow the study of molecular and physiological variables in a controlled and quantifiable experimental model environment. (C) 2004 Elsevier Inc. All rights reserved.

N1, P2 and T-complex of the auditory brain event-related potentials to tones with varying rise times in adults with and without dyslexia

Dyslexia is a learning difficulty affecting the acquisition of fluent reading and spelling skills due to poor phonological processing. Underlying deficits in processing sound rise time have also been found in children and adults with dyslexia. However, the neural basis for these deficits is unknown. In the present study event-related potentials were used to index neural processing and examine the effect of rise time manipulation on the obligatory N1. T-complex and P2 responses in English speaking adults with and without dyslexia. The Tb wave of the T-complex showed differences between groups, with the amplitudes for Tb becoming less negative with increased rise time for the participants with dyslexia only. Frontocentral N1 and P2 did not show group effects. Enhanced Tb amplitude that is modulated by rise time could indicate altered neural networks at the lateral surface of the superior temporal gyrus in adults with dyslexia. (C) 2011 Elsevier B.V. All rights reserved.

Effects of the organophosphorous pesticide, dimethoate, on cardiac and acetylcholinesterase (AChE) activity in the shore crab Carcinus maenas

The potential use of biochemical and physiological responses as biomarkers of organophosphate exposure and/or effect were assessed in the shore crab (Carcinus maenas). Male crabs were assigned to one of four dimethoate treatments (0, 0.5, 1.0 or 2.0 mg 1(-1)). Cardiac activity was measured non-invasively before and during dimethoate exposure using automated interpulse duration assessment. Heart rates decreased significantly in a concentration-dependent manner (p

Dual task performance of working memory and postural control in major depressive disorder

Objective: Previous studies with patients diagnosed with Major Depressive Disorder (MDD) revealed deficits in working memory and executive functions. In the present study we investigated whether patients with MDD have the ability to allocate cognitive resources in dual task performance of a highly challenging cognitive task (working memory) and a task that is seemingly automatic in nature (postural control). Method: Fifteen young (18–35 years old) patients with MDD and 24 healthy age-matched controls performed a working memory task and two postural control tasks (standing on a stable or on a moving platform) both separately (single task) and concurrently (dual task). Results: Postural stability under single task conditions was similar in the two groups, and in line with earlier studies, MDD patients recalled fewer working memory items than controls. To equate working memory challenges for patients and controls, task difficulty (number of items presented) in dual task was individually adjusted such that accuracy of working memory performance was similar for the two groups under single task conditions. Patients showed greater postural instability in dual task performance on the stable platform, and more importantly when posture task difficulty increased (moving platform) they showed deficits in both working memory accuracy and postural stability compared with healthy controls. Conclusions: We interpret our results as evidence for executive control deficits in MDD patients that affect their task coordination. In multitasking, these deficits affect not only cognitive but also sensorimotor task performance.

Exploring and comparing the experience and coping behaviour of men and women with colorectal cancer at diagnosis and during surgery

Aim. This paper is a report of a study exploring and comparing the experience of men and women with colorectal cancer at diagnosis and during surgery.

Background. Men have higher incidence and mortality rates for nearly all cancers and frequently use health behaviours that reflect their masculinity. There has been minimal investigation into the influence of gender on the experience of a ‘shared’ cancer.

Methods. From November 2006 to November 2008, a qualitative study was conducted involving 38 individuals (24 men, 14 women) with colorectal cancer. Data were generated using semi-structured interviews at four time points over an 18-month period. This paper reports the participants’ experience at diagnosis and during surgery (time point 1) with the purpose of examining the impact of gender on this experience.

Findings. In general, men appeared more accepting of their diagnosis. The majority of females seemed more emotional and more affected by the physical side effects. However, there was variation in both gender groups, with some men and women portraying both ‘masculine’ and ‘feminine’ traits. There was also individual variation in relation to context.

Conclusions. It appears that many men may have been experiencing side effects and/or psychological distress that they were reluctant to discuss, particularly as some men portrayed typical ‘masculine’ traits in public, but felt able to open up in private. Nurses should not make assumptions based on the traditional view of masculinity, and should determine how each man wants to deal with their diagnosis and not presume that all men need to ‘open up’ about their illness.

The effect of hypoxia on propranolol clearance during antegrade and retrograde flow in the isolated perfused rat liver preparation

We investigated, using the single-pass isolated perfused rat liver preparation, whether the centrilobular location of hepatic oxidative drug metabolism could be a contributing factor to the marked sensitivity of drug oxidation to hypoxia. Livers (N = 7) were each perfused for 130 min with 2 micrograms/mL (+)-propranolol, a drug metabolized almost entirely by oxidation in the rat. The direction of flow was reversed after 60 min, the order of flow direction being randomized. Normal oxygenation was used during the first 30 min of antegrade and of retrograde perfusion, but in the second 30 min perfusate was equilibrated with a N2/O2 mixture designed to reduce hepatic oxygen delivery by half. During normal oxygenation there was no significant difference between antegrade and retrograde perfusion in hepatic oxygen delivery and physiological parameters such as oxygen consumption and extraction, perfusion pressure and bile flow. During hypoxia, mean oxygen delivery was slightly lower with retrograde perfusion (retrograde: mean = 2.37 mumol/min/g liver, range = 1.56-3.17; antegrade: mean = 2.90 mumol/min/g liver, range = 1.96-4.08; P = 0.04), but there was no significant difference in physiological parameters within each liver (P > 0.05). Propranolol clearance during normal oxygenation was similar to the perfusion rate (10 mL/min) and was the same for both directions of perfusion (antegrade 9.88 +/- 0.07 mL/min, retrograde 9.88 +/- 0.13 mL/min, P > 0.05). Hypoxia reduced propranolol clearance substantially, but the decrease was significantly greater with antegrade perfusion (5.65 +/- 1.89 mL/min) than with retrograde perfusion (6.76 +/- 1.95 mL/min, P = 0.014). Oxidative drug metabolism is located primarily in the centrilobular zone and sinusoidal oxygen concentration is lowest in the "downstream" zone with both antegrade and retrograde perfusion. These findings suggest that the centrilobular location of propranolol metabolism may influence the effect of hypoxia on propranolol elimination, but is not a major contributor to the marked sensitivity of propranolol elimination to hypoxia antegrade perfusion.

Lichen-induced biomodification of calcareous surfaces: Bioprotection versus biodeterioration

Studies demonstrate the active and passive capability of lichens to inhibit or retard the weathering of calcareous surfaces. Lichen coverage may actively protect a surface through shielding by the thallus and the binding and waterproofing of the rock surface and subsurface by fungal hyphae. Passive protection of rock surfaces may be induced by the formation of an insoluble encrustation, such as calcium oxalate, at the lichen-rock interface. Recent research suggests that the decay of hyphae, induced by changes in microenvironmental conditions, necrosis, parasitism or the natural physiological traits of particular lichen species, may expose a chemically and physically weakened substrate to dissolution triggering relatively rapid weathering-related surface lowering. Consequently, certain epilithic crustose and endolithic lichens may induce a period of surface stability throughout the course of their lifespan, followed by a phase of instability and rapid episodic microtopographical evolution after death and decay. A series of conceptual models is proposed to illustrate this idea over short (single lichen lifespan) and long (multiple lichen lifespans) timescales. The models suggest that the microscale biogeomorphological system of lichen-rock interaction is underpinned by nonlinear dynamical system theory as it exhibits dynamical instability and is consequently difficult to predict over a long timescale. Dominance by biodeterioration or bioprotection may be altered by changes in lichen species or in environmental conditions over time.

The mechanistic basis of interactions between mycorrhizal associations and toxic metal cations

Mycorrhizal associations, including ericoid, arbuscular and ecto-mycorrhizas, are found colonising highly metal contaminated soils. How do mycorrhizal fungi achieve metal resistance, and does this metal resistance confer enhanced metal resistance to plant symbionts? These are the questions explored in this review by considering the mechanistic basis of mycorrhizal adaptation to metal cations. Recent molecular and physiological studies are discussed. The review reappraises what constitutes metal resistance in the context of mycorrhizal associations and sets out the constitutive and adaptive mechanisms available for mycorrhizas to adapt to contaminated sites. The only direct evidence of mycorrhizal adaptation to metal cation pollutants is the exudation of organic acids to alter pollutant availability in the rhizosphere. This is not to say that other mechanism of adaptation do not exist, but conclusive evidence of adaptive mechanisms of tolerance are lacking. For constitutive mechanisms of resistance, there is much more evidence, and mycorrhizas possess the same constitutive mechanisms for dealing with metal contaminants as other organisms. Rhizosphere chemistry is critical to understanding the interactions of mycorrhizas with polluted soils. Soil pH, mineral weathering, pollutant precipitation with plant excreted organic acids all may have a key role in constitutive and adaptive tolerance of mycorrhizal associations present on contaminated sites. The responses of mycorrhizal fungi to toxic metal cations are diverse. This, linked to the fact that mycorrhizal diversity is normally high, even on highly contaminated sites, suggests that this diversity may have a significant role in colonisation of contaminated sites by mycorrhizas. That is, the environment selects for the fungal community that can best cope with the environment, so having diverse physiological attributes will enable colonisation of a wide range of metal contaminated micro-habitats.

Cognitive maturation in preterm and term born adolescents

Background: Adolescence is a critical period of brain structural reorganisation and maturation of cognitive abilities. This relatively late developmental reorganisation may be altered in individuals who were born preterm.

Methods: We carried out longitudinal neuropsychological testing in 94 very preterm individuals (VPT; before 33 weeks' gestation) and 44 term born individuals at mean ages of 15.3 years ( adolescence) and 19.5 years (young adulthood).

Results: Full scale, verbal and performance IQ and phonological verbal fluency were significantly lower in the VPT group than the term group at both ages. Repeated measures ANOVA showed only one group by time point interaction for semantic verbal fluency (F= 10.25; df = 107; p = 0.002). Paired- sample t tests showed that semantic verbal fluency increased significantly in the term group over adolescence (t = -5.10; df = 42; p < 0.001), but did not increase in the VPT group (t = 0.141; df = 69; p = 0.889). For verbal IQ, there was a significant interaction between time point and sex (F = 4.48; df = 1; p = 0.036) with paired- sample t tests showing that verbal IQ decreased in males between adolescence and adulthood (t = 3.35; df = 71; p = 0.001), but did not change significantly in females (t = 0.20; df = 52; p = 0.845).

Conclusion: Decrements of intellectual functioning in VPT individuals persist into adulthood. Additionally, there is a deficit in the adolescent maturation of semantic verbal fluency in individuals born VPT.

Neonatal Ultrasound Results Following Very Preterm Birth Predict Adolescent Behavioral and Cognitive Outcome

This study investigated the association between different neonatal ultrasonographic classifications and adolescent cognitive, educational, and behavioral outcomes following very preterm birth. Participants included a group of 120 adolescents who were born very preterm (33 weeks of gestation), subdivided into three groups according to their neonatal cerebral ultrasound (US) classifications: (a) normal (N = 69), (b) periventricular hemorrhage (PVH, N = 37), and (c) PVH with ventricular dilatation (PVH + DIL, N = 14), and 50 controls. The cognitive functions assessed were full-scale IQ, phonological and semantic verbal fluency, and visual-motor integration. Educational outcomes included reading and spelling; behavioral outcomes were assessed with the Rutter Parents' Scale and the Premorbid Adjustment Scale (PAS). Adolescent outcome scores were compared among the four groups. A main effect for group was observed for full-scale IQ, Rutter Parents' Scale total scores, and PAS total scores, after controlling for gestational age, socioeconomic status and gender, with the PVH + DIL group showing the most impaired scores compared to the other groups. The current results demonstrate that routine neonatal ultrasound classifications are associated with later cognitive and behavioral outcome. Neonatal ultrasounds could aid in the identification of subgroups of children who are at increased risk of neurodevelopmental problems. These at risk subgroups could then be referred to appropriate early intervention services.