Systemic PTEN-Akt1-mTOR pathway activity in patients with normal tension glaucoma and ocular hypertension: A case series.

Glaucoma is the most common optic neuropathy in humans and the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP), while increasing evidence suggests that systemic mitochondrial abnormalities may also be implicated in its pathogenesis. We have recently shown that patients who have not developed glaucoma despite being exposed for many years to high IOP (ocular hypertension - OHT) have more efficient mitochondria, measured in peripheral blood lymphocytes, when compared to age-similar controls and fast progressing normal tension glaucoma (NTG) patients. In this prospective case series we aimed to explore some of the molecular pathways involved in mitochondrial efficiency in glaucoma resistance by measuring the systemic activity (in peripheral blood) of key mitochondrial regulators: the mammalian target of rapamycin (mTOR) and its major upstream regulators and downstream effectors that form the PTEN-Akt1-mTOR signalling pathway. We found no statistically significant difference in the systemic mTOR activity between the three groups (control, NTG and OHT). In line with the mTOR results, there was no significant difference in the activity of both the two major upstream mTOR regulators (PTEN and Akt1) and its two main downstream effectors (S6K and 4EBP1). In a single NTG patient, with history of Raynaud's, significantly higher mTOR activity was noted. We conclude that the PTEN-Akt1-mTOR pathway does not appear to play a central role in mitochondrial efficiency in OHT.

Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency.

Glaucomatous optic neuropathy, an important neurodegenerative condition and the commonest optic neuropathy in humans, is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP). Using glaucomatous optic neuropathy as an exemplar for neurodegeneration, this study investigates putative factors imparting resistance to neurodegeneration. Systemic mitochondrial function, oxidative stress and vascular parameters were compared from isolated lymphocytes, whole blood and urine samples between 30 patients who have not developed the neuropathy despite being exposed for many years to very high IOP ('resistant'), 30 fast deteriorating glaucoma patients despite having low IOP ('susceptible'), and 30 age-similar controls. We found that 'resistant' individuals showed significantly higher rates of ADP phosphorylation by mitochondrial respiratory complexes I, II and IV, hyperpolarised mitochondrial membrane potential, higher levels of mitochondrial DNA, and enhanced capacity to deal with cytosolic calcium overload and exogenous oxidative stress, as compared to both controls and glaucoma patients. While it has been known for some years that mitochondrial dysfunction is implicated in neurodegeneration, this study provides a fresh perspective to the field of neurodegeneration by providing, for the first time, evidence that systemic mitochondrial efficiency above normal healthy levels is associated with an enhanced ability to withstand optic nerve injury. These results demonstrate the importance of cellular bioenergetics in glaucomatous disease progression, with potential relevance for other neurodegenerative disorders, and raise the possibility for new therapeutic targets in the field of neurodegeneration.

The educational value of ward rounds for junior trainees.

The ward round (WR) is a complex task and medical teachers are often faced with the challenge of finding a balance between service provision and clinical development of learners. The educational value of WRs is an under-researched area. This short communication aims to evaluate the educational role of WRs for junior trainees and provides insight into current practices. It also identifies obstacles to effective teaching/training in this setting and provides suggestions for improving the quality of WR teaching.

A critical review of the core medical training curriculum in the UK: A medical education perspective.

This paper represents a systematic evaluation of the Core Medical Training Curriculum in the UK. The authors critically review the curriculum from a medical education perspective based mainly on the medical education literature as well as their personal experience of this curriculum. They conclude in practical recommendations and suggestions which, if adopted, could improve the design and implementation of this postgraduate curriculum. The systematic evaluation approach described in this paper is transferable to the evaluation of other undergraduate or postgraduate curricula, and could be a helpful guide for medical teachers involved in the delivery and evaluation of any medical curriculum.

Recharging mitochondrial batteries in old eyes. Near infra-red increases ATP.

Progressive accumulation of age related mitochondrial DNA mutations reduce ATP production and increase reactive oxygen species output, leading to oxidative stress, inflammation and degradation. The pace of this is linked to metabolic demand. The retina has the greatest metabolic demand and mitochondrial density in the body and displays progressive age related inflammation and marked cell loss. Near infra-red (670 nm) is thought to be absorbed by cytochrome c oxidase (COX), a key element in mitochondrial respiration and it has been demonstrated that it improves mitochondrial membrane potentials in aged eyes. It also significantly reduces the impact of experimental pathology and ameliorates age related retinal inflammation. We show ATP decline with ageing in mouse retina and brain. Also, in these tissues that ATP is significantly increased by 670 nm exposure in old mice. In the retina this was associated with increased COX and reduced acrolein expression. Acrolein, being a free radical marker of retinal oxidative stress, is up regulated in Alzheimer's and retinal degeneration. This is the first demonstration of ATP manipulation in vivo and may provide a simple non-invasive route to combating age related tissue decline.

Predictive factors for early mortality after percutaneous endoscopic and radiologically-inserted gastrostomy.

BACKGROUND: Gastrostomy insertion is of benefit to selected patients, but 30-day mortality is as high as 54% in some patient groups. The current study examines risk factors associated with 30-day mortality in a cohort of patients who underwent percutaneous endoscopic gastrostomy (PEG) or radiologically-inserted gastrostomy (RIG) in a district general hospital over a 2.5 year period. METHODS: A retrospective review of case notes was performed for all patients who underwent a PEG (n=53) or RIG (n=40) insertion in the period January 2009-July 2011. PEG/RIG re-insertions were excluded. Demographic, clinical, and biochemical data were analysed. Multivariate regression analysis was used to identify risk factors for early mortality after gastrostomy insertion. RESULTS: The indications for gastrostomy insertion were similar in the PEG and RIG groups and included mainly dysphagic stroke, chronic neuromuscular disease and head and neck cancer. The patients in the RIG group were older and had a higher incidence of cardiovascular co-morbidities. The overall 30-day mortality was 11% in the PEG and 40% in the RIG group. The multivariate regression analysis suggested that cardiovascular co-morbidities and RIG insertion were independent risk factors for early mortality. The main cause of death 30 days after gastrostomy insertion was pneumonia, which was significantly more common in the RIG group. CONCLUSIONS: Our data suggest that PEG should be the procedure of choice when considering gastrostomy insertion and RIG should be reserved as a second-line approach for cases in which PEG is technically difficult or contraindicated.

Alcoholic liver disease and bilateral multifocal central serous retinopathy: a case report.

INTRODUCTION: We present a unique case of a patient with bilateral, multifocal central serous retinopathy in a patient with alcoholic liver disease. CASE PRESENTATION: A 58-year-old Caucasian man with alcoholic liver disease, liver cirrhosis and ascites presented to the eye clinic. The ophthalmoscopic examination of both eyes revealed a symmetrical pattern of variably sized, slightly yellowish, translucent, raised lesions throughout the fundi which were confirmed to be caused by multifocal central serous retinopathy after optical coherence tomography and autofluoresence tests. CONCLUSION: This case highlights the possible link between central serous retinopathy and end-stage liver disease, with potential implications for the pathogenesis of central serous retinopathy in these patients.