Carotenoids and ocular disease: a review

Background: Carotenoids are not considered to be essential nutrients, but their antioxidant and photoprotective properties have prompted interest in their potential role in disease prevention. Our aim is to review the evidence In relation to ocular disease. Method: Web of Science and Medline via PubMed database search. Results Lutein and zeaxanthin intake has been associated with a 22% reduced risk of cataract extraction in women (RR 0.78, p = 0.04), and a 19% lower risk of cataract in men (RR 0.8, p = 0, 03). A randomised controlled trial (RCT) found a significant improvement in visual acuity in cataract patients supplemented with lutein. Two RCTs investigating the effect of P-carotene, in combination with other nutrients, on cataract report conflicting results. Several studies show no inverse association between cataract and P-carotene. Lutein and zeaxanthin are the only carotenoids found in the human macula. RCTs have found beneficial effects of both lutein and beta-carotene supplementation, in combination with other antioxidants, on visual function age-related macular disease affected subjects. Evidence for a role of lutein in preventing deterioration of visual function in retinitis pigmentosa patients is conflicting. CONCLUSIONS: Further research into the role of lutein and zeaxanthin in prevention of onset and progression of ocular disease is warranted.

Metformin in patients with type 2 diabetes and kidney disease:a systematic review

IMPORTANCE: Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE: To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION: In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining tometformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014.We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS: Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety ofmetformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus-use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE: Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Local-authority led economic regeneration strategies in the aftermath of the Foot-and-Mouth Disease crisis of 2001

The Foot-and-Mouth Disease (FMD) outbreak of 2001 in the UK was completely unprecedented in its scale and severity, with over four million animals culled and a cost to the Exchequer of over £4 billion. Local authorities were at the front line in dealing with the outbreak, in coordinating the cull of livestock, the disposal of carcasses as well as attempting to deal with its aftermath and, in particular, the impact on the wider rural economy. This article examines the impacts of this crisis on three local authorities, Devon, Herefordshire and Cumbria. It examines how far the crisis acted as a catalyst in developing strategies to deal with a future outbreak as well as new local initiatives to promote regeneration in the areas most adversely affected. It focuses on developments that can be directly attributed to the crisis and shows that FMD had a considerable impact on communications and 'joined-up' activity within local authorities and with local stakeholders. © 2006, LEPU, South Bank University.

The spatial patterns of beta-amyloid (Abeta) deposits in dementia with Lewy bodies and Alzheimer’s disease

The spatial patterns of diffuse, primitive and classic beta-amyloid (Abeta) deposits were studied in regions of the temporal lobe in cases of ‘pure’ Dementai with Lewy bodies (DLB), cases of DLB with associated Alzheimer’s disease (AD) (DLB/AD) and cases of ‘pure’ AD. Abeta deposits occurred in clusters in all patient groups. In the majority of brain areas studied, either a single large (=6400 micron) cluster of Abeta deposits was present or Abeta deposits occurred in smaller clusters which were regularly distributed parallel to the tissue boundary. No significant differences in the spatial patterns of Abeta deposits were observed in ‘pure’ DLB compared with DLB/AD. The spatial patterns of Abeta deposits in DLB/AD cases were generally similar to those observed in AD. However, in DLB/AD the primitive deposits occurred less often in a single large cluster and more often in smaller, regularly spaced clusters than in ‘pure’ AD. The data suggest a more specific pattern of degeneration associated with Abeta deposition in DLB/AD cases compared with ‘pure’ AD.

Community-Based Study of the Association of High Myopia in Children with Ocular and Systemic Disease

Purpose. High myopia in childhood is associated with important ocular and systemic conditions. However in the UK, high myopia in early childhood is not specifically identified in current ophthalmology, optometry, or orthoptic protocols for screening, referral, or investigation. An ongoing study in the West Midlands, UK, is investigating high myopia presenting to community health care clinics with the aim of compiling guidelines for assessment and subsequent referral. Methods. Children with high myopia were identified from community optometric and orthoptic sources and invited for an ophthalmology and optometry examination to ascertain possible ocular or systemic disease. Results. High myopia with no associated ocular or systemic condition was present in 15 (56%) of the children. In seven children (25%), associated ocular problems were found including unrecognized retinal dystrophies and amblyopia. Systemic disorders associated with high myopia were found in five children (19%) and included Sticklers syndrome, Weill-Marchesani syndrome, and homocystinuria. In one child, the diagnosis made before this study was found to be incorrect, and in another child, the results were inconclusive. In two cases, the diagnosis of a systemic condition in the child led to the identification of the disease in at least one relative. Conclusions. There is a high prevalence of ocular and systemic abnormality in young children seen in the community. Optometric and ophthalmologic assessment of children less than 10 years with myopia ≥5 D is likely to identify significant ocular or systemic disease, a proportion of which will respond to medical intervention. Detection and prompt referral of these cases by community health care services may be expected to prolong vision and possibly life expectancy.

Laminar distribution of Pick bodies, Pick cells and Alzheimer disease pathology in the frontal and temporal cortex in Pick's disease

Lesions in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have distinct laminar distributions in the cortex. The objective of the present study was to test the hypothesis that the lesions characteristic of Pick's disease (PD) and AD have distinctly different laminar distributions in cases of PD. Hence, the laminar distribution of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) was studied in the frontal and temporal cortex in nine patients with PD. In 57% of analyses of individual cortical areas, the density of PB was maximal in the upper cortex while in 25% of analyses, the distribution of PB was bimodal with density peaks in the upper and lower cortex. The density of PC was maximal in the lower cortex in 77% of analyses while a bimodal distribution was present in 5% of analyses. The density of NFT was maximal in the upper cortex in 50% of analyses, in the lower cortex in 15% of analyses, with a bimodal distribution in 4% of analyses. The density of SP did not vary significantly with cortical depth in 86% of analyses. The vertical densities of PB and PC were negatively correlated in 12/21 (57%) of brain areas. The maximum density of PB in the upper cortex was positively correlated with the maximum density of PC in the lower cortex. In 17/25 (68%) of brain areas, there was no significant correlation between the vertical densities of PB and NFT. The data suggest that the pathogenesis of PB may be related to that of the PC. In addition, although in many areas PB and NFT occur predominantly in the upper cortex, the two lesions appeared to affect different neuronal populations.

The spatial patterns of Pick bodies, Pick cells and Alzheimer’s disease pathology in Pick’s disease

The spatial patterns of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were studied in the frontal and temporal lobe in nine cases of Pick’s disease (PD). Pick bodies exhibited clustering in 41/44 (93%) of analyses and clusters of PB were regularly distributed parallel to the tissue boundary in 24/41 (58%) of analyses. Pick cells exhibited clustering with regular periodicity of clusters in 14/16 (88%) analyses, SP in three out of four (75%) analyses and NFT in 21/27 (78%) analyses. The largest clusters of PB were observed in the dentate gyrus and PC in the frontal cortex. In 10/17 (59%) brain areas studied, a positive or negative correlation was observed between the densities of PB and PC. The densities of PB and NFT were not significantly correlated in the majority of brain areas but a negative correlation was observed in 7/29 (24%) brain areas. The data suggest that PB and PC in patients with PD exhibit essentially the same spatial patterns as SP and NFT in Alzheimer’s disease (AD) and Lewy bodies (LB) in dementia with Lewy bodies (DLB). In addition, there was a spatial correlation between the clusters of PB and PC, suggesting a pathogenic relationship between the two lesions. However, in the majority of tissues examined there was no spatial correlation between the clusters of PB and NFT, suggesting that the two lesions develop in association with different populations of neurons.

Gene therapy and ocular disease

The objective of this article is to give an overview of the history of the development and problems of gene therapy, while also considering the ethical and moral issues surrounding the application of the technology.

Dysregulated adipokines in the pathogenesis of type 2 diabetes and vascular disease

Obesity is commonly associated with type 2 diabetes and vascular disease. Changes in body composition in the obese state lead to a dysregulation of secretion of adipocyte-secreted hormones known as adipokines. Adipokines such as leptin and adiponectin are known to be involved in many physiological and pathological processes. Current knowledge suggests that adipokines provide potential therapeutic targets against type 2 diabetes and vascular disease.

A quantitative study of abnormally enlarged neurons in cognitively normal brain and neurodegenerative disease

Abnormally enlarged neurons (AEN) occur in many neurodegenerative diseases. To define AEN more objectively, the frequency distribution of the ratio of greatest cell diameter(CD) to greatest nuclear diameter (ND) was studied in populations of cortical neurons in tissue sections of seven cognitively normal brains. The frequency distribution of CD/ND deviated from a normal distribution in 15 out of 18 populations of neurons studied and hence, the 95th percentile (95P) was used to define a limit of the CD/ND ratio excluding the5% most extreme observations. The 95P of the CD/ ND ratio varied from 2.0 to 3.0 in different cases and regions and a value of 95P = 3.0 was chosen to define the limit for normalneurons under non-pathological conditions. Based on the 95P = 3.0 criterion, the proportion of AEN with a CD/ND ≥ 3 varied from 2.6% in Alzheimer's disease (AD) to 20.3% in Pick's disease (PiD). The data suggest: (1) that a CL/ND ≥ 3.0 may be a useful morphological criterion for defining AEN, and (2) AEN were most numerous in PiD and corticobasal degeneration (CBD) and least abundant in AD and in dementia with Lewy bodies (DLB). © 2013 Dustri-Verlag Dr. K. Feistle.

Intermittent fasting:a dietary intervention for prevention of diabetes and cardiovascular disease?

Intermittent fasting, in which individuals fast on consecutive or alternate days, has been reported to facilitate weight loss and improve cardiovascular risk. This review evaluates the various approaches to intermittent fasting and examines the advantages and limitations for use of this approach in the treatment of obesity and type 2 diabetes. © The Author(s) 2013.

Cognitive systems associated with the hippocampus of the human brain and their role in behaviour and neurodegenerative disease

Cognitive systems research involves the synthesis of ideas from natural and artificial systems in the analysis, understanding, and design of all intelligent systems. This chapter discusses the cognitive systems associated with the hippocampus (HC) of the human brain and their possible role in behaviour and neurodegenerative disease. The hippocampus (HC) is concerned with the analysis of highly abstract data derived from all sensory systems but its specific role remains controversial. Hence, there have been three major theories concerning its function, viz., the memory theory, the spatial theory, and the behavioral inhibition theory. The memory theory has its origin in the surgical destruction of the HC, which results in severe anterograde and partial retrograde amnesia. The spatial theory has its origin in the observation that neurons in the HC of animals show activity related to their location within the environment. By contrast, the behavioral inhibition theory suggests that the HC acts as a ‘comparator’, i.e., it compares current sensory events with expected or predicted events. If a set of expectations continues to be verified then no alteration of behavior occurs. If, however, a ‘mismatch’ is detected then the HC intervenes by initiating appropriate action by active inhibition of current motor programs and initiation of new data gathering. Understanding the cognitive systems of the hippocampus in humans may aid in the design of intelligent systems involved in spatial mapping, memory, and decision making. In addition, this information may lead to a greater understanding of the course of clinical dementia in the various neurodegenerative diseases in which there is significant damage to the HC.