The effect of voluntary fasting and dehydration on flicker-induced retinal vascular dilation in a healthy individual: a case report

INTRODUCTION: Dynamic retinal vessel analysis represents a well-established method for the assessment of vascular reactivity during both normal conditions and after various provocations. We present a case where the subject showed abnormal retinal vessel reactivity after fasting voluntarily for 20 hours. CASE PRESENTATION: A healthy, 21-year-old man who fasted voluntarily for 20 hours exhibited abnormal retinal vascular reactivity (dilation and constriction) after flicker provocation as measured using the Dynamic Retinal Vessel Analyser (Imedos, Jena, Germany). CONCLUSION: The abnormal vascular reactivity induced by fasting was significant; abnormal levels of important nutrients due to fasting and dehydration could play a role through altering the concentration of vasoactive substances such as nitric oxide. This hypothesis needs further investigation.

Dietary enrichment with almond (Prunus amygdalis) supplementation: effects on CVD risk biomarkers

Epidemiological evidence suggests that diets rich in fruits, vegetables and pulses reduce the risk of CVD. The Physicians Health Study has demonstrated reduction of CHD death with regular nut consumption1. One major modifiable risk factor for CHD is an unhealthy diet. Thus, an almondenrichment study has been undertaken to examine the benefit of almonds (Prunus amygdalis) in healthy individuals either with or without significant risk of vascular disease. Almonds contain various macronutrients (low SFA content, absence of cholesterol and high MUFA content) and micronutrients, including vitamin E, polyphenols and arginine, which afford vascular benefit. The effects of almond consumption (25 g/d for 4 weeks followed by 50 g/d for 4 weeks) were evaluated in three non-smoking subject groups: healthy male volunteers between the ages of 18 and 35 years (n 15); men at risk of heart disease between the ages of 18 and 35 years (n 12); mature men and women >50 years of age (n 18). A fourth control group (n 14) were followed over 8 weeks without dietary almond enrichment as a treatment control. None of the subjects withdrew from the study and 90% completed the study. The interim results of the study showed that in the three active groups there was little evidence for a change in total cholesterol, LDL-cholesterol or HDL-cholesterol. In the mature group there was a trend towards increasing HDL-cholesterol. The mature and ‘at-risk’ groups also showed a significant changes in systolic blood pressure (P<0.05) during almond consumption. The healthy group showed a decrease in diastolic blood pressure (P<0.05). The ‘at-risk’ group showed a significant increase (P<0.05) in flowmediated dilation after 8 weeks of almond consumption. Data analysis is ongoing, with completion of the study in November 2007. The beneficial effects of almond consumption on flow-mediated dilation and blood pressure may be attributed to the high content in almonds of arginine, which serves as a precursor to the vasodilatory molecule, NO.

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.

Alzheimer's disease and vision: a proposed new diagnostic test

A potential non-invasive neurobiological test for Alzheimer's disease has been recently proposed and published. This test is likely to be of considerable interest to optometrists as it involves measurements of pupil dilation. This article decsribes some of the controversial issues surrounding the clinical diagnosis of Alzheimer's disease and discusses the advantages, limitations, and implications of the new test.

Rotational and centration stability of an aspheric intraocular lens with a simulated toric design

Purpose: To assess the stability of the Akreos AO intraocular lens (IOL) platform with a simulated toric design using objective image analysis. Setting: Six hospital eye clinics across Europe. Methods: After implantation in 1 eye of patients, IOLs with orientation marks were imaged at 1 to 2 days, 7 to 14 days, 30 to 60 days, and 120 to 180 days. The axis of rotation and IOL centration were objectively assessed using validated image analysis. Results: The study enrolled 107 patients with a mean age of 69.9 years ± 7.7 (SD). The image quality was sufficient for IOL rotation analysis in 91% of eyes. The mean rotation between the first day postoperatively and 120 to 180 days was 1.93 ± 2.33 degrees, with 96% of IOLs rotating fewer than 5 degrees and 99% rotating fewer than 10 degrees. There was no significant rotation between visits and no clear bias in the direction of rotation. In 71% of eyes, the dilation and image quality was sufficient for image analysis of centration. The mean change in centration between 1 day and 120 to 180 days was 0.21 ± 0.11 mm, with all IOLs decentering less than 0.5 mm. There was no significant decentration between visits and no clear bias in the direction of the decentration. Conclusion: Objective analysis of digital retroillumination images taken at different postoperative periods shows the aspheric IOL platform was stable in the eye and is therefore suitable for the application of a toric surface to correct corneal astigmatism.

Abnormal retinal vascular reactivity in individuals with impaired glucose tolerance:a preliminary study

To investigate the relationship between vascular function parameters measured at the retinal and systemic level and known markers for cardiovascular risk in patients with impaired glucose tolerance (IGT). Sixty age- and gender- matched White-European adults (30 IGT and 30 normal glucose tolerance -NGT) were recruited for the study. Fasting plasma glucose, lipids and 24-hour blood pressure (BP) was measured in all subjects. Systemic vascular and endothelial function was assessed using carotid-artery intimal media thickness (cIMT) and flow mediated dilation (FMD). Retinal vascular reactivity was assessed by the Dynamic Retinal Vessel Analyser (DVA). Additionally, blood glutathione (GSH, GSSG and tGSH) and plasma von-Willebrand (vWF) factor levels were also measured. Individuals with IGT demonstrated higher BP values (p<0.001), fasting TG and TG:HDL ratios (p<0.001) than NGT subjects. Furthermore, Total:HDL-C ratios and Framingham scores were raised (p=0.010 and p<0.001 respectively). Blood glutathione levels (GSH, GSSG and tGSH) were lower (p<0.001, p=0.039 and p<0.001 respectively) while plasma vWF was increased (p=0.014) in IGT subjects compared to controls. IGT individuals also demonstrated higher IMT in right and left carotid arteries (p=0.017 and p=0.005, respectively) alongside larger brachial artery diameter (p=0.015), lower FMD% (p=0.026) and GTN induced dilation (GID) (p=0.012) than healthy controls. At the retinal arterial level, the IGT subjects showed higher baseline fluctuations (BDF) (p=0.026), longer reaction time (RT) (p=0.032) and reduced baseline-corrected flicker response (bFR) (p=0.045). In IGT subjects retinal BDF correlated with and Total:HDL (p= 0.003) and HDL-C (p= 0.004). Arterial RT also correlated with FMD (p=0.017) in IGT but not NGT subjects. In IGT individuals there is a relationship between macro- and microvascular function, as well as a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD. Multifactorial preventive interventions to decrease vascular risk in these individuals should be considered.

Ocular and systemic endothelial function in the off spring of diabetics:a pilot study

Purpose To investigate ocular and systemic correlates of endothelial function in the normoglycaemic offspring of Type 2 Diabetics (T2DM). Methods Healthy participants aged between 25-65 with (n=30) and without (n=39) a family history were recruited. Retinal vessel reactivity was assessed by using the Retinal Vessel Analyser (RVA, Imedos GmBH). In addition, systemic endothelial function was assessed by using the flow mediated dilation (FMD) technique. Results Parametric testing showed no significant differences in anthropometric, blood assay or ocular and systemic function between both groups (p>0.05). The average maximum dilation in the measured retinal artery correlated significantly with the maximum dilation of the measured brachial artery (p=0.002 R=0.55) in healthy controls; however, this was not true for subjects with family history of T2DM. Conclusion Subjects with family history of T2DM show possibly early signs of endothelial dysfunction that, in certain conditions, could contribute to the higher risk of this group of developing similar pathology to their parents.

Perception while watching movies:effects of physical screen size and scene type

Over the last decade, television screens and display monitors have increased in size considerably, but has this improved our televisual experience? Our working hypothesis was that the audiences adopt a general strategy that “bigger is better.” However, as our visual perceptions do not tap directly into basic retinal image properties such as retinal image size (C. A. Burbeck, 1987), we wondered whether object size itself might be an important factor. To test this, we needed a task that would tap into the subjective experiences of participants watching a movie on different-sized displays with the same retinal subtense. Our participants used a line bisection task to self-report their level of “presence” (i.e., their involvement with the movie) at several target locations that were probed in a 45-min section of the movie “The Good, The Bad, and The Ugly.” Measures of pupil dilation and reaction time to the probes were also obtained. In Experiment 1, we found that subjective ratings of presence increased with physical screen size, supporting our hypothesis. Face scenes also produced higher presence scores than landscape scenes for both screen sizes. In Experiment 2, reaction time and pupil dilation results showed the same trends as the presence ratings and pupil dilation correlated with presence ratings, providing some validation of the method. Overall, the results suggest that real-time measures of subjective presence might be a valuable tool for measuring audience experience for different types of (i) display and (ii) audiovisual material.

Requirement for and optimisation of premium intraocular lenses

Premium intraocular lenses (IOLs) aim to surgically correct astigmatism and presbyopia following cataract extraction, optimising vision and eliminating the need for cataract surgery in later years. It is usual to fully correct astigmatism and to provide visual correction for distance and near when prescribing spectacles and contact lenses, however for correction with the lens implanted during cataract surgery, patients are required to purchase the premium IOLs and pay surgery fees outside the National Health Service in the UK. The benefit of using toric IOLs was thus demonstrated, both in standard visual tests and real-world situations. Orientation of toric IOLs during implantation is critical and the benefit of using conjunctival blood vessels for alignment was shown. The issue of centration of IOLs relative to the pupil was also investigated, showing changes with the amount of dilation and repeat dilation evaluation, which must be considered during surgery to optimize the visual performance of premium IOLs. Presbyopia is a global issue, of growing importance as life expectancy increases, with no real long-term cure. Despite enhanced lifestyles, changes in diet and improved medical care, presbyopia still presents in modern life as a significant visual impairment. The onset of presbyopia was found to vary with risk factors including alcohol consumption, smoking, UV exposure and even weight as well as age. A new technique to make measurement of accommodation more objective and robust was explored, although needs for further design modifications were identified. Due to dysphotopsia and lack of intermediate vision through most multifocal IOL designs, the development of a trifocal IOL was shown to minimize these aspects. The current thesis, therefore, emphasises the challenges of premium IOL surgery and need for refinement for optimum visual outcome in addition to outlining how premium IOLs may provide long-term and successful correction of astigmatism and presbyopia.

Patients with early age-related macular degeneration exhibit signs of macro- and micro-vascular disease and abnormal blood glutathione levels

Background: This pilot study aimed to investigate systemic and retinal vascular function and their relationship to circulatory markers of cardiovascular risk in early age-related macular degeneration (AMD) patients without any already diagnosed systemic vascular pathologies. Methods: Fourteen patients diagnosed with early AMD and 14 age- and gender-matched healthy controls underwent blood pressure, carotid intima-media thickness (C-IMT) and peripheral arterial stiffness measurements. Retinal vascular reactivity was assessed by means of dynamic retinal vessel analysis (DVA) using a modified protocol. Blood analyses were conducted for glutathione levels and plasma levels of total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Results: The AMD patients showed significantly greater C-IMT (p = 0.029) and augmentation index (AIx) (p = 0.042) than the age-matched controls. In addition, they demonstrated a shallower retinal arterial dilation slope (Slope AD) (p = 0.005) and a longer retinal venous reaction time (RT) to flickering light (p = 0.026). Blood analyses also revealed that AMD patients exhibited higher oxidized glutathione (GSSG) (p = 0.024), lower redox index (p = 0.043) and higher LDL-C (p = 0.033) levels than the controls. Venous RT parameter correlated positively with blood GSSG levels (r = 0.58, p = 0.038) in AMD subjects, but not in the controls (p > 0.05). Conclusions: Patients diagnosed with early AMD exhibit signs of systemic and retinal vascular alterations that correlated with known risk markers for future cardiovascular morbidity. © 2013 Springer-Verlag Berlin Heidelberg.

Coexistence of macro- and micro-vascular abnormalities in newly diagnosed normal tension glaucoma patients

Purpose: To investigate the coexistence of ocular microvascular and systemic macrovascular abnormalities in early stage, newly diagnosed and previously untreated normal tension glaucoma patients (NTG). Methods: Retinal vascular reactivity to flickering light was assessed in 19 NTG and 28 age-matched controls by means of dynamic retinal vessel analysis (IMEDOS GmbH, Jena, Germany). Using a newly developed computational model, the entire dynamic vascular response profile to flicker light was imaged and used for analysis. In addition, assessments of carotid intima-media thickness (IMT) and pulse wave analysis (PWA) were conducted on all participants, along with blood pressure (BP) measurements and blood analyses for lipid metabolism markers. Results: Patients with NTG demonstrated an increased right and left carotid IMT (p = 0.015, p = 0.045) and an elevated PWA augmentation index (p = 0.017) in comparison with healthy controls, along with an enhanced retinal arterial constriction response (p = 0.028), a steeper retinal arterial constriction slope (p = 0.031) and a reduced retinal venous dilation response (p = 0.026) following flicker light stimulation. Conclusions: Early stage, newly diagnosed, NTG patients showed signs of subclinical vascular abnormalities at both macro- and micro-vascular levels, highlighting the need to consider multi-level circulation-related pathologies in the development and progression of this type of glaucoma.

The effect of simulated cataract light scatter on retinal vessel oximetry

To assess the impact of light scatter, similar to that introduced by cataract on retinal vessel blood oxygen saturation measurements using poly-bead solutions of varying concentrations. Eight healthy, young, non-smoking individuals were enrolled for this study. All subjects underwent digital blood pressure measurements, assessment of non-contact intraocular pressure, pupil dilation and retinal vessel oximetry using dual wavelength photography (Oximetry Module, Imedos Systems, Germany). To simulate light scatter, cells comprising a plastic collar and two plano lenses were filled with solutions of differing concentrations (0.001, 0.002 and 0.004%) of polystyrene microspheres (Polysciences Inc., USA). The adopted light scatter model showed an artifactual increase in venous optical density ratio (p=0.036), with the 0.004% condition producing significantly higher venous optical density ratio values when compared to images without a cell in place. Spectrophotometric analysis, and thus retinal vessel oximetry of the retinal vessels, is altered by artificial light scatter. © 2013 Elsevier Ltd.

Cervicovaginal vascular endothelial growth factor (VEGF) and risk of preterm birth (PTB)

Objective - During pregnancy, the human cervix undergoes angiogenic transformations. VEGF is expressed in cervical stroma and is proposed to play key roles in the process of cervical ripening and dilation. This study was conducted to evaluate whether cervical secretion of VEGF can be of clinical value in predicting impending PTB. Study Design - In an observational prospective cohort study, we analyzed cervical fluid samples from 103 pregnant women (GA: median [IQR]: 28 [25-31] wks) who presented for either a routine prenatal visit (n=61) or for evaluation of threatened preterm labor (n=42). Cervical secretions were collected under a standard protocol which was followed in all cases. Cervical length (CL) was assessed by transvaginal ultrasound using well-established criteria. Dilation was evaluated by digital exam performed only after collection of the biological samples. VEGF levels were immunoassayed by investigators unaware of the clinical outcome. Main exclusion criteria were ruptured membranes, active labor, vaginal bleeding, vaginal exam or intercourse within 24h. Results were analyzed with and without normalization for total protein. Results - 1) Clinical characteristics of the cohort are presented in Table;2) VEGF was detectable in all specimens, with no correlation between its levels, CL, twins or GA at collection; 3) There was an inverse correlation between VEGF and cervical dilation (R=-0.646, P=0.003); 4) Women with cervical dilation =1 cm had lower VEGF compared to those with a closed cervix (P=0.003); 5) Women who experienced PTB within 14 days (n=11) had lower VEGF (P=0.003); 6) A free VEGF level of =600 pg/mL had a sensitivity, specificity, +LR and -LR of 70%, 95%, 13.5 and 0.3, respectively in predicting PTB within 14 days. Conclusions - Low VEGF levels in the cervicovaginal secretions of pregnant women are associated with an increased risk of PTB within 2 weeks of collection. Active engagement of VEGF in the process of cervical ripening and dilatation and/or increased affinity of extracellular matrix components for VEGF may provide explanation for our findings.

Systemic circulatory influences on retinal microvascular function in middle-age individuals with low to moderate cardiovascular risk

Purpose: To investigate the relationship between retinal microvascular reactivity, circulatory markers for CVD risk and systemic antioxidative defence capacity in healthy middle-aged individuals with low to moderate risk of CVD. Methods: Retinal vascular reactivity to flickering light was assessed in 102 healthy participants (46-60 years) by means of dynamic retinal vessel analysis (DVA). Other vascular assessments included carotid intima-media thickness (C-IMT) and blood pressure (BP) measurements. Total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and blood glutathione levels in its reduced (GSH) and oxidized (GSSG) forms were also determined for each participant, along with Framingham risk scores (FRS). Results: Retinal arterial baseline diameter fluctuation (BDF) was independently, significantly and negatively influenced by LDL-C levels (β = -0.53, p = 0.027). Moreover, the arterial dilation slope (SlopeAD) was independently, significantly and positively associated with redox index (GSH: GSSG ratio, β = 0.28, p = 0.016), while the arterial constriction slope (SlopeAC) was significantly and negatively influenced by blood GSH levels (β = -0.20, p = 0.042), and positively associated with FRS (β = 0.25, p = 0.009). Venous BDF and dilation amplitude (DA) were also negatively influenced by plasma LDL-C levels (β = -0.83, p = 0.013; and β = -0.22, p = 0.028, respectively). Conclusions: In otherwise healthy individuals with low to moderate cardiovascular risk, retinal microvascular dilation and constriction responses to stress levels are influenced by systemic antioxidant capacity, and circulating markers for cardiovascular risk.

Ageing effect on flicker-induced diameter changes in retinal microvessels of healthy individuals

Purpose: To compare flicker-induced retinal vessel diameter changes in varying age groups with low cardiovascular risk. Methods: Retinal vascular reactivity to flicker light was assessed by means of dynamic retinal vessel analysis in 57 participants aged 19-30 years, 75 participants aged 31-50 years and 62 participants aged 51-70 years participants. Other assessments included carotid intima-media thickness (c-IMT), augmentation index (AIx), blood pressure profiles, blood lipid metabolism markers and Framingham risk scores (FRS). Results: Retinal arterial dilation amplitude (DA) and postflicker percentage constriction (MC%) were significantly decreased in the oldest group compared to the middle-aged (p = 0.028; p = 0.021) and youngest group (p = 0.003; p = 0.026). The arterial constriction slope (SlopeAC) was also decreased in the oldest group compared to the youngest group (p = 0.027). On the venous side, MC% was decreased in the middle-aged and oldest groups in comparison with the youngest group (p = 0.015; p = 0.010, respectively). Additionally, men exhibited increased arterial DA (p = 0.007), and percentage dilation (MD%, p < 0.001) in comparison with women, but only in the youngest age group. Both AIx and c-IMT scores increased with age (both p < 0.001); however, no correlations were found between the observed differences in the measured retinal vascular function and systemic parameters. Conclusion: In individuals with low cardiovascular risk, there are age-related differences in flicker-induced retinal vessel diameter changes throughout the entire functional response curve for arteries and veins. Gender differences mainly affect the arterial dilatory phase and are only present in young individuals.