Retinal microvascular parameters are not significantly associated with mild cognitive impairment in the Northern Ireland Cohort for the Longitudinal Study of Ageing.

BACKGROUND: The retinal and cerebral microvasculature share similar embryological origins and physiological characteristics. Improved imaging technologies provide opportunistic non-invasive assessment of retinal microvascular parameters (RMPs) against cognitive outcomes. We evaluated baseline measures for associations between RMPs and mild cognitive impairment (MCI) from participants of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). METHODS: RMPs (central retinal arteriolar / venular equivalents, arteriole to venular ratio, fractal dimension and tortuosity) were measured from optic disc centred fundus images and analysed using semi-automated software. Associations between RMPs and MCI were assessed by multivariable logistic regression with adjustment for potential confounders including age, sex, alcohol consumption, smoking status, educational attainment, physical activity, cardiovascular disease (CVD), hypertension, mean arterial blood pressure, triglycerides, diabetes, body mass index, and high density lipoprotein levels. P < 0.05 was considered statistically significant. RESULTS: Data were available for 1431 participants, of which 156 (10.9%) were classified with MCI defined by a Montreal Cognitive Assessment (MoCA) score ≤ 26, with subjective cognitive decline, in the absence of depression or problems with activities of daily living. Participants had a mean age of 62.4 ± 8.5 yrs. and 52% were female. As expected, individuals with MCI had a lower MoCA score than those without (23.5 ± 2.6 versus 26.3 ± 2.7, respectively), were more likely to be female, have a lower level of educational attainment, be less physically active, more likely to have CVD, have higher levels of triglycerides and lower levels of high density lipoprotein. No significant associations between RMPs and MCI were detected in unadjusted, minimally adjusted or fully adjusted regression models or subsequent sensitivity analyses. CONCLUSION: Previous studies have reported both increased retinal venular calibre and reduced fractal dimension in association with mild cognitive impairment. Our study failed to detect any associations between RMPs and those individuals at an early stage of cognitive loss in an older community-based cohort.

Association of reduced retinal arteriolar tortuosity with depression in older participants from the Northern Ireland Cohort for the Longitudinal Study of Ageing.

INTRODUCTION: The retina shares similar anatomical and physiological features with the brain and subtle variations in retinal microvascular parameters (RMPs) may reflect similar vascular variation in the brain. The aim of this study was to assess associations between RMPs and measures of depression in the Northern Ireland Cohort for the Longitudinal Study of Ageing. METHODS: RMPs (arteriolar and venular caliber, fractal dimension and tortuosity) were measured from optic disc centred fundus images using semi-automated software. Depression was characterised by the Centre for Epidemiologic Studies Depression Scale (CES-D) in the absence of mild cognitive impairment or use of anti-depressive medications. Associations between depression and RMPs were assessed by regression analyses with adjustment for potential confounders. RESULTS: Data were available for 1376 participants of which 113 (8.2%) and 1263 (91.8%) were classified with and without depression. Participants had a mean age of 62.0 ± 8.4 yrs., 52% were female, and 8% were smokers. Individuals with depression had a higher CES-D score than those without (22.0 ± 6.2 versus 4.4 ± 3.9). Lower values of arteriolar tortuosity were significantly associated with depression, before and after adjustment for potential confounders (odds ratio = 0.79; 95% confidence intervals: 0.65, 0.96; P = 0.02). CONCLUSION: Decreased retinal arteriolar tortuosity, a measure of the complexity of the retinal microvasculature was associated with depression in older adults independent of potential confounding factors. Retinal measures may offer opportunistic assessment of microvascular health associated with outcomes of depression.

Association of retinal venular tortuosity with impaired renal function in the Northern Ireland Cohort for the Longitudinal Study of Ageing.

BACKGROUND: Previous studies have identified retinal microvascular features associated with renal dysfunction. Biopsies are necessary to confirm kidney microvascular damage and retinal imaging may enable evaluation of microangiopathic characteristics reflecting renal changes associated with chronic kidney disease (CKD). We evaluated retinal microvascular parameters (RMPs) for associations with renal function in a cross-sectional analysis of the Northern Ireland Cohort for the Longitudinal Study of Ageing. METHODS: RMPs (central retinal arteriolar/ venular equivalents [CRAE/CRVE], arteriolar to venular ratio [AVR], fractal dimension and tortuosity) were measured from optic disc centred fundus images using semi-automated software. Associations were assessed with multivariable regression analyses between RMPs and estimated glomerular filtration rate (eGFR) defined by serum creatinine (eGFRscr) and cystatin C (eGFRcys) and also CKD status characterised by eGFR < 60 mL/min/1.73m2. Regression models were adjusted for potential confounders including age, sex, diabetes, smoking status, educational attainment, cardiovascular disease, body mass index, antihypertensive medication, systolic blood pressure, triglycerides, high- and low-density lipoprotein levels. RESULTS: Data were included for 1860 participants that had measures of renal function and retinal fundus images of sufficient quality for analysis. Participants had a mean age of 62.0 ± 8.5 yrs. and 53% were female. The mean eGFR for scr and cys were 82.2 ± 14.9 mL/min/1.73m2 and 70.7 ± 18.6 mL/min/1.73m2 respectively. eGFRcys provided lower estimates than eGFRscr resulting in a greater proportion of participants categorised as having CKD stages 3-5 (eGFRcys 26.8%; eGFRscr 7.9%). Multivariable regression analyses showed that increased venular tortuosity (OR = 1.30; 95%CI: 1.10, 1.54; P < 0.01) was associated with CKD stages 3-5 characterised by eGFRscr < 60 mL/min/1.73 m2. No additional associations between CKD status characterised by eGFRscr or with eGFRcys, were detected (P > 0.05). Multivariable regression failed to detect associations between CRAE, CRVE, AVR, fractal dimension or tortuosity and eGFRscr or eGFRcys (P > 0.05). CONCLUSION: Increased retinal venular tortuosity was associated with CKD stages 3-5 defined by eGFRscr < 60 mL/min/1.73 m2, in an older population independent of potential confounding factors. These retinal measures may provide non-invasive microvascular assessment of associations with CKD.

Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans.

The aim of this study was to determine whether the duration of antecedent hypoglycemia regulates the magnitude of subsequent counterregulatory failure. A total of 31 lean healthy overnight-fasted individuals (16 men/15 women) were studied. There were 15 subjects (8 men/7 women) who underwent two separate 2-day randomized experiments separated by at least 2 months. On day 1, 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic (5.2 +/- 0.1 mmol/l) or hypoglycemic (2.9 +/- 0.1 mmol/l) glucose clamps (prolonged hypoglycemia) were carried out in the morning and afternoon. Of the other subjects, 16 participated in a 2-day study in which day 1 consisted of morning and afternoon short-duration hypoglycemia experiments (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 5 min), and 10 of these individuals underwent an additional 2-day study in which day 1 consisted of morning and afternoon intermediate-duration hypoglycemia (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 30 min). The next morning (day 2) all subjects underwent an additional 2-h hyperinsulinemic-hypoglycemic clamp (2.9 +/- 0.1 mmol/l). The rate of fall of glucose (0.07 mmol/min) was carefully controlled during all hypoglycemic studies so that the glucose nadir was reached at 30 min. Despite equivalent day 2 plasma glucose and insulin levels, there were significant differences in counterregulatory physiological responses. Steady-state epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels were similarly significantly blunted (P < 0.01) by the differing duration day 1 hypoglycemia compared with day 1 euglycemia. Muscle sympathetic nerve activity and endogenous glucose production were also similarly blunted (P < 0.01) by day 1 hypoglycemia (relative to day 1 euglycemia). Day 2 hypoglycemic symptoms were significantly reduced (P < 0.01) after day 1 prolonged intermediate- but not short-duration hypoglycemia. In summary, two episodes of short-duration moderate hypoglycemia can produce significant blunting of key neuroendocrine and metabolic counterregulatory responses. Hypoglycemic symptom scores are reduced by prolonged but not short-duration prior hypoglycemia. We conclude that in healthy overnight fasted humans, 1) neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses are sensitive to the blunting effects of even short-duration prior hypoglycemia, and 2) the duration of antecedent hypoglycemia results in a hierarchy of blunted physiological responses with hypoglycemic symptom awareness less vulnerable than neuroendocrine responses.

Effect of morning exercise on counterregulatory responses to subsequent, afternoon exercise.

The aim of this study was to determine whether a bout of morning exercise (EXE(1)) can alter neuroendocrine and metabolic responses to subsequent afternoon exercise (EXE(2)) and whether these changes follow a gender-specific pattern. Sixteen healthy volunteers (8 men and 8 women, age 27 +/- 1 yr, body mass index 23 +/- 1 kg/m(2), maximal O(2) uptake 31 +/- 2 ml x kg(-1) x min(-1)) were studied after an overnight fast. EXE(1) and EXE(2) each consisted of 90 min of cycling on a stationary bike at 48 +/- 2% of maximal O(2) uptake separated by 3 h. To avoid the confounding effects of hypoglycemia and glycogen depletion, carbohydrate (1.5 g/kg body wt po) was given after EXE(1), and plasma glucose was maintained at euglycemia during both episodes of exercise by a modification of the glucose-clamp technique. Basal insulin levels (7 +/- 1 microU/ml) and exercise-induced insulin decreases (-3 microU/ml) were similar during EXE(1) and EXE(2). Plasma glucose was 5.2 +/- 0.1 and 5.2 +/- 0.1 mmol/l during EXE(1) and EXE(2), respectively. The glucose infusion rate needed to maintain euglycemia during the last 30 min of exercise was increased during EXE(2) compared with EXE(1) (32 +/- 4 vs. 7 +/- 2 micromol x kg(-1) x min(-1)). Although this increased need for exogenous glucose was similar in men and women, gender differences in counterregulatory responses were significant. Compared with EXE(1), epinephrine, norepinephrine, growth hormone, pancreatic polypeptide, and cortisol responses were blunted during EXE(2) in men, but neuroendocrine responses were preserved or increased in women. In summary, morning exercise significantly impaired the body's ability to maintain euglycemia during later exercise of similar intensity and duration. We conclude that antecedent exercise can significantly modify, in a gender-specific fashion, metabolic and neuroendocrine responses to subsequent exercise.

Detecting target shifts under uniform field flicker.

An experiment was performed in which a small target, viewed foveally, underwent 1 degree lateral shifts at quasi-random intervals. Subjects' response latency to the shift was investigated under various square-wave flicker conditions and compared to non-flickering conditions. Flicker was found to raise latencies, the effect peaking between 8 and 14 Hz. Under constant luminance difference between target and background the high target contrast phase was found to dominate the response cueing. The results are discussed in terms of a simple model of cumulative signal strength and adaptation processes.

Effects of flicker modulation depth on the detection of changes in target location.

Response times to a change in location of a small, low contrast target in a uniform flickering field were investigated under a range of flicker modulation depths. Increasing depth of modulation gave an increased response time for modulation depths from 0% (no flicker, to approx. 35%. Further increases in modulation depth had only a marginal effect on response time. It is shown that this effect is not due to flicker adaptation. The functional form of the modulation dependence is qualitatively similar to that reported by Badcock and Smith (1989, Vision Research, 29, 803-808), but shows a large difference in the modulation at which a levelling of performance occurred. It is shown that this difference is consistent with the presence of a third temporal filter, as proposed by Mandler and Makous (1984, Vision Research, 24, 1881-1887).

Effects of movement in the background field on long-range apparent motion.

Two experiments are reported using time-till-breakdown as a measure of apparent motion (AM) in untrained subjects. In Experiment 1 centrally viewed dynamic random dot stereograms and non-disparate stimuli in dynamic random dot fields yielded higher optimal frequencies than did a standard binocular condition. In Experiment 2 a higher optimal frequency was observed for disparate dynamic random dot stimuli compared with both standard binocular and non disparate stimuli presented on a static random dot field. Interaction between short- and long-range AM processes is considered in the interpretation of the findings.

Stereoscopic evoked responses to crossed and uncrossed disparity accompanying simulated refractive error.

Evoked potentials were recorded to the occurrence of a disparate stimulus in dynamic random dot stereograms. Seven adult males, all of whom had vision which was normal or corrected to normal, participated in the experiment. Subjects viewed 100 ms duration stimuli which embodied 30 arc min of either crossed or uncrossed disparity under four conditions of spherical overcorrection: -0.25, +1.0, +2.0, +3.0 dioptres. The first condition, essentially normal refraction, yielded reliable behavioural reports of the stimulus and clear evoked potentials to both crossed and uncrossed disparity. With increasing overcorrection the behavioural reports became less reliable, and the evoked potentials were degraded for both conditions of disparity. The responses to the crossed disparity condition, however, showed significantly less degradation in both behavioural and electrophysiological measures. The implications of this finding may be that there are separate cortical subsystems for the processing of crossed and uncrossed disparity and that the former is more robust under non-ideal viewing conditions.

Detection threshold differences to crossed and uncrossed disparities.

Using a sample of 85 subjects measurements were made of minimum stimulus durations necessary for detection of crossed and uncrossed disparity stimuli which were presented in five positions in the visual field: centre, lower, upper, right, and left field. The results indicated large detection duration differences between the two disparity conditions, with a marked superiority for crossed disparity detection at all positions. A left-right visual field anisotropy was demonstrated for crossed disparity stimuli.

Enzymatic release of oligosaccharides from glycoproteins for chromatographic and electrophoretic analysis.

For most separations-based analyses of glycoprotein oligosaccharides, the first step is release of the oligosaccharides from the polypeptide. Historically, O-linked and N-linked oligosaccharides have been released from glycoproteins using chemical means, such as alkaline degradation (beta-elimination) or hydrazinolysis. In the last two decades, a growing repertoire of enzymes, including endoglycosidases and glycoamidases, able to release glycoprotein oligosaccharides under mild conditions, have become available. This review traces the discovery, characterization and use of these glycoprotein oligosaccharide releasing enzymes. Emphasis is placed on providing information of practical value for the researcher wishing to incorporate enzymatic oligosaccharide release into their study of glycoprotein oligosaccharide structure and function.

Multi-dimensional mapping of pyridylamine-labeled N-linked oligosaccharides by capillary electrophoresis.

A simple, sensitive and reproducible multi-dimensional capillary electrophoresis (CE) oligosaccharide mapping method is reported. The structures of 20 identified N-linked oligosaccharides have been assigned mapping positions from which co-migrating unknown oligosaccharides can be characterized. The separation protocols developed have been demonstrated to separate both charged and neutral oligosaccharides. One dimension involves electroendosmotic flow-assisted CE in a sodium acetate buffer, pH 4.0. A second dimension involves separation based on borate complexation electrophoresis in a polyethylene glycol-containing buffer. A third dimension developed specifically for neutral oligosaccharides, using a sodium phosphate buffer, pH 2.5, has been shown to resolve neutral species not able to be separated by the other two dimensions. Thus, a three-dimensional map was generated to facilitate structural characterization of these oligosaccharides.

The determinants of the non-motoric CNV in a complex, variable foreperiod, information processing paradigm.

The aim of the present study was to examine the determinants of the non-motoric CNV or E-wave elicited in a complex, variable foreperiod information processing task. Subjects were required to determine whether two sets of tones, one set presented back-to-back (S1/S2), the other separated by a variable foreperiod (S3/S4), were either matching or mismatching. Data were collected over two recording sessions; a baseline and an experimental run. The experimental session comprised three conditions; a match, a mismatch and no-response conditions. Mean amplitude and factor score comparisons showed the parietally-dominant E-wave to be dependent on the task relevance of the stimulus which it precedes. Differing midline distributions for the negative afterwave and the E-wave with increased processing requirements was taken to suggest that the two responses reflect functionally distinct phenomena.

Discrimination of motion in depth trajectory following acute alcohol ingestion.

Evoked potentials were recorded at four scalp sites O1, O2, T5, T6; before and after the consumption of one of two alcohol dose levels, to the occurrence of disparate stimuli in dynamic random dot stereograms. Twenty young adult subjects, all of whom had vision which was normal or corrected to normal, were randomly assigned to the two dosage groups. Subjects viewed stimuli which embodied crossed disparity and followed one of three trajectories in depth. The task was to distinguish between and identify, by specific button presses, these trajectories. One half of the stimuli were presented with monocular cues to motion in depth (dark condition); in the remainder only stereoscopic depth information was available (uniform condition). Responses to both conditions showed alcohol-related reduction of evoked responses across all sites. It was concluded that the visual systems associated with the processing of motion in depth were susceptible to alcohol effects, as revealed by reductions in the amplitude of evoked responses.

A detailed structural characterization of ribonuclease B oligosaccharides by 1H NMR spectroscopy and mass spectrometry.

The structures of ribonuclease B oligosaccharides have previously been shown to be high mannose type by methylation analyses and sequential exoglycosidase digestion. Due to the unique nature of these oligosaccharides, in that all mannosyl residues are attached by alpha-(1-->2)-linkages beyond the branch points, methylation analysis fails to solve the exact structures beyond Man5. Therefore, we have undertaken this study using 1H nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. In this study, bovine pancreatic ribonuclease B was first reduced and carboxymethylated, and was then deglycosylated by peptide/N-glycosidase F (PNGase F). The released oligosaccharides were fractionated by Bio-Gel P-4 chromatography to give five pools, Man5 through Man9. The structures of the oligosaccharide pools were then studied by laser desorption time of flight mass spectrometry and 1H NMR spectroscopy at 300 MHz. For Man5, Man-A and Man-B are attached in alpha-(1-->3)- and alpha-(1-->6)-linkages to the alpha-(1-->6)-linked Man-4' of the pentasaccharide core structure. For Man6, Man-C is linked alpha-(1-->2) to the alpha-(1-->3)-linked Man-4. Man7 exists as three structural isomers, and has the additional mannosyl residue (Man-D) linked alpha-(1-->2) to Man-A, Man-B, and Man-C is linked alpha-(1-->2) to the alpha-(1-->3)-linked Man-4. Man-7 exists as three structural isomers, with the additional two mannosyl residues linked alpha-(1-->2) to Man-A, Man-B, and Man-C. For each position, Man-A, Man-B, and Man-C, the extent of occupancy by one of the additional alpha-(-->)-linked mannosyl residues was 15, 94, and 91%, respectively. Man9 is a single component, with the three additional mannosyl residues linked alpha-(1-->2) to Man-A, Man-B, and Man-C, respectively. The relative molar proportions of Man5 to Man9 are 57, 31, 4, 7, and 1%, respectively. This report presents for the first time the complete structural characterization of the oligosaccharides from ribonuclease B.

Journal article content as a predictor of commitment to change among continuing medical education respondents.

BACKGROUND: Journal reading is a time-tested means of continuing medical education (CME) among physicians. Asking physicians to make a written statement of commitment to change has been shown to increase the likelihood of eventual change in practice behavior when used in conjunction with CME lectures. We describe the type and medical content of articles responsible for commitment to change comments among readers of a large circulation primary care journal. METHODS: Response to the question "what change(s) do you plan to make in your practice as a result of reading the articles in this issue?" were analyzed from CME response cards associated with six issues (1 year's publication) of the Archives of Family Medicine. Responses indicating a commitment to change were analyzed to characterize the type and content of articles responsible for their generation. RESULTS: During the 1-year study period, original contributions (reports of research trials) dealing with medicine and preventive medicine content accounted for the greatest number of comments. After adjusting for the frequency of article type and content, special articles and those dealing with complementary medicine accounted for the highest number of comments on a per-article basis. FINDINGS: Family physicians make commitment to change statements on the basis of a broad range of journal articles. Certain articles are more likely to generate statements of commitment to planned changes in practice.

Illustrations and implications of current models of HIV health service provision in rural areas.

Despite recent evidence of faster than average increases in HIV/AIDS cases in rural areas across the U.S., there is still a generally poor understanding of successful models of rural HIV/AIDS health-care delivery. Past research in rural Kentucky suggested several barriers to care resulting in most rural HIV-positive patients traveling from rural to urban areas for care. Patients sought urban areas for care for reasons including patient confidentiality, a perceived lack of expertise on the part of rural physicians in caring for HIV-positive patients, and outright referral from rural to urban areas. Case histories are used to illustrate a variety of models of care used by rural HIV-positive patients. These include splitting and sharing care between rural primary care physicians and urban medical specialists, as well as patients receiving all their care in urban areas. Implications of these models for quality of care are discussed.

Stereoscopic cerebral evoked potentials of Air Force pilots and civilian comparison groups.

Dynamic random-dot stereograms were presented to Air Force jet pilots (N = 14) through a new visual display system. Games which simulated target-detection exercises were included in the test sequence. Event-related potentials were recorded at scalp sites 01, 02, T5, T6, referenced to an anterior midline site. Comparisons were made where possible with the data from recent studies on three civilian groups. A pattern of response was revealed in the event-related potential measures. In general, left-hemisphere amplitudes exceeded right and the predominant response was recorded at the left-temporal site. Amplitudes of responses in subjects able to describe the stimuli in subjective report (perceivers) exceeded those of non-perceivers. Stimuli with definite boundaries evoked stronger and earlier-latency responses than stimuli with nebulous boundaries. The response patterns of subjects make a contribution to normative data on the cerebral electrical indices of stereoscopic vision.

Micellar electrokinetic chromatography of monosaccharides derivatized with 1-phenyl-3-methyl-2-pyrazolin-5-one.

Mono- and disaccharides derivatized with 1-phenyl-3-methyl-2-pyrazolin-5-one (PMP) were separated by micellar electrokinetic chromatography (MEKC), on the basis of their ability to differentially partition between an electroendosmotically driven aqueous phase and sodium dodecyl sulfate micelles. The use of a Tris phosphate buffer, pH 7.5, containing 50 mM sodium dodecyl sulfate, provided good resolution of neutral and basic monosaccharides and disaccharides. Baseline resolution was accomplished for the monosaccharides most commonly found in glycoproteins. A mass detection limit of 20 femtomoles, at a signal-to-noise ratio of three, was achieved by monitoring UV absorbance at 245 nm. The applicability of the system described to the identification and quantitation of monosaccharides obtained from carbohydrate hydrolysates from glycoproteins was investigated.