Type 2 diabetes (T2DM) patients develop vascular complications and have increased risk for neurophysiological impairment. Vascular pathophysiology may alter the blood flow regulation in cerebral microvasculature, affecting neurovascular coupling. Reduced fMRI signal can result from decreased neuronal activation or disrupted neurovascular coupling. The uncertainty about pathophysiological mechanisms (neurodegenerative, vascular, or both) underlying brain function impairments remains. In this cross-sectional study, we investigated if the hemodynamic response function (HRF) in lesion-free brains of patients is altered by measuring BOLD (Blood Oxygenation Level-Dependent) response to visual motion stimuli. We used a standard block design to examine the BOLD response and an event-related deconvolution approach. Importantly, the latter allowed for the first time to directly extract the true shape of HRF without any assumption and probe neurovascular coupling, using performance-matched stimuli. We discovered a change in HRF in early stages of diabetes. T2DM patients show significantly different fMRI response profiles. Our visual paradigm therefore demonstrated impaired neurovascular coupling in intact brain tissue. This implies that functional studies in T2DM require the definition of HRF, only achievable with deconvolution in event-related experiments. Further investigation of the mechanisms underlying impaired neurovascular coupling is needed to understand and potentially prevent the progression of brain function decrements in diabetes.

BACKGROUND

The use of inhaled nitric oxide (NO) has been studied for the treatment of hypoxic respiratory failure (HRF) in newborns who require mechanical ventilation. Although inhaled NO is typically used in patients with a greater severity of illness, the treatment response (eg, improvement in oxygenation) and the associated outcomes (eg, time on mechanical ventilation) may be affected by the timing of treatment and baseline severity of illness.

OBJECTIVE

This analysis was conducted to assess the effects of inhaled NO on measures of oxygenation, efficacy of inhaled NO across a range of illness severity strata, and duration of mechanical ventilation.

METHODS

This was a retrospective pooled analysis of 3 pivotal clinical trials comparing inhaled NO (starting dose, 20 ppm) with control (100% oxygen or nitrogen gas) in term and late preterm (gestational age>> or = 34 weeks) infants with HRF who required mechanical ventilation. Data on partial pressure of arterial oxygen (PaO2), inspired oxygen concentration, and mean airway pressure at 0 and 30 minutes after administration of inhaled NO were extracted from the case-report forms from the 3 clinical trials and used to calculate the oxygenation index (OI). The change in PaO2 was assessed by baseline severity of illness, stratified based on the OI (< or = 15 = mild, >15 to < or = 25 = moderate, >25 to < or = 40 = severe, >40 = very severe). The duration of mechanical ventilation was compared between the inhaled NO and control groups.

RESULTS

Five hundred twenty-four patients were analyzed (260 inhaled NO, 264 control). The overall mean (SD) birth weight and gestational age of the patients were 3.4 (0.58) kg and 39.1 (1.96) weeks, respectively. After 30 minutes of treatment, there was a significant increase from baseline in PaO2 with inhaled NO compared with control (54.91 vs 14.15 mm Hg, respectively; P < 0.001). The increases from baseline in PaO2 at 30 minutes were statistically significant for inhaled NO compared with controls across all severity strata (mild: 62.39 vs -23.03 mm Hg, respectively [P = 0.003]; moderate: 52.93 vs 18.28 mm Hg [P = 0.004]; severe: 62.07 vs 13.95 mm Hg [P < 0.001]; very severe: 45.17 vs 18.66 mm Hg [P < 0.001]). On Kaplan-Meier analysis, the median duration of mechanical ventilation was 11 and 14 days in the inhaled NO and control groups, respectively (P = 0.003).

CONCLUSIONS

This pooled analysis of data from 3 clinical trials in term and late preterm infants with HRF requiring mechanical ventilation found that inhaled NO at a starting dose of 20 ppm was associated with improved oxygenation acutely and a reduced median duration of mechanical ventilation. The improvements were significant across all severity-of-illness strata.

OBJECTIVE

To measure choroidal blood flow from foveal region in the eyes with idiopathic macular hole.

METHODS

Thirteen patients with macular hole and 20 age-matched healthy subjects were included into the study. While group 1 consisted of 13 eyes of idiopathic stage 4 macular hole, seven fellow eyes of the same patients with stage 1a macular hole formed the group 2. The control group (group 3) comprised the randomly selected eye of 20 age-matched healthy subjects. Mean values of blood perfusion parameters that were composed of volume, flow and velocity, were recorded from foveal region of fundus using Heidelberg Retinal Flowmeter (HRF). The differences between the three groups were compared with unpaired t-test, Wilcoxon Signed Rank and Fisher's Exact test using statistical package program.

RESULTS

The mean blood volume and velocity in the eyes with stage 4 macular hole (group 1) and in the eyes with stage 1a macular hole (group 2) were both significantly lower than the eyes in control eyes (group 3) (p < 0.05, unpaired t-test). Although, the mean blood "flow" parameter of group 2 was significantly lower than group 3 ( p < 0.05, unpaired t-test), there was no statistical difference in the "flow" parameter between group 1 and group 3 (p>> 0.05, unpaired t-test). The comparison between group 1 and group 2 revealed no significant difference in any perfusion parameter (p>> 0.05, Wilcoxon Signed Rank Test).

CONCLUSIONS

Although, it may be result of macular hole, not necessarily the cause of it, these findings suggest that the eyes with idiopathic macular hole are associated with reduced foveolar blood flow. The measurement of the foveolar blood flow from choriocapillaris may be useful for identifying the subjects who have increased risk of development of macular hole in future. The study showed the association of a decrease in foveolar choroidal blood flow in eyes with idiopathic macular hole using HRF. Authors suggested that quantitative measurement of foveolar choroidal blood flow may be helpful for identifying the subjects who have increased risk of development of idiopathic macular hole.

The purpose of this study was to examine the effect of a Comprehensive School Physical Activity Program (CSPAP) on physical activity and health-related fitness (HRF) in children from low-income families.

Participants included 1390 children recruited from kindergarten through sixth grade (mean age = 8.4 ± 1.8 years). Physical activity measures were collected at baseline and at 6 weeks and 12 weeks after program implementation, and HRF measures were collected at baseline and at 12 weeks after program implementation.

There were significant but weak-to-moderate increases in step counts (mean difference = 603.1 steps, P < .001, d = 0.39) and moderate-to-vigorous physical activity (mean difference = 4.9 minutes, P < .001, d = 0.39) at 12 weeks compared with baseline. There were also significant but moderate increases in Progressive Aerobic Cardiovascular Endurance Run laps (mean difference = 6.5 laps, P < .001, d = 0.47) at 12 weeks compared with baseline. Generalized mixed models respectively yielded 3.02 and 2.34 greater odds that a child would achieve step count and moderate-to-vigorous physical activity standards and 2.26 greater odds that a child would achieve aerobic fitness standards at 12 weeks compared with baseline (P < .001).

The 12-week CSPAP improved physical activity and HRF in children from low-income families; however, the magnitude of the effects was weak to moderate.

The experiment 'Dosimetric Mapping' conducted as part of the science program of NASA's Human Research Facility (HRF) between March and August 2001 was designed to measure integrated total absorbed doses (ionising radiation and neutrons), heavy ion fluxes and its energy, mass and linear energy transfer (LET) spectra, time-dependent count rates of charged particles and their corresponding dose rates at different locations inside the US Lab at the International Space Station. Owing to the variety of particles and energies, a dosimetry package consisting of thermoluminescence dosemeter (TLD) chips and nuclear track detectors with and without converters (NTDPs), a silicon dosimetry telescope (DOSTEL), four mobile silicon detector units (MDUs) and a TLD reader unit (PILLE) with 12 TLD bulbs as dosemeters was used. Dose rates of the ionising part of the radiation field measured with TLD bulbs applying the PILLE readout system at different locations varied between 153 and 231 microGy d(-1). The dose rate received by the active devices fits excellent to the TLD measurements and is significantly lower compared with measurements for the Shuttle (STS) to MIR missions. The comparison of the absorbed doses from passive and active devices showed an agreement within +/- 10%. The DOSTEL measurements in the HRF location yielded a mean dose equivalent rate of 535 microSv d(-1). DOSTEL measurements were also obtained during the Solar Particle Event on 15 April 2001.

BACKGROUND

Since 2007, the Mental Health Commission of Canada has worked collaboratively across all provinces to publish a framework and strategy for recovery and well-being. This federal document is now mandated as policy for implementation between 2012 and 2017. The proposed strategies have been written into provincial health plans, hospital accreditation standards, and annual objectives of psychiatric departments and community organizations. The core premise is: to empower persons with mental illness and their families to become participants in designing their own care, while meeting the needs of a diverse Canadian population. However, recovery principles do not come with an implementation guide to fit the variability of different local contexts. How can policy recommendations and accreditation standards be effectively tailored to support a diversity of stakeholder values? To our knowledge, there is little evidence indicating the most effective manner to accelerate the uptake of recovery-oriented services among providers in a given/particular mental health treatment setting.

METHODS

This three-year Canadian Institute of Health Research Partnership in Health System Improvement and The Rx&D Health Research Foundation (HRF) Fostering Canadian Innovation in Research study (2013 to 2017) proposed participatory approaches to implementing recovery principles in a Department of Psychiatry serving a highly diverse Canadian and immigrant population. This project will be conducted in overlapping and recursive phases: I) Conduct formative research to (a) measure the current knowledge and attitudes toward recovery and recovery-oriented practices among service providers, while concurrently (b) exploring the experiential knowledge of recovery service-users and family members; II) Collaborate with service-users and the network-identified opinion leaders among providers to tailor Recovery-in-Action Initiatives to fit the needs and resources of a Department of Psychiatry; and III) Conduct a systematic theory-based evaluation of changes in attitudes and practices within the service-user/service-provider partnership group relative to the overall provider network of the department and identify the barriers and supports within the local context.

CONCLUSIONS

Our anticipated outcome is a participatory toolkit to tailor recovery-oriented services, which will be disseminated to the Mental Health Commission of Canada and Accreditation Canada at the federal level, agencies at the provincial levels, and local knowledge end-users.

OBJECTIVE

To determine whether disorganization of retinal inner layers (DRIL) assessed by spectral-domain optical coherence tomography (SDOCT) correlates with visual acuity (VA) in eyes with uveitic cystoid macular edema (CME).

METHODS

Secondary analysis of randomized clinical trial data.

METHODS

Fifty-six eyes of 42 patients with uveitic CME were prospectively imaged as part of the VISUAL-1 trial (Clinicaltrials.gov identifier NCT01138657). Central subfield thickness (CFT), horizontal and vertical extent of DRIL, foveal DRIL (>500 μm DRIL) hyperreflective foci (HRF), average and largest area of intraretinal (IR) cysts, and extent of disruption of external limiting membrane (ELM) and ellipsoid zone (EZ) were determined within the 1-mm central subfield and correlated with VA at baseline and follow-up visits.

RESULTS

Regression analysis adjusted for clustered observations was used to examine the association between OCT morphologic parameters and VA. Across all visits (n = 168), significant associations were found for CFT (0.080 per 100 μm, P < .001), foveal DRIL (0.170, P < .001), horizontal DRIL length (0.055 per 100 μm, P < .001), vertical DRIL extent (0.001, P = .005), total area of IR cysts (0.204 per mm2, P < .001), area of largest IR cyst (1.407 per mm2, P < .001), presence of HRF (P = .026), and EZ disruption (0.042 per 100 μm, P = .02). ELM disruption did not show a significant association with VA (-0.013 per 100 μm, P = .61).

CONCLUSIONS

DRIL is a robust and easily obtained surrogate marker of VA in participants with current or resolved uveitic CME. CFT, DRIL, IR cyst area, EZ disruption, and HRF had a strong association with VA.

BACKGROUND

Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing.

OBJECTIVE

This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes: MEFV, TNFRSF1A, NLRP3 and MVK.

METHODS

We configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds.

RESULTS

Consensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFV gene.

CONCLUSIONS

Applying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http://github.com/molgenis/molgenis; the specific HRF configuration is available at http://molgenis.org/said/. The HRF pathogenicity classifications will be published on the INFEVERS database at https://fmf.igh.cnrs.fr/ISSAID/infevers/.

Functional magnetic resonance imaging (fMRI) has been used to infer age-differences in neural activity from the hemodynamic response function (HRF) that characterizes the blood-oxygen-level-dependent (BOLD) signal over time. BOLD literature in healthy aging lacks consensus in age-related HRF changes, the nature of those changes, and their implications for measurement of age differences in brain function. Between-study discrepancies could be due to small sample sizes, analysis techniques, and/or physiologic mechanisms. We hypothesize that, with large sample sizes and minimal analysis assumptions, age-related changes in HRF parameters could reflect alterations in one or more components of the neural-vascular coupling system. To assess HRF changes in healthy aging, we analyzed the large population-derived dataset from the Cambridge Center for Aging and Neuroscience (CamCAN) study (Shafto et al., 2014). During scanning, 74 younger (18-30 years of age) and 173 older participants (54-74 years of age) viewed two checkerboards to the left and right of a central fixation point, simultaneously heard a binaural tone, and responded via right index finger button-press. To assess differences in the shape of the HRF between younger and older groups, HRFs were estimated using FMRIB's Linear Optimal Basis Sets (FLOBS) to minimize a priori shape assumptions. Group mean HRFs were different between younger and older groups in auditory, visual, and motor cortices. Specifically, we observed increased time-to-peak and decreased peak amplitude in older compared to younger adults in auditory, visual, and motor cortices. Changes in the shape and timing of the HRF in healthy aging, in the absence of performance differences, support our hypothesis of age-related changes in the neural-vascular coupling system beyond neural activity alone. More precise interpretations of HRF age-differences can be formulated once these physiologic factors are disentangled and measured separately.

We propose a method to do constrained parameter estimation and inference from neuroimaging data using general linear model (GLM). Constrained approach precludes unrealistic hemodynamic response function (HRF) estimates to appear at the outcome of the GLM analysis. The permissible ranges of waveform parameters were determined from the study of a repertoire of plausible waveforms. These parameter intervals played the role of prior distributions in the subsequent Bayesian analysis of the GLM, and Gibbs sampling was used to derive posterior distributions. The method was applied to artificial null data and near infrared spectroscopy (NIRS) data. The results show that constraining the GLM eliminates unrealistic HRF waveforms and decreases false activations, without affecting the inference for "realistic" activations, which satisfy the constraints.

Inter-subject fMRI analyses have specific issues regarding the reliability of the results concerning both the detection of brain activation patterns and the estimation of the underlying dynamics. Among these issues lies the variability of the hemodynamic response function (HRF), that is usually accounted for using functional basis sets in the general linear model context. Here, we use the joint detection-estimation approach (JDE) (Makni et al., 2008; Vincent et al., 2010) which combines regional nonparametric HRF inference with spatially adaptive regularization of activation clusters to avoid global smoothing of fMRI images. We show that the JDE-based inference brings a significant improvement in statistical sensitivity for detecting evoked activity in parietal regions. In contrast, the canonical HRF associated with spatially adaptive regularization is more sensitive in other regions, such as motor cortex. This different regional behavior is shown to reflect a larger discrepancy of HRF with the canonical model. By varying parallel imaging acceleration factor, SNR-specific region-based hemodynamic parameters (activation delay and duration) were extracted from the JDE inference. Complementary analyses highlighted their significant departure from the canonical parameters and the strongest between-subject variability that occurs in the parietal region, irrespective of the SNR value. Finally, statistical evidence that the fluctuation of the HRF shape is responsible for the significant change in activation detection performance is demonstrated using paired t-tests between hemodynamic parameters inferred by GLM and JDE.

Neuroimaging methodology predominantly relies on the blood oxygenation level dependent (BOLD) signal. While the BOLD signal is a valid measure of neuronal activity, variances in fluctuations of the BOLD signal are not only due to fluctuations in neural activity. Thus, a remaining problem in neuroimaging analyses is developing methods that ensure specific inferences about neural activity that are not confounded by unrelated sources of noise in the BOLD signal. Here, we develop and test a new algorithm for performing semiblind (i.e., no knowledge of stimulus timings) deconvolution of the BOLD signal that treats the neural event as an observable, but intermediate, probabilistic representation of the system's state. We test and compare this new algorithm against three other recent deconvolution algorithms under varied levels of autocorrelated and Gaussian noise, hemodynamic response function (HRF) misspecification and observation sampling rate. Further, we compare the algorithms' performance using two models to simulate BOLD data: a convolution of neural events with a known (or misspecified) HRF versus a biophysically accurate balloon model of hemodynamics. We also examine the algorithms' performance on real task data. The results demonstrated good performance of all algorithms, though the new algorithm generally outperformed the others (3.0% improvement) under simulated resting-state experimental conditions exhibiting multiple, realistic confounding factors (as well as 10.3% improvement on a real Stroop task). The simulations also demonstrate that the greatest negative influence on deconvolution accuracy is observation sampling rate. Practical and theoretical implications of these results for improving inferences about neural activity from fMRI BOLD signal are discussed.

Fifty-two eyes of 26 healthy volunteers were recruited for evaluating the effects of 0.005% latanoprost on optic nerve head (ONH) and peripapillary retinal blood flow. In a randomized double-blind design, one eye received one drop of 0.005% latanoprost and its fellow eye received one drop of a placebo eyedrop. Intraocular pressure (IOP), ONH and peripapillary retinal blood flow were measured with Heidelberg retinal flowmetry (HRF) before, 2 and 24 h after administration of eyedrops. IOP was decreased significantly in latanoprost-treated eyes at 2 and 24 h after administration (p < 0.05). In the volume, flow or velocity of ONH and peripapillary retina, there were no significant changes from the baseline values at 2 and 24 h after latanoprost administration in either latanoprost-treated eyes or their fellow eyes (p>> 0.05). No significant differences were found in the measured quantities between latanoprost-treated eyes and their fellow eyes at each time point (p>> 0.05). This result may suggest that 0.005% latanoprost in healthy subjects does not have any adverse effect on ONH and peripapillary retinal blood flow.

The hemodynamic response function (HRF) describes the local response of brain vasculature to functional activation. Accurate HRF modeling enables the investigation of cerebral blood flow regulation and improves our ability to interpret fMRI results. Block designs have been used extensively as fMRI paradigms because detection power is maximized; however, block designs are not optimal for HRF parameter estimation. Here we assessed the utility of block design fMRI data for HRF modeling. The trueness (relative deviation), precision (relative uncertainty), and identifiability (goodness-of-fit) of different HRF models were examined and test-retest reproducibility of HRF parameter estimates was assessed using computer simulations and fMRI data from 82 healthy young adult twins acquired on two occasions 3 to 4 months apart. The effects of systematically varying attributes of the block design paradigm were also examined. In our comparison of five HRF models, the model comprising the sum of two gamma functions with six free parameters had greatest parameter accuracy and identifiability. Hemodynamic response function height and time to peak were highly reproducible between studies and width was moderately reproducible but the reproducibility of onset time was low. This study established the feasibility and test-retest reliability of estimating HRF parameters using data from block design fMRI studies.

Host range factor 1 (HRF-1) of Lymantria dispar multinucleocapsid nucleopolyhedrovirus promotes Autographa californica MNPV replication in nonpermissive Ld652Y cells derived from L. dispar. Here we demonstrate that restricted Hyphantria cunea NPV replication in Ld652Y cells was not due to apoptosis but was likely due to global protein synthesis arrest that could be restored by HRF-1. Our data also showed that HRF-1 promoted the production of progeny virions for two other baculoviruses, Bombyx mori NPV and Spodoptera exigua MNPV, whose replication in Ld652Y cells is limited to replication of viral DNA without successful production of infectious progeny virions. Thus, HRF-1 is an essential viral factor required for productive infection of NPVs in Ld652Y cells.

The cytolytic protein (C9RP) of human cytotoxic lymphocytes was isolated from large granular lymphocytes (LGL) and anti-CD3 activated cytotoxic T cells (CTL). It is immunochemically related to the channel-forming proteins of complement. Whereas LGL constitutively contain C9RP, peripheral resting CTL do not. C9RP synthesis is induced, however, in CD8+ cells upon stimulation of the T cell antigen receptor-CD3 structure. Comparison of cellular cytotoxicity and C9RP content at various times during anti-CD3 activation of CTL yielded a coefficient of correlation, r = 0.92. Isolated C9RP (Mr approximately 70,000) readily lysed a large variety of metabolically active cells tested. Certain monoclonal antibodies to C9RP inhibited target cell killing by LGL or activated CD8+ lymphocytes. Homologous restriction factor (HRF) is a normal membrane protein of blood cells that inhibits transmembrane channel formation by the membrane attack complex of complement. It has recently been found that isolated HRF (Mr approximately 65,000), bound to sheep erythrocytes, inhibited their lysis mediated by the antibody-dependent cellular cytotoxicity reaction or by isolated C9RP. Further, stimulation of resting peripheral lymphocytes with anti-CD3 resulted in increased expression of cell surface HRF. Acquisition of HRF expression conferred upon CTL relative resistance to lysis by C9RP. A soluble form of HRF (Mr approximately 65,000) was isolated from the cytoplasmic granules of LGL, which also contain C9RP, and shown to inhibit cytotoxicity of LGL and CTL. It is conceivable that HRF is opertive in self-protection of cytotoxic lymphocytes.

OBJECTIVE

The Heidelberg retina flowmeter (HRF) is designed to measure retinal capillary blood flow. Previous studies however showed weak reproducibility of data. The intraindividual reproducibility of circadian HRF measurements was examined in healthy subjects in three locations of the retina.

METHODS

36 healthy volunteers (27.3 (SD 4.3) years) were examined by HRF seven times a day (t0-t6). Using a default window of 10 x 10 pixels, three consecutive measurements were performed in three precise focusing planes: superficial, intermediate and deep layer, peripapillary retina, neuroretinal rim and cup, respectively. Images of identical tissue locations identified by capillary landmarks of each layer were selected to quantify the retinal microcirculation of each volunteer. Means and standard deviations of all flow results of a given subject were calculated, at t0-t6 and the coefficients of variation as a measure of reproducibility.

RESULTS

The coefficients of variation ranged between 8.4% and 41.0% in the superficial layer (mean 19.8% (SD 8.4%)), 10.6%, and 43.0% in the intermediate layer (mean 24.0% (SD 8.4%)), and 9.9% and 84.0% (mean 29.6% (SD 15.8%)) in the deep layer.

CONCLUSIONS

These data show the best reproducibility of measurements in the superficial layer followed by the intermediate and the deep layer. Clinically, this is an unsatisfactory intraindividual reproducibility of flow values in each studied layer.

BACKGROUND

To investigate retinal capillary blood flow characteristics in patients with age-related maculopathy (ARM).

METHODS

Retinal capillary blood volume (VOL), blood flow (FLOW), and velocity (VEL) were measured in four macular sectors (I, II, III, IV) and in two areas beyond the temporal superior and inferior major vessel arcades (V and VI) in: 10 eyes with early ARM (drusen>> or = 63 microns and/or atrophy of the retinal pigment epithelium, RPE, < 175 microns and/or proliferation of RPE), 13 with late ARM (exudative), 10 with late ARM (fibrotic), 14 normal eyes of 14 children of patients with ARM, and in 4 age- and sex-matched control groups using the Heidelberg retinal flowmeter (HRF). Statistical analysis was performed with the exact Wilcoxon test using an additional adjustment procedure by Bonferroni-Holm.

RESULTS

As compared to the control group, there was no significant change of VOL, FLOW, and VEL in patients with early ARM. In patients with late ARM (exudative), there was a significant higher FLOW in sectors I, II, and IV and a higher VOL and VEL in sectors III and IV. The group with late ARM (fibrotic) showed a reduction of VOL and FLOW in sectors I-IV and of VEL in sectors II and IV. In children of ARM patients, VOL, FLOW, and VEL of sectors I-VI did not differ from the control group.

CONCLUSIONS

HRF measurements in patients with ARM indicate an increased macular retinal capillary blood flow in patients with the exudative form of late ARM and a decreased macular perfusion in those with the fibrotic form.

We have previously shown that local infection of tobacco plants with tobacco mosaic virus (TMV) or oilseed rape mosaic virus (ORMV) results in a systemic increase in the homologous recombination frequency (HRF). Here, we analyzed what other changes in the genome are triggered by pathogen infection. For the analysis of HRF, mutation frequency (MF) and microsatellite instability (MI), we used three different transgenic Arabidopsis lines carrying β-glucuronidase (GUS)-based substrates in their genome. We found that local infection of Arabidopsis with ORMV resulted in an increase of all three frequencies, albeit to differing degrees. The most prominent increase was observed in microsatellite instability. The increase in HRF was the lowest, although still statistically significant. The analysis of methylation of the 35S promoter and transgene expression showed that the greater instability of the transgene was not attributed to these changes. Strand breaks brought about a significant increase in non-treated tissues of infected plants. The expression of genes associated with various repair processes, such as KU70, RAD51, MSH2, DNA POL α and DNA POL δ, was also increased. To summarize, our data demonstrate that local ORMV infection destabilizes the genome in systemic tissues of Arabidopsis plants in various ways resulting in large rearrangements, point mutations and microsatellite instability.

The study aims to investigate the effect of cerebral ischemia or hypoperfusion in the evaluation of neural activity with blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI), and to examine whether the severity of the compromised hemodynamic status in patients with major cerebral artery diseases could, conversely, be assessed with the use of neural activity as endogenous vasodilator. 28 neurological impairment-free patients with anterior-circulation-territory ischemia performed a bimanual hand-grasping task. Magnitude and temporal shift of evoked BOLD response, baseline cerebral blood flow (CBF) and its increment, and the severity of hemodynamic impairment stratified by blood flow pattern were evaluated. For fMRI data, both conventional analysis with a canonical HRF and an HRF-model-free analysis were performed. The severity of hemodynamic impairment was significantly correlated (p<0.0001) with baseline CBF, CBF increment, and magnitude and delay of BOLD response. BOLD response delay was also significantly correlated (p<0.0001) with baseline CBF, CBF increment, and response magnitude. In 10 out of 45 ischemic motor cortices, conventional analysis completely failed to detect areas of activation that were demonstrated by HRF-model-free analysis. These data suggest that delay and reduced magnitude of BOLD response can be an indicator of the severity of compromised hemodynamic status, and that reduced regional baseline CBF and its increment underlie impaired BOLD response, which necessitates an alternative approach to conventional analysis with any single HRF.

We have recently described the molecular basis of HIV-1 resistance factor (HRF)-mediated anti-viral activity in primary and transformed CD4 T cells. HRF+ cell culture supernatants or partially purified HRF were found to incapacitate the formation of the NF-kappaB/DNA complex, which is indispensable for long terminal promoter-driven transcription of virus genes. In this study, we tested whether HRF might have much broader activity against other organisms whose pathogenesis is linked to NF-kappaB activation. Specifically, we tested the effects of HRF on the NF-kappaB-mediated responses of primary macrophages to HIV-1 or several bacterial antigens. We found that exposure to HRF inhibited HIV-1 expression in macrophages and also induced the production of HRF-like activity by macrophages, which prevented replication of virus in HIV-1-infected peripheral blood lymphocytes cultured in the adjacent compartment. We investigated the mechanism of this inhibition and found that HRF impeded NF-kappaB/DNA binding in macrophages induced by either HIV-1 or lipopolysaccharide from several bacteria species, resulting in impaired tumor necrosis factor-alpha responses to these organisms.

OBJECTIVE

To assess the effects of adding dorzolamide to timolol monotherapy on ocular haemodynamics and retinal oxygen saturation in patients with primary open-angle glaucoma (POAG).

METHODS

Twenty-four patients (12 healthy, 12 with POAG) were treated with dorzolamide/timolol combination (DT) versus timolol maleate 0.5% twice daily in a randomized, crossover, double-blind study conducted over a period of 18 months. Patients received each treatment for 8 months then crossed over to the other treatment after a 1-month washout and second baseline. Goldmann applanation tonometry, Heidelberg retinal flowmetry (HRF), colour Doppler imaging (CDI) and retinal photographic oximetry were performed at each visit.

RESULTS

DT significantly reduced intraocular pressure (IOP) in both glaucomatous [right eye (OD) -13.15%, left eye (OS) -14.43%; p < 0.036] and non-glaucomatous (OD -12.4%, OS -13.88%; p < 0.039) patients compared to timolol after 8 months of treatment. DT significantly reduced the number of zero blood flow pixels in the superior (-39.72%; p < 0.014) and inferior (-51.44%; p < 0.008) retina in the non-glaucomatous group and inferior retina in the glaucomatous group (-55.38%, p < 0.006). The continuation of timolol monotherapy from baseline did not change (p < 0.05) any measured parameter and neither treatment had a significant effect (p < 0.05) on retinal oximetry or CDI parameters.

CONCLUSIONS

The addition of dorzolamide to timolol monotherapy decreases IOP and increases retinal blood flow in the superficial retinal vasculature in both glaucomatous and healthy patients following 8 months of treatment. The combination of increased retinal blood flow with consistent oxygen saturation may potentially increase oxygen delivery to the retina.

Environmental factors that damage DNA have various lengths of exposure and intensity levels. Although the results of increasing the intensity of a DNA damaging agent is often predictable, it is not clear whether the stage during development when the exposure is received has any influence on the amount of DNA damage. In this paper we analyzed the influence of UVB on the stability of Arabidopsis thaliana and the Nicotiana tabacum genomes. Our experiments showed that the acute exposure to UVB produces a significantly greater increase in homologous recombination frequency (HRF) and recombination rate (RR) compared with that produced by chronic exposure. The increase in HRF showed a positive correlation with UVB dose and a negative correlation with plant age. In other words, as the UVB dose was increased, there was a concomitant increase in HRF. Conversely, older plants had a lower HRF increase as compared to younger plants. Our experiments suggest that exposure to UVB makes the most significant impact on genome stability during the early stages of plant development.

OBJECTIVE

To develop a simple, clinically practical, optical coherence tomography (OCT)-based scoring system for early age-related macular degeneration (AMD) to prognosticate risk for progression to late AMD.

METHODS

We retrospectively reviewed OCT images (512 × 128 macular cube, Cirrus) from 138 patients diagnosed of early AMD in at least one eye and follow-up of at least 12 months. For patients with early AMD in both eyes, only the right eye was chosen as the study eye for longitudinal assessment. Scans were graded on four SD-OCT criteria associated with disease progression in previous studies: drusen volume within a central 3-mm circle ≥0.03 mm3, intraretinal hyperreflective foci (HRF), hyporeflective foci (hRF) within a drusenoid lesion (DL), and subretinal drusenoid deposits (SDD). Each criterion was assigned one point. For risk assessment of the study eye, the baseline status of the fellow eye was also considered, and thus these four features were also assessed in the fellow eye. The number of risk factors were summed for both eyes, yielding a total score (TS) of 0 to 8 for each patient. A fellow eye with evident choroidal neovascularization (CNV) or atrophy automatically received 4 points. Scores were then grouped into four categories to facilitate comparative analysis: I. (TS of 0, 1, 2), II. (TS of 3, 4), III. (TS of 5, 6) and IV. (TS of 7, 8). Correlation of baseline category assignment with progression to late AMD (defined as the presence of atrophy or CNV on OCT) by the last follow-up visit was evaluated with logistic regression analysis.

RESULTS

The rate of progression to late AMD was 39.9% (55/138). Progression rates by category (I to IV) were 0, 14.3, 47.5, and 73.3%, respectively. Logistic regression analysis showed risk of progression to late AMD was 3.0 times (95% CI: 1.2-7.9) higher for an eye assigned to category IV than for an eye in category III and 16.4 (95% CI: 4.7-58.8) times higher than for an eye in category II.

CONCLUSIONS

A simple scoring system relevant to prognosis for early AMD, and practical for use in a busy clinic, can be developed using SD-OCT criteria alone.