Activation of monocytes and cytokine production in patients with peripheral atherosclerosis obliterans

Background: Arterial peripheral disease is a condition caused by the blocked blood flow resulting from arterial cholesterol deposits within the arms, legs and aorta. Studies have shown that macrophages in atherosclerotic plaque are highly activated, which makes these cells important antigen-presenting cells that develop a specific immune response, in which LDLox is the inducing antigen. As functional changes of cells which participate in the atherogenesis process may occur in the peripheral blood, the objectives of the present study were to evaluate plasma levels of anti-inflammatory and inflammatory cytokines including TNF-alpha, IFN-gamma, interleukin-6 (IL-6), IL-10 and TGF-beta in patients with peripheral arteriosclerosis obliterans, to assess the monocyte activation level in peripheral blood through the ability of these cells to release hydrogen peroxide (H(2)O(2)) and to develop fungicidal activity against Candida albicans (C. albicans) in vitro.Methods: TNF-alpha, IFN-gamma, IL-6, IL-10 and TGF-beta from plasma of patients were detected by ELISA. Monocyte cultures activated in vitro with TNF-alpha and IFN-gamma were evaluated by fungicidal activity against C. albicans by culture plating and Colony Forming Unit (CFU) recovery, and by H(2)O(2) production.Results: Plasma levels of all cytokines were significantly higher in patients compared to those detected in control subjects. Control group monocytes did not release substantial levels of H(2)O(2) in vitro, but these levels were significantly increased after activation with IFN-gamma and TNF-alpha. Monocytes of patients, before and after activation, responded less than those of control subjects. Similar results were found when fungicidal activity was evaluated. The results seen in patients were always significantly smaller than among control subjects. Conclusions: The results revealed an unresponsiveness of patient monocytes in vitro probably due to the high activation process occurring in vivo as corroborated by high plasma cytokine levels.

BLOQUEIO PERIDURAL E TERMOMETRIA CUTANEA COMO CRITERIO PARA INDICACAO CIRURGICA DE SIMPATECTOMIA LOMBAR

To find a valuable tool in achieving a good accuracy in predicting the outcome from sympathectomy, changes in limb skin temperatures (LST) before and after epidural lumbar anesthesia (ELA) and before and after lumbar sympathectomy were studied in 13 patients with thrombangiitis obliterans or arteriosclerosis obliterans. The results were compared with the clinical course and follow-up from 1 to 5 years. In seven patients there was a rise in LST after ELA and after sympathectomy, and this pattern of variation was associated with good clinical course. In three patients there was decrease in the LST after ELA and after sympathectomy and they did not do well. In two patients there was no change in temperature before or after the procedure; one of them had a good and the other a bad clinical course. The same measurements were performed in three other patients who had had a sympathectomy some years previously and the data showed that LST was lowered after ELA. It is concluded that the measurement of limb skin temperature before and after epidural lumbar anesthesia aids in determining which patients are more likely to benefit from sympathectomy.

The role of microRNA 21 in the development of in-stent restenosis

Coronary heart disease is a major cause of morbidity and mortality worldwide. Percutaneous coronary intervention (PCI) has become the most widely used method of coronary artery revascularisation. The use of stents to hold open atherosclerosis induced arterial narrowing has significantly reduced elastic recoil and acute vessel occlusion following balloon angioplasty. However, bare metal stents have been associated with in-stent restenosis attributed to vascular smooth muscle cell (VSMC) hyperplasia and excessive neointimal formation. The resultant luminal renarrowing may manifest clinically with the return of symptoms such as chest pain or shortness of breath. The development of drug eluting stents has significantly reduced the incidence of in-stent restenosis (ISR). Unfortunately the antiproliferative medications used not only inhibit VSMC proliferation but also re-endothelialisation of the stented vessel. In addition, the drug impregnated polymer coating has been associated with a chronic inflammatory response within the vessel wall predisposing patients to stent thrombosis. Thus the identification of novel therapies which promote vessel healing without excessive proliferative or inflammatory response may improve long term outcome and reduce the need for repeated revascularisation. MicroRNAs (miRs) are short (18-25 nucleotide) non-coding RNAs acting to regulate gene expression. By binding to the 3’untranslated region of mRNA they act to fine tune gene expression either by mRNA degradation or translational repression. Originally identified in coordinating tissue development microRNAs have also been shown to play important roles coordinating the inflammatory response and in numerous cardiovascular diseases. MiR-21 has been identified in human atherosclerotic plaques, arteriosclerosis obliterans and abdominal aortic aneurysms. In addition, its up regulation has been documented in preclinical models of vascular injury. This study sought to identify the role of miR-21 in the development of ISR. Utilising a small animal model of stenting and in vitro techniques, we sought to investigate its influence upon VSMC and immune cell response following stenting. 19 The refinement of a murine stenting model within the Baker laboratory and the electrochemical dissolution of the metal stent from within harvested vascular tissues significantly improved the ability to perform detailed histological analysis. In addition, identification of miRNAs using in situ hybridisation was achieved for the first time within stented tissue. Neointimal formation and ISR was significantly reduced in mice in which miR-21 had been genetically deleted. In addition, neointimal composition was found to be altered in miR-21 KO mice with reductions in VSMC and elastin content demonstrated. Importantly, no difference in re-endothelialisation was observed. In vitro analysis demonstrated that VSMCs from miR-21 KO mice had both reduced proliferative and migratory capacity following platelet derived growth factor stimulation. Molecular analysis revealed that these differences may, at least in part, be due to de-repression of programmed cell death 4 (PDCD4). PDCD4 is a known miR-21 target within VSMCs implicated in the suppression of proliferation and promotion of apoptosis. Unfortunately, initial attempts at antimiR mediated knockdown of miR-21 in vivo, failed to produce a similar change in the suppression of ISR. Furthermore, a significant alteration in macrophage polarisation state within the neointima of miR-21 WT and KO mice was noted. Immunohistochemical staining revealed a preponderance of anti-inflammatory M2 macrophages in KO mice. Analysis of bone marrow derived macrophages from miR-21 KO mice demonstrated an increased level of the peroxisome proliferation activating receptor-γ (PPARγ) which facilitates M2 polarisation. Importantly, significant alterations in numerous pro-inflammatory cytokines, which also have mitogenic effects, were also found following genetic deletion of miR-21. In Summary, this is the first study to look at miRs in the development of ISR. MiR-21 plays an important role in the development of ISR by influencing the proliferative response of VSMCs and modulating the immune response following stent deployment. Further attempts to modulate miR-21 expression following PCI may reduce ISR and the need for repeat revascularisation while also reducing the risk of stent thrombosis.

Imbalanced matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 activities in patients with thromboangiitis obliterans

The pathogenic mechanisms of thromboangiitis obliterans (TAO) are not entirely known and the imbalance of matrix metalloproteinases (MMPs) plays a role in vascular diseases. We evaluated the MMP-2 and MMP-9 circulating levels and their endogenous tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in TAO patients with clinical manifestations. The study included 20 TAO patients (n = 10 female, n = 10 male) aged 38-59 years under clinical follow-up. The patients were classified into two groups: (1) TAO former smokers (n = 11) and (2) TAO active smokers (n = 9); the control group included normal volunteer non-smokers (n = 10) and active smokers without peripheral artery disease (n = 10). Patient plasma samples were used to analyze MMP-2 and MMP-9 levels using zymography, and TIMP-1 and TIMP-2 concentrations were determined by enzyme-linked immunosorbent assays. The analysis of MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios (which were used as indices of net MMP-2 and MMP-9 activity, respectively) showed significantly higher MMP-9/TIMP-1 ratios in TAO patients (p < 0.05). We found no significant differences in MMP-2/TIMP-2 ratios (p > 0.05). We found higher MMP-9 levels and decreased levels of TIMP-1 in the TAO groups (active smokers and former smokers), especially in active smokers compared with the other groups (all p < 0.05). MMP-2 and TIMP-2 were not significantly different in patients with TAO as compared to the control group (p > 0.05). In conclusion, our results showed increased MMP-9 and reduced TIMP-1 activity in TAO patients, especially in active smokers compared with non-TAO patients. These data suggest that smoke compounds could activate MMP-9 production or inhibit TIMP-1 activity.

Clinically indicated replacement versus routine replacement of peripheral venous catheters (Review)

Background Centers for Disease Control Guidelines recommend replacement of peripheral intravenous (IV) catheters every 72 to 96 hours. Routine replacement is thought to reduce the risk of phlebitis and bacteraemia. Catheter insertion is an unpleasant experience for patients and replacement may be unnecessary if the catheter remains functional and there are no signs of inflammation. Costs associated with routine replacement may be considerable. Objectives To assess the effects of removing peripheral IV catheters when clinically indicated compared with removing and re-siting the catheter routinely.

Corneal sensitivity and slit scanning in vivo confocal microscopy of the subbasal nerve plexus of the normal central and peripheral human cornea

Purpose: To determine the subbasal nerve density and tortuosity at 5 corneal locations and to investigate whether these microstructural observations correlate with corneal sensitivity. Method: Sixty eyes of 60 normal human subjects were recruited into 1 of 3 age groups, group 1: aged ,35 years, group 2: aged 35–50 years, and group 3: aged .50 years. All eyes were examined using slit-lamp biomicroscopy, noncontact corneal esthesiometry, and slit scanning in vivo confocal microscopy. Results: The mean subbasal nerve density and the mean corneal sensitivity were greatest centrally (14,731 6 6056 mm/mm2 and 0.38 6 0.21 millibars, respectively) and lowest in the nasal mid periphery (7850 6 4947 mm/mm2 and 0.49 6 0.25 millibars, respectively). The mean subbasal nerve tortuosity coefficient was greatest in the temporal mid periphery (27.3 6 6.4) and lowest in the superior mid periphery (19.3 6 14.1). There was no significant difference in mean total subbasal nerve density between age groups. However, corneal sensation (P = 0.001) and subbasal nerve tortuosity (P = 0.004) demonstrated significant differences between age groups. Subbasal nerve density only showed significant correlations with corneal sensitivity threshold in the temporal cornea and with subbasal nerve tortuosity in the inferior and nasal cornea. However, these correlations were weak. Conclusions: This study quantitatively analyzes living human corneal nerve structure and an aspect of nerve function. There is no strong correlation between subbasal nerve density and corneal sensation. This study provides useful baseline data for the normal living human cornea at central and mid-peripheral locations

New Patterns in Global Television : Peripheral Vision

Over recent decades, the flow of television programmes and services between nations has prompted concerns about `Cultural Imperialism', the idea that the powerful metropolitan nations at the centre of the world system are breaking down the integrity and autonomy of the peripheral countries. New Patterns in Global Television challenges that notion by showing that some of the countries outside the traditionally dominant centres have now developed strong television industries of their own, and have been expanding into regional markets, especially - but not exclusively - where linguistic and cultural similarities exist. This book brings together contributions from specialist researchers on the most dynamic of these regions: Latin America, India, the Middle East, Greater China and, in the English-speaking world, Canada and Australia. It provides the first comprehensive overview of the new patterns of flow in international television programme exchange and service provision in the satellite era, patterns unrecognised by the perspective of the prevailing theoretical orthodoxies in international communication research and policy.

Effect of orthokeratology on peripheral aberrations of the eye

Purpose: To investigate the effect of orthokeratology on peripheral aberrations in two myopic volunteers. Methods: The subjects wore reverse geometry orthokeratology lenses overnight and were monitored for 2 weeks of wear. They underwent corneal topography, peripheral refraction (out to ±34° along the horizontal visual field) and peripheral aberration measurements across the 42° × 32° central visual field using a modified Hartmann-Shack aberrometer. Results: Spherical equivalent refraction was corrected for the central 25° of the visual fields beyond which it gradually returned to its preorthokeratology values. There were increases in axial coma, spherical aberration, higher order root mean square aberrations, and total root-mean-squared aberrations (excluding defocus). The rates of change of vertical and horizontal coma across the field changed in sign. Total root mean square aberrations showed a quadratic rate of change across the visual field which was greater subsequent to orthokeratology. Conclusion: Although orthokeratology can correct peripheral relative hypermetropia it induces dramatic increases in higher-order aberrations across the field

The influence of oblique viewing on axial and peripheral refraction for emmetropes and myopes

Refraction may be affected by the forces of lids and extraocular muscles when eye direction and head direction are not aligned (oblique viewing) which might potentially influence past findings on peripheral refraction of the eye. We investigated the effect of oblique viewing on axial and peripheral refraction. In a first experiment, cycloplegic axial refractions were determined when subjects' heads were positioned to look straight-ahead through an open-view autorefractor and when the heads were rotated to the right or left by 30° with compensatory eye rotation (oblique viewing). Subjects were 16 young emmetropes (18–35 years), 22 young myopes (19–36 years) and 15 old emmetropes (45–60 years). In a second experiment, cycloplegic peripheral refraction measurements were taken out to ±34° horizontally from fixation while the subjects rotated their heads to match the peripheral refraction angles (eye in primary position with respect to the head) or the eyes were rotated with respect to the head (oblique viewing). Subjects were 10 emmetropes and 10 myopes. We did not find any significant changes in axial or peripheral refraction upon oblique viewing for any of the subject groups. In general for the range of horizontal angles used, it is not critical whether or not the eye is rotated with respect to the head during axial or peripheral refraction.

Peripheral ocular monochromatic aberrations

Aberrations affect image quality of the eye away from the line of sight as well as along it. High amounts of lower order aberrations are found in the peripheral visual field and higher order aberrations change away from the centre of the visual field. Peripheral resolution is poorer than that in central vision, but peripheral vision is important for movement and detection tasks (for example driving) which are adversely affected by poor peripheral image quality. Any physiological process or intervention that affects axial image quality will affect peripheral image quality as well. The aim of this study was to investigate the effects of accommodation, myopia, age, and refractive interventions of orthokeratology, laser in situ keratomileusis and intraocular lens implantation on the peripheral aberrations of the eye. This is the first systematic investigation of peripheral aberrations in a variety of subject groups. Peripheral aberrations can be measured either by rotating a measuring instrument relative to the eye or rotating the eye relative to the instrument. I used the latter as it is much easier to do. To rule out effects of eye rotation on peripheral aberrations, I investigated the effects of eye rotation on axial and peripheral cycloplegic refraction using an open field autorefractor. For axial refraction, the subjects fixated at a target straight ahead, while their heads were rotated by ±30º with a compensatory eye rotation to view the target. For peripheral refraction, the subjects rotated their eyes to fixate on targets out to ±34° along the horizontal visual field, followed by measurements in which they rotated their heads such that the eyes stayed in the primary position relative to the head while fixating at the peripheral targets. Oblique viewing did not affect axial or peripheral refraction. Therefore it is not critical, within the range of viewing angles studied, if axial and peripheral refractions are measured with rotation of the eye relative to the instrument or rotation of the instrument relative to the eye. Peripheral aberrations were measured using a commercial Hartmann-Shack aberrometer. A number of hardware and software changes were made. The 1.4 mm range limiting aperture was replaced by a larger aperture (2.5 mm) to ensure all the light from peripheral parts of the pupil reached the instrument detector even when aberrations were high such as those occur in peripheral vision. The power of the super luminescent diode source was increased to improve detection of spots passing through the peripheral pupil. A beam splitter was placed between the subjects and the aberrometer, through which they viewed an array of targets on a wall or projected on a screen in a 6 row x 7 column matrix of points covering a visual field of 42 x 32. In peripheral vision, the pupil of the eye appears elliptical rather than circular; data were analysed off-line using custom software to determine peripheral aberrations. All analyses in the study were conducted for 5.0 mm pupils. Influence of accommodation on peripheral aberrations was investigated in young emmetropic subjects by presenting fixation targets at 25 cm and 3 m (4.0 D and 0.3 D accommodative demands, respectively). Increase in accommodation did not affect the patterns of any aberrations across the field, but there was overall negative shift in spherical aberration across the visual field of 0.10 ± 0.01m. Subsequent studies were conducted with the targets at a 1.2 m distance. Young emmetropes, young myopes and older emmetropes exhibited similar patterns of astigmatism and coma across the visual field. However, the rate of change of coma across the field was higher in young myopes than young emmetropes and was highest in older emmetropes amongst the three groups. Spherical aberration showed an overall decrease in myopes and increase in older emmetropes across the field, as compared to young emmetropes. Orthokeratology, spherical IOL implantation and LASIK altered peripheral higher order aberrations considerably, especially spherical aberration. Spherical IOL implantation resulted in an overall increase in spherical aberration across the field. Orthokeratology and LASIK reversed the direction of change in coma across the field. Orthokeratology corrected peripheral relative hypermetropia through correcting myopia in the central visual field. Theoretical ray tracing demonstrated that changes in aberrations due to orthokeratology and LASIK can be explained by the induced changes in radius of curvature and asphericity of the cornea. This investigation has shown that peripheral aberrations can be measured with reasonable accuracy with eye rotation relative to the instrument. Peripheral aberrations are affected by accommodation, myopia, age, orthokeratology, spherical intraocular lens implantation and laser in situ keratomileusis. These factors affect the magnitudes and patterns of most aberrations considerably (especially coma and spherical aberration) across the studied visual field. The changes in aberrations across the field may influence peripheral detection and motion perception. However, further research is required to investigate how the changes in aberrations influence peripheral detection and motion perception and consequently peripheral vision task performance.

Effects of age on peripheral ocular aberrations

On-axis monochromatic higher-order aberrations increase with age. Few studies have been made of peripheral refraction along the horizontal meridian of older eyes, and none of their off-axis higher-order aberrations. We measured wave aberrations over the central 42°x32° visual field for a 5mm pupil in 10 young and 7 older emmetropes. Patterns of peripheral refraction were similar in the two groups. Coma increased linearly with field angle at a significantly higher rate in older than in young emmetropes (−0.018±0.007 versus −0.006±0.002 µm/deg). Spherical aberration was almost constant over the measured field in both age groups and mean values across the field were significantly higher in older than in young emmetropes (+0.08±0.05 versus +0.02±0.04 µm). Total root-mean-square and higher-order aberrations increased more rapidly with field angle in the older emmetropes. However, the limits to monochromatic peripheral retinal image quality are largely determined by the second-order aberrations, which do not change markedly with age, and under normal conditions the relative importance of the increased higher-order aberrations in older eyes is lessened by the reduction in pupil diameter with age. Therefore it is unlikely that peripheral visual performance deficits observed in normal older individuals are primarily attributable to the increased impact of higher-order aberration.

Peripheral higher order aberrations in emmetropes and myopes

Purpose: Poor image quality in the peripheral field may lead to myopia. Most studies measuring the higher order aberrations in the periphery have been restricted to the horizontal visual field. The purpose of this study was to measure higher order monochromatic aberrations across the central 42º horizontal x 32º vertical visual fields in myopes and emmetropes. ---------- Methods: We recruited 5 young emmetropes with spherical equivalent refractions +0.17 ± 0.45D and 5 young myopes with spherical equivalent refractions -3.9 ± 2.09D. Measurements were taken with a modified COAS-HD Hartmann-Shack aberrometer (Wavefront Sciences Inc). Measurements were taken while the subjects looked at 38 points arranged in a 7 x 6 matrix (excluding four corner points) through a beam splitter held between the instrument and the eye. A combination of the instrument’s software and our own software was used to estimate OSA Zernike coefficients for 5mm pupil diameter at 555nm for each point. The software took into account the elliptical shape of the off-axis pupil. Nasal and superior fields were taken to have positive x and y signs, respectively. ---------- Results: The total higher order RMS (HORMS) was similar on-axis for emmetropes (0.16 ± 0.02 μm) and myopes (0.17 ± 0.02 μm). There was no common pattern for HORMS for emmetropes across the visual field where as 4 out of 5 myopes showed a linear increase in HORMS in all directions away from the minimum. For all subjects, vertical and horizontal comas showed linear changes across the visual field. The mean rate of change of vertical coma across the vertical meridian was significantly lower (p = 0.008) for emmetropes (-0.005 ± 0.002 μm/deg) than for myopes (-0.013 ± 0.004 μm/deg). The mean rate of change of horizontal coma across the horizontal meridian was lower (p = 0.07) for emmetropes (-0.006 ± 0.003 μm/deg) than myopes (-0.011 ± 0.004 μm/deg). ---------- Conclusion: We have found differences in patterns of higher order aberrations across the visual fields of emmetropes and myopes, with myopes showing the greater rates of change of horizontal and vertical coma.