Variation of selected genotoxic and epigenetic markers due to therapeutic exposure to PAHs and ultraviolet radiation.

BACKGROUND: Goeckerman therapy (GT) of psoriasis involves dermal application of crude coal tar containing polycyclic aromatic hydrocarbons (PAHs) and exposure to ultraviolet radiation (UVR). Little is known about GT influence on DNA epigenetics. OBJECTIVE: The study aim was to discover epigenetic mechanisms altered by the exposure related to the GT of psoriasis. METHODS: Observed group of patients with plaque psoriasis (n = 23) was treated by GT with 3 % CCT. Before and after GT, we analyzed the levels of benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts (BPDE-DNA), p53 protein in serum, 5-methylcytosine (5-mC, global DNA methylation), and methylation in selected CpG sites of p53 gene. RESULTS: We found a significant increase in the levels of BPDE-DNA (p < 0.01) and serum levels of p53 protein (p < 0.01) after GT, and an insignificant decrease in the percentage of 5-mC in peripheral blood DNA. Methylation of p53 CpG sites was affected neither by psoriasis nor by GT. The study confirmed good effectiveness of GT (significantly reduced psoriasis area and severity index; p < 0.001). CONCLUSION: Our findings indicate that there is a significantly increased genotoxic hazard related to the exposure of PAHs and UV radiation after GT of psoriasis. However, global DNA methylation and p53 gene methylation evade the effect of GT, as they remained unchanged (Tab. 4, Fig. 3, Ref. 50).

Serum Levels of Aryl Hydrocarbon Receptor, Cytochromes P450 1A1 and 1B1 in Patients with Exacerbated Psoriasis Vulgaris.

The aryl hydrocarbon receptor (AhR) is highly expressed in psoriasis skin lesions. The aim of this study was to investigate serum concentrations of AhR, cytochromes P450 (CYP) 1A1 and 1B1 in patients with exacerbated psoriasis vulgaris treated with combined therapy of ultraviolet radiation (UVR) and crude coal tar. The analyses were performed by using enzyme-linked immunosorbent assays. Before the treatment, the patients had significantly higher serum levels of AhR and CYP1A1 than healthy controls. AhR median noticeably decreased after the therapy; nevertheless, it remained significantly higher compared to the controls. CYP1A1 levels measured before and after the therapy did not differ significantly. Serum CYP1A1 positively correlated with AhR values before and after the treatment. The serum values of CYP1B1 were very low and we did not see any differences between the study group and the control group. The study demonstrated that serum levels of AhR and CYP1A1 could indicate their immunopathological and metabolic roles in exacerbated psoriasis.

Elevated levels of circulating biomarkers of cell death (nucleosomes) in the patients with plaque psoriasis treated with the Goeckerman regimen.

BACKGROUND: Nucleosomes are complexes that are formed during apoptosis. Psoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation and anti-apoptotic features. Presented study was focused to expression of circulating biomarkers of cell death (circulating nucleosomes, CN) during Goeckerman therapy of psoriasis (UV, PAHs). METHODS: In a group of patients with psoriasis (19), treated with Goeckerman regimen (GR), we evaluated their level of CN, level of chromosomal aberration in peripheral lymphocytes (CA), level of urinary 1-hydroxypyrene (1-OHP) and their value of Psoriasis Area and Severity Index (PASI). RESULTS: Following the treatment, the serum level of CN and urinary level of 1-OHP (p<0.05) were significantly increased (p<0.01). We found significant correlation between CN and urinary level of 1-OHP after GR (r=0.57; p<0.05). Immediately after the treatment we found significantly increased total numbers of abnormal chromosomes (ABB; p<0.01) and structurally abnormal chromosomes (SAB; p<0.05). CONCLUSIONS: We found slightly (but statistically significant) elevated level of circulating biomarkers of cell death (nucleosomes) in patients with plaque psoriasis treated with GR (PAHs, UV radiation). We suppose that elevated level of CN is a result of combination of the positive effects of GR and its weak genotoxic effect (mainly PAHs). Conclusions are supported by significant correlation between CN and urinary level of 1-OHP after GR and significantly elevated level of CA after GR (Tab. 2, Fig. 1, Ref. 28).

Motion onset VEPs can see through the blur.

Motion-onset visual evoked potentials (MO VEPs) are robust to dioptric blur when low contrast and low spatial frequency patterns are used for stimulation. To reveal mechanisms of MO VEPs robustness, we studied whether the resistance to defocus persists even when using a high-contrast checkerboard using digital defocus in the emmetropic eyes of 13 subjects (males 20-60 years). We compared the dominant components of MO VEPs to pattern-reversal VEPs (PR VEP), which are sensitive to the blur. For stimulation, we used checkerboard patterns with 15´ and 60´ checks. To defocus the checkerboard, we rendered it with a second-order Zernike polynomial ( Z 2 0 ) with an equivalent defocus of 0, 2, or 4 D. For PR VEP, the checkerboards were reversed in terms of their contrast. To evoke MO VEP, the checkerboard of 60´ checks moved for 200 ms with a speed of 5 or 10 deg/s in the cardinal directions. The MO VEP did not change in peak time (P ≥ 0.0747) or interpeak amplitude (P > 0.0772) with digital blur. In contrast, for PR VEP, the results showed a decrease in interpeak amplitude (P ≤ 6.65ˑ10-4) and an increase in peak time (P ≤ 0.0385). Thus, we demonstrated that MO VEPs evoked by checkerboard, structure containing high spatial content, can be robust to defocus.

True pattern-reversal LED stimulator and its comparison to LCD and CRT displays: visual evoked potential study.

A rapid checkerboard pattern change is used to elicit pattern-reversal visual evoked potentials (PR VEPs). CRT or LCD monitors do not allow immediate reversal of the entire pattern. The study aimed to construct a new stimulator whose characteristics approximate an instantaneous reversal and verify whether the improvement is reflected in PR VEPs. A new stimulator using a matrix of 12 × 48 independent white square LEDs was designed and compared with LCDs and CRTs. The effect on the PR VEP peak times and amplitudes of N70, P100, and P140 waves was evaluated in ten subjects. The LED stimulator showed significantly better performance in the rate of change of illuminance, change of pattern, luminance settling and stability. The PR VEP amplitudes of N75, P100, and N140 did not show significant differences. The sum of interpeak amplitudes was significantly larger for the LCD than for the other monitors. The peak times of the waves evoked by the LED were shorter than those evoked by the LCD and CRT for the N75 wave and a check size of 30´. LED stimulators are a better alternative to CRTs for PR VEPs than current LCDs. LEDs also seem to be better than CRTs, but further research is necessary to obtain significant results.

Role of latency jittering correction in motion-onset VEP amplitude decay during prolonged visual stimulation.

Visual evoked potentials to motion-onset stimulation (M-VEPs) gradually attenuate in amplitude during examination. The observed decline in averaged responses can be caused by decreases in single response magnitudes and/or increased variability in a response delays, that is, latency jittering. To illuminate the origins of the suppression of M-VEPs during stimuli repetition, we used correlation technique to estimate an upper bound of possible latency jittering of single sweeps and we evaluated the effect of its correction on the amplitudes of three M-VEP dominant peaks P1, N2 and P3. During prolonged visual motion stimulation, the variability of corrective latency shifts in the occipital region increased (r = 0.35: 0.44) and the number of single responses corresponding to the average curve declined in occipital and parietal derivations (r = -0.48: -0.62). While the P1 peak amplitude did not exhibit any time-specific behaviour, the N2 amplitude exhibited a significant decay of 29.4% that was partially reduced to 16.6% in the central occipital derivation by the latency jitter and non-correspondence corrections. The strongest attenuation (32.7%) was observed in the P3 amplitude and was less sensitive to the corrections, dropping only to 27.9%. The main part of the response suppression to repeated motion stimulation was caused by amplitude drop and represents non-stationary process that likely correspond to a fatigue model. The rise of variability in latency jitter correction and the reduction in single responses correlated with the M-VEP were significant factors associated with prolonged motion stimulation. The relation of these parameters to a hypothetical veridical response is ambiguous and can be caused by a time shift of the response or by a change of signal-to-noise ratio. Using selective averaging and latency jitter correction, the effect of response suppression was partially removed.

C-reactive protein, chemerin, fetuin-A and osteopontin as predictors of cardiovascular risks in persons with psoriasis vulgaris.

The study aimed to contribute to understanding the role of CRP, chemerin, fetuin-A and osteopontin and to assess their suitability as biomarkers of early stages of cardiovascular diseases in psoriasis vulgaris. Serum levels measured in 28 patients and 22 controls. Patients: increased levels of CRP (p<0.001), chemerin (p<0.05), osteopontin (p<0.05) and decreased levels of fetuin-A (p<0.05), significant relationships between CRP and fetuin-A (rho=0.530, p<0.01), CRP and chemerin (rho=0.543, p<0.01), CRP and age (rho=0.590, p<0.001), osteopontin and fetuin-A (r=-0.415, p<0.05), chemerin and PASI score (rho=-0.424, p<0.05). We confirmed specific roles of the biomarkers in psoriasis. CRP, fetuin-A and osteopontin could be considered appropriate markers for the detection of early stages of cardiovascular diseases.

Visual evoked potentials to pattern, motion and cognitive stimuli in Alzheimer's disease.

The aim of our study was to verify reported visual dysfunctions of patients with Alzheimer disease with the use of several variants of VEPs and visual ERPs and to learn whether these methods can be useful in diagnostics of AD. We tested 15 patients (6 women and 9 men, aged from 58 to 87) with mild to moderate Alzheimer disease (12-23 points of Mini Mental State Examination) and 15 age, gender and education level matched controls. The examination consisted of VEPs to pattern-reversal and motion-onset stimulation (to translational and radial movement) and of visual ERPs recorded during an odd-ball test. The subjects were instructed to signalize target stimuli by pressing of a button, which enabled to evaluate also the reaction time. While pattern-reversal VEPs were comparable in patients and controls, there were significantly smaller N2 peak amplitudes of motion-onset VEPs in patients with AD (in particular in radial moving stimuli outside the central 20 deg of the visual field), which suggests a dysfunction of the motion-processing (magnocellular) system or the dorsal cortical stream. ERPs, having significantly longer latencies in patients than in controls, distinguished well both groups. However, the individual AD diagnostics based on ERPs seems to be limited by rather high inter-individual variability of the ERP latencies. The ERPs might, however, be useful in disease progress and therapy effect estimation. Electrophysiological parameters did not correlate with neuropsychological ADAS cog test (Alzheimer Disease Assessment Scale--cognitive part).

Plasma levels of p53 protein and chromosomal aberrations in patients with psoriasis treated with the Goeckerman regimen.

The Goeckerman regimen (GR) is one of the oldest effective treatments for psoriasis. It involves daily dermal application of crude coal tar with dermal exposure to ultraviolet (UV) radiation. A study was carried out to evaluate the genotoxic risk of GR by comparing p53 protein plasma level and chromosomal aberrations (CA) in peripheral lymphocytes in 33 patients with psoriasis, before and after GR. Psoriasis Area and Severity Index (PASI) was used to evaluate the efficacy of GR. PASI significantly decreased after GR (P < 0.001), confirming the excellent efficacy of the treatment, However, significant increases in level of p53 protein (P < 0.05) and CA (P < 0.001) after treatment indicates that this method carries an increased genotoxic risk in patients with psoriasis.

The use of optical coherence tomography in chiasmal compression.

The objective of this prospective study is to explore the benefits of optical coherence tomography (OCT) in cases of optic chiasm (OC) compression by measuring the thickness of the Retinal Nerve Fiber Layer (RNFL) and the Ganglion Cell Layer (GCL). MATERIAL AND METHODS: 16 patients (32 eyes) with chiasmal compression were included in the study. They presented no other pathology of the visual pathway or of the eye globe. The second inclusion criterion was a subsequent indication of decompressive surgery, either by transcranial or transnasal approach. Measurements of visual acuity, visual field, RNFL and GCL were performed once preoperatively and three times postoperatively (one week, 3 and 6 months postoperatively). The observed peripapillary and perifoveal regions were divided into quadrants. The degree (grade 0-5) of chiasmal compression was determined on preoperative brain MRI (magnetic resonance imaging). In need of some data analysis, participants were split into a group with no or minimal (grade 0-1) and with substantial pressure (grade 2-4) on OC. RESULTS: The median global peripapillary RNFL was 87 μm, the perifoveal nasal GCL 41,2 µm and the temporal 44,2 µm. There was a pronounced preoperative RNFL thinning in nasal (63,5 μm) and temporal (65 μm) quadrant, in comparison to the age-matched normative database for RNFL thickness in the OCT protocol. There is a statistically important connection between bitemporal hemianopia and RNFL, resp. GCL. Larger perimetric outages is related to important OC compression, seen on MRI. CONCLUSION: There exists a correlation between the thickness of the peripapillary RNFL, resp. perifoveal GCL, and visual field defects in chiasmal compression. Thinner preoperative RNFL does not present a statistically important limiting factor for better functional outcomes after surgical decompression. Horizontal asymmetry of perifoveal GCL is an indicator of compressive ophthalmopathy. The grade of preoperative OC compression presents another important prognostic factor.

Methods of improving the quality of life in patients with stable maculopathy-pilot results of a new study.

PURPOSE: To present pilot results of the project in which the primary goal is to optimize way how to increase the quality of life of patients with the stable maculopathy by implanting intraocular Scharioth macular lens (SML) and modulating visual plasticity by a transcranial electrical stimulation (tES) together with a visual rehabilitation. MATERIALS AND METHODS: The study will include 20 patients with stable maculopathy (mainly age-related macular degeneration - AMD) who underwent cataract surgery in past and are eligible for SML implantation. The duration of the project is 3 years. During the first year of the project 17 patients were screened, SML implantation was recommended to 4 of them. They met the indication criteria of SML implantation and SML was implanted into the better seeing eye. The third postoperative day, the tES sessions started and were applied 20 times in the first month after SML implantation. The stimulation was delivered in double blind design (a stimulated and a shame group). Visual exercises and rehabilitation took place during the tES. The patients were examined ophthalmologically and also using electrophysiological methods. RESULTS: Before the implantation, the best corrected distance visual acuity was 0.23. At near it was Jaeger number 15 uncorrected, with +3.0 sphere dioptres J.No.10.5 and with +6.0 sph dpt J.No. 4.5. After the surgery and visual rehabilitation BCVA was 0.13 after 3 weeks, 0.2 after 2 months and 0.14 after 6 months. At near it was uncorrected J.No.7.5 after 3 weeks, J.No.7 after 2 months and J.No.5 after 6 months. CONCLUSION: According to a few participants, the impact of SML implantation together with intensive visual rehabilitation on vision at near and on satisfaction of patients with AMD could not be significantly established. Nevertherless, these patients are limited in their daily activities and SML is one of the solutions for them. The project is ongoing and blinded still, there is also a need of more participants to assess the effect of tES on vision, the results will be presented. We have proven the safety of methods used in the project.

Motion-onset VEPs: characteristics, methods, and diagnostic use.

This review article summarises the research on the motion-onset visual evoked potentials (VEPs) and important motion stimulus parameters which have been clarified. For activation of the visual motion processing system and evocation of the motion-onset specific N2 peak (with latency of 160-200ms) from the extra-striate temporo-occipital and/or parietal cortex, the following stimulus parameters can be recently recommended: low luminance (

[The usefulness of carpal tunnel pressure measurement during endoscopic surgery of carpal tunnel syndrome]. / Vyuzití merení tlaku v karpálním tunelu behem operace syndromu karpálního tunelu.

The usefulness of carpal tunnel pressures measurement during surgery of carpal tunnel syndrome is documented by the authors. 31 patients underwent endoscopic uniportal approach, the pressure in different positions (neutral position, flexion and extension in wrist, grip of the fingers) and in different levels (distal forearm, proximal, central and distal part of carpal tunnel, palm) was measured. The significant drop of pressure was observed after dissection of ligament in all levels. The results are presented in the form of several graphs.

Roles of miR-31 and endothelin-1 in psoriasis vulgaris: pathophysiological functions and potential biomarkers.

Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation of keratinocytes resistant to apoptosis and inflammation. miR-31 plays pro-proliferative, pro-differentiative and pro-inflammatory roles and modulates apoptosis in psoriatic keratinocytes. Endothelin-1 (ET-1) is produced by psoriatic keratinocytes and suppresses apoptosis. Inflammation increases the production of ET-1, which in turn leads to the chronic stimulation of keratinocyte proliferation. The aim of this study was to identify the putative link between two potential biomarkers (miR-31 and ET-1) in patients with psoriasis. The study design included experimental group (29 patients with psoriasis), and the control group (22 blood donors). The PASI score evaluated the state of the disease (median: 18.6; interquartile range 14.5-20.9). Both, the serum level of ET-1 and the whole blood level of miR-31 were significantly increased (p<0.001 and p<0.05, respectively) in patients compared to the controls. However, a significant negative relationship between ET-1 and miR-31 was observed (Spearman's rho=-037, p=0.05). It is possible that a negative feedback loop will be present between miR-31 and ET-1. Our results indicate that miR-31 and ET-1, potential biomarkers of the disease, play significant roles in the pathophysiology of psoriasis.

Visual mismatch negativity elicited by magnocellular system activation.

The processing of visual motion was tested by means of event related potentials recording (ERP) using a paradigm designed to produce a visual mismatch negativity effect. The stimuli were unattended and presented in the peripheral visual field (outside the central 15 degrees). The standard stimulus consisted of an up/down motion sequence, whilst the deviant stimulus of a down/up motion sequence. Significant ERP differences between the standard and deviant conditions were found in 8 out of 10 adult subjects already in 80 ms and prevailingly in interval 145-260 ms from the initial stimulus presentation. The results demonstrate that the magnocellular information undergoes processing capable of detecting differences in the sequence of unattended peripheral motion stimuli.

Motion-onset VEPs reflect long maturation and early aging of visual motion-processing system.

Pattern-reversal and motion-onset visual evoked potentials (VEPs) were simultaneously tested in a group of 70 healthy subjects between the ages of 6-60 years to verify suspected differences in maturation and aging dynamics of the pattern and motion processing subsystems of the visual pathway. The motion-onset VEPs displayed dramatic configuration development and shortening of latencies up to 18 years of age (correl. coeff. -0.85; p < 0.001) and systematic prolongation from about 20 years of age (correl. coeff. 0.70; p < 0.001). This confirms long-lasting maturation of the magnocellular system and/or motion processing cortex and their early age related changes. Less significant changes of pattern-reversal VEPs in the tested age range can be interpreted as a sign of early maturation of the parvocellular system and its enhanced functional endurance in the elderly.

Selected immunological changes in patients with Goeckerman's therapy TNF-alpha, sE-selectin, sP-selectin, sICAM-1 and IL-8.

Psoriasis is one of the most frequent inflammatory skin diseases in which abnormal individual immune reactivity plays an important role. The aim of the present study was to describe selected immunological changes, concerning pro-inflammatory cytokines (TNF-alpha, IL-8) and adhesion molecules (sE-selectin, sP-selectin, sICAM-1), in 56 patients cured by Goeckerman's therapy (GT). GT includes dermal application of crude coal tar (containing polycyclic aromatic hydrocarbons) and exposure to UV radiation. When compared with the control group (healthy blood donors), the patients before GT had significantly increased serum levels of sE-selectin (p<0.001), sP-selectin (p<0.001), sICAM-1 (p<0.001) and IL-8 (p<0.001). Significantly decreased serum levels of sE-selectin (p<0.05) and significantly increased serum levels of IL-8 (p<0.05) were found after GT therapy. Serum levels of sICAM significantly correlated with the disease activity and with serum levels of sE-selectin. The level of PASI score (Psoriasis Area and Severity Index) significantly decreased after GT (p<0.001) and confirms the high efficiency GT. These findings confirmed that pro-inflammatory chemokine (IL-8) and adhesion molecules (sE-selectin, sP-selectin, sICAM-1) play an important role in the development and regulation of inflammation in psoriasis. Determination of sE-selectin and sICAM seems to be a promising marker of psoriasis's activity. Chemokine pathway (IL-8) and TNF-alpha activity seem to be modulated by Goeckerman's therapy (polycyclic aromatic hydrocarbons).

Cytogenetic and immunological changes after dermal exposure to polycyclic aromatic hydrocarbons and UV radiation.

Goeckerman's therapy (GT), which combines exposure to coal tar (polycyclic aromatic hydrocarbons - PAHs) and UV radiation (UV) is often used as the first option for treatment of psoriasis. However, PAHs and UV represent mutagenic, carcinogenic and immunotoxic agents. Therefore GT can represent a health risk for the patients. The group under observation consisted of thirty patients undergoing GT. Before and after the treatment, blood samples were collected and chromosomal aberrations and selected immunological markers were determined. The relationships between chromosomal aberrations and immunological markers and the extent (duration) of exposure to GT were evaluated. The Psoriasis Area and Severity Index (PASI) score confirmed the high efficacy of GT. However, significantly elevated levels of chromosomal aberrations of peripheral lymphocytes were also found after the therapy (p<0.001). The levels of chromosomal abnormalities correlated to the extent and the total duration of exposure to PAHs (r = 0.682, p<0.01 and r = 0.605, p<0.05). After the therapy, significantly decreased levels of IgE, IgM isotypes of immunoglobulin, alpha(2)-macroglobulin and transferrin together with beta(2)-microglobulin were found. From the immunological markers listed above only the decreased level of alpha(2)-macroglobulin correlated to the extent of exposure to PAHs (r = -0.568, p<0.05). No correlation was found between chromosomal aberrations, significantly changed immunological markers and the duration of UV exposure. Our study revealed that GT has a significant impact on both genetic and immunological parameters of psoriatic patients. The results indicate that GT could increase genotoxic risk and modulates immunity of treated patients.

Visual evoked potentials and event related potentials in congenitally deaf subjects.

The purpose was to test parameters of visual evoked potentials (VEPs) and of event-related potentials (ERPs) in deaf subjects to verify visual and cognitive CNS functions in a handicapped group of the population. Three types of visual stimuli (with dominating parvocellular or magnocellular system activation or with cognitive tasks) were used in the study. Six deaf persons (4 women, 2 men, mean age 17 years) and 6 persons with normal hearing (sex- and age-matched) were included in this pilot study. In all types of stimulation, latencies and amplitudes of main VEPs and ERPs components were evaluated. No significant latency differences were found. However, significantly reduced amplitudes were found in the occipital area for responses to motion and cognitive stimuli which might be interpreted as a part of functional reorganization of the extrastriate and cognitive cortical areas of deaf subjects.

Influence of physiological changes of glycaemia on VEPs and visual ERPs.

Since hypoglycemia is known to influence cognitive functions, we checked whether the physiological changes in glycemia (after fasting or exertion) can explain the rather high intra-individual variability of event-related potentials (ERPs). Besides the ERPs to "change in coherence of a moving pattern" with reaction time (RT) recording, binocular pattern reversal VEPs and motion-onset VEPs (to linear and radial motion) were also examined in 14 healthy subjects prior to and after 24-h fasting that decreased glycemia from 5.3 to 3.9 mmol/l on the average. We only found one significant change in the latencies and amplitudes of VEPs and ERPs (with no change of RT). The N160 peak in the motion-onset VEPs to radial (expansive) motion (EM-VEPs) showed a larger amplitude at lower glycemia. For evaluation of the exertion influence, we tested glycemia prior to and after 90 min long exercise -- bicycle ergometry with the load set to 2 W/kg in women and 2.5 W/kg in men (average age-related values for W170/kg index). The changes of glycemia to exertion were, however, less distinct than those to fasting. We conclude that in healthy subjects the glycemia decrease due to 24-h fasting or intensive time-limited exercise never reaches the critical value to change the VEP, ERPs and RTs.