DNA methylation and differential gene regulation in photoreceptor cell death.

Retinitis pigmentosa (RP) defines a group of inherited degenerative retinal diseases causing progressive loss of photoreceptors. To this day, RP is still untreatable and rational treatment development will require a thorough understanding of the underlying cell death mechanisms. Methylation of the DNA base cytosine by DNA methyltransferases (DNMTs) is an important epigenetic factor regulating gene expression, cell differentiation, cell death, and survival. Previous studies suggested an involvement of epigenetic mechanisms in RP, and in this study, increased cytosine methylation was detected in dying photoreceptors in the rd1, rd2, P23H, and S334ter rodent models for RP. Ultrastructural analysis of photoreceptor nuclear morphology in the rd1 mouse model for RP revealed a severely altered chromatin structure during retinal degeneration that coincided with an increased expression of the DNMT isozyme DNMT3a. To identify disease-specific differentially methylated DNA regions (DMRs) on a genomic level, we immunoprecipitated methylated DNA fragments and subsequently analyzed them with a targeted microarray. Genome-wide comparison of DMRs between rd1 and wild-type retina revealed hypermethylation of genes involved in cell death and survival as well as cell morphology and nervous system development. When correlating DMRs with gene expression data, we found that hypermethylation occurred alongside transcriptional repression. Consistently, motif analysis showed that binding sites of several important transcription factors for retinal physiology were hypermethylated in the mutant model, which also correlated with transcriptional silencing of their respective target genes. Finally, inhibition of DNMTs in rd1 organotypic retinal explants using decitabine resulted in a substantial reduction of photoreceptor cell death, suggesting inhibition of DNA methylation as a potential novel treatment in RP.

Clopidogrel cessation triggers aspirin rebound in patients with coronary stent.

WHAT IS KNOWN AND OBJECTIVE: Premature discontinuation of clopidogrel in patients undergoing percutaneous coronary intervention is a significant risk factor for thrombotic adverse outcomes. However, recent studies indicate that even discontinuation of long-term use of clopidogrel may be associated with multiple adverse outcomes, that is, rebound phenomenon whose mechanism is not definitely clear. The aim of the study was to examine the effect of clopidogrel withdrawal in those on combined aspirin and clopidogrel therapy. METHODS: This prospective, multicenter study enrolled 200 patients who underwent coronary stent implantation and were on dual antiplatelet therapy (100 mg aspirin + 75 mg clopidogrel) 1 year after the stent placement. In all patients, we measured the platelet aggregation, by multiplate electrode aggregometry, using two agonists [adenosine diphosphate with PGE1 (ADPHS) and arachidonic acid (ASPI)] two times: on the day of cessation of clopidogrel and 90 days after clopidogrel was stopped. RESULTS AND DISCUSSION: Following clopidogrel discontinuation, we registered an increase in ASPI values (P < 0·001), linear correlation between changes in ASPI and ADPHS values (P = 0·009) and significant difference in the values of ASPI first quartile of ADPHS compared with the other three (P < 0·001, P = 0·016, P < 0·001, I vs. II, I vs. III and I vs. IV quartile of ADPHS, respectively). WHAT IS NEW AND CONCLUSION: Our findings show that cessation of clopidogrel causes loss of antiplatelet synergism with aspirin, leading to a weakening of the response to aspirin, which may be one explanation for the rebound after the clopidogrel cessation.

Duplication of the superior vena cava associated with atrial termination of the left hepatic vein.

Duplication of the superior vena cava (SVC), associated with an aberrant left hepatic vein (LHV), was found in one of the 58 dissected specimens. The right SVC virtually showed a typical appearance. The persistent left SVC, which drained into the right atrium via the enlarged coronary sinus, was formed by the persistence of the left anterior cardinal vein. The LHV opened into the right atrium, due to the persistent left hepatocardiac channel. The left common carotid artery arose from the brachiocephalic trunk as a consequence of a regression of the embryonic aortic sac. The revealed venous and arterial variations seem to be the first reported vascular combination of this type.

Neuroprotective strategies for the treatment of inherited photoreceptor degeneration.

Photoreceptor degeneration is the hallmark of several groups of inherited neurodegenerative diseases causing blindness in humans. These diseases are a major cause of visual handicap and to date no satisfactory treatment is available. Here, we briefly review different approaches for the treatment of photoreceptor degeneration, to then focus on neuroprotection. Up to date, translation of experimental neuroprotection into a clinical setting has faced major obstacles, which are in part due to an incomplete understanding of the regulation of pro-survival as well as neurodegenerative mechanisms. Previous approaches were often based on the hypothesis that photoreceptor cell death was governed by a single, apoptotic cell death mechanism. This perception has turned out too simple as recent work has demonstrated that photoreceptor cell death is governed by non-apoptotic mechanisms as well. Moreover, there is evidence, that several different destructive processes are executed in parallel. Briefly reviewing the complexity of degenerative mechanisms, this review discusses relevant pathways, options to target signaling cascades, final common denominators of cell death, and the interplay of events executing cell death. In particular, we focus on cGMP-signaling, epigenetic and proteolytic processes and the corresponding enzymatic activities that were recently shown to be causally related to retinal degeneration. Finally, we illustrate how a better understanding of destructive mechanisms may enable identification and validation of novel targets for neuroprotection, and allow development of next generation neuroprotective treatments as well as combination therapy.

Autonomic nervous system adjustment (ANSA) in patients with hypertension treated with enalapril.

BACKGROUND AND AIM: Reduced baroreflex sensitivity (BRS), decreased heart rate variability (HRV) and increased blood pressure (BP) variability have serious consequences for target organ damage in patients with hypertension, beside the BP level. The study was aimed to evaluate acute and long-term effects of enalapril, on BRS and HRV in individuals with prehypertension and mild essential hypertension. METHODOLOGY: We enrolled in the study 85 patients (male 53%, age 42-67) with prehypertension and mild hypertension (systolic blood pressure ≥120 mmHg or diastolic blood pressure ≥80 mmHg). All patients were tested before, 30 minutes after first oral enalapril dose and three weeks after monotherapy with enalapril. The methodology included: beat to beat HRV analysis, BRS measurements with sequence technique, ECG with short term and 24-hour HRV analysis, 24-hour ambulatory blood pressure monitoring with systolic and diastolic BP variability analysis. Patients were divided into groups with sympathetic or vagal predominance based on Autonomic Nervous System Adjustment (ANSA) method. RESULTS: 1) 30 min after initial dose enalapril significantly and effectively reduced systolic BP with shift towards the parasympathetic predominance as reflected in decreased heart rate and low frequency (LF) to high frequency (HF) ratio (LF/HF ratio); 2) chronic enalapril therapy effectively reduced BP, including both systolic BP, diastolic BP and pulls pressure, had positively influence on dipping status, but did not significantly change BP variability; 3) in the whole patient group chronic enalapril therapy did not significantly change HRV, but it significantly decreased LF(nu) in the patient with high basal sympathetic activity, and significantly increased LF(nu) in patients with high basal vagal activity; enalapril also significantly decreased HF (nu) in patients with high basal parasympathetic activity; 4) despite initial, transit changes in maximal and minimal slope of BRS enalapril did not significantly affect sensitivity of spontaneous baroreflex activation. CONCLUSION: Initial enalapril dose significantly reduced systolic BP and had beneficial effects on autonomic tone and baroreflex sensitivity. Chronic enalapril therapy effectively reduced BP without significant influence on BRS, but had significant autonomic effects on HRV when initial autonomic profile in each patient was analyzed by ANSA. Analyzed by ANSA method chronic enalapril therapy managed to retrieve disturbed sympathovagal balance and established autonomic equilibrium.

Modelling the long-term consequences of a hypothetical dispersal of radioactivity in an urban area including remediation alternatives.

The Urban Remediation Working Group of the International Atomic Energy Agency's EMRAS (Environmental Modelling for Radiation Safety) program was organized to address issues of remediation assessment modelling for urban areas contaminated with dispersed radionuclides. The present paper describes the second of two modelling exercises. This exercise was based on a hypothetical dispersal of radioactivity in an urban area from a radiological dispersal device, with reference surface contamination at selected sites used as the primary input information. Modelling endpoints for the exercise included radionuclide concentrations and external dose rates at specified locations, contributions to the dose rates from individual surfaces, and annual and cumulative external doses to specified reference individuals. Model predictions were performed for a "no action" situation (with no remedial measures) and for selected countermeasures. The exercise provided an opportunity for comparison of three modelling approaches, as well as a comparison of the predicted effectiveness of various countermeasures in terms of their short-term and long-term effects on predicted doses to humans.

Improvement of modelling capabilities for assessing urban contamination: the EMRAS Urban Remediation Working Group.

The Urban Remediation Working Group of the International Atomic Energy Agency's Environmental Modelling for Radiation Safety (EMRAS) programme was established to improve modelling and assessment capabilities for radioactively contaminated urban situations, including the effects of countermeasures. An example of the Working Group's activities is an exercise based on Chernobyl fallout data in Ukraine, which has provided an opportunity to compare predictions among several models and with available measurements, to discuss reasons for discrepancies, and to identify areas where additional information would be helpful.

[Radiographic study of teeth restored with porcelain and gold veneered crowns]. / Rendgenoloska analiza zuba zbrinutih porcelanskim i fasetiranim krunicama.

Radiographic study was performed to assess the results of the prosthetic therapy of teeth restored with porcelain and gold veneered crowns. Retroalveolar radiographs were used to evaluate the cast post-core-root ratio the presence of empty spaces between post-core and root canal filling. Also, bone resorption, marginal fit of the crowns, caries and proximal contacts were investigated. The failures were registered in a very high percentage for the teeth restored with gold veneered crowns. The poor marginal fit of the crowns, the presence of the secondary caries, and the bone resorption were at a very high level which could alarm the practitioner. The obtained results warn therapists that much greater attention should be paid to the construction of artificial crowns and to the radiographic analysis that gives very useful data on that regard.

[Study of Co-Cr-Mo alloys in metal-ceramics]. / Ispitivanje Co-Cr-Mo legura u metal-keramici.

The new interest of dental workers in Co-Cr-Mo alloys has increased because of the potential risk of nickel-related allergic responses and berylium-related toxic effects. The aim of the present study was to assess the transverse bond strength, rigidity modulus and compatibility of ceramics in four selected Co-Cr-Mo alloys. The obtained results indicate that oxide formation was not easily controlled and that additional sand-blasting was necessary after oxidation of the metal. The bond strength and rigidity modulus were the highest in the alloy containing titanium. Thermal shock tests confirmed the results of mechanical testing.

[Microbiological investigation of supragingival dental plaque in patients treated with porcelain jacket and gold veneered resin crowns]. / Mikrobioloska istrazivanja supragingivnog dentalnog plaka u pacijenata zebrinutih porcelanskim i fasetiranium krunicama.

The majority of periodontologists agree that the primary aetiological factor of periodontal disease is dental plaque. The purpose of the study was to investigate the accumulation of dental plaque on the with porcelain jackets and gold veneered resin crowns, and to correlate these findings with the data obtained on the uncrowned control teeth in the same patients. The qualitative analysis of microorganisms in dental plaque did not show a great difference between porcelain jacket and gold veneered resin crowns. However, a high difference was found in the quantitative accumulation of microorganisms in the mature dental plaque (considerably less on porcelain jacket crowns). These findings indicate that dental porcelain is less susceptible to accumulation of bacterial plaque in comparation to resin and even to hard tooth structures.