Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in Gypsies.

Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 (CYP1B1) gene detected in an average of approximately 50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations - four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for approximately 30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation.

Metabolic activation of chemicals: in-silico simulation.

The role of metabolism in prioritising chemicals according to their potential adverse health effects is extremely important given the fact that innocuous parents can be transformed into toxic metabolites. Our recent efforts in simulating metabolic activation of chemicals are reviewed in this work. The application of metabolic simulators to predict biodegradation (microbial degradation pathways), bioaccumulation (fish liver metabolism), skin sensitisation (skin metabolism), mutagenicity (rat liver S-9 metabolism) are discussed. The ability of OASIS approach to predict metabolism (toxicokinetics) and toxicity (toxicodynamics) of chemicals resulting from their metabolic activation in a single modelling platform is an important advantage of the method. It allows prioritisation of chemicals due to predicted toxicity of their metabolites.

Retrobulbar circulation in myopic patients with or without myopic choroidal neovascularisation.

AIM: To investigate the effect of myopia and myopic choroidal neovascularisation (CNV) on retrobulbar circulation in central retinal artery (CRA) and vein (CRV) and posterior ciliary artery (PCA). METHODS: 52 subjects with and without myopia were included in the study. Retrobulbar circulation was measured using colour Doppler imaging. Analysis of correlation of degree of myopia with blood flow velocity parameters was done. Circulatory differences between eyes of patients with unilateral neovascular degenerative myopia were estimated. RESULTS: The analysis of correlation between dioptry and blood flow velocity in the CRA, CRV, and PCA showed a significant positive correlation. Axial length was also significantly correlated with CRA and CRV blood velocity and had a tendency to be correlated with PCA blood velocity. When compared with the fellow eye, the eye with myopic CNV had significantly higher resistivity index (RI) (p=0.048) in the PCA and no significant difference in the circulatory parameters of the CRA and CRV. CONCLUSION: Central retinal and posterior ciliary blood velocity decreases with the increase of the degree of myopia. PCA RI is higher in myopic CNV.

Relation between retrobulbar circulation and progression of diabetic retinopathy.

AIMS: To investigate retrobulbar circulatory parameters in type 2 diabetic patients with and without diabetic retinopathy (DR) progression. METHODS: This was a prospective cohort study. One eye of 35 diabetic patients with background DR (BDR) were included in the study. Eyes without DR, with proliferative DR, photocoagulation, past surgical procedures, or other ophthalmic disease except BDR and cataract were excluded. The study was masked. Colour Doppler imaging (CDI) was used to measure the retrobulbar circulation at the beginning of the study and after a mean follow up interval of 21 months. Peak systolic velocity (PSV), end diastolic velocity (EDV), and resistivity index (RI) in the central retinal artery and vein and the posterior ciliary artery were measured. RESULTS: 18 patients who developed DR progression showed significantly increased central retinal vein PSV ( 5.6 (3.5-9.1) p = 0.003), EDV ( 3.4 (2.3-4.4) p = 0.04), and RI ( 0.43 (0.20-0.56) p = 0.02) at the final measurement compared to the initial measurement (PSV = 4.6 (3.2-7.0); EDV = 3.0 (2.3-3.7); RI = 0.40 (0.17-0.52)). Circulatory parameters in the central retinal artery and the posterior ciliary artery did not alter significantly after progression of DR. 17 patients were without DR progression and they did not show any significant differences in the measured circulatory parameters on entry compared to the final measurement. CONCLUSION: The authors suggest that the initial changes in the retrobulbar circulation during DR progression occur in the central retinal vein.

TIMES-SS--recent refinements resulting from an industrial skin sensitisation consortium.

The TImes MEtabolism Simulator platform for predicting Skin Sensitisation (TIMES-SS) is a hybrid expert system, first developed at Bourgas University using funding and data from a consortium of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic 3D QSARs. The model estimates semi-quantitative skin sensitisation potency classes and has been developed with the aim of minimising animal testing, and also to be scientifically valid in accordance with the OECD principles for (Q)SAR validation. In 2007 an external validation exercise was undertaken to fully address these principles. In 2010, a new industry consortium was established to coordinate research efforts in three specific areas: refinement of abiotic reactions in the skin (namely autoxidation) in the skin, refinement of the manner in which chemical reactivity was captured in terms of structure-toxicity rules (inclusion of alert reliability parameters) and defining the domain based on the underlying experimental data (study of discrepancies between local lymph node assay Local Lymph Node Assay (LLNA) and Guinea Pig Maximisation Test (GPMT)). The present paper summarises the progress of these activities and explains how the insights derived have been translated into refinements, resulting in increased confidence and transparency in the robustness of the TIMES-SS predictions.

Perioperative management of antiplatelet therapy in patients with drug-eluting stents.

Significant advancements in percutaneous treatment of coronary artery disease have been achieved with the introduction of bare metal stents. They have two major drawbacks: acute/subacute stent thrombosis, successfully managed with antiplatelet therapy immediately after stent implantation; and in-stent restenosis, prevention of which has been achieved with the development of drug-eluting stents. Drug-eluting stents have become preferred therapy for patients undergoing coronary artery intervention, though reports of late stent thrombosis have led to uncertainty about the duration of antiplatelet therapy after drug-eluting stents placement. Much controversy remains regarding perioperative management of patients with these devices, presenting for surgery or other invasive procedures. The purpose of this review is to provide an overview of the changing culture of coronary artery stenting, in addition to discussing perioperative management strategies and controversies surrounding coronary stents and antiplatelet therapy. A comprehensive literature search of MEDLINE was conducted using as keywords: antiplatelet therapy, non-coronary surgery, drug-eluting stents, and stent thrombosis. There is no definite standard of care for the perioperative management of drug-eluting stents in patients with drug-eluting stents. However, there is a growing understanding of the importance of continuation of drug-eluting stents in the perioperative period in order to prevent stent thrombosis along with a concern about the possibility of increased bleeding. Appropriate timing of surgery after coronary artery stenting, team approach to the perioperative management of such patients with involvement of cardiologist, anesthesiologist, and surgeon, and development of an individual plan for each patient, weighing that patient's risk of thrombosis vs the risk of bleeding, could improve patient safety and optimize outcome.

Simulation of chemical metabolism for fate and hazard assessment. V. Mammalian hazard assessment.

Animals and humans are exposed to a wide array of xenobiotics and have developed complex enzymatic mechanisms to detoxify these chemicals. Detoxification pathways involve a number of biotransformations, such as oxidation, reduction, hydrolysis and conjugation reactions. The intermediate substances created during the detoxification process can be extremely toxic compared with the original toxins, hence metabolism should be accounted for when hazard effects of chemicals are assessed. Alternatively, metabolic transformations could detoxify chemicals that are toxic as parents. The aim of the present paper is to describe specificity of eukaryotic metabolism and its simulation and incorporation in models for predicting skin sensitization, mutagenicity, chromosomal aberration, micronuclei formation and estrogen receptor binding affinity implemented in the TIMES software platform. The current progress in model refinement, data used to parameterize models, logic of simulating metabolism, applicability domain and interpretation of predictions are discussed. Examples illustrating the model predictions are also provided.

Can mutagenicity information be useful in an Integrated Testing Strategy (ITS) for skin sensitization?

Our previous work has investigated the utility of mutagenicity data in the development and application of Integrated Testing Strategies (ITS) for skin sensitization by focusing on the chemical mechanisms at play and substantiating these with experimental data where available. The hybrid expert system TIMES (Tissue Metabolism Simulator) was applied in the identification of the chemical mechanisms since it encodes a comprehensive set of established structure-activity relationships for both skin sensitization and mutagenicity. Based on the evaluation, the experimental determination of mutagenicity was thought to be potentially helpful in the evaluation of skin sensitization potential. This study has evaluated the dataset reported by Wolfreys and Basketter (Cutan. Ocul. Toxicol. 23 (2004), pp. 197-205). Upon an update of the experimental data, the original reported concordance of 68% was found to increase to 88%. There were several compounds that were 'outliers' in the two experimental evaluations which are discussed from a mechanistic basis. The discrepancies were found to be mainly associated with the differences between skin and liver metabolism. Mutagenicity information can play a significant role in evaluating sensitization potential as part of an ITS though careful attention needs to be made to ensure that any information is interpreted in the appropriate context.

[Electrocardiographic data on ischemic heart disease in hyperlipoproteinemia patients]. / Elektrokardiografski danni za iskhemichna bolest na surtseto pri bolni s khiperlipoproteinemii.

The electrocardiograms (ECG) were studied according to Minnesota Code: 103 patients with hyperlipoproteinemia (HLP)--49 with type IIA--49, IIB--37 and type IV--17. A high incidence was established of the patients with positive--17.48 per cent and probable--22.34 per cent ECG data on IHD. Type IIB is most frequent among the patients with IHD, followed by HLP type IIA and IV. The average age of the patients with positive IHD data was 42.2 and of the probable--49.9 years. Total cholesterol and atherogenic index is significantly higher in the patients with a past history of myocardial infarction as compared with those with probable ECG data on IHD.

[Ischemic heart disease as a cause of death in occupational groups of workers]. / Iskhemichnata bolest na surtseto kato prichina za smurt pri niakoi profesionalni grupi rabotnitsi.

The authors studied the ischemic heart disease spread as a lethality cause in 5673 workers, retired due to a disease (general, occupational disease and accident). The workers in 2.9 per cent were found to die of ischemic heart disease with a 15 years length of service and at the age of 60. The miners die in 0.2 per cent of ischemic heart disease, teachers--in 5.1 per cent, drivers--8.9 per cent, engineers (management personnel)--in 13.5 per cent etc. The deceased of ischemic heart disease in 2 per cent have worked in favourable working conditions, in 13 per cent--in contact with poisons, in 20 per cent--with unfavourable microclimate, in 41 per cent with mental work etc. The work in unfavourable working conditions and nervous-psychic strain was proved to appear as a risk factor for the origination of ischemic heart disease.

Retrobulbar circulation in patients with age-related maculopathy.

PURPOSE: To investigate retrobulbar circulation in stages of age-related maculopathy (ARM) and in normal fellow eyes of patients with unilateral exudative ARM. METHODS: Color Doppler Imaging was used to measure circulatory parameters (peak-systolic velocity--PSV, end-diastolic velocity--EDV, pulsatility index--PI and resistivity index--RI) in the central retinal, posterior ciliary and ophthalmic arteries of 44 patients with age-related maculopathy (ARM) and 32 control subjects. Patients with ARM consisted of 11 with early ARM and 33 with late ARM. Twenty-one patients from the exudative ARM group were also included in a study of unilateral exudative ARM circulation. RESULTS: In the study of patients with ARM divided into stages, the PI and RI in the posterior ciliary artery of patients with late ARM were significantly higher than that of the control group (P = 0.0064; P = 0.0124). In the early ARM group, circulatory parameters did not differ significantly from those of the control group. In the study of unilateral exudative ARM, the affected eye showed significantly higher RI, as compared to the control group (P = 0.0157), and the fellow eye had significantly decreased EDV as compared to the control group (P = 0.0164). There was no significant difference in circulatory parameters between the affected and normal fellow eyes of patients with unilateral exudative ARM. CONCLUSION: PI and RI in patients with late ARM and EDV in fellow eyes of patients with unilateral exudative ARM showed significant changes in the posterior ciliary artery compared to normal controls. Altered circulation in the posterior ciliary artery may be involved in the pathogenesis of ARM.

The relationship of endogenous cortisol to psychiatric disorder: a review.

OBJECTIVES: To focus on hypothalamic-pituitary-adrenal (HPA) axis activity, especially endogenous hypercortisolemia, to study its role in the maintenance of psychiatric illness, and to entertain the probability that the elderly are vulnerable. METHOD: Case presentation, clinical and research literature review, and theoretical discussion. RESULTS: Clinical and research evidence overwhelmingly suggest that hypercortisolemia is toxic to the hippocampus. Some research supports the position that it can be a treatable perpetuating factor in a subset of affective disorders and psychoses. Pharmacological treatments to correct hypercortisolemia have been used by endocrinologists. Hypercortisolemic treatment-resistant and nontreatment-resistant psychoses and affective disorders have been successfully treated by a small number of researchers who remain interested in this subject. Data pertaining to geriatric psychoses may be germane but are sparse. CONCLUSIONS: It behooves us to research diagnostic methods pertaining to psychoses and affective disorders associated with hypercortisolemic states. Very little research is available, but we must be alert to the possibility that the elderly are more susceptible to cortisol endotoxicosis than the younger adult population. Without accurate diagnosis, we cannot take advantage of existing antiglucocorticoid strategies.

[Clincial aspects and treatment of exacerbated chronic respiratory insufficiency in silicosis patients]. / Klinika i lechenie na izostrenata khronichna dikhatelna nedostatuchnost pri bolni ot silikoza.

The clinical picture and treatment of exacerbated chronic respiratory insufficiency is studied in 189 silicosis patients with different stage and degree of decompensation. It is found out that chronic respiratory insufficiency determination in these patients is conditioned by the exacerbation of a chronic inflammtory process in the bronchi and lungs (68.2 per cent), or by intercurrent acute inflammtory pulmonary process (15.9 per cent). The clinical manifestation of the disease is aggravated and modified by the appearance of new clinical elements, resulting in the typical clinical picture of inflammatory decompensation of silicosis. It is stressed that the effect of treatment is greater, the milder the stage of the disease, and the earlier and less marked the decompensation-induced derangements. Lethality in patients with III degree silicosis amounts to 8,2 per cent, and in patients with III degree respiratory insufficiency -- to 30.7 per cent. A complex active therapy program for silicosis patients with exacerbated chronic respiratory insufficiency is proposed.

Choroidal circulation in diabetic patients.

PURPOSE: To evaluate choroidal circulatory changes in diabetic patients with and without background diabetic retinopathy (BDR) by measuring the retrobulbar circulation with colour Doppler imaging (CDI). METHODS: CDI was used to measure circulatory parameters of the PCA (posterior ciliary artery), CRA (central retinal artery), OA (ophthalmic artery) and the respective veins in 73 diabetic patients and 22 controls in a sitting posture. Among the diabetic patients, 38 patients were without diabetic retinopathy (NDR) and 35 had BDR. A non-parametric Kruskal-Wallis test with a Dunn correction was used for data analysis. RESULTS: End-diastolic velocity (EDV) in the PCA was decreased (2.55+/-0.80 cm/s) and resistivity index (RI) in the PCA was increased (0.70+/-0.08) in BDR patients compared with the control patients' EDV (3.23+/-1.08 cm/s, p = 0.01) and RI (0.62+/-0.06, p = 0.0003). RI in the CRA was significantly higher in the BDR group (0.74+/-0.09) than in the control group (0.68+/-0.08, p = 0.006). RI in the OA was significantly higher in the BDR group (0.87+/-0.06) compared both with the NDR group (0.83+/-0.07) and with the control group (0.81+/-0.06; p = 0.007, p = 0.004). NDR patients had a significantly higher RI in the PCA (0.67+/-0.08) than control patients (0.62+/-0.06, p = 0.01, while the CRA RI (0.71+/-0.09) did not show significant differences from the control group (0.69+/-0.08, p = 0.32). Decreased EDV in the CRA was detected in NDR patients (2.16+/-0.76 cm/s) compared with the controls (2.72+/-0.92 cm/s, p = 0.007). CONCLUSION: The results from this study suggest that not only the retinal but also the choroidal circulation is affected in NDR and BDR patients.

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations.

During a study of hereditary motor and sensory neuropathy-Lom in Bulgaria, a previously unrecognized neurological disorder was encountered, mainly in Wallachian Gypsies, who represent a relatively recent genetic isolate. The disorder has been termed the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome to emphasize its salient features. Fifty individuals from 19 extended pedigrees were identified and examined clinically and electrophysiologically. At least 1 patient from each family was admitted to the hospital in Sofia for full investigation. Pedigree analysis indicates autosomal recessive inheritance. The disorder is recognized in infancy by the presence of congenital cataracts and microcorneas. A predominantly motor neuropathy beginning in the lower limbs and later affecting the upper limbs develops during childhood and leads to severe disability by the third decade. Associated neurological features are a moderate nonprogressive cognitive deficit in most affected individuals together with pyramidal signs and mild chorea in some. Accompanying nonneurological features include short stature, characteristic facial dysmorphism, and hypogonadotrophic hypogonadism. Nerve conduction studies suggest a hypomyelinating/demyelinating neuropathy, confirmed by nerve biopsy. The CCFDN syndrome is thus a pleomorphic autosomal recessive disorder displaying a combination of neurological and nonneurological features.