Autism Spectrum Disorder - A Complex Genetic Disorder.

Autism spectrum disorder is an entity that reflects a scientific consensus that several previously separated disorders are actually a single spectrum disorder with different levels of symptom severity in two core domains - deficits in social communication and interaction, and restricted repetitive behaviors. Autism spectrum disorder is diagnosed in all racial, ethnic and socioeconomic groups and because of its increased prevalence, reported worldwide through the last years, made it one of the most discussed child psychiatric disorders. In term of aetiology as several other complex diseases, Autism spectrum disorder is considered to have a strong genetic component.

Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children.

Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population. The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history. We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families.

Epigenetic aspects in schizophrenia etiology and pathogenesis.

Epidemiological evidence suggests that etiology of schizophrenia may involve both the influence of genetic factors specific for the individual and the impact of the environment. It is quite likely that a crucial role in the disease development is played by molecular mechanisms mediating the interaction between genes and environment. Modern research have shown that epigenetic mechanisms or chemical modifications of deoxyribonucleic acids (DNA) and histone proteins remain unstable throughout life and can be changed by environmental factors. Thus the epigenetic mechanisms outline an attractive molecular hypothesis of the environment modelling role and the environmental contribution to schizophrenia progression. We give in the present study a general outline of schizophrenia as a pathological entity and discuss the role and involvement of environment versus genetic determinant (nature versus nurture) in the pathophysiolgical processes. Additionally, we focus on DNA methylation discussing the evidence for the role of that process in schizophrenia. Thirdly, we review the post-translational histone modifications and their role in schizophrenia. These investigations might surely lead further to the development of epigenetic therapy that looks promising in regard to symptom alleviation and the disease-associated cognitive deficit.

Analysis and evaluation of correlation between DNA polymorphism in the genes MTHFR, PAI-1 and serum creatinine, creatinine clearance and albumin/creatinine ratio in morning urine of patients with type 2 diabetes mellitus and diabetic nephropathy.

INTRODUCTION: Diabetic nephropathy is a major microangiopathic complication of type 2 diabetes and a leading cause of chronic kidney disease (CKD).

Application of pharmacogenetics in oncology.

The term "pharmacogenetics" is used to describe the study of variability in drug response due to heredity. It is associated with "gene - drug interactions". Later on, the term "pharmacogenomics" has been introduced and it comprises all genes in the genome that can define drug response. The application of pharmacogenetics in oncology is of a great significance because of the narrow therapeutic index of chemotherapeutic drugs and the risk for life-threatening adverse effects. Many cancer genomics studies have been focused on the acquired, somatic mutations; however, increasing evidence shows that inherited germline genetic variations play a key role in cancer risk and treatment outcome. The aim of this review is to summarize the state of pharmacogenomics in oncology, focusing only on germline mutations. Genetic polymorphisms can be found in the genes that code for the metabolic enzymes and cellular targets for most of the chemotherapy drugs. Nevertheless, predicting treatment outcome is still not possible for the majority of regimens. In this review, we discuss the most comprehensively studied drug-gene pairs - present knowledge and current limitations. However, further studies in larger groups of cancer patients are necessary to be conducted with precise validation of pharmacogenetic biomarkers before these markers could be routinely applied in clinical diagnosis and treatment.

Assessment of left ventricular structure and function in rats subjected to pressure-overload hypertrophy in time.

BACKGROUND: Left ventricular hypertrophy (LVH) is an adaptive response to increased haemodynamic load and an independent risk factor for the development of heart failure. Although the pathophysiological features during the development of cardiac hypertrophy have been extensively studied, the time course of LVH is less clearly defined. AIM: To define the time-dependency of the LVH process in vivo and compare the data by necropsy. METHODS: Using abdominal aortic banding (AAB) in male Wistar strain albino rats we assessed the changes of LV structure and function in short intervals of 5 days for a period of 45 days. We determined the changes by serial echocardiography and confirmed the results in a second echocardiographic experiment and by necropsy. RESULTS: In our model the magnitude of the pressure overload was sufficient to produce significant LVH within a 10-day time frame and further progression on the 15th day after AAB. Interestingly, on the 20th day after banding a short-lasting regression of LVH (and heart weight and LV wall thickness) was found. It was followed by an increase in the next 15 days (till the 35th day), after which LVH was roughly complete (as measured at the 45th day). CONCLUSIONS: Following the development of LVH over a relatively long period of time and providing the changes in short intervals, a short lasting regression during ongoing pressure overload was noted. Understanding and targeting the associated signalling underlying this regression may have considerable clinical consequences.

Mutations Associated with Imatinib Mesylate Resistance - Review.

Chronic myeloid leukemia (CML) arises from the fusion of the BCR and the ABL1 genes. The BCR gene (chromosome 22q11.2) and the ABL1 gene (chromosome 9q34) fuse together due to reciprocal chromosome translocation forming the Philadelphia chromosome (Ph). This fusion gene codes tyrosine kinase which accelerates the cell division and reduces DNA repair. Imatinib mesylate is a selective inhibitor of this tyrosine kinase. It is the first-line treatment for CML-patients. However, it became clear that Philadelphia-positive (Ph+) cells could evolve to elude inhibition due to point mutations within the BCR-ABL kinase domain. To date more than 40 mutations have been identified and their early detection is important for clinical treatment. With the development of the new tyrosine kinase inhibitors (TKIs), associated with these mutations, the resistance problem seems to diminish, as some of the new drugs are less prone to resistance. The aim of this review is to focus on the diff erent mutations leading to resistance.

Time course and progression of pressure overload-induced cardiac hypertrophy in rats.

AIM: To study the time course and progression of pressure overload-induced left ventricular hypertrophy METHODS: Left ventricular hypertrophy was induced in rats by abdominal aorta constriction and assessed at different time points (10, 15, 20, 25, 35, and 45 days) after operation. RESULTS: The cardiac index (the ratio of heart weight to body weight) in aortic-banded animals was characterised by phasic changes when compared with the sham operated and the control animals. In aortic-banded rats the cardiac index rose sharply at days 10 and 15 after operation. This sharp increase was followed by a phase of slight increase (day 20), and then it again sharply increased (day 25). At the remaining time points (days 35 and 45) the cardiac index was significantly increased in comparison with that of the sham operated and the control animals but the increase diminished gradually. CONCLUSION: Our results suggest that left ventricular hypertrophy develops not in a linear but in a phasic way. Yet, the experimental model we used produced a relatively stable left ventricular hypertrophy.

A reproducible model of cardiac hypertrophy in rats. Problems and obstacles we faced.

AIM: To develop a reproducible model of significant left ventricular hypertrophy in order to study the role played by the tumor suppressor protein 53 (P53) in the mechanisms of cardiac hypertrophy, the cross-talk with the other factors and the connection between expression and activity of P53, cardiac myocyte apoptosis and heart hypertrophy; to discuss the problems and obstacles we faced. METHODS: Male Wistar rats were used in the experiments. Left ventricular hypertrophy was induced by banding the abdominal aorta. Three series of the experiment were performed differing in the place of banding and the size of constriction in order to find the most suitable model for our further research. RESULTS: Forty five days after banding the abdominal aorta just below the diaphragm the cardiac index increased by 30% in comparison with that in the controls. CONCLUSION: We have developed a reproducible model of significant left ventricular hypertrophy in rats. The main advantages of the model are: a) it is technically simple; b) it may be realised in any laboratory all over the world; c) it allows the most common lab animals (male Wistar rats) to be used for studies without having to be subjected to thoracotomy and hence requiring a long recovery period.