Intermittent catheterization with single- or multiple-reuse catheters: clinical study on safety and impact on quality of life

International Urology and Nephrology - Intermittent catheterization (IC) is a proven effective long-term bladder management strategy for individuals who have lower urinary tract dysfunction. This...     

High Precision DNA Modification Analysis of HCG9 in Major Psychosis

New epigenetic technologies may uncover etiopathogenic mechanisms of major psychosis. In this study, we applied padlock probe-based ultra-deep bisulfite sequencing for fine mapping of modified cytosines of the HLA complex group 9 (nonprotein coding) gene in the postmortem brains of individuals affected with schizophrenia or bipolar disorder and unaffected controls. Significant differences between patients and controls were detected in both CpG and CpH modifications. In addition, we identified epigenetic age effects, DNA modification differences between sense and anti-sense strands, and demonstrated how DNA modification data can be used in clustering of patient populations. Our findings revealed new epigenetic complexities but also highlighted the potential of DNA modification approaches in the search of heterogeneous causes of major psychiatric disease.Key words: epigenetics, brain, schizophrenia, bipolar disorder, bisulfite sequencing, padlock probes     

Computational analysis of drug transport in tumor microenvironment as a critical compartment for nanotherapeutic pharmacokinetics

Over the last decade, nanotherapeutics gained increasingly important role in drug delivery because of their frequently beneficial pharmacokinetics (PK) and lower toxicity when compared to classical systemic drug delivery. In view of therapeutic payload delivery, convective transport is crucial for systemic distribution via circulatory system, but the target domain is tissue outside vessels where transport is governed by diffusion. Here, we have computationally investigated the understudied interplay of physical transports to characterize PK of payload of nanotherapeutics. The analysis of human vasculature tree showed that convective transport is still 5 times more efficient than diffusion suggesting that circulating and payload releasing drug vectors can contribute mostly to systemic delivery. By comparing payload delivery using systemic circulation and drug vectors to microenvironment, internalized vectors were the most efficient and showed Area under the Curve almost 100 higher than in systemic delivery. The newly introduced zone of influence parameter indicated that vectors, especially internalized, lead to the largest tissue fraction covered with therapeutically significant payload concentration. The internalization to microenvironment minimizes effects of plasma domain on payload extravasation from nanotherapeutics. The computed results showed that classical PK, which mostly relies on concentration profiles in plasma, sometimes might be inadequate or not sufficient in explaining therapeutic efficacy of nanotherapeutics. These results provide a deeper look into PK of drug vectors and can help in the design of better drug delivery strategies.     

Complex disease, gender and epigenetics

Gender differences in susceptibility to complex disease such as asthma, diabetes, lupus, autism and major depression, among numerous other disorders, represent one of the hallmarks of non-Mendelian biology. It has been generally accepted that endocrinological differences are involved in the sexual dimorphism of complex disease; however, specific molecular mechanisms of such hormonal effects have not been elucidated yet. This paper will review evidence that sex hormone action may be mediated via gene-specific epigenetic modifications of DNA and histones. The epigenetic modifications can explain sex effects at DNA sequence polymorphisms and haplotypes identified in gender-stratified genetic linkage and association studies. Hormone-induced DNA methylation and histone modification changes at specific gene regulatory regions may increase or reduce the risk of a disease. The epigenetic interpretation of sexual dimorphism fits well into the epigenetic theory of complex disease, which argues for the primary pathogenic role of inherited and/or acquired epigenetic misregulation rather than DNA sequence variation. The new experimental strategies, especially the high throughput microarray-based epigenetic profiling, can be used for testing the epigenetic hypothesis of gender effects in complex diseases.     

New non-invasive sonographic modality for intracranial pressure/volume monitoring

INTRODUCTION: The wide use of intracranial pressure and cerebral perfusion pressure monitoring has improved the management of patients with severe head injuries. The rare but worrying complications associated with the application of such monitoring makes the idea of a non-invasive method of monitoring very attractive. MATERIALS AND METHODS: A new non-invasive ultrasonographic technology was used to measure cerebral perfusion pressure in 27 normal volunteers. The average monitoring time was 45.3+/-0.2 min, and the average perfusion pressure recorded was 77.4+/-0.3 mmHg. No complications were reported during the procedure, which was performed while the subjects were in regular ward beds. CONCLUSION: The non-invasive character of this method could extend the use of cerebral perfusion pressure measurement to several other neurosurgical entities, such as hydrocephalus, pseudotumor cerebri, chronic headache, and spinal cord injuries.     

Age and sex based genetic locus heterogeneity in type 1 diabetes

BACKGROUND: Two genome scans for susceptibility loci for type 1 diabetes using large collections of families have recently been reported. Apart from strong linkage in both studies of the HLA region on chromosome 6p, clear consistent evidence for linkage was not observed at any other loci. One possible explanation for this is a high degree of locus heterogeneity in type 1 diabetes, and we hypothesised that the sex of affected offspring, age of diagnosis, and parental origin of shared alleles may be the bases of heterogeneity at some loci. METHODS: Using data from a genome wide linkage study of 356 affected sib pairs with type 1 diabetes, we performed linkage analyses using parental origin of shared alleles in subgroups based on (1) sex of affected sibs and (2) age of diagnosis. RESULTS: Among the results obtained, we observed that evidence for linkage to IDDM4 on chromosome 11q13 occurred predominantly from opposite sex, rather than same sex sib pairs. At a locus on chromosome 4q, evidence for linkage was observed in sibs where one was diagnosed above the age of 10 years and the other diagnosed below 10 years of age. CONCLUSIONS: We show that heterogeneity tests based on age of diagnosis, sex of affected subject, and parental origin of shared alleles may be helpful in reducing locus heterogeneity in type 1 diabetes. If repeated in other samples, these findings may assist in the mapping of susceptibility loci for type 1 diabetes. Similar analyses can be recommended in other complex diseases.     

Age of diagnosis-based linkage analysis in type 1 diabetes

Genetic linkage studies of type 1 diabetes have produced a number of conflicting results, suggesting a high degree of locus heterogeneity in this disease. Approaches which model such heterogeneity will increase the power to fine map susceptibility loci. Here, using data from a genome scan of 356 affected sib pairs with type 1 diabetes, we performed heterogeneity analysis based on similarity of age at diagnosis of the sib pairs. We observed linkage to the region on chromosome 4p16.3 in sib pairs both diagnosed over the age of 10 years, whilst there was no evidence for linkage in sib pairs diagnosed before age 10 years. In contrast the sib pairs diagnosed before the age of 10 years demonstrated linkage to IDDM10, on chromosome 10p. Age of diagnosis-based heterogeneity analyses in complex diseases may be particularly helpful in mapping some susceptibility loci.