[DOXYCYCLINE (UNIDOX SOLUTAB®) AND/OR JOSAMYCIN (WILPRAFEN®) IN TREATMENT OF PATIENTS WITH PROSTATITIS IN REAL CLINICAL PRACTICE. RESULTS OF THE TAURUS OBSERVATIONAL PROGRAM].

Treatment of chronic prostatitis is a vital and complicated problem, in which a large number of stamps and "stereotyped" approaches often result in uncured patients. The increasing use of intracellular microorganisms in prostatitis etiology requires a modification in the standard approaches. TAURUS study shows high efficacy of doxycycline (Unidox Solutab®) and/or josamycin (Wilprafen®) in chronic prostatitis. Therapy, studied in this program, according to physicians, was effective in 93.2% of patients. Treatment failure was observed in 1.3% of all patients, another 5.5% of patients had insufficient data for assessment. Low incidence of adverse reactions was observed. In the study population, adverse reactions occurred in 2.6% of patients, of them serious adverse events were registered in 0.7% of patients. The most common adverse event in all treatment groups was diarrhea.

The dual effect of the lupus-associated polymorphism rs10516487 on BANK1 gene expression and protein localization.

Numerous loci have been found genetically associated with complex diseases, but only in a few cases has the functional variant and the molecular mechanism behind it been identified. Recently, the association of the BANK1 gene with systemic lupus erythematosus (SLE) was described. Here, we investigated the role of the associated polymorphisms on gene function and found that SNP rs17266594 located in the branch point consensus sequence has negligible effect on splicing or gene expression. The non-synonymous SNP rs10516487 located in exon 2 influenced splicing efficiency by creating an exonic splicing enhancer site for the SRp40 factor. Further, this same SNP generates protein isoforms with differential and measurable self-association properties. The full-length protein isoform containing the R61 variant forms larger protein scaffold complexes in the cell cytoplasm compared with the protective BANK1-61H variant. We also observed that, contrary to the full-length isoforms, the short Δ2 isoform of BANK1 displays a homogeneous cytoplasmic distribution, underscoring the potential role of the exon 2-coded protein domain in the scaffolding function of BANK1. We provide evidence that the non-synonymous SNP rs10516487 (G>A; R61H) shows a dual nature by first, influencing mRNA splicing and consequently the quantity of protein, and, second, by producing a risk variant-containing protein isoform with increased potential for multimerization.

Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene.

A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.

STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk.

OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.

2-Adic clustering of the PAM matrix.

In this paper we demonstrate that the use of the system of 2-adic numbers provides a new insight to some problems of genetics, in particular, degeneracy of the genetic code and the structure of the PAM matrix in bioinformatics. The 2-adic distance is an ultrametric and applications of ultrametric in bioinformatics are not surprising. However, by using the 2-adic numbers we match ultrametric with a number theoretic structure. In this way we find new applications of an ultrametric which differ from known up to now in bioinformatics. We obtain the following results. We show that the PAM matrix A allows the expansion into the sum of the two matrices A=A((2))+A((infinity)), where the matrix A((2)) is 2-adically regular (i.e. matrix elements of this matrix are close to locally constant with respect to the discussed earlier by the authors 2-adic parametrization of the genetic code), and the matrix A((infinity)) is sparse. We discuss the structure of the matrix A((infinity)) in relation to the side chain properties of the corresponding amino acids. We introduce the family of substitution matrices A(alpha,beta)=alpha A((2))+beta A((infinity)), alpha,beta>or=0 which should allow to vary the alignment procedure in order to take into account the different chemical and geometric properties of the amino acids.

[Trospium chloride in the treatment of idiopathic and neurogenic detrusor overactivity].

The aim of the study was to investigate safety and efficacy of spasmex (trospium chloride) in patients with idiopathic and neurogenic detrusor overactivity. The study included 66 patients with idiopathic and neurogenic detrusor overactivity. The diagnostic scheme consisted of voiding dairy for 72 hours, laboratory tests, ultrasound investigation with measurement of residual urine volume, urodynamic investigation and neurologic examination. The patients were divided into 4 groups: 15 patients with idiopathic detrusor overactivity (DOA), 16 with neurogenic DOA, 23 with combination of DOA with benign prostatic hyperplasia, 12 with overactive bladder without DOA. Initial trospium chloride dose of 15 mg/day (5 mg 3 times a day) followed by dose titration to obtain clinical efficacy was used under residual urine volume control every week. The maximal dose was 45 mg. After 12 weeks reduction of micturation frequency was registered in all the groups. Administration of small dose trospium chloride (15 mg) resulted in subjective improvement in 63 (94.5%) patients. Only 3 patients persisted with the symptoms in whom the dose was raised to 30 mg and then to 45 mg/day. Thus, spasmex demonstrated high efficacy in patients with bladder overactivity. High efficacy and safety with low cost make spasmex a drug of choice in the majority of patients with overactive bladder symptoms.

Structure of the human CpG-island-containing lung Kruppel-like factor (LKLF) gene and its location in chromosome 19p13.11-13 locus.

We have cloned earlier a short human genomic fragment which showed strong similarity with the mouse cDNA encoding lung Kruppel-like zinc finger transcription factor (LKLF), predominantly expressed in mouse developing lung, spleen, and vascular system, which might play a key role in programming the quiescent state of single positive T cells and blood vessel wall morphogenesis. Here we report the successful cloning of the human LKLF cDNA, its genomic structure and chromosomal localization at the 19p13.11-p13.13 locus. The full-length human LKLF cDNA has longer 5'-UTR with higher GC content than mouse cDNA and encodes a predicted protein of 355 amino acids which has three zinc fingers at the C-terminus and a proline-rich N-terminal domain. Human and mouse proteins share 87.3% identity and 90.2% amino acid similarity. The human LKLF gene consists of three exons. From the proximal promoter to the end of the second exon, we have found a CpG island with an average 76% GC content and two regions of unusually high GC density.

No evidence of association between genetic variants of the PDCD1 ligands and SLE.

PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.