Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency

Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.     

Defensins: Natural component of human innate immunity

The widespread use of antibiotics has contributed to a huge increase in the number of resistant bacteria. New classes of drugs are therefore being developed of which defensins are a potential source. Defensins are a group of antimicrobial peptides found in different living organisms, involved in the first line of defense in their innate immune response against pathogens. This review summarizes the results of studies of this family of human antimicrobial peptides (AMPs). There is a special emphasis on describing the entire group and individual peptides, history of their discovery, their functions and expression sites. The results of the recent studies on the use of the biologically active peptides in human medicine are also presented. The pharmaceutical potential of human defensins cannot be ignored, especially considering their strong antimicrobial activity and properties such as low molecular weight, reduced immunogenicity, broad activity spectrum and resistance to proteolysis, but there are still many challenges and questions regarding the possibilities of their practical application.     

Immobility in the tail suspension test predicts quinine but not saccharin intake in mice

It is assumed that depressive symptomatology can alter taste preferences in humans. The aim of the present study was to search for correlations between immobility in the tail suspension test (TST) and consumption of saccharin (0.0025–0.1%, w/w) and quinine (0.0024–0.04%) solutions. Male C57BL/6J mice were divided into high immobility and low immobility groups based on their immobility scores in the TST. The groups consumed similar amounts of saccharin solutions in the two-bottle choice test. There were significant differences between the groups in quinine intake and preference. Intake of, and preference for, 0.0024% quinine was significantly higher in the high immobility than in low immobility subjects. In line with some animal and human studies, our results suggest that behavioral despair in the TST can correlate with taste responses to bitter stimuli.     

Reduction of soluble adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) and vascular endothelial growth factor levels in serum of rheumatoid arthritis patients following multiple intravenous infusions of infliximab

INTRODUCTION: The purpose of this study was to determine the effect of repeated infusions of infliximab, a chimeric anti-tumor necrosis factor (anti-TNF)-alpha antibody, on the levels of soluble adhesion molecules and vascular endothelial growth factor (VEGF) in patients with active rheumatoid arthritis (RA). MATERIALS AND METHODS: The treatment design consisted of 9 infusions of infliximab (3 mg/kg) at weeks 0, 2, 6, and every 8 weeks thereafter. All patients had been receiving methotrexate (MTX; 7.5-20 mg/week). Serum levels of soluble intercellular adhesion molecule (sICAM)-1, vascular cell adhesion molecule (sVCAM)-1, E-selectin (sE-selectin), and VEGF were measured by ELISA at weeks 0, 2, 6, 14, and 38 prior to infusion, and at week 62. RESULTS: A remarkable decrease in serum sICAM-1 (p<0.001), sVCAM-1 (p<0.01), sE-selectin (p<0.01) and VEGF (p<0.001) levels was observed in RA patients after the initial dose of infliximab. The second administration of the drug was followed by an even more significant suppression of serum sICAM-1, sVCAM-1, sE-selectin, and VEGF (p<0.001 in all cases). Further infliximab infusions also significantly reduced serum soluble adhesion molecules and VEGF concentrations, although these were less effective. Infliximab treatment induced a significant decrease in the number of monocytes observed until the end of the study. CONCLUSIONS: Our study, besides a rapid suppression of disease activity, showed that serum soluble adhesion molecules and VEGF concentrations are down-regulated following anti-TNF-alpha antibody therapy combined with MTX. Repeated doses of infliximab sustained the reductions in the soluble adhesion molecules and VEGF concentrations, although they were less effective than the first and second infusions of infliximab.     

Clinical and molecular-cytogenetic evaluation of a family with partial Jacobsen syndrome without thrombocytopenia caused by an approximately 5 Mb deletion del(11)(q24.3)

Clinical manifestations of Jacobsen syndrome (JBS) depend on the size of the 11qter deletion, which usually varies between approximately 7 and 20 Mb. Typical JBS features include developmental delay/mental retardation, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. We report on a family in which a 4-year-old girl as well as her mother and maternal uncle present with subtle features of JBS. Notably, neither thrombocytopenia nor congenital anomalies were detected in this family. Cytogenetic analyses revealed normal karyotypes. Using fluorescence in situ hybridization (FISH) and whole-genome oligonucleotide array CGH analyses, we identified an approximately 5 Mb deletion of the terminal part of chromosome 11q in all the three affected family members. The deletion breakpoint was mapped between 129,511,419 and 129,519,794 bp. This is the smallest deletion reported in a JBS patient. Interestingly, the FLI1 (friend leukemia virus integration 1) hematopoiesis factor gene located approximately 6.5 Mb from 11qter and usually deleted in patients with JBS, is intact. Our data support previous hypotheses that FLI1 haploinsufficiency is responsible for thrombocytopenia in patients with JBS.     

Medical errors – not only patients’ problem

Introduction

Medical error is often a traumatic experience not only for patients but also for doctors. However, patients as victims get much more publicity than those responsible for actual errors. The authors of the study conducted research to learn about Polish doctors'' opinions on and reactions to medical errors and how they affect their further professional activity and psychological status. The aim of this study was to evaluate the impact of involvement in medical errors of doctors of different specialties and different age.

Material and methods

The research was conducted in a group of 100 doctors of different specialties. Respondents anonymously completed an experimental survey comprising 6 groups of multiple choice questions concerning such issues as awareness of the nature of medical error, legal liability of the perpetrator, consequences of medical error for further professional activity, the function of the Patients'' Rights Representative and consequences of publishing the problem.

Results

The results indicate many negative effects of medical errors on physicians, such as common fear of making an error (82%), increased caution (52%), disadvantageous security measures while performing one''s duties (57%), worsening of doctor-patient relations (67%), loss of social trust (62%) and increased treatment costs (40%). Forty five percent of the surveyed doctors declared that patients need the Patients'' Rights Representative and 39% claimed it does not affect their work.

Conclusions

Given the significant burden on physicians'' health, well-being and performance associated with medical errors, health care institutions should take this into account and provide physicians with formal systems of support.     

Cribriform adenocarcinoma of the tongue

We report a case of a 73-year-old female with a tumour of the tongue, operated with two relapses. A single metastasis to the lymph node was present. Currently, the patient is alive without evidence of disease. The histological diagnosis of cribriform adenocarcinoma of the tongue was rendered. The differential diagnosis of adenocarcinomas of the tongue is discussed.     

Mild CFTR mutations and genetic predisposition to lactase persistence in cystic fibrosis

Taking into account the reported incidence of hypolactasia in cystic fibrosis (CF) and the possible impact of milk products on nutritional status we aimed to assess the genetic predisposition to adult-type hypolactasia (ATH) and its incidence in CF. Single nucleotide polymorphism upstream of the lactase gene (LCT) was assessed in 289 CF patients. In subject with -13910C/C genotype (C/C) predisposing to ATH, hydrogen-methane breath test (BT) with lactose loading was conducted and clinical symptoms typical for lactose malabsorption were assessed. The percentage of CF patients with C/C was similar to that observed in healthy subjects (HS) (31.5 vs 32.5% ). Eleven out of 52 (24.5%) CF C/C patients had abnormal BT results. The recalculated frequency of lactose malabsorption was similar for the entire CF and HS populations (6.9 vs 7.2%). Similarly as in the control group, few CF patients have identified and linked to lactose consumption clinical symptoms. The frequency of LCT polymorphic variants in CF patients having and not having severe mutations of CFTR gene showed significant differences. The C allele was more frequent in homozygotes of the severe mutations than in patients carrying at least one mild/unknown mutation (P<0.0028) and in patients with at least one mild mutation (P < 0.0377). In conclusion, CF patients carrying mild CFTR mutations seem to have lower genetic predisposition to ATH. Lactose malabsorption due to ATH in CF is not more frequent than in the general population. Symptomatic assessment of lactose malabsorption in CF is not reliable.