Beware of the LASP! A structure with thrombogenic potential

The left atrial septal pouch (LASP) is a recently identified anatomical variant of the interatrial septum. It is the result of the incomplete fusion of septum primum and septum secundum and defined as a recessus communicating with the left atrium without interatrial shunt. Such anatomical feature has been suspected representing a potential thrombogenic source, but its actual role as risk factor for cryptogenic stroke still remains unclear. In this case report, we show two distinct thrombotic masses emerging from the LASP and its related areas.     

Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case control study

CHEK2 is a key cell cycle control gene encoding a pluripotent kinase that can cause arrest or apoptosis in response to unrepaired DNA damage. We report a large case-control study of a non-functional variant that had previously been expected to increase cancer rates. Four thousand and fifteen cancer patients (2250 lung, 811 squamous upper aero-digestive and 954 kidney) and 3052 controls in central Europe were genotyped for the mis-sense variant rs17879961 (replacement of T by C), which changes an amino acid (I157T) in an active site of the gene product. The heterozygous (T/C) genotype was associated with a highly significantly lower incidence of lung cancer than the common T/T genotype [relative risk (RR), T/C versus T/T, 0.44, with 95% confidence interval (CI) 0.31-0.63, P < 0.00001] and with a significantly lower incidence of upper aero-digestive cancer (RR 0.44, CI 0.26-0.73, P = 0.001; P = 0.000001 for lung or upper aero-digestive cancer). Protection was significantly greater for squamous than adenomatous lung cancer (P = 0.001). There was an increase of borderline significance in kidney cancer (RR 1.44, CI 0.99-2.00, P = 0.06). This unexpected halving of tobacco-related cancer (since replicated independently) implies much greater absolute risk reduction in smokers than in non-smokers. The mechanism is unknown: perhaps squamous stem cell apoptosis following smoke exposure causes net harm (e.g. by forcing nearby stem cells to divide before they have repaired their own DNA damage from tobacco smoke). If so, reducing the rate of apoptosis by reducing CHEK2 activity could be protective-although not smoking would be far more so.     

Exon 5 polymorphisms in the O6-alkylguanine DNA alkyltransferase gene and lung cancer risk in non-smokers exposed to second-hand smoke.

PURPOSE: The objective of the study was to examine the association of three exon 5 variants in the O(6)-alkylguanine DNA alkyltransferase (AGT) gene involved in the repair of the mutagenic DNA lesion O(6)-alkylguanine formed by nitrosamines, with lung cancer risk in never-smokers. EXPERIMENTAL DESIGN: Exon 5 of the AGT gene was sequenced in genomic DNA from 136 cases and 133 hospital- or population-based controls for whom questionnaire information on second-hand smoke and diet was available to determine the frequencies of the Gly(160)Arg, Ile(143)Val, and Lys(178)Arg variant alleles. RESULTS: No codon (160)Arg variant alleles were found in the study population. The codon (143)Val and (178)Arg variant alleles, present at allele frequencies of 0.07, showed 100% linkage. The odds ratio (OR) of lung cancer for these variant carriers was 2.05 [95% confidence interval (CI) 1.03-4.07]. The risk varied between the different lung cancer pathologies with an increased risk for adenocarcinoma (OR 2.67, 95% CI 1.21-5.87) or small cell carcinoma (OR 4.83, 95% CI 0.91-25.7) but not for squamous cell carcinoma (OR 1.07, 95% CI 0.27-4.18). Compared with individuals carrying the mutant alleles unexposed to second-hand smoke, the OR for exposed variant carriers was 1.95 (95% CI 0.53-1.15); a similar interaction, although not significative, was observed for low consumption of cruciferous vegetables and for green vegetables and tomatoes. CONCLUSIONS: These results point toward a role of AGT polymorphisms in lung cancer susceptibility among never-smokers, in particular among subjects exposed to environmental carcinogens.     

Characteristics and short-term survival of individuals with out-of-hospital cardiac arrests in the East Bohemian region

AIM: We describe survival after admission to hospital from out-of-hospital cardiac arrest (OHCA) in the East Bohemian region, according to the Utstein Style guidelines and have identified the main diagnosis including in those who died and had an autopsy. PATIENT GROUP: Over a period of 29 months we used a questionnaire supplied to 24 rescue stations, to identify 718 individuals (511 men and 207 women, aged 16-97 years) with confirmed cardiac arrest who were considered for resuscitation. RESULTS: Out of 560 patients in whom cardiopulmonary resuscitation for OHCA of confirmed cardiac aetiology was attempted, 350 patients (62.5%) died in the field and 61 (10.9%) died during transport. Hospital admission was achieved in 149 cases (26.6%) and, of these, 96 patients died. Fifty-three patients (9.5%) were discharged home alive, 36 (6.4%) with an intact CNS. The first monitored rhythm showed asystole in 264 cases (47.1%) followed by ventricular fibrillation in 227 cases (40.5%). The main diagnosis of coronary heart disease (CHD) was established clinically in 467 cases (83.4%). In 175 autopsy reports this diagnosis was noted in 152 cases (86.9%). CONCLUSION: Of patients resuscitated for OHCA of cardiac aetiology, 9.5% survived to leave the acute hospital. CHD was the principle diagnosis in the entire group and this correlated with the same finding in the group of patients who received an autopsy.     

Feeding practices of babies and the development of atopic dermatitis in children after 12 months of age in Armenia: Is there a signal?

We investigated the influence of feeding practices on development of atopic dermatitis (AD) in Armenian children (n = 240). In multivariate models early introduction to solids, family history of atopy, and breastfeeding by a mother with atopic condition were associated with the development of AD after 12 months post-term. A prospective study in Armenia is recommended to confirm our findings.     

O6-Alkylguanine-DNA-alkyltransferase activity in peripheral leukocytes, smoking and risk of lung cancer

The level of activity of O6-alkylguanine-DNA-alkyltransferase (AGT), a DNA repair enzyme, in blood lymphocytes may be a marker of susceptibility to lung cancer. We measured the AGT activity level, expressed as pmoles of repaired bases/mg protein, in leukocytes of 153 lung cancer cases (of whom 80 were never smokers) and 106 controls (76 never smokers) enrolled in eight centres from seven countries. Subjects were interviewed with respect to active smoking and exposure to environmental tobacco smoke (ETS). Among never smokers, the odds ratios (ORs) of lung cancer were 1.3 (95% confidence interval 0.5-3.9), 1.5 (0.6-4.1) and 1.4 (0.5-3.8) in quartiles of decreasing AGT activity level, as compared to the upper quartile (P value of test for linear trend 0.6). Corresponding ORs among smokers were 3.4 (0.9-13), 2.0 (0.5-8.3) and 0.4 (0.1-1.6) (P value of test for linear trend 0.4). No interaction was suggested between AGT activity level and either cumulative smoking or exposure to ETS. Reduced AGT activity was not clearly associated with increased lung cancer risk in either smokers or non-smokers. However, the small size of our study argues for a prudent interpretation of our results.     

Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors

PURPOSE: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. EXPERIMENTAL DESIGN: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. RESULTS: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. CONCLUSION: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.     

Synthesis and antimicrobial activity of new 2‐piperazin‐1‐yl‐N‐1,3‐thiazol‐2‐ylacetamides of cyclopenta[c]pyridines and pyrano[3,4‐c]pyridines

In this study, we report the synthesis and antimicrobial activity of some new disubstituted piperazines. Thus, 3‐chlorocyclopenta[c]pyridines and 6‐chloropyrano[3,4‐c]pyridine 1 under mild reaction conditions with piperazine gave the 3(6)‐piperazine‐substituted cyclopenta[c]pyridines and pyrano[3,4‐c]pyridine 2 . Furthermore, the latter, by alkylation with 2‐chloro‐N‐1,3‐thiazol‐2‐ylacetamide, led to the formation of the target compounds. The evaluation of the antibacterial activity revealed that 3k was the most potent compound. The most sensitive bacterium was found to be Listeria monocytogenes, whereas Staphylococcus aureus was the most resistant one. Three compounds, 3d , 3g , and 3k , were tested also against the following resistant strains: methicillin‐resistant S. aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa. All three compounds appeared to be more potent than ampicillin against MRSA. Moreover, compound 3d showed a better activity than the reference drug ampicillin against P. aeruginosa, whereas 3g was more efficient against E. coli. The best antifungal activity was observed again for compound 3k . The most resistant fungi appeared to be Aspergillus fumigatus, whereas Trichoderma viride seemed the most sensitive one toward the compounds tested. Molecular docking studies on E. coli MurB, as well as on Candida albicans CYP51 and dihydrofolate reductase, were used for the prediction of the mechanisms of the antibacterial and antifungal activities, confirming the experimental results.