A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis.

Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in M. tuberculosis is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative tests. This study provides a comprehensive assessment of PZA molecular diagnostics in M/XDR TB cases. A set of 296, mostly XDR, clinical M. tuberculosis isolates from four countries were subjected to DST for eight drugs, confirmatory Wayne's assay, and whole-genome sequencing. Three genes implicated in PZA resistance, pncA, rpsA, and panD were investigated. Assuming all non-synonymous mutations cause resistance, we report 90% sensitivity and 65% specificity for a pncA-based molecular test. The addition of rpsA and panD potentially provides 2% increase in sensitivity. Molecular heterogeneity in pncA was associated with resistance and should be evaluated as a diagnostic tool. Mutations near the N-terminus and C-terminus of PZase were associated with East-Asian and Euro-American lineages, respectively. Finally, Euro-American isolates are most likely to have a wild-type PZase and escape molecular detection. Overall, the 8-10% resistance without markers may point to alternative mechanisms of resistance. Confirmatory mutagenesis may improve the disconcertingly low specificity but reduce sensitivity since not all mutations may cause resistance

Kepler observations of A-F pre-main sequence stars in Upper Scorpius: Discovery of six new δ\delta~Scuti and one γ\gamma~Doradus stars

We present light curves and periodograms for 27 stars in the young Upper Scorpius association (age=$11 \pm 1$\,Myr) obtained with the Kepler spacecraft. This association is only the second stellar grouping to host several pulsating pre-main sequence (PMS) stars which have been observed from space. From an analysis of the periodograms, we identify six $\delta$~Scuti variables and one $\gamma$~Doradus star. These are most likely PMS stars or else very close to the zero-age main sequence. Four of the $\delta$~Scuti variables were observed in short-cadence mode, which allows us to resolve the entire frequency spectrum. For these four stars, we are able to infer some qualitative information concerning their ages. For the remaining two $\delta$~Scuti stars, only long-cadence data are available, which means that some of the frequencies are likely to be aliases. One of the stars appears to be a rotational variable in a hierarchical triple system. This is a particularly important object, as it allows the possibility of an accurate mass determination when radial velocity observations become available. We also report on new high-resolution echelle spectra obtained for some of the stars of our sample.Comment: 19 pages, 9 figures. Accepted for publication on MNRA

A case of primary Hodgkin's lymphoma of the parotid gland. Case report and differentian diagnosis from Kuttner's Syndrom

Abstract We report a rare case of primary Hodgkin’s lymphoma (HL) of the submandibular gland, with initially diagnosis of Kuttner’s Syndrom. A 48 years old man was referred to our hospital foe evaluation of a submandibular mass. Although the initial Fine Needle Aspiration and subsequent cytology was highly suggestive for a cronic sialadenitis with lymphoid cells. After surgical gland removal we obtained a definitive diagnosis of Hodgkin’s lymphoma in submandibular gland a seat where the most common lymphoma tipe is B

Which is the most accurate diagnostic procedure in Tamoxifen treated breast cancer patients

Purpose: The aim of this study was to evaluate the diagnostic accuracy of bi-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound (TVUS), hysterosonography (HSSG) and hysteroscopy in the detection of endometrial pathology in women treated with tamoxifen (TMX) for breast cancer. Methods: Forty-two patients, affected by breast cancer under treatment with TMX, underwent 2D-3D TVUS, HSSG and hysteroscopy completed by biopsy, after abnormal findings following a routine 2D TVUS examination. Results: 3D-TVUS was more accurate than 2D-TVUS in the detection of atrophic endometrium confirmed by biopsy and in the detection of endometrial polyps. HSSG and hysteroscopy detected atrophic endometrium and endometrial polyps significantly better than ultrasound scan. Endometrial carcinoma was detected in two cases, and in both HSSG and hysteroscopy were 100% diagnostic. Conclusion: In TMX treated breast cancer patients, HSSG and hysteroscopy provide more accurate diagnosis than 2D-3D ultrasound in the detection of treatment related endometrial lesions

Sonic hedgehog medulloblastoma cancer stem cells mirnome and transcriptome highlight novel functional networks

Molecular classification has improved the knowledge of medulloblastoma (MB), the most common malignant brain tumour in children, however current treatments cause severe side effects in patients. Cancer stem cells (CSCs) have been described in MB and represent a sub population characterised by self-renewal and the ability to generate tumour cells, thus representing the reservoir of the tumour. To investigate molecular pathways that characterise this sub population, we isolated CSCs from Sonic Hedgehog Medulloblastoma (SHH MB) arisen in Patched 1 (Ptch1) heterozygous mice, and performed miRNA-and mRNA-sequencing. Comparison of the miRNA-sequencing of SHH MB CSCs with that obtained from cerebellar Neural Stem Cells (NSCs), allowed us to obtain a SHH MB CSC miRNA differential signature. Pathway enrichment analysis in SHH MB CSCs mirnome and transcriptome was performed and revealed a series of enriched pathways. We focused on the putative targets of the SHH MB CSC miRNAs that were involved in the enriched pathways of interest, namely pathways in cancer, PI3k-Akt pathway and protein processing in endoplasmic reticulum pathway. In silico analysis was performed in SHH MB patients and identified several genes, whose expression was associated with worse overall survival of SHH MB patients. This study provides novel candidates whose functional role should be further investigated in SHH MB

Role and importance of polymorphisms with respect to DNA methylation for the expression of CYP2E1 enzyme

Different individuals possess slightly different genetic information and show genetically-determined differences in several enzyme activities due to genetic variability. Following an integrated approach,we studied the polymorphisms andmethylation of sites contained in the 5′ flanking region of themetabolizing enzyme CYP2E1 in correlation to its expression in both tumor and non-neoplastic liver cell lines, since to date little is known about the influence of these (epi)genetic elements in basal conditions and under induction by the specific inductor and a demethylating agent. In treated cells, reduced DNA methylation, assessed both at genomic and gene level, was not consistently associatedwith the increase of enzyme expression. Interestingly, the Rsa/Pst haplotype differentially influenced CYP2E1 enzyme expression. In addition, regarding the Variable Number of Tandem Repeats polymorphism, cells with A4/A4 genotype showed a greater expression inhibition (ranging from 20% to 30%) compared with others carrying the A2/A2 one, while those cells bringing A2/A3 genotype showed an increase of expression (of 25%, about). Finally, we demonstrated for the first time that the A2 and A3 CYP2E1 alleles play a more important role in the expression of the enzyme, compared with other (epi)genetic factors, since they are binding sites for trans-acting proteins

Abundances in HD27411 and the helium problem in Am stars

We analyze a high-resolution spectrum of the A3m star HD27411. We compare abundances derived from ATLAS9 model atmospheres with those using the more computationally-intensive ATLAS12 code. We found very little differences in the abundances, suggesting that ATLAS9 can be used for moderate chemical peculiarity. Our abundances agree well with the predictions of diffusion theory, though for some elements it was necessary to calculate line profiles in non-thermodynamic equilibrium to obtain agreement. We investigate the effective temperatures and luminosities of Am/Fm stars using synthetic Stromgren indices derived from calculated spectra with the atmospheric abundances of HD27411. We find that the effective temperatures of Am/Fm stars derived from Stromgren photometry are reliable, but the luminosities are probably too low. Caution is required when deriving the reddening of these stars owing to line blanketing effects. A comparison of the relative proportions of pulsating and non-pulsating Am stars with delta Scuti stars shows quite clearly that there is no significant decrease of helium in the driving zone, contrary to current models of diffusion.Comment: 10 pages, 8 figures, 6 tables, accepted for publication in MNRA