Prevention and modulation of aminoglycoside ototoxicity (Review)

More than 60 years after their isolation and characterization, aminoglycoside (AG) antibiotics remain powerful agents in the treatment of severe gram-negative, enterococcal or mycobacterial infections. However, the clinical use of AGs is hampered by nephrotoxicity and ototoxicity, which often develop as a consequence of prolonged courses of therapy, or of administration of increased doses of these drugs. The discovery of non-ototoxic antibacterial agents, showing a wider spectrum of activity, has gradually decreased the use of AGs as first line antibiotics for many systemic infections. However, AGs are now undergoing an unexpected revival, being increasingly indicated for the treatment of severe emerging infections caused by organisms showing resistance to most first-line agents (e.g., multidrug-resistant tuberculosis, complicated nosocomially-acquired acute urinary tract infections). Increasing adoption of aminoglycosides poses again to scientists and physicians the problem of toxicity directed to the kidneys and to the inner ear. In particular, aminoglycoside-induced deafness can be profound and irreversible, especially in genetically predisposed patients. For this reason, an impressive amount of molecular strategies have been developed in the last decade to counteract the ototoxic effect of aminoglycosides. The present article overviews: i) the molecular mechanisms by which aminoglycosides exert their bactericidal activity, ii) the mechanisms whereby AGs exert their ototoxic activity in genetically-predisposed patients, iii) the drugs and compounds that have so far proven to prevent or modulate AG ototoxicity at the preclinical and/or clinical level, and iv) the dosage regimens that have so far been suggested to decrease the incidence of episodes of AG-induced ototoxicity

Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg).

In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms

Analytical and mathematical methods for revealing hidden details in ancient manuscripts and paintings: A review

In this work, a critical review of the current nondestructive probing and image analysis approaches is presented, to revealing otherwise invisible or hardly discernible details in manuscripts and paintings relevant to cultural heritage and archaeology. Multispectral imaging, X-ray fluorescence, Laser-Induced Breakdown Spectroscopy, Raman spectroscopy and Thermography are considered, as techniques for acquiring images and spectral image sets; statistical methods for the analysis of these images are then discussed, including blind separation and false colour techniques. Several case studies are presented, with particular attention dedicated to the approaches that appear most promising for future applications. Some of the techniques described herein are likely to replace, in the near future, classical digital photography in the study of ancient manuscripts and paintings

Lessons from Mycobacterium avium complex-associated pneumonitis: a case report

ABSTRACT: INTRODUCTION: Mycobacterium avium complex (MAC) is an increasingly recognized cause of pulmonary disease in immunocompetent individuals. An acute form of MAC lung disease, MAC-associated pneumonitis, has generally been associated with the use of hot tubs. There is controversy in the literature about whether MAC-associated pneumonitis is a classic hypersensitivity pneumonitis or is a direct manifestation of mycobacterial infection. CASE PRESENTATION: We report the second case in the literature of MAC-associated pneumonitis not related to the use of hot tubs. The source of MAC in a 52-year-old immunocompetent patient was an intrapulmonary cyst containing numerous acid-fast bacilli. The patient developed disseminated miliary nodules throughout both lung fields. Histological examination of resected lung tissue revealed well-formed, acid-fast negative granulomas composed predominantly of CD4+ T-cells and CD68+ histiocytes. The granulomas were strongly positive for tumor necrosis factor-alpha, a pro-inflammatory cytokine. CONCLUSION: The attempt to classify MAC-associated pneumonitis as either a classic hypersensitivity pneumonitis or a direct manifestation of mycobacterial infection is not particularly useful. Our case demonstrates that MAC-associated pneumonitis is characterized by a vigorous T-helper 1-like, pro-inflammatory, immune response to pulmonary mycobacterial infection. The immunopathology provides a rationale for clinical studies of anti-MAC therapy with the addition of anti-inflammatory agents (for example, corticosteroids) to hasten the resolution of infection and symptoms

Measurement of the branching ratios of the decays Xi0 --> Sigma+ e- nubar and anti-Xi0 --> anti-Sigma+ e+ nu

From 56 days of data taking in 2002, the NA48/1 experiment observed 6316 Xi0 --> Sigma+ e- nubar candidates (with the subsequent Sigma+ --> p pi0 decay) and 555 anti-Xi0 --> anti-Sigma+ e+ nu candidates with background contamination of 215+-44 and 136+-8 events, respectively. From these samples, the branching ratios BR(Xi0 --> Sigma+ e- nubar)= (2.51+-0.03stat+-0.09syst)E(-4) and BR(anti-Xi0 --> anti-Sigma+ e+ nu)= (2.55+-0.14stat+-0.10syst)E(-4) were measured allowing the determination of the CKM matrix element |Vus| = 0.209+0.023-0.028. Using the Particle Data Group average for |Vus| obtained in semileptonic kaon decays, we measured the ratio g1/f1 = 1.20+-0.05 of the axial-vector to vector form factors.Comment: 16 pages, 11 figures Submitted to Phys.Lett.

First observation of the KS->pi0 gamma gamma decay

Using the NA48 detector at the CERN SPS, 31 KS->pi0 gamma gamma candidates with an estimated background of 13.7 +- 3.2 events have been observed. This first observation leads to a branching ratio of BR(KS->pi0 gamma gamma) = (4.9 +- 1.6(stat) +- 0.9(syst)) x 10^-8 in agreement with Chiral Perturbation theory predictions.Comment: 10 pages, 4 figures submitted to Phys. Lett.

Search for CP violation in K0 -> 3 pi0 decays

Using data taken during the year 2000 with the NA48 detector at the CERN SPS, a search for the CP violating decay K_S -> 3 pi0 has been performed. From a fit to the lifetime distribution of about 4.9 million reconstructed K0/K0bar -> 3 pi0 decays, the CP violating amplitude eta_000 = A(K_S -> 3 pi0)/A(K_L -> 3 pi0) has been found to be Re(eta_000) = -0.002 +- 0.011 +- 0.015 and Im(eta_000) = -0.003 +- 0.013 +- 0.017. This corresponds to an upper limit on the branching fraction of Br(K_S -> 3 pi0) < 7.4 x 10^-7 at 90% confidence level. The result is used to improve knowledge of Re(epsilon) and the CPT violating quantity Im(delta) via the Bell-Steinberger relation.Comment: 18 pages, 7 figures, submitted to Phys. Lett.

Measurement of the Ratio Gamma(KL -> pi+ pi-)/Gamma(KL -> pi e nu) and Extraction of the CP Violation Parameter |eta+-|

We present a measurement of the ratio of the decay rates Gamma(KL -> pi+ pi-)/Gamma(KL -> pi e nu), denoted as Gamma(K2pi)/Gamma(Ke3). The analysis is based on data taken during a dedicated run in 1999 by the NA48 experiment at the CERN SPS. Using a sample of 47000 K2pi and five million Ke3 decays, we find Gamma(K2pi)/Gamma(Ke3) = (4.835 +- 0.022(stat) +- 0.016(syst)) x 10^-3. From this we derive the branching ratio of the CP violating decay KL -> pi+ pi- and the CP violation parameter |eta+-|. Excluding the CP conserving direct photon emission component KL -> pi+ pi- gamma, we obtain the results BR(KL -> pi+ pi-) = (1.941 +- 0.019) x 10^-3 and |eta+-| = (2.223 +- 0.012) x 10^-3.Comment: 20 pages, 7 figures, accepted by Phys. Lett.

Identification of a founder BRCA2 mutation in Sardinia

Sardinian population can be instrumental in defining the molecular basis of cancer, using the identity-by-descent method. We selected seven Sardinian breast cancer families originating from the northern-central part of the island with multiple affected members in different generations. We genotyped 106 members of the seven families and 20 control nuclear families with markers flanking BRCA2 locus at 13q12–q13. The detection of a common haplotype shared by four out of seven families (60%) suggests the presence of a founder BRCA2 mutation. Direct sequencing of BRCA2 coding exons of patients carrying the shared haplotype, allowed the identification of a ‘frame-shift’ mutation at codon 2867 (8765delAG), causing a premature termination-codon. This mutation was found in breast cancer patients as well as one prostate and one bladder cancer patient with shared haplotype. We then investigated the frequency of 8765delAG in the Sardinian breast cancer population by analysing 270 paraffin-embedded normal tissue samples from breast cancer patients. Five patients (1.7%) were found to be positive for the 8765delAG mutation. Discovery of a founder mutation in Sardinia through the identity-by-descent method demonstrates that this approach can be applied successfully to find mutations either for breast cancer or for other types of tumours. © 2000 Cancer Research Campaig