Giordano Dicuonzo

Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients.

Purpose: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies. Experimental Design: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1 mg of ZA every week for four times (days 1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion. Results: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA. This effect on VEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after each ZA infusion. Conclusions: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.

Molecular Epidemiology and Distribution of Serotypes, Surface Proteins, and Antibiotic Resistance among Group B Streptococci in Italy

ABSTRACT Group B streptococci (GBS) comprising three different sets of isolates (31 invasive, 36 noninvasive, and 24 colonizing isolates) were collected in Italy during the years 2002 to 2005. Clonal groups were established by pulsed-field gel electrophoresis (PFGE), and selected isolates were studied by multilocus sequence typing (MLST). GBS isolates were also characterized by classical and molecular techniques for serotyping and protein gene and antibiotic resistance profiling. Some serotypes were significantly associated with a particular isolate population: serotype Ia more frequently corresponded to invasive strains than other strains, serotype V was more frequently encountered among noninvasive strains, and nontypeable strains were more common among isolates from carriers. Four major clonal groups accounted for 52.7% of all isolates: PFGE type 1/clonal complex 1 (CC1) comprised mainly serotype V isolates carrying the alp3 gene, PFGE type 2/CC23 encompassed serotype Ia isolates with the alp1 or alpha gene, PFGE type 3/CC17 comprised serotype III isolates carrying the rib gene, and PFGE type 4/CC19 consisted mainly of serotype II isolates possessing the rib gene. The same serotypes were shared by isolates of different clonal groups, and conversely, isolates belonging to the same clonal groups were found to be of different serotypes, presumably due to capsular switching by the horizontal transfer of capsular genes. Erythromycin resistance (prevalence, 16.5%; 15 resistant isolates of 91) was restricted to strains isolated from patients with noninvasive infections and carriers, while tetracycline resistance was evenly distributed (prevalence, 68.1%; 62 resistant isolates of 91). Most erythromycin-resistant GBS strains were of serotype V, were erm(B) positive, and belonged to the PFGE type 1/CC1 group, suggesting that macrolide resistance may have arisen both by clonal dissemination and by the horizontal transfer of resistance genes.

Fever After Zoledronic Acid Administration Is Due to Increase in TNF-α and IL-6

The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-α, interferon-γ (IFN-γ), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-α circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p < 0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to ...

Phenotypic and genotypic characterization of Stenotrophomonas maltophilia isolates from patients with cystic fibrosis: Genome diversity, biofilm formation, and virulence

BackgroundStenotrophomonas maltophilia is emerging as one of the most frequently found bacteria in cystic fibrosis (CF) patients. In the present study, phenotypic and genotypic traits of a set of 98 isolates of S. maltophilia obtained from clinical (CF and non-CF patients) and environmental sources were comparatively evaluated.ResultsS. maltophilia exhibited a high level of genomic diversity in both CF and non-CF group, thus possibly allowing this bacterium to expand its pathogenic potentials. Strains sharing the same pulsotype infected different patients, thus likely indicating the occurrence of clonal spread or acquisition by a common source. CF isolates differed greatly in some phenotypic traits among each other and also when compared with non-CF isolates, demonstrating increased mean generation time and susceptibility to oxidative stress, but reduced ability in forming biofilm. Furthermore, in CF isolates flagella- and type IV pili-based motilities were critical for biofilm development, although not required for its initiation. Sequential isogenic strains isolated from the same CF patient displayed heterogeneity in biofilm and other phenotypic traits during the course of chronic infection. CF and non-CF isolates showed comparable virulence in a mouse model of lung infection.ConclusionsOverall, the phenotypic differences observed between CF and non-CF isolates may imply different selective conditions and persistence (adaptation) mechanisms in a hostile and heterogeneous environment such as CF lung. Molecular elucidation of these mechanisms will be essential to better understand the selective adaptation in CF airways in order to design improved strategies useful to counteract and eradicate S. maltophilia infection.

Comparative evaluation of the Vitek-2 Compact and Phoenix systems for rapid identification and antibiotic susceptibility testing directly from blood cultures of Gram-negative and Gram-positive isolates.

We performed a comparative evaluation of the Vitek-2 Compact and Phoenix systems for direct identification and antimicrobial susceptibility testing (AST) from positive blood culture bottles in comparison to the standard methods. Overall, 139 monomicrobial blood cultures, comprising 91 Gram-negative and 48 Gram-positive isolates, were studied. Altogether, 100% and 92.3% of the Gram-negative isolates and 75% and 43.75% of the Gram-positive isolates showed concordant identification between the direct and the standard methods with Vitek and Phoenix, respectively. AST categorical agreements of 98.7% and 99% in Gram-negative and of 96.2% and 99.5% in Gram-positive isolates with Vitek and Phoenix, respectively, were observed. In conclusion, direct inoculation procedures for Gram-negative isolates showed an excellent performance with both automated systems, while for identification of Gram-positive isolates they proved to be less reliable, although Vitek provided acceptable results. This approach contributes to reducing the turnaround time to result of blood cultures, with a positive impact on patient care.

High Versus Standard Clopidogrel Maintenance Dose After Percutaneous Coronary Intervention and Effects on Platelet Inhibition, Endothelial Function, and Inflammation : Results of the ARMYDA-150 mg (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty) Randomized Study

OBJECTIVES This study was done to compare effects of high versus standard clopidogrel maintenance doses on platelet inhibition, inflammation, and endothelial function in patients undergoing percutaneous coronary intervention. BACKGROUND Previous data suggested that clopidogrel has various biological actions in addition to antiplatelet effects. METHODS Fifty patients were randomly assigned 1 month after intervention (T-0) to receive standard (75 mg/day; n = 25) or high (150 mg/day; n = 25) clopidogrel maintenance dose for 30 days (until T-1); at this time-point, cross-over was performed, and the assigned clopidogrel maintenance regimen was switched and continued for a further 30 days (until T-2). Platelet reactivity (expressed as P2Y(12) reaction units by the point-of-care VerifyNow assay [Accumetrics, San Diego, California]), endothelial function (evaluated by flow-mediated vasodilation), and high-sensitivity C-reactive protein levels were measured at T-0, T-1, and T-2. RESULTS Patients in the 150-mg/day arm had higher platelet inhibition (50 ± 20% vs. 31 ± 20% in the 75-mg/day group; p < 0.0001), better flow-mediated vasodilation (16.9 ± 12.6% vs. 7.9 ± 7.5%; p = 0.0001), and lower high-sensitivity C-reactive protein levels (3.6 ± 3.0 mg/l vs. 7.0 ± 8.6 mg/l; p = 0.016). Higher clopidogrel dose was associated with decreased proportion of patients with P2Y(12) reaction units ≥ 240 (12% vs. 32%; p = 0.001), flow-mediated vasodilation <7% (16% vs. 58%; p = 0.0003), and high-sensitivity C-reactive protein levels >3 mg/l (46% vs. 64%; p = 0.07). CONCLUSIONS For patients undergoing percutaneous coronary intervention, the 150-mg/day clopidogrel maintenance dose is associated with stronger platelet inhibition, improvement of endothelial function, and reduction of inflammation, compared with the currently recommended 75-mg/day regimen; those effects might have a role in the clinical benefit observed with clopidogrel and may provide the rationale for using the higher maintenance regimen in selected patients.

Neutralizing and Binding Antibodies to IFN-β: Relative Frequency in Relapsing-Remitting Multiple Sclerosis Patients Treated with Different IFN-β Preparations

The frequencies of anti-interferon-β (IFN-β) antibody development reported to date in patients treated with different IFN-β preparations are not readily comparable mainly because of differences in ...

Prognostic value of interleukin-1 receptor antagonist in patients undergoing percutaneous coronary intervention.

Elevated plasma levels of inflammatory markers, such as C-reactive protein (CRP), have been associated with adverse outcome in selected patients with coronary artery disease (CAD) treated with coronary angioplasty or stenting. The aim of this study was to evaluate the predictive value of preprocedural interleukin-1 receptor antagonist (IL-1Ra) plasma levels for long-term major adverse cardiac events (MACE) in a series of unselected patients with symptomatic CAD treated with percutaneous coronary intervention (PCI). Seventy-three consecutive patients (62 men, aged 62 +/- 9 years) undergoing PCI were enrolled in a prospective follow-up study. IL-1Ra and CRP plasma levels were measured before the procedure; 36 patients (49%) had unstable angina pectoris on admission, 37 (51%) had chronic stable angina pectoris, and 30 (41%) had multivessel CAD, 15 of whom underwent multivessel PCI. Success was achieved in all 73 patients, with coronary stenting performed in 63 (86%). Follow-up clinical assessment included occurrence of MACE at 3, 6, 12, and 18 months. Logistic regression analysis, performed to determine independent predictors of MACE, identified IL-1Ra levels in the upper quartile as the only independent predictive factor of MACE at 18 months (19% in the fourth quartile vs 0% in the first quartile; p = 0.032). Patients with high preprocedural CRP levels (fourth quartile) had a nonsignificant increased risk of MACE (p = 0.09). Thus, preprocedural IL-1Ra plasma levels appear to be a valuable independent predictive factor of MACE in unselected patients undergoing PCI.

Routine molecular identification of enterococci by gene-specific PCR and 16S ribosomal DNA sequencing.

ABSTRACT For 279 clinically isolated specimens identified by commercial kits as enterococci, genotypic identification was performed by two multiplex PCRs, one with ddlE. faecalis andddlE. faecium primers and another withvanC-1 and vanC-2/3 primers, and by 16S ribosomal DNA (rDNA) sequencing. For 253 strains, phenotypic and genotypic results were the same. Multiplex PCR allowed for the identification of 13 discordant results. Six strains were not enterococci and were identified by 16S rDNA sequencing. For 5 discordant and 10 concordant enterococcal strains, 16S rDNA sequencing was needed. Because many supplementary tests are frequently necessary for phenotypic identification, the molecular approach is a good alternative.

Group A Streptococcal Genotypes from Pediatric Throat Isolates in Rome, Italy

ABSTRACT In a study assessing genetic diversity, 114 group A streptococcus (GAS) isolates were recovered from pediatric pharyngitis patients in Rome, Italy. These isolates comprised 22 different M protein gene (emm) sequence types, 14 of which were associated with a distinct serum opacity factor/fibronectin binding protein gene (sof) sequence type. Isolates with the same emmgene sequence type generally shared a highly conserved chromosomal macrorestriction profile. In three instances, isolates with dissimilar macrorestriction profiles had identical emm types; in each of these cases multilocus sequence typing revealed that isolates with the same emm type were clones having the same allelic profiles. Ninety-eight percent of the pharyngeal isolates hademm types previously found to be highly associated withmga locus gene patterns commonly found in pharyngeal GAS isolates.