Z Boson Decay into Light and Darkness.

We study the Z→γγ[over ¯] process in which the Z boson decays into a photon γ and a massless dark photon γ[over ¯], when the latter couples to standard-model fermions via dipole moments. This is a simple yet nontrivial example of how the Landau-Yang theorem-ruling out the decay of a massive spin-1 particle into two photons-is evaded if the final particles can be distinguished. The striking signature of this process is a resonant monochromatic single photon in the Z-boson center of mass together with missing momentum. LEP experimental bounds allow a branching ratio up to about 10^{-6} for such a decay. In a simplified model of the dark sector, the dark-photon dipole moments arise from one-loop exchange of heavy dark fermions and scalar messengers. The corresponding prediction for the rare Z→γγ[over ¯] decay width can be explored with the large samples of Z bosons foreseen at future colliders.

Saccharomyces cerevisiae-based probiotic as novel anti-fungal and anti-inflammatory agent for therapy of vaginal candidiasis.

Previously we demonstrated that the treatment with live Saccharomyces cerevisiae exerts beneficial therapeutic effects against vaginal candidiasis. Here, we address potential mechanisms particularly examining the probiotic capacity to modulate both fungus and host-related factors. We show that the S. cerevisiae-based probiotic markedly affects the expression of virulence traits of Candida albicans such as aspartyl proteinases (SAPs) as well as hyphae-associated proteins Hwp1 and Ece1 in the vaginal cavity. On the host side, the probiotic suppression of the influx of neutrophils caused by the fungus into the vaginas of the mice is likely related to: (1) lower production of interleukin-8; and (2) inhibition of SAPs expression. However, these neutrophils displayed reactive oxygen species hyperproduction and increased killing activity as compared to the neutrophils of placebo-treated mice. There was no evidence of any cytotoxic effect by the probiotic, either when used in vivo on vaginal epithelial cell and organ architecture, or in in vitro in human vaginal epithelium. Inactivated yeast cells did not affect any of the factors above. In summary, the data suggest that the beneficial effect exerted by this S. cerevisiae-based probiotic is the result of its interference with the expression of fungus virulence factors coupled with the modulation of the inflammatory response of the host.

Hunting Down Massless Dark Photons in Kaon Physics.

If dark photons are massless, they couple to standard-model particles only via higher dimensional operators, while direct (renormalizable) interactions induced by kinetic mixing, which motivates most of the current experimental searches, are absent. We consider the effect of possible flavor-changing magnetic-dipole couplings of massless dark photons in kaon physics. In particular, we study the branching ratio for the process K^{+}→π^{+}π^{0}γ[over ¯] with a simplified-model approach, assuming the chiral quark model to evaluate the hadronic matrix element. Possible effects in the K^{0}-K[over ¯]^{0} mixing are taken into account. We find that branching ratios up to O(10^{-7}) are allowed-depending on the dark-sector masses and couplings. Such large branching ratios for K^{+}→π^{+}π^{0}γ[over ¯] could be of interest for experiments dedicated to rare K^{+} decays like NA62 at CERN, where γ[over ¯] can be detected as a massless invisible system.

Observational study to evaluate the impact of internet reminders for GPs on colorectal cancer screening uptake in Northern Italy in 2013.

INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer worldwide and CRC-related mortality can be effectively reduced by population-based screening. Screening uptake is a key indicator of performance, susceptible of several implementation methods. Participation in ASL Milano 1 area (northern Italy) is increasing thanks to reminder invitation sent to non-responders. Here we evaluate the implementation of another strategy among those proved to be effective. METHODS: In the years 2013-2014 we conducted an observational study in patients non-responder to first invitation and subsequent mailed reminder. A list of them was sent to their own GP, who had the task to evaluate possible exclusion criteria and make a reminder, either by personal interview, telephone call or via e-mail. Intervention could be conducted either by the GP himself or by an assistant. Primary outcomes were to assess the overall efficacy of the intervention and the efficacy of its single features (type of intervention and provider), measuring the consequent uptake of CRC screening. RESULTS: Participation in CRC screening was significantly higher (33,5%) in patients who received a reminder from GP, regardless of the type, vs those who did not (19,0%, p < 0.01). No statistically significant difference was detected either by method or by provider of the intervention. DISCUSSION: The results of our study demonstrate that even a modest intervention can have a significant effect in improving compliance to screening for CRC, one of the cancers with highest incidence in developed countries, for which an effective treatment is available in case of early diagnosis.

A Simplified HAART Regimen with Raltegravir and Lamivudine, and Pharmacokinetic Interactions with a Combined Immunosuppressive Therapy with Tacrolimus and Everolimus in an HIV/HCV/HBV/HDV Patient after Liver Transplantation.

In this case report, we examine the impact of a simplified two-drug highly active antiretroviral therapy (HAART) regimen of raltegravir and lamivudine in a patient co-infected with human immunodeficiency virus (HIV) and hepatitis C, D and B viruses (HCV/HDV/HBV) under immunosuppressive therapy after liver transplantation. Pharmacokinetic interactions between integrase inhibitors and immunosuppressant drugs are described. Raltegravir, the first integrase inhibitor, associated with lamivudine, was introduced because its metabolism does not interfere with immunosuppressant therapy. During post-orthotopic liver transplantation follow-up, the patient's transaminases level increased and his antiretroviral therapy (HAART) of tenofovir/emtricitabine and fosamprenavir was changed, due to suspected drug toxicity. After seven months of follow-up, the patient showed good tolerance, good viro-immunological control with undetectable HIV viraemia and stable concentrations of immunosuppressive drugs. This case indicates that the combination of raltegravir and lamivudine is an optimal and effective strategy because it resulted in an important reduction of hepatic transaminases in a patient with very critical clinical conditions.

Osteomyelitis caused by Aspergillus species: a review of 310 reported cases.

Aspergillus osteomyelitis is a rare infection. We reviewed 310 individual cases reported in the literature from 1936 to 2013. The median age of patients was 43 years (range, 0-86 years), and 59% were males. Comorbidities associated with this infection included chronic granulomatous disease (19%), haematological malignancies (11%), transplantation (11%), diabetes (6%), pulmonary disease (4%), steroid therapy (4%), and human immunodeficiency virus infection (4%). Sites of infection included the spine (49%), base of the skull, paranasal sinuses and jaw (18%), ribs (9%), long bones (9%), sternum (5%), and chest wall (4%). The most common infecting species were Aspergillus fumigatus (55%), Aspergillus flavus (12%), and Aspergillus nidulans (7%). Sixty-two per cent of the individual cases were treated with a combination of an antifungal regimen and surgery. Amphotericin B was the antifungal drug most commonly used, followed by itraconazole and voriconazole. Several combination or sequential therapies were also used experimentally. The overall crude mortality rate was 25%.

A purified capsular polysaccharide markedly inhibits inflammatory response during endotoxic shock.

Capsular material of the opportunistic fungus Cryptococcus neoformans is composed mainly of a polysaccharide named glucuronoxylomannan (GXM). In this study, the effects of GXM were analyzed in an in vivo experimental system of lipopolysaccharide (LPS)-induced shock. Endotoxic shock was induced in mice by a single intraperitoneal injection of LPS from Escherichia coli. GXM treatment reduced the mortality of mice at early stages. Mice treated with LPS alone showed markedly increased plasma levels of tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6, whereas mice that were also treated with GXM showed significantly lower plasma levels of these cytokines. This effect was related to a marked suppression of Akt and IκBα activation. Importantly, the inhibitory effect of GXM on proinflammatory cytokine secretion was reproduced by treatment with wortmannin, an inhibitor of the Akt transcription pathway. Our results indicate that GXM has a beneficial effect on endotoxic shock, resulting in a significant increase in the rate of survival by dampening the hyperinflammatory response.

Sustained increase of serum creatine phosphokinase levels and progressive muscle abnormalities associated with raltegravir use during 32-week follow-up in an HIV-1 experienced patient on simplified HAART regimen, intolerant to protease inhibitors and abacavir: a case report.

Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and penicillin during 32 weeks of continuous drug monitoring.

Sustained increase of serum creatine phosphokinase levels and progressive muscle abnormalities associated with raltegravir use during a 32-week follow-up in an HIV-1 experienced patient on simplified HAART regimen, intolerant to protease inhibitors and abacavir: a case report / Aumento sostenido de los niveles de creatina fosfoquinasa sérica y las anormalidades musculares progresivas asociadas con el uso de raltegravir durante un seguimiento de 32 semanas en un paciente de VIH-1 experimentado en régimen de terapia TAAA simplificada, con intolerancia a los inhibidores de proteasa y abacavir: un reporte de caso

Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and pencillin during 32 weeks of continuous drug monitoring.

Un aumento sostenido de las concentraciones de creatina fosfoquinasa sérica (CPK) y las anormalidades musculares ha sido reportado en relación con pacientes que toman raltegravir (RAL). En este reporte, describimos un caso de aumento sostenido y asintomático de concentraciones séricas de CPK asociadas con raltegravir, zidovudina y lamivudina en un paciente experimentado de VIH-1 con intolerancia al inhibidor de la proteasa, al abacavir y la penicilina durante 32 semanas de monitoreo farmacológico continuo.

In vitro activity of the lipopeptide PAL-Lys-Lys-NH2, alone and in combination with antifungal agents, against clinical isolates of Candida spp.

Candida albicans is known to be the organism most often associated with serious fungal infection, but other Candida spp. are emerging as clinical pathogens associated with opportunistic infections. Among antimycotic treatments, increasing attention is currently given to anti-infective drugs based upon naturally occurring peptides, such as the short lipopeptide palmitoyl PAL-Lys-Lys-NH2 (PAL). The aim of this study is to evaluate the activity of this peptide compared to the traditional antifungal agents Fluconazole (FLU), amphotericin B (AMB) and caspofungin (CAS) on Candida spp. 24 clinical isolates of Candida spp. were tested against PAL, FLU, AMB and CAS using in vitro susceptibility tests, time killing and checkerboard assay. All of the drugs studied showed good activity against clinical isolates of candida; in particular CAS and AMB which have MICs value lower than PAL and FLU. Moreover we observed synergistic interactions for PAL/FLU (81.25%), PAL/AMB (75%) and particularly for PAL/CAS (87.5). We think that our results are interesting since synergy between PAL and CAS might be useful in clinic trails to treat invasive fungal infections.

Daptomycin and rifampin alone and in combination prevent vascular graft biofilm formation and emergence of antibiotic resistance in a subcutaneous rat pouch model of staphylococcal infection.

OBJECTIVE: To investigate the efficacy of daptomycin and rifampin either alone or in combination in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. DESIGN: Prospective, randomised, controlled animal study. MATERIALS: Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2×10(7) colony forming units of Staphylococcus aureus, strain Smith diffuse. METHODS: The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis and three contaminated groups that received intra-peritoneal daptomycin, rifampin-soaked graft and daptomycin plus rifampin-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro antibiotic susceptibility assay for S. aureus biofilms was performed to elucidate the same activity. RESULTS: When tested alone, daptomycin and rifampin showed good efficacies. Their combination showed efficacies significantly higher than that of each single compound. The in vitro studies showed that minimum inhibitory concentration and minimum bactericidal concentration values for daptomycin were lower in presence of rifampin. Daptomycin prevented the emergence of rifampin resistance. CONCLUSION: Daptomycin is an important candidate for prevention of staphylococcal biofilm-related infection and rifampin could serve as an interesting anti-staphylococcal antibiotic enhancer.

In vitro activity of Tachyplesin III alone and in combination with terbinafine against clinical isolates of dermatophytes.

Aim of our study was to investigate the in vitro effects of Tachyplesin III (TP), a potent disulfide-linked peptide, in dermatophytes infections, with respect to or in combination with terbinafine (TERB), against 20 clinical isolates of dermatophytes belonging to four species. A broth microdilution method following the CLSI recommendations (M38-A) was used for testing drugs alone and in combination. TERB MICs were significantly lower than those observed for TP (p<0.001). Testing for antifungal agents in combination was performed for TERB with TP for all the 20 isolates. TERB activity in combination with TP showed indifferent activity for 14 of the 20 isolates (70%); synergic activity for 6 of the 20 isolates (30%); no antagonistic activity was observed. Further experiments were conducted with Microsporum canis 133, Trichophyton rubrum 62 and Trichophyton mentagrophytes 91 for fungal biomass. TP and TERB did not show a significant growth reduction compared to the control against T. mentagrophytes and T. rubrum. A significant difference of growth reduction both for TP and TERB compared to controls was observed for M. canis (p<0.01). In conclusion our study demonstrated that Tachyplesin III has potential activity against dermatophytes. In addition, we observed that the in vitro activity of Tachyplesin III can be enhanced upon combination with terbinafine. Synergy could permit lower doses of the individual antifungal agents to be used more effectively and/or safely.

In vitro activity of the lipopeptide derivative (Pal-Lys-Lys-NH), alone and in combination with antifungal agents, against clinical isolates of dermatophytes.

BACKGROUND: An increasing number of antimycotics have become available for the treatment of dermatophytoses; however, there are reports suggesting recalcitrance to therapy or resistance of a dermatophyte against conventional treatment. Lipopeptides represent novel therapeutic drugs with a new mode of action. OBJECTIVES: The aim of this study was to investigate the in vitro effects of the lipopeptide Pal-Lys-Lys-NH(2) (PAL) alone and in combination with standard antifungal agents, such as fluconazole (FLU), itraconazole (ITRA) and terbinafine (TER) against 24 clinical isolates of dermatophytes belonging to four species. METHODS: A broth microdilution method following the Clinical and Laboratory Standards Institute recommendations (M38-A) was used for testing drugs alone and in combination. RESULTS: PAL minimum inhibitory concentrations (MICs) ranged from < or = 0.25 to > 16 microg mL(-1) and they were similar to those of FLU and higher than those of either ITRA or TER. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or = 0.50, was observed in 67%, 52% and 15% of PAL/ITRA, PAL/TER and PAL/FLU interactions, respectively. None of these combinations yielded antagonistic interactions (FIC index > 4). When synergy was not achieved, there was still a decrease in the MIC of one or both drugs used in the combination. CONCLUSIONS: Our study demonstrates that PAL has potential activity against dermatophytes. In addition, the in vitro activity of PAL can be enhanced upon combination with standard drugs. This lipopeptide applied in the form of lacquer, spray or ointment, could represent an interesting new therapy, particularly when combined with conventional treatment in recalcitrant or resistant dermatophyte infections.