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Baldanti F.,Virology Unit | Baldanti F.,Experimental Research Laboratory | Paolucci S.,Virology Unit | Gulminetti R.,Experimental Research Laboratory | And 4 more authors.
Journal of Medical Virology | Year: 2010

The emergence of drug-resistance mutations in HIV-1 integrase of patients receiving HAART salvage regimens including raltegravir was investigated in 11 heavily pretreated patients (median number of treatment failures 12, range 5-22) within an expanded access program in Pavia, Italy. HIV-1 RNA levels in plasma, CD4 + T-cell counts and sequencing of HIV-1 reverse transcriptase (RT), protease (PR), gp41, and integrase geneswere performed at baseline and after 1, 2, 3, 6, and 12months. The treatment baseline median HIV-1 RNA levels in plasma decreased from 7,510 (range118-407,107) to<50 copies/ml (range< 50-7,562), while median CD4 + T-cell counts remained unchanged (from 212 cells/ml, range 10-764 to 262 cells/μl, range 13-760). Mutations at positions involved in raltegravir resistance (E92G, G140S, Q148H, and N155H) were detected in 4 of 11 (36.3%) patients as early as 1month after initiating salvage HAART. Of note, the E→G change at codon 92 was not reported previously. In two patients with raltegravir resistance, the simultaneous appearance of additionalmutations (Y143R and E170A) with an unclear impact on susceptibility to raltegravir or on integrase activity was observed. It is concluded that raltegravir resistant HIV-1 strains may emerge as early as 1month after initiating HAART salvage regimens. A newmutation associated with the emergence of raltegravir resistance is described, and the simultaneous appearance of primary and secondary mutations was observed. The effect of single and multiple mutations on integrase activity, raltegravir susceptibility, and on the capacity of viral replication remains to be elucidated. © 2009 Wiley-Liss, Inc.


Dragoni S.,University of Pavia | Laforenza U.,University of Pavia | Bonetti E.,Center for the Study of Myelofibrosis | Lodola F.,University of Pavia | And 7 more authors.
Stem Cells and Development | Year: 2013

Endothelial colony-forming cells (ECFCs) are the only endothelial progenitor cells (EPCs) that are capable of acquiring a mature endothelial phenotype. ECFCs are mainly mobilized from bone marrow to promote vascularization and represent a promising tool for cell-based therapy of severe ischemic diseases. Vascular endothelial growth factor (VEGF) stimulates the proliferation of peripheral blood-derived ECFCs (PB-ECFCs) through oscillations in intracellular Ca2+ concentration ([Ca2+]i). VEGF-induced Ca2+ spikes are driven by the interplay between inositol-1,4,5-trisphosphate (InsP3)-dependent Ca2+ release and store-operated Ca2+ entry (SOCE). The therapeutic potential of umbilical cord blood-derived ECFCs (UCB-ECFCs) has also been shown in recent studies. However, VEGF-induced proliferation of UCB-ECFCs is faster compared with their peripheral counterpart. Unlike PB-ECFCs, UCB-ECFCs express canonical transient receptor potential channel 3 (TRPC3) that mediates diacylglycerol-dependent Ca2+ entry. The present study aimed at investigating whether the higher proliferative potential of UCB-ECFCs was associated to any difference in the molecular underpinnings of their Ca 2+ response to VEGF. We found that VEGF induces oscillations in [Ca2+]i that are patterned by the interaction between InsP3-dependent Ca2+ release and SOCE. Unlike PB-ECFCs, VEGF-evoked Ca2+ oscillations do not arise in the absence of extracellular Ca2+ entry and after pharmacological (with Pyr3 and flufenamic acid) and genetic (by employing selective small interference RNA) suppression of TRPC3. VEGF-induced UCB-ECFC proliferation is abrogated on inhibition of the intracellular Ca2+ spikes. Therefore, the Ca 2+ response to VEGF in UCB-ECFCs is shaped by a different Ca 2+ machinery as compared with PB-ECFCs, and TRPC3 stands out as a promising target in EPC-based treatment of ischemic pathologies. © Mary Ann Liebert, Inc.


Regazzi M.,Foundation IRCCS Policlinico San Matteo | Billaud E.M.,University of Paris Descartes | Lefeuvre S.,University of Paris Descartes | Stronati M.,Neonatal Intensive Care Unit
Current Medicinal Chemistry | Year: 2012

The prevention and treatment of pediatric fungal infections are limited by the fact that not all antifungal drugs are approved for the pediatric age and appropriate dosages have not been established for each age group. The management of neonates and infants with invasive fungal infection is becoming more complex with an increasing number of antifungal agents available. Dosing information, is not available for newer antifungals and is limited with older antifungal agents. Insufficient neonatal studies have been performed with newer agents and there are numerous differences between neonates, children and adults with invasive fungal infection. Kinetic parameters such as the half-life [t1/2], clearance [CL], and volume of distribution [Vd] change with development, therefore the kinetics of antifungals need to be studied in order to optimize therapy with these drugs. A reasonable aim of pediatric dosing is to ensure levels of drug exposure which are comparable to those achievable in adults and which approximate those for which antifungal efficacy has been established. Therefore it will be of clinical relevance to ascertain the dosages of antifungals which produce an equivalent magnitude of exposure to that observed in adults. Drug therapy, studies on prescription and dosing should consider differences between neonates, infants and toddlers, children and adolescents in terms of drug disposition: absorption, metabolism and elimination/excretion. Determining the safety and pharmacokinetics of antifungals in neonates addresses an unfulfilled medical need given that data are sparse in neonates; at present, reports of antifungal pharmacokinetics in the treatment of neonatal fungal infections are limited to case series. The aim of this article is to review the pharmacokinetics of old and new antifungal drugs in neonates and young infants in a single article in order to provide a critical analysis of the literature. It will be important to evaluate all newly developed antifungals in neonates and infants to assure their maximum efficacy and safety. More pharmacokinetic data are required to ensure that the dose recommended for the treatment of fungal infections in the neonate achieves evidence based medicine. © 2012 Bentham Science Publishers.


Antoniazzi E.,Foundation IRCCS Policlinico San Matteo | Pezzotta S.,Foundation IRCCS Policlinico San Matteo | Delfino A.,Foundation IRCCS Policlinico San Matteo | Bianchi P.E.,Foundation IRCCS Policlinico San Matteo
European Journal of Ophthalmology | Year: 2010

PURPOSE. Laser iridotomy is the standard first-line intervention in both acute and chronic forms of angle closure because it prevents the recurrence of acute attacks and virtually eliminates the risk of an acute attack in the fellow eye. Pentacam is a new imaging modality which does not require probe contact or an immersion bath. The instrument will allow anterior segment morphology before and after laser peripheral iridotomy (LPI) to be quantified. The aim of the study is to evaluate the objective difference in changes of anterior chamber morphology after LPI with Pentacam. METHODS. Twenty eyes with a high risk of angle closure were evaluated with Pentacam rotating Scheimpflug camera before and after LPI. We measured anterior chamber volume, anterior chamber depth, and chamber angle before and after laser treatment. RESULTS. Statistically significant difference before and after LPI was noted in all anterior chamber measurements except central anterior chamber depth. CONCLUSIONS. This study confirms previous reports of increased anterior chamber volume and angle after LPI and Pentacam is a good objective instrument to demonstrate the efficacy of LPI. © 2010 Wichtig Editore.


Bozzani A.,Foundation Irccs Policlinico San Matteo | Arici V.,Foundation Irccs Policlinico San Matteo | Ragni F.,Foundation Irccs Policlinico San Matteo
Vascular and Endovascular Surgery | Year: 2013

Aortic coarctation (CoA) is the fifth most common congenital heart defect, accounting for 6% to 8% of live births with congenital heart disease. Traditional treatment for CoA consists of open surgical repair, and the endovascular procedures have been proposed as an alternative treatment. We describe the case of a 50-year-old man presented to our department with mild lower limbs claudication and hypertension. The computed tomography scan diagnosed an aortic postductal coarctation, which we treated with aortoplasty with Dacron patch. The open surgery, in our opinion, is nowadays still preferable due to the time-stable and effective outcome. © The Author(s) 2013.


Crimi G.,Foundation IRCCS Policlinico San Matteo | Leonardi S.,Foundation IRCCS Policlinico San Matteo | Costa F.,Erasmus University Rotterdam | Ariotti S.,Erasmus University Rotterdam | And 3 more authors.
Catheterization and Cardiovascular Interventions | Year: 2015

Background Contrast-induced acute kidney injury (CI-AKI) is associated with poor outcome. Whether this association differs in stable coronary artery disease (CAD) as compared to acute coronary syndrome (ACS) patients is unknown. Definitions and Methods: PRODIGY trial patients were defined as stable CAD or ACS according to the initial presentation. CI-AKI was defined as an increase (Δ) of serum creatinine (SCr) ≥25% above baseline. Two endpoints were considered: all-cause death and the composite of death, stroke, or myocardial infarction (MI). The interaction between CI-AKI, clinical setting, and the impact of increasing ΔSCr% cut-offs were also explored. Results Two thousand three patients were enrolled in the PRODIGY trial, 85 patients were excluded for missing SCr data, leading to a population of 1,918 patients. CI-AKI incidence was 6.7% in stable CAD and 12.2% in ACS patients. CI-AKI was associated with all-cause mortality [adjusted hazard ratio (aHR) of 2.05, 95% confidence interval (CI) 1.38-3.05, P<0.001] and the composite of death, stroke, or MI [aHR of 1.49, 95% CI 1.13-1.97, P<0.001]. The risk of CI-AKI for the composite endpoint was higher in stable CAD, P for interaction: 0.048. A ΔSCr of 35% was associated with the highest aHR for all-cause mortality: 2.34 [95% CI, 1.46-3.76, P<0.001] and the composite of death, stroke, or MI: 1.70 [95% CI, 1.20-2.40, P>0.001]. Conclusions In a large, contemporary, all-comers percutaneous coronary intervention population, CI-AKI was associated with an increased risk of all-cause death and the composite of death, stroke, or MI. While CI-AKI is more common in ACS than in stable CAD patients, its adjusted prognostic impact on the composite endpoint appears to be more pronounced in patients with stable CAD. © 2015 Wiley Periodicals, Inc.


Bozzani A.,Foundation Irccs Policlinico San Matteo | Arici V.,Foundation Irccs Policlinico San Matteo | Ragni F.,Foundation Irccs Policlinico San Matteo | Sagrada P.F.,Ospedale Maggiore di Lodi
Annals of Vascular Surgery | Year: 2014

Carotid body tumor (CBT) is the most common of the head and neck paragangliomas (PGLs). Conversely, synovial sarcomas are usually located around knee and ankle joint and rare variants occur in the oral cavity. A 68-year-old man presented with a left voluminous painless cervical mass. The diagnosis of CBT of type III Shamblin was suspected. The cervical mass was removed en bloc. Unexpectedly, pathologic examination showed monophasic synovial sarcoma. Excision of PGLs remains the therapy of choice, especially to make a correct histologic diagnosis. © 2014 by Elsevier Inc. All rights reserved.


Borghesi A.,Foundation IRCCS Policlinico San Matteo
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians | Year: 2011

Severe infections represent the main cause of neonatal mortality and morbidity. Strategies of proven effectiveness in reducing the incidence of infection in neonatal intensive care units (NICUs) include hand hygiene practices and prevention of central venous catheter-related bloodstream infections. In recent years, new strategies have been developed to prevent infections in NICU including prevention of neonatal sepsis with lactoferrin, the use of heparin for the prevention of CRBSIs, the judicious use of antibiotics and chemoprophylaxis, prevention of invasive fungal infections with fluconazole, the use of specific anti-staphylococcal immunoglobulins, and the early identification of infants at higher risk of infection with the use of specific markers (mannose-binding lectin). This review will focus on these new strategies and on their role in clinical practice in order to further reduce the incidence of infection in NICU.


Regazzi M.,Foundation IRCCS Policlinico San Matteo | Carvalho A.C.,University of Brescia | Carvalho A.C.,Oswaldo Cruz Foundation | Villani P.,Foundation IRCCS Policlinico San Matteo | Matteelli A.,University of Brescia
Clinical Pharmacokinetics | Year: 2014

Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-rifampicin, rifabutin, and rifapentine-with antiretroviral drugs are reviewed and discussed. A rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co-infected patients whenever efavirenz cannot be used and rifabutin is not available. Despite significant pharmacokinetic interactions between antiretrovirals and antitubercular drugs, adequate clinical response of both infections can be achieved with an acceptable safety profile when the pharmacological characteristics of drugs are known, and appropriate combination regimens, dosing, and timing of initiation are used. However, more clinical research is needed for newer drugs, such as rifapentine and the recently introduced integrase inhibitor antiretrovirals, and for specific population groups, such as children, pregnant women, and patients affected by multidrug-resistant TB. © 2014 Springer International Publishing.


Arici V.,Foundation Irccs Policlinico San Matteo | Bozzani A.,Foundation Irccs Policlinico San Matteo | Odero A.,Foundation Irccs Policlinico San Matteo
Annals of Vascular Surgery | Year: 2013

Bronchial artery aneurysm (BAA) is a rare entity, detected in <1% of all patients who undergo selective bronchial arteriography. BAAs are potentially life-threatening when untreated. We describe the first BAA case, in the English language, treated only by thoracic aorta endografting, with an uneventful postoperative course with exclusion and thrombosis of the BAA. The endovascular stent graft provides a safe, reliable tool complementing the armamentarium of surgical and percutaneous techniques in the treatment of patients with BAA. © 2013 Elsevier Inc. All rights reserved.

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