Showing papers by "University of Siena published in 2013"

Observation of a new boson with mass near 125 GeV in pp collisions at $ \sqrt{s}=7 $ and 8 TeV

Abstract: A detailed description is reported of the analysis used by the CMS Collaboration in the search for the standard model Higgs boson in pp collisions at the LHC, which led to the observation of a new boson. The data sample corresponds to integrated luminosities up to 5.1 inverse femtobarns at sqrt(s) = 7 TeV, and up to 5.3 inverse femtobarns at sqrt(s) = 8 TeV. The results for five Higgs boson decay modes gamma gamma, ZZ, WW, tau tau, and bb, which show a combined local significance of 5 standard deviations near 125 GeV, are reviewed. A fit to the invariant mass of the two high resolution channels, gamma gamma and ZZ to 4 ell, gives a mass estimate of 125.3 +/- 0.4 (stat) +/- 0.5 (syst) GeV. The measurements are interpreted in the context of the standard model Lagrangian for the scalar Higgs field interacting with fermions and vector bosons. The measured values of the corresponding couplings are compared to the standard model predictions. The hypothesis of custodial symmetry is tested through the measurement of the ratio of the couplings to the W and Z bosons. All the results are consistent, within their uncertainties, with the expectations for a standard model Higgs boson.

Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review

Abstract: OBJECTIVE: To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review. METHODS: The response to treatment was studied in a web-based registry in which clinical information on anonymised patients with autoinflammatory diseases was collected retrospectively as part of the Eurofever initiative. Participating hospitals included paediatric rheumatology centres of the Paediatric Rheumatology International Trial Organisation network and adult centres with a specific interest in autoinflammatory diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12-related periodic fever and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Cases were independently validated by experts for each disease. A literature search regarding treatment of the abovementioned diseases was also performed using Medline and Embase. RESULTS: 22 months from the beginning of the enrolment, complete information on 496 validated patients was available. Data from the registry in combination with evidence from the literature confirmed that colchicine is the treatment of choice for FMF and IL-1 blockade for DIRA and CAPS. Corticosteroids on demand probably represent a valid therapeutic strategy for PFAPA, but also for MKD and TRAPS. Patients with poorly controlled MKD, TRAPS, PAPA or FMF may benefit from IL-1 blockade; anti-TNF treatment may represent a possible valuable alternative. CONCLUSIONS: In the absence of high-grade evidence, these results could serve as a basis for therapeutic guidelines and to identify candidate drugs for future therapeutic trials.

Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial

Abstract: Summary Background Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4) have therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety, and immunological activity of the anti-CTLA4 monoclonal antibody, tremelimumab, in advanced malignant mesothelioma. Methods In our open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or older with measurable, unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. Patients received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Analyses were done according to intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and ClinicalTrials.gov, number NCT01649024. Findings Between May 27, 2009, and Jan 10, 2012, we enrolled 29 patients. All patients received at least one dose of tremelimumab (median two doses, range one to nine). No patients had a complete response and two patients (7%) had a durable partial response (one lasting 6 months and one lasting 18 months); one partial response occurred after initial progressive disease. Thus, the study did not reach its primary endpoint. However, we noted disease control in nine (31%) patients and a median progression-free survival of 6·2 months (95% CI 1·3–11·1) and a median overall survival of 10·7 months (0·0–21·9). 27 patients (93%) had at least one grade 1–2 treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or diarrhoea), and four patients (14%) had at least one grade 3–4 treatment-emergent adverse event (two gastrointestinal, one neurological, two hepatic, and one pancreatic). Interpretation Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma. Funding Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.

In Vivo Emergence of Colistin Resistance in Klebsiella pneumoniae Producing KPC-Type Carbapenemases Mediated by Insertional Inactivation of the PhoQ/PhoP mgrB Regulator

Abstract: Colistin is one of the few agents that retain activity against extensively drug-resistant strains of Klebsiella pneumoniae producing KPC-type carbapenemases (KPC-KP). However, resistance to colistin is increasingly reported among KPC-KP. Comparative genomic analysis of a pair of sequential KPC-KP isolates from the same patient including a colistin-susceptible isolate (KKBO-1) and a colistin-resistant isolate (KKBO-4) selected after colistin exposure revealed that insertional inactivation of the mgrB gene, encoding a negative regulator of the PhoQ/PhoP signaling system, is a genetic mechanism for acquired colistin resistance. The role of mgrB inactivation in acquired colistin resistance was confirmed by complementation experiments with wild-type mgrB, which restored colistin susceptibility in KKBO-4, and by construction of an mgrB deletion mutant from KKBO-1, which exhibited a colistin-resistant phenotype. Insertional mgrB inactivation was also detected in 60% of colistin-resistant mutants selected from KKBO-1 in vitro, following plating on colistin-containing medium, confirming the role (although not unique) of this mechanism in the emergence of acquired colistin resistance. In colistin-resistant mutants carrying insertional inactivation or deletion of the mgrB gene, upregulated transcription of phoP, phoQ, and pmrK (which is part of the pmrHFIJKLM operon) was detected. These findings confirmed the MgrB regulatory role in K. pneumoniae and were in agreement with the known association between upregulation of the PhoQ/PhoP system and activation of the pmrHFIJKLM operon, which eventually leads to resistance to polymyxins by modification of the lipopolysaccharide target.

Searches for long-lived charged particles in pp collisions at sqrt(s) = 7 and 8 TeV

Abstract: Results of searches for heavy stable charged particles produced in pp collisions at sqrt(s) = 7 and 8 TeV are presented corresponding to an integrated luminosity of 5.0 inverse femtobarns and 18.8 inverse femtobarns, respectively. Data collected with the CMS detector are used to study the momentum, energy deposition, and time-of-flight of signal candidates. Leptons with an electric charge between e/3 and 8e, as well as bound states that can undergo charge exchange with the detector material, are studied. Analysis results are presented for various combinations of signatures in the inner tracker only, inner tracker and muon detector, and muon detector only. Detector signatures utilized are long time-of-flight to the outer muon system and anomalously high (or low) energy deposition in the inner tracker. The data are consistent with the expected background, and upper limits are set on the production cross section of long-lived gluinos, scalar top quarks, and scalar tau leptons, as well as pair produced long-lived leptons. Corresponding lower mass limits, ranging up to 1322 GeV for gluinos, are the most stringent to date.

Drug-Eluting Balloon in Peripheral Intervention for Below the Knee Angioplasty Evaluation (DEBATE-BTK) A Randomized Trial in Diabetic Patients With Critical Limb Ischemia

Abstract: Background—The 1-year restenosis rate after balloon angioplasty of long lesions in below-the-knee arteries may be as high as 70%. Our aim was to investigate the efficacy of a paclitaxel drug-eluting balloons versus conventional percutaneous transluminal angioplasty (PTA) for the reduction of restenosis in diabetic patients with critical limb ischemia undergoing endovascular intervention of below-the-knee arteries. Methods and Results—The Drug-Eluting Balloon in Peripheral Intervention for Below the Knee Angioplasty Evaluation (DEBATE-BTK) is a randomized, open-label, single-center study comparing drug-eluting balloons and PTA. Inclusion criteria were diabetes mellitus, critical limb ischemia (Rutherford class 4 or higher), significant stenosis or occlusion >40 mm of at least 1 below-the-knee vessel with distal runoff, and life expectancy >1 year. Binary in-segment restenosis at a 1-year angiographic or ultrasonographic follow-up was the primary end point. Clinically driven target lesion revascularization,...

Brain atrophy and lesion load predict long term disability in multiple sclerosis

Abstract: Objective To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS). Design From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1–2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing–remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0–3.5, n=111) or moderately impaired (EDSS=4–6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores. Results In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R 2 =0.74 in the whole group and R 2 =0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R 2 =0.68), lesion volumes in moderately impaired relapse onset patients (R 2 =0.21) and whole brain atrophy in primary progressive MS (R 2 =0.34). Conclusions This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.

Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update

Abstract: Context: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients. Evidence Acquisition: We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin. Evidence Synthesis: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confo...

Towards Wearability in Fingertip Haptics: A 3-DoF Wearable Device for Cutaneous Force Feedback

Abstract: Wearability will significantly increase the use of haptics in everyday life, as has already happened for audio and video technologies. The literature on wearable haptics is mainly focused on vibrotactile stimulation, and only recently, wearable devices conveying richer stimuli, like force vectors, have been proposed. This paper introduces design guidelines for wearable haptics and presents a novel 3-DoF wearable haptic interface able to apply force vectors directly to the fingertip. It consists of two platforms: a static one, placed on the back of the finger, and a mobile one, responsible for applying forces at the finger pad. The structure of the device resembles that of parallel robots, where the fingertip is placed in between the static and the moving platforms. This work presents the design of the wearable display, along with the quasi-static modeling of the relationship between the applied forces and the platform's orientation and displacement. The device can exert up to 1.5 N, with a maximum platform inclination of 30 degree. To validate the device and verify its effectiveness, a curvature discrimination experiment was carried out: employing the wearable device together with a popular haptic interface improved the performance with respect of employing the haptic interface alone.

Energy calibration and resolution of the CMS electromagnetic calorimeter in pp collisions at √s = 7 TeV

Abstract: The article is the pre-print version of the final publishing paper that is available from the link below.

Analysis of GSH and GSSG after derivatization with N -ethylmaleimide

Abstract: t his protocol describes a procedure for determining glutathione (G sH) and glutathione disulfide (G ssG) concentrations in blood and other tissues. artifactual oxidation to G ssG of 5–15% of the G sH found in a sample can occur during deproteination of biological samples with any of the commonly used acids, with consequent marked overestimation of G ssG. t his can be prevented by derivatizing G sH with the alkylating agent N-ethylmaleimide ( neM) to form Gs-neM before acid deproteination, followed by back-extraction of excess neM from the deproteinized samples with dichloromethane. G ssG concentration is then measured by spectrophotometry with the G sH recycling method, on the basis of conversion of GssG to G sH by glutathione reductase and naDpH and reaction with 5,5 ′-dithiobis-(2-nitrobenzoic acid). G sH concentration is instead measured by either of two methods: by analysis of Gs-neM conjugates by H plc in the same sample that is used to measure G ssG or, alternatively, by analysis of G sH by spectrophotometry (G sH recycling method) on one additional sample aliquot that has not been derivatized with neM. t he procedure can assay GsH and GssG in blood and other tissues in 30 min or less.

Scoring treatment response in patients with relapsing multiple sclerosis.

Abstract: Background:We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosisObjective:To optimize and validate a sc

Measurement of proton-proton elastic scattering and total cross-section at \chem{\sqrt {s} = 7\,TeV}

Abstract: At the LHC energy of , under various beam and background conditions, luminosities, and Roman Pot positions, TOTEM has measured the differential cross-section for proton-proton elastic scattering as a function of the four-momentum transfer squared t. The results of the different analyses are in excellent agreement demonstrating no sizeable dependence on the beam conditions. Due to the very close approach of the Roman Pot detectors to the beam center (?5?beam) in a dedicated run with ?*?=?90?m, |t|-values down to 5?10?3?GeV2 were reached. The exponential slope of the differential elastic cross-section in this newly explored |t|-region remained unchanged and thus an exponential fit with only one constant B?=?(19.9???0.3)?GeV?2 over the large |t|-range from 0.005 to 0.2?GeV2 describes the differential distribution well. The high precision of the measurement and the large fit range lead to an error on the slope parameter B which is remarkably small compared to previous experiments. It allows a precise extrapolation over the non-visible cross-section (only 9%) to t?=?0. With the luminosity from CMS, the elastic cross-section was determined to be (25.4???1.1)?mb, and using in addition the optical theorem, the total pp cross-section was derived to be (98.6???2.2)?mb. For model comparisons the t-distributions are tabulated including the large |t|-range of the previous measurement (TOTEM Collaboration (Antchev G. et al), EPL, 95 (2011) 41001).

Luminosity-independent measurement of the proton-proton total cross section at √s=8 TeV.

Abstract: The TOTEM collaboration has measured the proton-proton total cross section at $\sqrt{s}=8\text{ }\text{ }\mathrm{TeV}$ using a luminosity-independent method. In LHC fills with dedicated beam optics, the Roman pots have been inserted very close to the beam allowing the detection of $\ensuremath{\sim}90%$ of the nuclear elastic scattering events. Simultaneously the inelastic scattering rate has been measured by the T1 and T2 telescopes. By applying the optical theorem, the total proton-proton cross section of $(101.7\ifmmode\pm\else\textpm\fi{}2.9)\text{ }\text{ }\mathrm{mb}$ has been determined, well in agreement with the extrapolation from lower energies. This method also allows one to derive the luminosity-independent elastic and inelastic cross sections: ${\ensuremath{\sigma}}_{\mathrm{el}}=(27.1\ifmmode\pm\else\textpm\fi{}1.4)\text{ }\text{ }\mathrm{mb}$; ${\ensuremath{\sigma}}_{\mathrm{inel}}=(74.7\ifmmode\pm\else\textpm\fi{}1.7)\text{ }\text{ }\mathrm{mb}$.

Luminosity-independent measurements of total, elastic and inelastic cross-sections at \chem{\sqrt {s} = 7\,TeV}

Abstract: The TOTEM experiment at the LHC has performed the first luminosity-independent determination of the total proton-proton cross-section at . This technique is based on the optical theorem and requires simultaneous measurements of the inelastic rate – accomplished with the forward charged-particle telescopes T1 and T2 in the range 3.1 < |η| < 6.5 – and of the elastic rate by detecting the outcoming protons with Roman Pot detectors. The data presented here were collected in a dedicated run in 2011 with special beam optics (β* = 90 m) and Roman Pots approaching the beam close enough to register elastic events with squared four-momentum transfers |t| as low as 5·10−3 GeV2. The luminosity-independent results for the elastic, inelastic and total cross-sections are σel = (25.1 ± 1.1) mb, σinel = (72.9 ± 1.5) mb and σtot = (98.0 ± 2.5) mb, respectively. At the same time this method yields the integrated luminosity, in agreement with measurements by CMS. TOTEM has also determined the total cross-section in two complementary ways, both using the CMS luminosity measurement as an input. The first method sums the elastic and inelastic cross-sections and thus does not depend on the ρ parameter. The second applies the optical theorem to the elastic-scattering measurements only and therefore is free of the T1 and T2 measurement uncertainties. The methods, having very different systematic dependences, give results in excellent agreement. Moreover, the ρ-independent measurement makes a first estimate for the ρ parameter at possible: |ρ| = 0.145 ± 0.091.

Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse.

Abstract: In patients with severe mitral regurgitation (MR) referred for cardiac surgery, left atrial (LA) remodeling and enlargement are accompanied by mechanical stress, mediated cellular hypertrophy, and interstitial fibrosis that finally lead to LA failure. Speckle tracking echocardiography is a novel non–Doppler-based method that allows an objective quantification of LA myocardial deformation, becoming useful for LA functional analysis. We conducted a study to evaluate the relation between the traditional and novel atrial indexes and the extent of ultrastructural alterations, obtained from patients with severe MR who were undergoing surgical correction of the valvular disease. The study population included 46 patients with severe MR, referred to our echocardiographic laboratory for a diagnostic examination before cardiac surgery. The global peak atrial longitudinal strain (PALS) was measured in all subjects by averaging all atrial segments. LA tissue samples were obtained from all patients. Masson's trichrome staining was performed to assess the extent of the fibrosis. The LA endocardial thickness was measured. A close negative correlation between the global PALS and grade of LA myocardial fibrosis was found (r = −0.82, p

Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis

Abstract: BACKGROUND The recruitment of immune cells by chemokines and the regulation of endometrial cell apoptosis are critical aspects of endometriosis biology. Here, we review the local (paracrine) and systemic hormone (endocrine) modulation of these two specific, but highly related phenomena.

Measurement of the top quark forward-backward production asymmetry and its dependence on event kinematic properties

Abstract: We present new measurements of the inclusive forward-backward ttbar production asymmetry, AFB, and its dependence on several properties of the ttbar system. The measurements are performed with the full Tevatron data set recorded with the CDF II detector during ppbar collisions at sqrt(s) = 1.96 TeV, corresponding to an integrated luminosity of 9.4 fb^(-1). We measure the asymmetry using the rapidity difference Delta-y=y_(t)-y_(tbar). Parton-level results are derived, yielding an inclusive asymmetry of 0.164+/-0.047 (stat + syst). We observe a linear dependence of AFB on the top-quark pair mass M(ttbar) and the rapidity difference |Delta-y| at detector and parton levels. Assuming the standard model, the probabilities to observe the measured values or larger for the detector-level dependencies are 7.4*10^(-3) and 2.2*10^(-3) for M(ttbar) and |Delta-y| respectively. Lastly, we study the dependence of the asymmetry on the transverse momentum of the ttbar system at the detector level. These results are consistent with previous lower-precision measurements and provide additional quantification of the functional dependencies of the asymmetry.

Patterns and meanings in discourse : theory and practice in corpus-assisted discourse studies (CADS)

Abstract: This work is designed, firstly, to both provoke theoretical discussion and serve as a practical guide for researchers and students in the field of corpus linguistics and, secondly, to offer a wide-ranging introduction to corpus techniques for practitioners of discourse studies. It delves into a wide variety of language topics and areas including metaphor, irony, evaluation, (im)politeness, stylistics, language change and sociopolitical issues. Each chapter begins with an outline of an area, followed by case studies which attempt both to shed light on particular themes in this area and to demonstrate the methodologies which might be fruitfully employed to investigate them. The chapters conclude with suggestions on activities which the readers may wish to undertake themselves. An Appendix contains a list of currently available resources for corpus research which were used or mentioned in the book.

Serum Interleukin 6 Is Predictive of Early Functional Decline and Mortality in Interstitial Lung Disease Associated with Systemic Sclerosis

Abstract: Objective. Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD). Methods. A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD. Results. In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4–7.2, p = 0.007), but not in those with severe ILD. Conclusion. In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.

Erythrocyte caspase-3 activation and oxidative imbalance in erythrocytes and in plasma of type 2 diabetic patients.

Abstract: An increased oxidative stress and a decreased life span of erythrocytes (RBCs) are reported in patients with diabetes. Aim of this study was to assess in RBCs from patients with type 2 diabetes whether downstream effector mechanisms of apoptosis, such as activation of caspase-3, is operative, and whether an iron-related oxidative imbalance, occurring inside RBCs and in plasma, could be involved in caspase-3 activation. In 26 patients with type 2 diabetes and in 12 healthy subjects, oxidative stress was evaluated by means of different markers; non-protein-bound iron, methemoglobin and glutathione were determined in RBCs, and non-protein-bound iron was also determined in plasma. Erythrocyte caspase-3 activation was evaluated by an immunosorbent enzyme assay. Arterial hypertension, demographic and standard biochemical data were also evaluated. The results show, for the first time, that type 2 diabetic RBCs put into motion caspase-3 activation, which is significantly higher than in control RBCs. Such an effector mechanism of “eryptosis” was positively correlated to blood glucose levels and to the increased plasma NPBI level. Caspase-3 activation was also positively correlated to occurrence of arterial hypertension. The results suggest that an extracellular oxidative milieu can be responsible for erythrocyte caspase-3 activation in patients with type 2 diabetes. In turn, caspase-3 activation can be envisaged as a novel mechanism which, by impairing the maintenance of erythrocyte shape and function, might contribute to the shortened life span of RBCs from patients with type 2 diabetes and to hemorheological disorders observed in these patients.

Structural Insight into Potent Broad-Spectrum Inhibition with Reversible Recyclization Mechanism: Avibactam in Complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-Lactamases

Abstract: Although β-lactams have been the most effective class of antibacterial agents used in clinical practice for the past half century, their effectiveness on Gram-negative bacteria has been eroded due to the emergence and spread of β-lactamase enzymes that are not affected by currently marketed β-lactam/β-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-β-lactam β-lactamase inhibitor presently in clinical development in combination with either ceftaroline or ceftazidime. In vitro studies show that avibactam may restore the broad-spectrum activity of cephalosporins against class A, class C, and some class D β-lactamases. Here we describe the structures of two clinically important β-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum β-lactamase and the class C Pseudomonas aeruginosa AmpC β-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structures reveal similar binding modes in both enzymes and thus provide a rationale for the broad-spectrum inhibitory activity of avibactam. Identification of the key residues surrounding the binding pocket allows for a better understanding of the potency of this scaffold. Finally, avibactam has recently been shown to be a reversible inhibitor, and the structures provide insights into the mechanism of avibactam recyclization. Analysis of the ultra-high-resolution CTX-M-15 structure suggests how the deacylation mechanism favors recyclization over hydrolysis.