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A mixture of seven-membered and five-membered platinacycle complexes are eventually formed after a series of substitution, oxidative addition, and reductive elimination reactions between the platinum dimer, cis -[Pt 2 Me 4 ( μ -SMe 2 ) 2 ] and the naphthyl-derived CˆN chelate ligands, (8-XC 10 H 6 CH = N-R), X = I, Br; R = phenyl and 4-Cl-benzyl. From the tethered ligand, either an sp 2 C H bond can be activated forming a five-membered ring or an sp 3 C H bond can be activated forming a seven-membered ring. All compounds have the imine included in the platinacycle. The ratio of complexes as a function of ring size varies depending on ligand architecture of the chelate ligand and the nature of other ligands in the coordination sphere. The cyclometalated platinum complexes have been characterized by NMR spectroscopy. One complex with a seven-membered ring was characterized crystallographically. Reductive elimination reactions of isolated and/or identified cyclometalated, six-membered platinum(IV) compounds [PtMe 2 Br{C 10 H 6 CH = NCH 2 (4-ClC 6 H 4 )}L] and [PtMe 2 Br{C 10 H 6 CH = N(C 6 H 5 )}L] (L = SMe 2 ) to form C sp3 C sp2 bonds, followed by competition between C sp2 H and C sp3 H bond activation are also reported.

Introduction. This study aimed at evaluating the efficacy and safety of dapagliflozin in patients with type 2 diabetes (T2D) who also received metformin in clinical practice in Italy. Methods. This was a retrospective observational study and it included data from patients who received dapagliflozin 10 mg once daily in conjunction with metformin for 12 months (DAPA + MET). In those with inadequate glycemic control, insulin or glimepiride was added after 30 days (DAPA + MET + other glucose-lowering drugs). Efficacy assessments included glycosylated hemoglobin (HbA1c) levels at 6 and 12 months, as well as body mass index (BMI) and lipid parameters at 12 months. Safety was also assessed. Results. Data on 66 patients were included. In both groups, HbA1c was significantly reduced at 6 and 12 months compared with baseline and significant reductions in HbA1c were observed at 12 months compared with 6 months. Over the 12-month treatment period, dapagliflozin significantly reduced BMI in both groups. No significant changes in lipid parameters were observed in either group and no detrimental effects on renal function were detected. Conclusions. Dapagliflozin is effective and safe in patients with T2D also receiving metformin. Glycemic control was already achieved with dapagliflozin + metformin, and add-on therapy was not associated with further improvements.

A positive lymphocytotoxic crossmatch represents an absolute contraindication to kidney transplantation. This paradigm is widely accepted for IgG antibodies but few data on the clinical relevance of IgM antibodies are available and so their role is still controversial. Some studies report that they can be protective for transplant, while other suggest that IgM antibodies are harmful for the graft. Pre-transplant antibody screening by CDC technique does not allow to discriminate IgG and IgM isotype. Instead, serum treatment with DTT can indirectly highlight because is able to inactivate the IgM pentamer. Moreover, in both cases it is not possible to know if these antibodies are or not specific for HLA molecules. The new solid-phase techniques permit to evidence anti-HLA antibodies and to discriminate their isotype. Since September 2016, 189 kidney transplant candidates were analyzed to evaluate the incidence of IgM antibodies. The antibody characterization was performed using FlowPRA Screening Test to detected either anti-HLA IgM alone, otherwise unknown, or in combination with IgG antibodies and by Luminex Single Antigen Beads to identify antibody specificity. The incidence of anti-HLA IgM antibodies was 10% (19/189). Only IgM antibodies were detected in 10 (53%) patients, both IgM/IgG antibodies were presented in 9 (47%) patients. IgM positive-group showed in 6 cases only anti-HLA class I antibodies (2000>=MFI=MFI

The purpose of this study is to evaluate continuous glucose monitoring (CGM) in predicting diabetes mellitus in children with incident hyperglycemia (IH) and negativity for some insular autoantibodies.Thirty-one autoantibody-negative children who presented at our center with IH underwent a baseline assessment and were followed up for 23.8 months (range, 6-48 months). At the end of the follow-up, we compared the receiver operating characteristic (ROC) areas under the curve (AUCs) of metabolic markers from 17 children who developed diabetes (Group A; n=17) and 14 children who did not develop diabetes (Group B; n=14).Only two oral glucose tolerance test (OGTT)-derived markers and three CGM-derived markers showed a good prognostic performance, with ROC AUCs indicating significant results (P0.0001) for the following markers: 2-h glucose, OGTT (0.813; 95% confidence interval [CI] 0.621-0.954); AUC glucose, OGTT (0.832; 95% CI 0.611-0.950); CGM glucose measurement peak (0.803; 95% CI 0.621-0.923); percentage of CGM glucose measurements inside the range 70-125 mg/dL (0.866; 95% CI 0.695-0.961); and percentage of CGM measurements ≥126 mg/dL (0.889; 95% CI 0.724-0.973). The combination of the OGTT-derived markers did not increase the predictive value, but the combination of CGM markers with each other or with the OGTT markers yielded higher ROC AUCs (ranging from 0.828 to 0.945).This is the first study showing that CGM is useful in predicting diabetes mellitus in children with IH.

International audience; Human rhinoviruses (HRV) have been re-classified into three species (A-C), but the recently discovered HRV-C strains are not fully characterized yet. This study aimed to undertake a molecular and epidemiological characterization of HRV strains infecting children hospitalized over one year in two large research hospitals in Rome. Nasal washings from single HRV infections were retrospectively subjected to phylogenetic analysis on two genomic regions: the central part of the 5'Untranslated Region (5'UTR) and the Viral Protein (VP) 4 gene with the 5' portion of the VP2 gene (VP4/2). Forty-five different strains were identified in 73 HRV-positive children: 55 % of the cases were HRV-A, 38 % HRV-C and only 7 % HRV-B. HRV-C cases were less frequent than HRV-A during summer months and more frequent in cases presenting wheezing with respect to HRV-A. Species distribution was similar with respect to patient age, and seasonality differed during summer months with fewer HRV-C than HRV-A cases. On admission, a significantly higher number of HRV-C cases presented with wheezing with respect to HRV-A. The inter- and intra-genotype variability in VP4/2 was higher than in 5'UTR; in particular, HRV-A patient VP4/2 sequences were highly divergent (8-14 %) at the nucleotide level from those of their reference strains, but VP4 amino acid sequence was highly conserved. In HRV-C isolates, the region preceding the initiator AUG, the amino acids involved in VP4 myristoylation, the VP4-VP2 cleavage site and the cis-acting replication element were highly conserved. Differently, VP4 amino acid conservation was significantly lower in HRV-C than in HRV-A strains, especially in the transiently exposed VP4 N-terminus. This study confirmed the high number of different HRV genotypes infecting hospitalized children over one year and reveals a greater than expected variability in HRV-C VP4 protein, potentially suggestive of differences in replication.

The mechanisms of Usutu virus (USUV) pathogenesis are largely unknown. The aim of this study was to evaluate the sensitivity of USUV to interferon (IFN) and the capacity of USUV to stimulate IFN production. Initial experiments were conducted to characterize the susceptibility of human cell lines to USUV infection and to evaluate the single-growth cycle replication curve of USUV. Results indicate that USUV is able to infect a variety of human cell lines, completing the replication cycle in Hep-2 and Vero cells within 48 h. Pre-treatment of cells with types I and III IFNs significantly inhibited the replication of USUV. However, the inhibitory effects of IFNs were considerably less if IFN was added after viral infection had been initiated. Also, USUV weakly induced types I and III IFNs.

Interferons (IFNs) are critically important in the control of influenza A virus infections. To better understand the pathogenic characteristics of the pandemic 2009 H1N1 influenza virus (pH1N1) from an innate immunity viewpoint, we investigated whether in vitro pH1N1 is sensitive to the antiviral activity of IFN beta, leukocyte IFN alpha, and several IFN alpha subtypes in a human lung adenocarcinoma epithelial cell line under single-growth cycle conditions. The results showed that 50% inhibitory concentration values against pH1N1 for various type I IFN preparations were higher than those against the IFN-sensitive encephalomyocarditis virus. Leukocyte IFN alpha and IFN alpha 5, 7, 8, 10, 14, 17, and 21 subtypes also appeared to be less active against pH1N1 than the Puerto Rico/8/34 H1N1 human influenza strain A. Taken together, the results provide new insights into the contributions of the various IFN alpha subtypes toward the regulation of innate immunity against pH1N1.

Human metapneumovirus (hMPV) has been recognized as an important respiratory pathogen. Due to its relatively recent discovery, only limited information is available on the relationship between hMPV and type I interferons (IFN). This study was designed to determine whether in vitro hMPV is sensitive to the antiviral activity of IFN-β, leukocyte IFN-α, and several IFN-α subtypes in a human Hep-2 cell line. The results showed that 50% inhibitory concentration values against hMPV for the various type I IFN preparations were significantly higher than those against the IFN-sensitive vesicular stomatitis virus, and some IFN-α subtypes appeared to be more active against hMPV than others, with IFN-α subtypes 5, 6, 8, and 10 being the most potent, and IFN-α2, 17, and 21 the least potent. The results show that hMPV grown in Hep-2 is partially resistant to the antiviral activity of type I IFNs. Additional studies are required to understand whether and to what extent the relatively low sensitivity of hMPV to IFNs influences the clinical outcomes of infected individuals.

Aim Preformed HLA cytotoxic antibodies, specific for mismatched HLA molecules of the potential donor, represent an absolute contraindication in kidney transplantation. New techniques, like the Luminex-Single Antigen Beads assay, are very sensitive allowing detection of HLA donor specific antibodies (DSAs) at low mean fluorescence intensity (MFI) values. However, few evidence on the clinical relevance of such low “strength” DSAs have been reported. Methods Graft outcome (follow-up 34.2 ± 19.8 months) of 99 pre-sensitized patients (%FlowPRA class I = 41 ± 33; %FlowPRA class II = 30 ± 36), transplanted between May 2007 and June 2014 on the basis of both CDC-XM and FC-XM negative results, was analyzed. Five patients were excluded from the study because of primary non-function of the graft (3 patients) or death for non-immunologic causes with non-functional graft (2 patients). Forty-seven (47%) patients did not have pre-formed HLA DSAs; the remaining 52 (53%) patients had “acceptable” DSAs (MFI ⩽ 5000) specific for HLA-A/B/C/DR/DQB molecules or anti-DPB/DQA DSAs with high MFI values (>5000). HLA class I DSAs were present in 28 patients; five of these showed DSAs against more than one donor HLA molecules. HLA class II DSAs were present in 19 patients; three of these showed anti-DPB/DQA DSAs with MFI > 5000. The remaining five patients had both HLA class I and class II DSAs; one of these had high level of anti-DP DSA. Results Analyzing graft outcome of the remaining 94 transplanted patients with functioning graft, we did not evidenced any significant difference between DSA positive patients and DSA negative patients (rejection: 10.4% vs. 6.5%, P = ns; graft loss: 12.5% vs. 10.9%, P = ns). In particular, among the 48 DSA positive patients, three (6.2%) had humoral rejection without graft loss; two (4.2%) had cellular rejection, one of these lost the graft. Six DSA positive patients suffered graft failure that was never due to antibody-mediated rejection related to pre-formed DSAs. Conclusion The results of this study show that pre-formed DSAs with low mean fluorescence intensity values do not represent a contraindication in kidney transplantation. An accurate evaluation of the “strength” of Luminex-detected DSA allows transplanting patients with clinically “irrelevant” HLA antibodies.

Summary Objectives The airway expression of type III interferons (IFNs) was evaluated in infants hospitalized for respiratory syncytial virus (RSV) or rhinovirus (HRV) bronchiolitis. As an additional objective we sought to determine whether a different expression of IFN lambda 1–3 was associated with different harboring viruses, the clinical course of bronchiolitis or with the levels of well established IFN stimulated genes (ISGs), such as mixovirus resistance A (MxA) and ISG56. Methods The analysis was undertaken in 118 infants with RSV or HRV bronchiolitis. Nasopharyngeal washes were collected for virological studies and molecular analysis of type III IFN responses. Results RSV elicited higher levels of IFN lambda subtypes when compared with HRV. A similar expression of type III IFN was found in RSVA or RSVB infected infants and in those infected with HRVA or HRVC viruses. Results also indicate that IFN lambda 1 and IFN lambda 2–3 levels were correlated with each other and with MxA and ISG56-mRNAs. In addition, a positive correlation exists between the IFN lambda1 levels and the clinical score index during RSV infection. In particular, higher IFN lambda 1 levels are associated to an increase of respiratory rate. Conclusions These findings show that differences in the IFN lambda 1–3 levels in infants with RSV or HRV infections are present and that the expression of IFN lambda 1 correlates with the severity of RSV bronchiolitis.