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Background: CoviD-19 in-hospital mortality rates show variations across time, setting, patient populations and health-systems. Aim: The aim of the present study was to explore the association of patient characteristics with in-hospital mortality taking into consideration temporal changes of CoViD-19 prevention and treatment, focusing on the negative predictive value of specific biomarker thresholds for death and oxygen requirements. Methods: This retrospective study included a sample of 425 vaccine-naive patients hospitalized for CoViD-19 in Crete, Greece. Time-specific mortality rates and negative predictive values of biomarkers on admission were calculated. The association of patient characteristics with mortality was assessed using multivariate logistic regression models. Results: The overall in hospital case fatality rate (CFR) was 19.53%. The in-hospital CFR [95% CI] dropped from 22.74% [17.96-27.52] to 11.9% [6.17-17.63] before and after 31/03/2021, as did the mean age of hospitalized patients. LDH & D-dimers ≥240 or ≥0.5), CRP & D-dimers (≥3 or ≥0.5), CRP & Ferritin (≥3 or ≥205) had negative predictive values [95% CI] for mortality of 100% [86.7-100], 96.1% [80.3-99.9] and 95.4% [84.5-99.4] %, but the respective negative predictive values for oxygen requirements were 19.2% [6.5-39.3], 19.2% [6.5-39.3] and 27.2% [14.9-42.7] . Conclusion: A decreasing trend of in-hospital case fatality rates over the course of our study was associated with a decreasing age of hospitalized patients, which could be associated with community vaccination uptake in people over 60 in Greece through reduction of persons “susceptible” to severe disease. Mortality prediction formulas incorporating biomarkers should be used cautiously for the risk stratification of patients with CoViD-19 in the setting of the emergency department assessment.

Introduction With the long-term goal of developing a diagnostic (99mTc) and therapeutic (186Re) agent pair for targeting somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs), we developed novel metal-cyclized peptides through direct labeling of the potent SSTR2 antagonist Ac-4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2 (1) with Re (in Re-1), 99mTc (in [99mTc]Tc-1) and 186Re (in [186Re]Re-1). Methods Re-1 was characterized by LC-ESI-MS and HR-ESI-MS and was tested for receptor affinity in SSTR-expressing cells (AR42J). Radiolabeling of the peptide was achieved via ligand exchange from 99mTc-labeled glucoheptonate or [186Re]ReOCl3(PPh3)2, yielding [99mTc]Tc-1 or [186Re]Re-1, respectively. In vitro stability of [99mTc]Tc-1/[186Re]Re-1 in PBS (10 mM) at pH 7.4 and 37 °C was determined by HPLC analysis. Moreover, [99mTc]Tc-1 stability was tested in cysteine (1 mM) and rat serum under the same conditions. Results Re-1 consisted of two isomers, confirmed by LC-ESI-MS, with good SSTR2 affinity (IC50 = 43 ± 6 nM). Optimization of the 99mTc labeling through varying reaction parameters such as pH, reaction time, and Sn2+ and ligand concentrations resulted in high radiochemical yield (RCY ≥92%). Similarly, [186Re]Re-1 was prepared in reasonable RCY (≥50%). Both 99mTc/186Re-tracers consisted of two product isomers as identified by HPLC co-injection with Re-1. While [99mTc]Tc-1 was sufficiently stable in vitro (≥71% intact through 4 h in PBS, cysteine and rat serum), [186Re]Re-1 exhibited more moderate in vitro stability (58% intact after 1 h in PBS). Conclusions Novel 99mTc/186Re-cyclized SSTR2 antagonist peptides were synthesized and characterized using the Re-cyclized analogue as a reference. Due to the nanomolar SSTR2 affinity of Re-1 and good in vitro stability of [99mTc]Tc-1, the latter shows early promise for development as a radiodiagnostic agent for SSTR-expressing NETs. Advances in knowledge and implications for patient care The 99mTc-cyclized complex showed promising in vitro properties, and future in vivo studies will determine the potential for translating such a design into the human clinic.

We report herein the preclinical evaluation of new [64Cu]Cu-gastrin-releasing peptide receptor (GRPR)-targeting tracers, employing the potent peptide antagonist DPhe-Gln-Trp-Ala-VaI-Gly-His-Sta-Leu-NH2 conjugated to NOTA (in 1) or NODAGA (in 2) chelators via a 6-aminohexanoic acid linker. The Cu-1/2 metalated peptides were synthesized by reacting 1/2 with CuCl2 and were characterized by LC-ESI-MS and HR-ESI-MS. Cu-1/2 exhibited high GRPR-binding affinities with IC50 values

The goal of this work was to develop hydrophilic gastrin-releasing peptide receptor (GRPR)-targeting complexes of the general formula fac-[M(CO)3(L)]+ [M = natRe, 99mTc, 186Re; L: NOTA for 1, NODAGA for 2] conjugated to a powerful GRPR peptide antagonist (DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) via a 6-aminohexanoic acid linker. Metallated-peptides were prepared employing the [M(OH2)3(CO)3]+ [M = Re, 99mTc, 186Re] precursors. Re-1/2 complexes were characterized with HR-MS. IC50 studies were performed for peptides 1/2 and their respective Re-1/2 complexes in a binding assay utilizing GRPR-expressing human PC-3 prostate cancer cells and [125I]I-Tyr4-BBN as the competing ligand. The 99mTc/186Re-complexes were identified by HPLC co-injection with their Re-analogues. All tracers were challenged in vitro at 37 °C against cysteine/histidine (phosphate-buffered saline 10 mM, pH 7.4) and rat serum. Biodistribution and micro-SPECT/CT imaging of [99mTc]Tc-1/2 and [186Re]Re-2 were performed in PC-3 tumor-bearing ICR SCID mice. High in vitro receptor affinity (IC50 2–3 nM) was demonstrated for all compounds. The 99mTc/186Re-tracers were found to be hydrophilic (log D7.4 ≤ − 1.35) and highly stable. Biodistribution in PC-3 xenografted mice revealed good tumor uptake (%ID/g at 1 h: 4.3 ± 0.7 for [99mTc]Tc-1, 8.3 ± 0.9 for [99mTc]Tc-2 and 4.2 ± 0.8 for [186Re]Re-2) with moderate retention over 24 h. Rapid renal clearance was observed for [99mTc]Tc-2 and [186Re]Re-2 (> 84 % at 4 h), indicating favorable pharmacokinetics. Micro-SPECT/CT images for the 99mTc-tracers clearly visualized PC-3 tumors in agreement with the biodistribution data and with superior imaging properties found for [99mTc]Tc-2. [99mTc]Tc-2 shows promise for further development as a GRPR-imaging agent. [186Re]Re-2 demonstrated very similar in vivo behavior to [99mTc]Tc-2, and further studies are therefore justified to explore the theranostic potential of our approach for targeting of GRPR-positive cancers.

Introduction The aim of this work was to develop diagnostic (99mTc) and therapeutic (186Re) agents for targeting somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). In this regard, we evaluated in vitro complexes of the general formula [M(CO)3(L-sst2-ANT)] (M = 99mTc, 186Re), where L denotes NODAGA or NOTA and sst2-ANT denotes the potent SSTR2 antagonist 4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2. Moreover, we assessed the in vivo properties of the 99mTc-complexes in an animal SSTR-tumor model. Methods The [99mTc]/[186Re][Tc/Re(OH2)3(CO)3]+ precursors were utilized to prepare the 99mTc/186Re-complexes, which were identified by HPLC co-injection with their natRe analogues. The tracers were challenged in vitro at 37 °C against cysteine and histidine in phosphate-buffered saline (pH 7.4) and in rat serum. Biodistribution and micro-SPECT/CT imaging studies of the 99mTc-tracers were performed in AR42J tumor-bearing female ICR SCID mice. Results The 99mTc-complexes were prepared in high radiochemical yield (RCY > 90%, by HPLC), with lower RCY (≤30%) obtained for 186Re-complexes. Tracers remained intact in vitro and displayed low non-specific binding (10–25%) to rat serum proteins. Biodistribution of [99mTc]Tc-NODAGA-sst2-ANT revealed low tumor uptake (2.78 ± 0.27 %ID/g) at 1 h, while high tumor uptake (16.70 ± 3.32 %ID/g) was found for [99mTc]Tc-NOTA-sst2-ANT. Moderate to low tumor retention was observed for both tracers after 4 and 24 h. Tumor uptake for [99mTc]Tc-NOTA-sst2-ANT was receptor-mediated, as demonstrated by parallel SSTR blocking studies. Rapid renal clearance was observed for both tracers, and SPECT/CT images clearly delineated the tumors, in agreement with the biodistribution data. Conclusions The [99mTc]Tc-NOTA-sst2-ANT complex demonstrated high tumor uptake and rapid clearance in a SSTR-tumor mouse model, showing potential for further development. Advances in knowledge and implications for patient care Preclinical data support the feasibility of the [99mTc]Tc/[186Re]Re-NOTA/NODAGA labeling strategy for use in the development of theranostic radiopharmaceuticals for translation into the human clinic for targeting of SSTR-expressing NETs.

Purpose: Minimal change disease (MCD) is considered a relatively benign glomerulopathy, as it rarely progresses to end-stage kidney disease. The aim of this study was to describe the characteristics and outcomes of adults with MCD and identify potential risk factors for relapse. Patients &amp, Methods: We retrospectively studied a cohort of adults with biopsy-proven MCD in terms of clinical features and treatment outcomes. Baseline characteristics and outcomes were recorded and predictors of relapse were analyzed using logistic regression multivariate analysis. Results: 59 patients with adult-onset primary MCD with nephrotic syndrome were included. Mean serum creatinine at diagnosis was 0.8 mg/dL (±2.5) and estimated GFR (eGFR) was 87 mL/min/1.73 m2 (±29.5). Mean serum albumin was 2.5 g/dL (±0.8) and 24 h proteinuria 6.8 g (±3.7). Microscopic hematuria was detected in 35 (58.5%) patients. 42 patients received prednisone alone, six patients received prednisone plus cyclophosphamide, five patients received prednisone plus cyclosporine, one patient received prednisone plus rituximab and five patients did not receive immunosuppression at all since they achieved spontaneous remission. During a mean follow up time of 34.7(22.1) months, 46.1% of patients experienced at least one episode of relapse. The mean age of patients who did not experience a relapse was significantly higher than that of patients who relapsed while relapsers had a significantly longer duration of 24 h proteinuria prior to biopsy compared to non-relapsers. Overall, 10% of patients experienced acute kidney injury while the mean eGFR at the end was 82 mL/min/1.73 m2 (±29.1) and one patient ended up in chronic dialysis. Overall, the proportion of non-relapsers, who experienced acute kidney injury (17%) was significantly higher than the one recorded among relapsers (0%).Conclusion: In this series of patients, almost 46% of adult-onset nephrotic MCD patients experienced a relapse, although their renal progression was rare. Younger onset age was an independent risk factor for relapse in adult-onset MCD patients.

An unresponsive paediatric patient may present a diagnostic challenge for health professionals, as rapid identification of the cause is needed to provide proper interventions. The following report details a challenging diagnosis of unresponsiveness in a refugee child. In the migratory context, observed unresponsiveness states are frequently attributed to psychologic factors, and overlapping psychiatric classifications (resignation syndrome, functional coma and catatonia) are common. Our patient fell into an unresponsive state for 6 months after witnessing a traumatic event. Diagnostic workup for multiple medical comorbidities led to surgical intervention for tethered cord syndrome. Shortly after that, the patient’s responsiveness improved, putting to question her condition’s underlying cause. This case highlights the need for a biopsychosocial approach in such cases, reflected in thorough clinical examination and diagnostic investigations. A multidisciplinary perspective and expertise proved crucial and may help in the rehabilitation of children in similar situations.

We report herein the preclinical evaluation of new [

With the long-term goal of developing a diagnostic (Re-1 was characterized by LC-ESI-MS and HR-ESI-MS and was tested for receptor affinity in SSTR-expressing cells (AR42J). Radiolabeling of the peptide was achieved via ligand exchange fromRe-1 consisted of two isomers, confirmed by LC-ESI-MS, with good SSTR2 affinity (ICNovelThe

The goal of this work was to develop hydrophilic gastrin-releasing peptide receptor (GRPR)-targeting complexes of the general formula fac-[M(CO)Metallated-peptides were prepared employing the [M(OHHigh in vitro receptor affinity (IC[

With the long-term goal of developing theranostic agents for applications in nuclear medicine, in this work we evaluated the well-known NOTA and NODAGA chelators as bifunctional chelators (BFCs) for the [99mTc/186Re]Tc/Re-tricarbonyl core. In particular, we report model complexes of the general formula fac-[M(L)(CO)3]+ (M = Re, 99mTc, 186Re) where L denotes NOTA-Pyr (1) or NODAGA-Pyr (2), which are derived from conjugation of NOTA/NODAGA with pyrrolidine (Pyr). Further, as proof-of-principle, we synthesized the peptide bioconjugate NODAGA-sst2-ANT (3) and explored its complexation with the fac-[Re(CO)3]+ and fac-[99mTc][Tc(CO)3]+ cores; sst2-ANT denotes the somatostatin receptor (SSTR) antagonist 4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2. Rhenium complexes Re-1 through Re-3 were synthesized and characterized spectroscopically, and receptor binding affinity was demonstrated for Re-3 in SSTR-expressing cells (AR42J, IC50 = 91 nM). Radiolabeled complexes [99mTc]Tc/[186Re]Re-1/2 and [99mTc]Tc-3 were prepared in high radiochemical yield (>90%, determined by radio-HPLC) by reacting [99mTc]/[186Re][Tc/Re(OH2)3(CO)3]+ with 1-3 and correlated well with the respective Re-1 through Re-3 standards in comparative HPLC studies. All radiotracers remained intact through 24 h (99mTc-labeled complexes) or 48 h (186Re-labeled complexes) against 1 mM l-histidine and 1 mM l-cysteine (pH 7.4, 37 °C). Similarly, rat serum stability studies displayed no decomposition and low nonspecific binding of 9-24% through 4 h. Biodistribution of [99mTc]Tc-3 in healthy CF-1 mice demonstrated a favorable pharmacokinetic profile. Rapid clearance was observed within 1 h post-injection, predominantly via the renal system (82% of the injected dose was excreted in urine by 1 h), with low kidney retention (% ID/g: 11 at 1 h, 5 at 4 h, and 1 at 24 h) and low nonspecific uptake in other organs/tissues. Our findings establish NOTA and NODAGA as outstanding BFCs for the fac-[M(CO)3]+ core in the design and development of organometallic radiopharmaceuticals. Future in vivo studies of [99mTc]Tc- and [186Re]Re-tricarbonyl complexes of NODAGA/NOTA-biomolecule conjugates will further probe the potential of these chelates for nuclear medicine applications in diagnostic imaging and targeted radiotherapy, respectively.

Background Methylation of the human papillomavirus (HPV) DNA has been proposed as a novel biomarker. Here, we correlated the mean methylation level of 12 CpG sites within the L1 gene, to the histological grade of cervical precancer and cancer. We assessed whether HPV L1 gene methylation can predict the presence of high-grade disease at histology in women testing positive for HPV16 genotype. Methods Pyrosequencing was used for DNA methylation quantification and 145 women were recruited. Results We found that the L1 HPV16 mean methylation (±SD) significantly increased with disease severity (cervical intraepithelial neoplasia [CIN] 3, 17.9% [±7.2] vs CIN2, 11.6% [±6.5], P < .001 or vs CIN1, 9.0% [±3.5], P < .001). Mean methylation was a good predictor of CIN3+ cases; the area under the curve was higher for sites 5611 in the prediction of CIN2+ and higher for position 7145 for CIN3+. The evaluation of different methylation thresholds for the prediction of CIN3+ showed that the optimal balance of sensitivity and specificity (75.7% and 77.5%, respectively) and positive and negative predictive values (74.7% and 78.5%, respectively) was achieved for a methylation of 14.0% with overall accuracy of 76.7%. Conclusions Elevated methylation level is associated with increased disease severity and has good ability to discriminate HPV16-positive women that have high-grade disease or worse.

BACKGROUND There have been various attempts to assess endometrial lesions on cytological material obtained via direct endometrial sampling. The majority of efforts focus on the description of cytological criteria that lead to classification systems resembling histological reporting formats. These systems have low reproducibility, especially in cases of atypical hyperplasia and well differentiated carcinomas. Moreover, they are not linked to the implied risk of malignancy. METHODS The material was collected from women examined at the outpatient department of four participating hospitals. We analyzed 866 consecutive, histologically confirmed cases. The sample collection was performed using the EndoGyn device, and processed via Liquid Based Cytology, namely ThinPrep technique. The diagnostic categories and criteria were established by two cytopathologists experienced in endometrial cytology; performance of the proposed reporting format was assessed on the basis of histological outcome; moreover, the implied risk of malignancy was calculated. RESULTS The proposed six diagnostic categories are as follows: (i) nondiagnostic or unsatisfactory; (ii) without evidence of hyperplasia or malignancy; (iii) atypical cells of endometrium of undetermined significance; (iv) atypical cells of endometrium of low probability for malignancy; (v) atypical cells of endometrium of high probability for malignancy; and (vi) malignant. The risk of malignancy was 1.42% ± 0.98%, 44.44% ± 32.46% (nine cases), 4.30% ± 4.12%, 89.80% ± 8.47%, and 97.81% ± 2.45%, respectively. CONCLUSION We propose a clinically oriented classification scheme consisting of diagnostic categories with well determined criteria. Each diagnostic category is linked with an implied risk of malignancy; thus, clinicians may decide on patient management and eventually reduce unnecessary interventional diagnostic procedures. Diagn. Cytopathol. 2016;44:888-901. © 2016 Wiley Periodicals, Inc.

In this work, the synthesis of new fac-[99mTc/Re(CO)3(N,S,N)]+ complexes is presented with a novel tridentate bifunctional chelator, 3-(2-aminoethylthio)-3-(1H-imidazol-4-yl)propanoic acid (1), its pyrrolidine amide derivative (2), as well as with the 1-sst2-ANT bioconjugate amide (3), where the somatostatin receptor seeking peptide sst2-ANT [4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2] is linked to 1 via its N-terminus. The rhenium complexes of ligands 1, 2 and 3 (complexes 4, 5 and 6, respectively) were synthesized in high yield and were characterized spectroscopically. The fac-[Re(CO)3(N,S,N)]+ coordination mode of complexes 4 and 5 via the imidazole N, thioether S, and amine N donor atoms was determined by NMR. The 99mTc tracer complexes of ligands 1 and 2 (complexes 7 and 8, respectively) were synthesized quantitatively, and their identities were confirmed by HPLC co-elution with the Re analogues. In vitro stability studies of both 7 and 8 in histidine and cysteine showed that the complexes remained intact (>98%) after 24 h incubations. Furthermore, rat serum analysis of the small molecule bioconjugate model complex, 8, showed high stability at 4 h, and rat urine analysis showed that 8 was excreted intact through 4 h. Future studies with the sst2-ANT peptide linked to the fac-[99mTc(CO)3(N,S,N)]+ chelate will determine if targeted delivery of this attractive diagnostic radionuclide to neuroendocrine cancers that over-express somatostatin receptors can be achieved.

The synthesis and biological evaluation of three new biotinylated fac-[(99m)Tc/Re(CO)3](+) complexes with the tridentate ligands L1, L2, and L3 are reported. L1-L3 contain the chelators 2-((5-aminopentyl)(pyridin-2-ylmethyl)amino)acetic acid, 2-(2-aminoethylthio)-3-(1H-imidazol-4-yl)propanoic acid, and 2-amino-3-(1-carboxy-2-(1H-imidazol-4-yl)ethylthio)propanoic acid, respectively, which are conjugated to biotin's carboxylate via their amine group. The fac-[Re(CO)3(L1-L3)] complexes were synthesized and characterized by NMR and IR, where the (N,N,O) coordination for ReL1 and the (N,S,O) coordination for ReL2 and ReL3 were confirmed. The tracer complexes fac-[(99m)Tc(CO)3(L1-L3)] were synthesized in high yield and were found highly stable in 10(-3) M L-histidine and L-cysteine over 24 h. Furthermore, they exhibited high binding affinity (>90%) for avidin. Rat plasma studies showed complete cleavage of biotin from (99m)TcL1 after 1 h and a low percentage of intact (99m)TcL2 and (99m)TcL3 with no biotin cleavage metabolites present, over 24 h. Similarly, rat urine analysis showed the presence of intact (99m)TcL2 and (99m)TcL3, while (99m)TcL1 was cleaved. Biodistribution studies of (99m)TcL2 and (99m)TcL3 revealed fast blood and tissue clearance.

INTRODUCTION: Modern medicine is based on teamwork and communication. Bullying and discrimination can have a serious effect on these, affecting the standard of medical training and patient care. AIM: To determine the incidence of bullying and sex discrimination in the Greek health care system. METHODS: An online questionnaire was designed and circulated among Greek medical professionals. RESULTS: We received 1349 completed questionnaires with a response rate of 48% and with 45% of them being female. Equal opportunities in specialty training were reported by 55% of the participants. Female doctors in medicine and in surgery reported no equal opportunities at an incidence of 15% and 30%, respectively (p < 0.001). Family obligations and lack of family support were considered as the main obstacles in female doctors’ professional development by 92% and 59% of the participants, respectively. Both sexes appeared to have suffered from various forms of abusive behavior with characteristics that vary between them. Verbal abuse, threatening behavior, and sexual harassment were reported by 50%, 38%, and 20%, respectively, with women being 3 times more likely to be victims of sexual harassment (34% vs. 9%, p < 0.001). Finally, the availability of official support mechanisms was reported in only 15% of the cases, whereas friends and colleagues were the main support for 46.17% of the cases. CONCLUSION: This is the first study attempting to preliminary describe the extent of bullying and sexual discrimination in the Greek national health care system. Despite the limitations of this study, it is imperative that more research is performed on this issue from the appropriate national authorities. (C) 2017 Association of Program. Directors in Surgery. Published by Elsevier Inc. All rights reserved.

A novel bisphosphonate, 1-(3-aminopropylamino)ethane-1,1-diyldiphosphonic acid (3), was coupled to the tridentate chelators di-2-picolylamine, 2-picolylamine-N-acetic acid, iminodiacetic acid, 3-((2-aminoethyl)thio)-3-(1H-imidazol-4-yl)propanoic acid, and 2-((2-carboxyethyl)thio)-3-(1H-imidazol-4-yl)propanoic acid to form ligands 6, 9, 11, 15, and 19, respectively. Organometallic complexes of the general formula [Re/(99m)Tc(CO)3(κ(3)-L)] were synthesized, where L denotes ligand 6, 9, 11, 15, or 19. The rhenium complexes were prepared at the macroscopic level and characterized by spectroscopic methods. The technetium-99m organometallic complexes were synthesized in high yield and were identified by comparative reversed-phase HPLC with their Re analogues. The (99m)Tc tracers were stable in vitro and exhibited binding to hydroxyapatite. In biodistribution studies, all of the (99m)Tc complexes exhibited high bone uptake superior to that of 25, which is the directly (99m)Tc-labeled bisphosphonate 3, and comparable to that of (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). The tracers [(99m)Tc(CO)3(6)] (26), [(99m)Tc(CO)3(9)] (27), [(99m)Tc(CO)3(11)] (28), and [(99m)Tc(CO)3(15)] (29) exhibited higher bone/blood ratios than (99m)Tc-MDP. 26 had the highest bone uptake at 1 h p.i. The new bisphosphonates showed no substantial growth inhibitory capacity in PC-3, Saos-2, and MCF-7 established cancer cell lines at low concentrations. Incubation of 26 with the same cancer cell lines indicated a rapid and saturated uptake. The promising properties of 26-29 indicate their potential for use as bone-imaging agents.

Magnetic nanoparticles (MNPs) can play a distinct role in magnetic drug delivery via their distribution to the targeted area. The preparation of such MNPs is a challenging multiplex task that requires the optimization of size, magnetic, and surface properties for the achievement of desirable target selectivity, along with the sustained drug release as a prerequisite. In that context, CoFe2O4 MNPs with a small size of ∼7 nm and moderate saturation magnetization of ∼60 emu g(-1) were solvothermally synthesized in the presence of octadecylamine (ODA) with a view to investigate the functionalization route effect on the drug release. Synthetic regulations allowed us to prepare MNPs with aminated (AmMNPs) and amine-free (FAmMNPs) surface. The addition of the nonsteroidal anti-inflammatory drug with a carboxylate donor, Naproxen (NAP), was achieved by direct coupling with the NH2 groups, rendered by ODA, through the formation of an amide bond in the case of AmMNPs. In the case of FAmMNPs, indirect coupling of NAP was performed through an intermediate linker (polyethylenimine) and on PEG-ylated MNPs. FT-IR, (1)H NMR, (13)C NMR, and UV-vis data confirmed the addition of NAP, whereas diverse drug-release behavior was observed for the different functionalization approaches. The biological behavior of the MNPs@NAP was evaluated in vitro in rat serum and in vivo in mice, after radiolabeling with a γ-emitting radionuclide, (99m)Tc. The in vivo fate of MNPs@NAP carriers was in straightforward relation with the direct or indirect coupling of NAP. Furthermore, an inflammation was induced intramuscularly, where the directly coupled (99m)Tc-MNPs@NAP carriers showed increased accumulation at the inflammation site.

Background— Ticagrelor and prasugrel provide stronger platelet inhibition compared with clopidogrel. Direct pharmacodynamic comparison between them has not yet been reported in ST-segment–elevation myocardial infarction patients. Methods and Results— In a prospective, single-center, single-blind study, 55 out of 117 (47%) screened consecutive ST-segment–elevation myocardial infarction patients undergoing primary percutaneous coronary intervention were randomized to either ticagrelor 180 mg loading followed by 90 mg bid, or prasugrel 60 mg loading followed by 10 mg od for 5 days. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay and the Multiplate Analyzer at 0, 1, 2, 6, 24 hours, and 5 days postrandomization. The primary end point, PR with VerifyNow at hour 1, did not differ significantly between patients randomized to ticagrelor versus prasugrel (257.3 P2Y12 reaction unit [PRU], 95% CI 230.8–283.8 versus 231.3 PRU, 95% CI 205.3–257.4; P =0.2). PR did not differ at 2, 6, and 24 hours, although at day 5 it was lower with ticagrelor than prasugrel (25.6 PRU, 95% CI 12.3–38.9 versus 50.3 PRU, 95% CI 36.4–64.1; P =0.01). At hour 2, high on-treatment PR rates (cutoff 208 PRU) were 46.2% and 34.6% for ticagrelor and prasugrel, respectively, decreased significantly thereafter, whereas did not differ significantly between the 2 agents at all the time points of the study. Conclusions— In patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, both ticagrelor and prasugrel exhibit an initial delay in the onset of their antiplatelet action. Ticagrelor did not appear superior to prasugrel in reducing PR during the first 24 hours of ST-segment–elevation myocardial infarction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01463163.

Objectives The study aimed to compare the antiplatelet action of ticagrelor with prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) while on clopidogrel after percutaneous coronary intervention (PCI). Background Newer P2Y12 inhibitors like prasugrel and ticagrelor provide stronger platelet inhibition compared with clopidogrel. Both agents are efficacious in patients with HTPR while on clopidogrel, but direct comparison between them has not yet been reported. Methods In a prospective, single-center, single-blind study, 44 (of 139 screened, 31.7%) ACS patients with HTPR while on clopidogrel 24 h post-PCI were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a crossover directly to the alternate treatment for another 15 days. HTPR was defined as platelet reactivity units (PRU) ≥235 as assessed by the VerifyNow P2Y12 function assay. Results The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 PRU, 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of –68.3 PRU (95% CI: –88.6 to –48.1; p Conclusions In patients with ACS exhibiting HTPR while on clopidogrel 24 h post-PCI, ticagrelor produces a significantly higher platelet inhibition compared with prasugrel. (Ticagrelor Versus Prasugrel in Acute Coronary Syndromes After Percutaneous Coronary Intervention; NCT01360437 )

The reactions of the NSO ligands 2-[2-(pyridin-2-yl)ethylthio]acetic acid (HL1), 3-[2-(pyridin-2-yl)ethylthio]propanoic acid (HL2), 2-(carboxymethylthio)-3-(1H-imidazol-4-yl)propanoic acid (H2L3), and 2-(carboxyethylthio)-3-(1H-imidazol-4-yl)propanoic acid (H2L4) with [NEt4]2[ReBr3(CO)3] are presented. Ligands HL1, H2L3, and H2L4 act as tridentate NSO chelators and readily generate the fac-[Re(NSO)(CO)3]complexes Re-L1, Re-HL3, and Re-HL4. Ligand HL2 acts as NSO tridentate chelator only in the presence of base to give complex Re-L2, while without base it coordinates as a NS bidentate chelator to generate complex fac-[ReBr(NS)(CO)3], Re-HL2. All complexes were isolated and characterized by elemental analysis, IR and 1H, 13C NMR spectroscopy. Complex Re-L1, Re-HL2, and Re-HL3 were characterized also by X-ray crystallography. Furthermore, the analogous technetium complexes fac-[99mTc(NSO)(CO)3]+, 99mTc-L1, 99mTc-L2, 99mTc-HL3, and 99mTc-HL4 were synthesized by reacting ligands HL1–H2L4 with the fac-[99mTc(OH2)3(CO)3]+ precursor for 30 min at 75 °C. The tracer complexes 99mTc-L1–99mTc-HL4 were found to be stable in L-cysteine and L-histidine challenge experiments. The bifunctional chelating agents that bear a second carboxylate group are promising for the development of targeted 99mTc radiopharmaceuticals.

The development of new rhenium(I)- and technetium(I)–tricarbonyl complexes can lead to potentially useful radiopharmaceuticals. In this work, the synthesis of the neutral rhenium complex fac-[Re(NSO)(CO)3], Re-1, where NSO is the tridentate chelating agent 3-(1H-imidazol-4-yl)-2-(p-methoxy-benzylthio)propionic acid 1 was effected via reaction with (NEt4)2[ReBr3(CO)3] in the presence of NaHCO3. Complex Re-1 crystallized from methanol/water and its structure was established by IR, 1H and 13C NMR spectroscopies, ESI-MS analysis and X-ray crystallography. When the reaction took place in the absence of base, HPLC analysis revealed the presence of a second product (yield 7%) that was assigned by NMR and ESI analysis to be complex fac-[Re(NS)(CO)3Br] Re-2. At the tracer level, the analogous complexes fac-[99mTc(NSO)(CO)3], 99mTc-1 and fac-[188Re(NSO)(CO)3], 188Re-1, were synthesized and their radiochemical stability in physiological conditions was determined. Both tracer complexes 99mTc-1 and 188Re-1 are stable in solution as well as in the presence of strongly coordinating agents like histidine or cysteine.

The synthesis and structural characterization of the neutral rhenium complex fac-[Re(NSO)(CO)3], Re-1, where (NSO) is a tridentate bifunctional chelating agent, 3-(carboxymethylthio)-3-(1H-imidazol-4-yl)propanoic acid (1), is presented. The complex crystallized from methanol–water and its structure was assigned by IR and 1H, 13C NMR spectroscopies and X-ray crystallography. Furthermore, the analogous technetium complex fac-[99mTc(NSO)(CO)3], 99mTc-1, was synthesized in high yield by reacting ligand 1 with the fac-[99mTc(OH2)3(CO)3]+ precursor for 30 min at 85 °C. The tracer complex was found to be more than 95% stable in the L-histidine challenge experiment. Our data indicate that the bifunctional NSO chelating agent 1 can be successfully applied for the development of potential 99mTc-radiopharmaceuticals.

Galantamine, a drug used to treat Alzheimer's disease, has recently emerged as a potential medical countermeasure against the toxicity of organophosphorus (OP) compounds, including the nerve agent soman. Here, magnetic resonance imaging (MRI) was used to characterize the neurotoxic effects of soman and the ability of galantamine to prevent these effects in guinea pigs, the best non-primate model to predict the effectiveness of antidotes against OP toxicity in humans. The brains of treated and untreated guinea pigs were imaged using a clinical 3.0 Tesla MRI scanner at 48 h before and 6–7 h, 48 h and 7 days after their challenge with 1.0xLD50 soman (26.6 μg/kg, sc). Significant brain atrophy was observed among all untreated animals at 7 days after their challenge with soman. In mildly intoxicated animals, significant shortening of spin–spin relaxation times (T2) was observed in the thalamus and amygdala at 7 h after the challenge. In severely intoxicated animals, T2 values and T2-weighted signal intensities increased significantly in the piriform cortex, hippocampus, thalamus and amygdala; in most regions, changes were long-lasting. Voxel-based morphometric analysis of the images revealed that other brain regions were also damaged in these animals. Neuronal loss was confirmed histopathologically. In animals that were treated with galantamine (8 mg/kg, im) 30 min prior to the exposure to soman, T2, T2-weighted signal intensities, and CSF volumes were largely unaffected. It is, therefore, concluded that galantamine can effectively prevent the structural brain damage induced by an acute exposure to soman.

Cryptography with Chaos was proposed by Shannon in his classic 1949 paper, although the word chaos was not mentioned. This idea has been extended and realized by Chaotic i.e. Entropy producing Torus Automorphisms. The corresponding algorithms and the software have been developed for any Torus Automorphism, adapted to be applicable for encryption in real time. We may select and combine in an arbitrary way several chaotic maps, creating in this way an infinite number of keys. Decryption is simply the reverse application of the selected maps. Therefore, the cryptography is effectively symmetric. The novelties of our work are summarized as follows: a) The possibility to design classes of chaotic torus maps with any desirable entropy production. The Torus parameters are computed as functions of the selected entropy production. b) We demonstrate how to design Torus Automorphisms with integer parameters determined from the entropy production. c) For Torus Automorphisms constructed from the Fibonacci sequence, the parameters are uniquely determined from the entropy production. d) The Encryption Mechanisms are designed and implemented by selecting and combining the Torus Maps in an arbitrary way. These Encryptions are in fact new classes and examples of MonoBlock Ciphers. e) The application of Cryptography with Chaos to content with texts and images.

The synthesis and biological evaluation of three new biotinylated fac-[(99m)Tc/Re(CO)3](+) complexes with the tridentate ligands L1, L2, and L3 are reported. L1-L3 contain the chelators 2-((5-aminopentyl)(pyridin-2-ylmethyl)amino)acetic acid, 2-(2-aminoethylthio)-3-(1H-imidazol-4-yl)propanoic acid, and 2-amino-3-(1-carboxy-2-(1H-imidazol-4-yl)ethylthio)propanoic acid, respectively, which are conjugated to biotin's carboxylate via their amine group. The fac-[Re(CO)3(L1-L3)] complexes were synthesized and characterized by NMR and IR, where the (N,N,O) coordination for ReL1 and the (N,S,O) coordination for ReL2 and ReL3 were confirmed. The tracer complexes fac-[(99m)Tc(CO)3(L1-L3)] were synthesized in high yield and were found highly stable in 10(-3) M L-histidine and L-cysteine over 24 h. Furthermore, they exhibited high binding affinity (90%) for avidin. Rat plasma studies showed complete cleavage of biotin from (99m)TcL1 after 1 h and a low percentage of intact (99m)TcL2 and (99m)TcL3 with no biotin cleavage metabolites present, over 24 h. Similarly, rat urine analysis showed the presence of intact (99m)TcL2 and (99m)TcL3, while (99m)TcL1 was cleaved. Biodistribution studies of (99m)TcL2 and (99m)TcL3 revealed fast blood and tissue clearance.

The crystallization and data collection of topoisomerase IV from S. aureus is described. Phasing by molecular replacement proved difficult owing to the presence of translational NCS and strategies used to overcome this are discussed., DNA topoisomerase IV removes undesirable topological features from DNA molecules in order to help maintain chromosome stability. Two constructs of 56 and 59 kDa spanning the DNA-cleavage domain of the A subunit of topoisomerase IV from Staphylococcus aureus (termed GrlA56 and GrlA59) have been crystallized. Crystals were grown at 291 K using the sitting-drop vapour-diffusion technique with PEG 3350 as a precipitant. Preliminary X-­ray analysis revealed that GrlA56 crystals belong to space group P21, diffract to a resolution of 2.9 Å and possess unit-cell parameters a = 83.6, b = 171.5, c = 87.8 Å, β = 90.1°, while crystals of GrlA59 belong to space group P21212, with unit-cell parameters a = 41.5, b = 171.89, c = 87.9 Å. These crystals diffract to a resolution of 2.8 Å. This is the first report of the crystallization and preliminary X-ray analysis of the DNA-cleavage domain of a topoisomerase IV from a Gram-positive organism.

The hyaluronate lyase (HL) gene ofStaphylococcus aureus8325-4 (hysA) was inactivatedin vitrowith the insertion of the erythromycin determinant,ermC, from plasmid pE194. ThehysA : : ermCmutation was introduced intoS. aureusvia a temperature-sensitive shuttle vector, where it underwent homologous recombination with the wild-type (w.t.) allele. The insertion ofermCin the chromosomalhysAlocus was confirmed by Southern blot hybridization and the loss of HL activity was demonstrated macroscopically by a plate assay. The importance of HL for pathogenicity was assessed by comparing the virulence of the HL−mutant strain to that of the w.t. in an established mouse abscess model ofS. aureusinfection. A significantly higher cell recovery was obtained from lesions infected with the w.t. strain compared to the lesions infected with the HL−strain (P=0·01). Although the lesion areas from both groups were not significantly different (P=0·9) they were of different morphology. A colorimetric assay was used to measure HL activity from culture supernatants of theS. aureus8325-4 strains w.t., WA250 (agr) and PC1839 (sar) grown in a chemically defined medium. HL activity reached a maximum in the w.t. strain during mid-exponential phase (t=5 h) and while it showed a 16-fold decrease in theagrmutant it increased 35-fold in thesarmutant background. These results strongly suggest that HL is a virulence factor which is important in the early stages of subcutaneous infections.

We would like to thank Drs Grove and Kristensen for their interest in our recently published article on ticagrelor versus prasugrel antiplatelet action in the acute phase of ST elevation myocardial infarction.1 The authors have proposed that an increased platelet turnover in ST elevation myocardial infarction may reduce the effect of antiplatelet drugs. Their suggestion is on the basis of previous observations involving 16 patients, …

We develop a novel platform based on a tele-operated robot to perform high-resolution optical coherence tomography (OCT) imaging under continuous large field-of-view magnetic resonance imaging (MRI) guidance. Intra-operative MRI (iMRI) is a promising guidance tool for high-precision surgery, but it may not have sufficient resolution or contrast to visualize certain small targets. To address these limitations, we develop an MRI-compatible OCT needle probe, which is capable of providing microscale tissue architecture in conjunction with macroscale MRI tissue morphology in real time. Coregistered MRI/OCT images on ex vivo chicken breast and human brain tissues demonstrate that the complementary imaging scales and contrast mechanisms have great potential to improve the efficiency and the accuracy of iMRI procedure.

We developed a novel platform based on a teleoperated robot to perform high-resolution optical coherence tomography (OCT) imaging under continuous MRI guidance. The combination of large-scale MRI tissue morphology and high-resolution OCT micro-architecture in a concurrent and co-registered manner has great potential to improve the accuracy of various neurosurgical procedures. In this study, we developed the first MRI-compatible OCT imaging system. We demonstrated that a thin OCT fiber probe (0.23 mm) integrated within surgical tools can provide microstructure information from the ROI under continuous MRI guidance. We tested the system's performance on chicken breast and simulated stereotactic neurosurgery on human brain ex vivo.

Introduction In patients with ST elevation myocardial infarction (STEMI) increased platelet reactivity has been described to affect the primary percutanuous coronary intervention (PPCI) outcome. We aimed to evaluate the predictive accuracy of intrinsic platelet reactivity for intracoronary thrombus burden in P2Y12 inhibitor- naive STEMI patients. Patients and Methods In a prospective, observational, cohort study we enrolled 94 consecutive STEMI patients undergoing PPCI, subjected to platelet reactivity assessment prior to any P2Y12 blockade, with visible angiographic thrombus in the infarct related artery (stratified as Grade A, B and C). Platelet-function testing was performed with the VerifyNow point-of-care P2Y12 assay immediately prior to intervention. Results Intrinsic platelet reactivity was higher with greater thrombus burden: Grade A 158.8 ± 51.1 PRU, Grade B 217.4 ± 62.1 PRU and Grade C 243.4 ± 58.6 PRU, p = 0.009 and Spearman r = 0.32 (0.12-0.49 95% CI), p = 0.002. ROC analysis revealed an AUC = 0.7 (Standard error 0.07, p = 0.03). An intrinsic platelet reactivity value of > 220 PRU had 65% sensitivity (53–76 95%CI), 76% specificity (55–91 95%CI), 88% positive predictive value (76–96 95%CI) and 44% negative predictive value (29–60 95%CI) for detection of high thrombus burden. In multivariate analysis intrinsic platelet reactivity > 220 PRU emerged as an independent predictor of high thrombus burden (RR = 1.5, 1.15-2.07 95% CI, p = 0.004). Conclusions In patients admitted with STEMI the intrinsic platelet reactivity -as assessed by a point-of-care assay- is positively associated with the degree of intracoronary thrombus, while having a moderate accuracy in predicting high thrombus burden.

The study aimed to compare the antiplatelet action of ticagrelor with prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) while on clopidogrel after percutaneous coronary intervention (PCI).Newer P2Y12 inhibitors like prasugrel and ticagrelor provide stronger platelet inhibition compared with clopidogrel. Both agents are efficacious in patients with HTPR while on clopidogrel, but direct comparison between them has not yet been reported.In a prospective, single-center, single-blind study, 44 (of 139 screened, 31.7%) ACS patients with HTPR while on clopidogrel 24 h post-PCI were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a crossover directly to the alternate treatment for another 15 days. HTPR was defined as platelet reactivity units (PRU) ≥ 235 as assessed by the VerifyNow P2Y12 function assay.The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 PRU, 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of -68.3 PRU (95% CI: -88.6 to -48.1; p0.001). The secondary endpoint of HTPR rate was 0% for ticagrelor and 2.4% for prasugrel (1 of 42, p = 0.5). No patient exhibited a major bleeding event at either treatment group.In patients with ACS exhibiting HTPR while on clopidogrel 24 h post-PCI, ticagrelor produces a significantly higher platelet inhibition compared with prasugrel. (Ticagrelor Versus Prasugrel in Acute Coronary Syndromes After Percutaneous Coronary Intervention; NCT01360437).

To the Editor: Early and strong platelet inhibition is highly desirable in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Ticagrelor, which has direct action on the P2Y12 receptor and no need for previous metabolic

Transplantation is the transfer of tissue or an organ from 1 site to another in the same person or between different persons. A transplantation in which donor and recipient are the same individual has been termed autogenous transplantation, autoplastic transplantation, or autotransplantation. The purpose of this report was to describe a patient undergoing autotransplantation of an impacted mandibular canine to its normal position in the mandible and the 12-year follow-up. Five years after the surgical procedure, the patient presented with pulp canal obliteration in the autotransplanted tooth. Twelve years after the autotransplantation, the tooth position was stable despite pulp canal obliteration, but with no sign of inflammatory resorption or a periapical lesion. In addition, there was no sign of replacement resorption (ankylosis). The endodontic literature has shown that the prognosis of patients undergoing autotransplantation may be good under specific considerations. Therefore, the technique may be a treatment plan option for the replacement of missing teeth.

Asialoglycoprotein receptor (ASGP-R) is a well-known cell surface receptor specific for liver, present in normal mammalian hepatocyte membrane. Detection of its number and activity is an excellent method for evaluating the status and function of liver [1]. Copolymer based radiotracers with controllable ratio of targeting moiety (VLA) were developed as potential ASGP-R targeted imaging agents. P(VLA-co-VNI) were synthesized by free-radical copolymerization and lyophilized for Tc instant kit labeling with high yield and RCP (N99%) [2]. Static 3D SPECT/CT images were acquired at 1 h and 4 h after injection of 18 MBq series of Tc-tracers in normalmice. The results showed that liver has specific high uptake at 1 h p.i. with good retention. (NSFC (21271030) and 973 Program of China (2014CB744503)).

Significant wear-through and dissociation failures of metal-backed, point and line contact patellar replacements are associated with excessive contact stresses on the polyethylene-bearing surfaces. Analytical mathematical contact-stress analysis was used to evaluate various patellar component geometries under loading conditions consistent with walking, stair descent, and deep knee bends, respectively. Typical point- and line-contact patellar-surface geometries exceeded the manufacturer's recommended maximum permissible compressive stress level of 10 MPa by a factor greater than three, which also exceeds the yield stress of ultra-high, molecular-weight polyethylene. A metal-backed, rotating-bearing, area contact geometry patellar replacement maintained safe contact stress levels at less than half of the maximum permissible compressive stress level. These contact stress analyses predict early fatigue failure of all-polyethylene or metal-backed, point- and line-contact patellar replacements, while predicting long-term survival of area-contact, rotating-patellar replacements. Clinical evaluation of these various implants support the conclusions of these analyses. Contact stress analysis should precede any clinical use of patellar implants to avoid predictable failure mechanisms.