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Background Klebsiella pneumoniae is armed with a wide range of antibiotic resistance mechanisms that mostly challenge effective treatment. The aims of the current study were to identify the clinical strains of K. pneumoniaealso to determine their phenotypes and molecular characterization related to antimicrobial resistance and virulence genes. Research design and methods In this investigation, clinical specimens from different hospitals located in Tehran, Iran, were collected during a nine-month period (December 2018 to August 2019). The K. pneumoniae strains were isolated and identified through standard microbial and biochemical assays. Additionally, disk diffusion, combined disk, Modified Hodge Test (MHT) and PCR were performed for antibiotic resistance and virulence gene analysis, respectively. Results Eighty-four isolates of K. pneumoniae were subjected to the study. According to the combined disk and modified Hodge test results, 27 (52%) and 15 pathotypes (62.5%) out of resistant strains of isolated K. pneumoniae were detected as ESBL and KPC producers. The virulence genes of mrkD (94%) and magA (11%) were the highest and lowest among isolates, respectively. Conclusions The high prevalence of antibiotic resistance and virulence genes in conjunction with a significant relationship between the strains revealed a high pathogenic capacity of the isolated pathotypes of K. pneumoniae.

Myocardial insulin resistance (IR) could be a predictive factor of cardiovascular events. This study aimed to introduce a new method using 123I-6-deoxy-6-iodo-d-glucose (6DIG), a pure tracer of glucose transport, for the assessment of IR using cardiac dynamic nuclear imaging. The protocol evaluated first in rat-models consisted in two 6DIG injections and one of insulin associated with planar imaging and blood sampling. Compartmental modeling was used to analyze 6DIG kinetics in basal and insulin conditions and to obtain an index of IR. As a part of a translational approach, a clinical study was then performed in 5 healthy and 6 diabetic volunteers. In rodent models, the method revealed reproducible when performed twice at 7 days apart in the same animal. Rosiglitazone, an insulin-sensitizing drug, induced a significant increase of myocardial IR index in obese Zucker rats from 0.96 ± 0.18 to 2.26 ± 0.44 (P

In this investigation, clinical specimens from different hospitals located in Tehran, Iran, were collected during a nine-month period (December 2018 to August 2019). TheEighty-four isolates ofThe high prevalence of antibiotic resistance and virulence genes in conjunction with a significant relationship between the strains revealed a high pathogenic capacity of the isolated pathotypes of

International audience; PURPOSE:Insulin resistance is a key feature of the metabolic syndrome and type 2 diabetes, in which noninvasive assessment is not currently allowed by any methodology. We previously validated an iodinated tracer of glucose transport (6DIG) and a new methodology for the in vivo quantification of cardiac insulin resistance in rodents. The aim of this study was to investigate the safety, biodistribution, and radiation dosimetry of this method using I-6DIG in 5 healthy and 6 diabetic volunteers.METHODS:The collection of adverse effects (AEs) and medical supervision of vital parameters and biological variables allowed the safety evaluation. Biodistribution was studied by sequentially acquiring whole-body images at 1, 2, 4, 8, and 24 hours postinjection. The total number of disintegrations in each organ normalized to the injected activity was calculated as the area under the time-activity curves. Dosimetry calculations were performed using OLINDA/EXM.RESULTS:No major adverse events were observed. The average dose corresponding to the 2 injections of I-6DIG used in the protocol was 182.1 ± 7.5 MBq. A fast blood clearance of I-6DIG was observed. The main route of elimination was urinary, with greater than 50% of urine activity over 24 hours. No blood or urine metabolite was detected. I-6DIG accumulation mostly occurred in elimination organs such as kidneys and liver. Mean radiation dosimetry calculations indicated an effective whole-body absorbed dose of 3.35 ± 0.57 mSv for the whole procedure.CONCLUSIONS:I-6DIG was well tolerated in human with a dosimetry profile comparable to that of other commonly used iodinated tracers, thereby allowing further clinical development of the tracer.

Aim of the study Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease which could be associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). The aim of this study was to compare GGT and IgG4 levels among children with UC with PSC and without PSC. Material and methods In this cross sectional study children with UC with PSC and UC without PSC were included. Serum immunoglobulin G4 (IgG4) and gamma-glutamyl transpeptidase (GGT) levels of the 90 UC patients with and without concomitant PSC were measured. Children with serum IgG4 concentration > 175 mg/dl were considered to have elevated IgG4. Results Elevated serum IgG4 was found in 8 of 30 (26.6%) patients with PSC vs. 3 of 60 (5.0%) patients without PSC. Compared with the group without symptoms of PSC, the group with PSC showed significantly higher levels of aspartate aminotransferases (AST; 22.5 U/l vs. 70.0 U/l, p < 0.001), alkaline phosphatase (ALP; 359.0 U/l vs. 602.0 U/l, p < 0.001), and IgG4 (56.0 vs. 73.0, p = 0.02). The odd ratio of the elevated IgG4 and GGT in predicting PSC was 6.9 (95% CI: 1.6-28.4) and 18 (95% CI: 5.7-55.9), respectively. Conclusions AST, alanine aminotransferase (ALT), GGT, ALP, and serum IgG4 were significantly higher in UC patients with sclerosing cholangitis (SC) compared to UC patients without SC. GGT and IgG-4 measurements are recommended for evaluation of UC.

Background Klebsiella pneumoniae is armed with a wide range of antibiotic resistance mechanisms which mostly challenges effective treatment. Due to this fact, the aims of the current study were to identify the clinical strains of K . pneumoniae as well as to determine their phenotypes and molecular characterization related to antimicrobial resistance and virulence genes. Methods In this investigation, specimens from a hospital and different laboratories located in Shahr-e-Qods, Tehran, Iran were collected during a period of nine-month (December 2018 to August 2019). The isolated strains of K. pneumoniae were then identified through standard microbial and biochemical assays. Additionally, disk diffusion, combined disk, modified Hodge test and PCR were performed for antibiotic resistance of the strains and virulence genes profiling, respectively. The molecular typing was accomplished by ERIC-PCR. Results Eighty-four isolates of K. pneumoniae were identified and subjected to the study. Fifty- two percent of the isolated strains of K. pneumoniae were detected as multidrug resistant (MDR) pathotypes with the highest resistance to ceftriaxone (65%) and the lowest resistance to colistin (23%). Twenty-seven (52%) out of 52 (100%) MDR pathotypes of isolated K. pneumoniae were identified as ESBL producers. According to Modified Hodge Test (MHT) results, out of 24 resistant strains of isolated K. pneumoniae to imipenem and meropenem, 15 pathotypes (62.5%) were detected as KPC producers. The gene of blaCTX (encoding carbapenemase) with 96% ranked first, while the blaKPC gene with the prevalence of 71% ranked second among ESBL producers. The aminoglycoside resistance gene of Aac6-Ib showed the highest frequency with the prevalence percentage of 90%. The virulence genes of mrkD (94%) and magA (11%) were the highest and lowest among isolates, respectively. According to ERIC-PCR results the isolated strains of K. pneumoniae were divided into four clusters in which the cluster 4 was predominant group. Conclusions The high prevalence of antibiotic resistance and virulence genes in conjunction with a significant relationship between the strains reveals a high pathogenic capacity of the isolated pathotypes of K. pneumoniae . These findings emphasize the choose of more effective antibiotic regimens for treatment of infections caused by K. pneumoniae. Keywords: Klebsiella pneumoniae , antibiotic resistance, ESBL, virulence genes, molecular typing.

NeoB is a radiotracer targeting the gastrin-releasing peptide receptor (GRPR), a G-protein–coupled receptor expressed in various cancers. The aim of the present study was to evaluate the biodistribution and efficacy of this new therapeutic agent in Gastrointestinal Stromal Tumors (GIST). Eighty-two SCID mice bearing GIST-882 tumors were employed. [177Lu]Lu-NeoB biodistribution was evaluated up to seven days by organ sampling (200 pmol/0.8 MBq, i.v.). For efficacy evaluation, mice received either saline, 400 pmol or 800 pmol of [177Lu]Lu-NeoB (37MBq, 1/w, 3 w, i.v.). SPECT/CT imaging was performed at 24 h, and tumor volume was determined up to 100 days. Elevated and specific [177Lu]Lu-NeoB uptake was found in the GIST tumor, as demonstrated by in vivo competition (19.1 ± 3.9 %ID/g vs. 0.3 ± 0.1 %ID/g at 4h). [177Lu]Lu-NeoB tumor retention (half-life of 40.2 h) resulted in elevated tumor-to-background ratios. Tumor volumes were significantly reduced in both treated groups (p &lt, 0.01), even leading to complete tumor regression at the 400 pmol dose. [177Lu]Lu-NeoB exhibited excellent pharmacokinetics with elevated and prolonged tumor uptake and low uptake in non-target organs such as pancreas. The potential of this new theragnostic agent in different indications, including GIST, is under evaluation in the FIH [177Lu]Lu-NeoB clinical trial.

Introduction: Diarrheal disorders remain a major disease burden throughout the world in pediatrics that remains a health problem. Several treatment methods have been proposed to treat diarrhea, however each of them has some problems. Objectives: The aim of this study was the evaluation the effect of oral Saccharomyces boulardii on the duration and severity of colitis. Patients and Methods: This randomized clinical trial study included ninety-four patients with acute colitis were enrolled. The children were divided randomly into case and control groups. The control group received supportive treatment including intravenous or oral fluid therapy (ORS solution), antibiotic treatment with azithromycin suspension, and zinc sulfate syrup daily for five days. In addition to the mentioned treatments, the intervention group received S. boulardii as a probiotic capsule. Then, the duration and severity of diarrhea based on the Vesikari score were evaluated for all the patients for five first days. Results: The mean of Vesikari score after the first day in both groups was similar, while after the third and fifth day in the probiotic group this score was lower than the control group (5.11 ± 1.73 versus 6.13 ± 2.25, P=0.031 and 2.36 ± 1.16 versus 4.28 ±1.19, P

Functional abdominal pain (FAP) is one of the major gastrointestinal complaints in childhood. Studies have reported occult constipation (OC) as one of the leading causes of abdominal pain. Recent researches have proposed laxatives as potent therapeutic targets for abdominal pain in patients with OC. However, no study has compared effect of poly ethylene glycol (PEG) and lactulose on occult constipation.51 patients aged 4 to 18 years with abdominal pain who had OC (defined as fecal impaction in abdominal X ray) were studied. Demographic and clinical data including age, sex, body weight, height, abdominal pain duration, abdominal pain rate and fecal odor were registered. They were randomly assigned to receive PEG (1gr/kg) or Lactulose (1cc/kg) for at least two weeks. All patients were reevaluated by pain measurement scale after at least two weeks of treatment.It is indicated that the efficacy of PEG for reducing abdominal pain in OC was 48% while it was 37% for Lactulose. This study indicated that this efficacy is not affected significantly by sex and fecal odor, however this efficacy is influenced by age, body weight, abdominal pain duration and abdominal pain rate for both PEG and Lactulose.It could be concluded that PEG is a more efficient drug for treating abdominal pain in occult constipation than Lactulose and its optimum effect can be achieved in elder patients with more severe abdominal pain.

Background & aim: Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants. Method: With the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10-related genes. Result: In 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway. Conclusion: Our study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate-gene or genes sequencing to the firstly parallel genomic screening followed by functional studies. (C) 2017 Elsevier Masson SAS. All rights reserved

Recent progress in breast cancer research has led to the identification of Vascular Cell Adhesion Molecule-1 (VCAM-1) as a key actor of metastatic colonization. VCAM-1 promotes lung-metastases and is associated with clinical early recurrence and poor outcome in triple negative breast cancer (TNBC). Our objective was to perform the in vivo imaging of VCAM-1 in mice models of TNBC. The Cancer Genomic Atlas (TCGA) database was analyzed to evaluate the prognostic role of VCAM-1 in TNBC. MDA-MB-231 (VCAM-1+) and control HCC70 (VCAM-1-) TNBC cells were subcutaneously xenografted in mice and VCAM-1 expression was assessed in vivo by single-photon emission computed tomography (SPECT) imaging using 99mTc-cAbVCAM1-5. Then, MDA-MB-231 cells were intravenously injected in mice and VCAM-1 expression in lung metastasis was assessed by SPECT imaging after 8 weeks. TCGA analysis showed that VCAM-1 is associated with a poor prognosis in TNBC patients. In subcutaneous tumor models, 99mTc-cAbVCAM1-5 uptake was 2-fold higher in MDA-MB-231 than in HCC70 (p < 0.01), and 4-fold higher than that of the irrelevant control (p < 0.01). Moreover, 99mTc-cAbVCAM1-5 uptake in MDA-MB-231 lung metastases was also higher than that of 99mTc-Ctl (p < 0.05). 99mTc-cAbVCAM1-5 is therefore a suitable tool to evaluate the role of VCAM-1 as a marker of tumor aggressiveness of TNBC.

International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.

Salmonella is an important cause of food-borne infection worldwide. Detection of outbreaks caused by Salmonella spp. relies on suitable and robust methods for genotyping. Little is known about the genetic diversity of the Salmonella enterica subspecies enterica serotype Infantis strains isolated from human sources in Iran. In this study, 40 isolates of S. Infantis, which were previously recovered from patients with gastroenteritis or diarrhea in Tehran between years 2007 and 2009, were subjected to multiple-locus variable-number of tandem repeat (VNTR) analysis (MLVA), pulsed-field gel electrophoresis (PFGE), and ERIC-PCR. Using MLVA method, 31 types were identified. The MLVA clustering of the isolates by the unweighted pair group method with arithmetic mean (UPGMA) revealed the presence of two major clusters. The discriminatory power of MLVA was superior to that of PFGE and ERIC-PCR. Overall, our data showed that MLVA assay could effectively differentiate closely related strains. It is technically simple and inexpensive to perform. Furthermore, MLVA can be used as a helpful method for epidemiological investigations.

New strategies allowing the transfer of molecules, especially peptides, through the blood-brain barriers are a major pharmacological challenge for the treatment of brain diseases. The present study aims at evaluating in vivo the cerebral bioavailability of carrier systems, based on small and functionalizable 2,5-diketopiperazine (DKP) motifs. We studied 2 different cyclo(Lys-Lys) DKP scaffolds alone and a cyclo(Lys-Gly) DKP carrier bearing as peptide model, the tau protein hexapeptide VQIVYK sequence. The different carrier systems were synthesized and radiolabeled using one of the free domains. The stability, biodistribution, and ability to cross blood-brain barrier were investigated in vivo in mice for 99mTc-DKP scaffolds, 99mTc-HVQIVYK peptide alone, and 99mTc-DKP-VQIVYK. 125I-labelled bovine serum albumin was used as negative control for brain uptake. Both radiolabeled DKPs scaffolds and 99mTc-DKP-VQIVYK showed a high stability, while peptide 99mTc-HVQIVYK alone was quickly degraded in vivo. The presence of 99mTc-DKPs scaffolds and 99mTc-DKP-VQIVYK was observed in the ventricular and subarachnoid spaces and to a lower extent in the brain parenchyma up to 45 minutes post-injection in mice. This work highlights the potentiality of DKP scaffolds as vectors to transport peptides into the brain by limiting proteolysis and favoring cerebral bioavailability.

The objective of this study is to develop (1) a pose-categorization model that classifies the poses of an occupant based on their image in an indoor space and (2) an activity-decision algorithm that identifies the activity being performed by the occupant. For developing an automated intelligent model, a deep neural network is adopted. The model considers the coordinates of the joints of the occupant in the image as input data and returns the pose of the occupant. Datasets composed of indoor images of home and office environments are used for training and testing the model. The training and testing accuracies of the optimized model were 100% for both the home and office environments. A representative activity of an occupant for a certain period has to be decided to control an indoor environment for comfort. The activity-decision algorithm employs a frequency-based method to determine the representative activity type for real-time occupant poses using the pose-categorization model. This study highlights the potential of the developed model and algorithm to determine the activity of occupants to provide an optimal thermal environment corresponding to the individual&rsquo, s metabolic rate.

International audience; Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triple-negative breast cancer not responding to trastuzumab or hormone-based therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99mTc-A1 and 99mTc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99mTc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triple-negative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99mTc-A1 and 99mTc-C6 bound mesothelin with high affinity in vitro, with 99mTc-A1 affinity being 2.4-fold higher than that of 99mTc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P < 0.05). 99mTc-A1 and 99mTc-C6 remained stable in vivo in murine blood (>80% at 2 h) and ex vivo in human blood (>90% at 6 h). In vivo 99mTc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99mTc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P < 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99mTc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99mTc-A1 and 99mTc-C6. Considering its superior characteristics, 99mTc-A1 was selected as the most suitable tool for further clinical translation.

In this research, the equilibrium sorption of nickel(II) by inexpensive dead fungal biomass of Aspergillus awamori was explained using the linear and nonlinear regression analysis of Freundlich, Langmuir, Temkin, and Redlich–Peterson isotherms. In the case of nonlinear regression method, the best fitting model was evaluated using six different error functions, namely coefficient of determination (r2), chi-square test (χ2), hybrid fractional error function (HYBRID), Marquardt’s percent standard deviation (MPSD), average relative error (ARE), and sum of the errors squared (SSE). The r2 function was found to be a better option to minimize the error distribution between the experimental equilibrium data and the predicted two-parameter isotherms. In the case of three-parameter isotherm, HYBRID was found to be the best error function to minimize the error distribution structure between experimental equilibrium data and theoretical isotherms.

In this study, a comparison between linear and nonlinear methods of estimating the kinetic parameters of Nickel(II) removal onto calcium alginate was examined. The kinetic data were analyzed using the four different type of pseudo-second-order linear kinetic model. The coefficient of determination r2 and chi-square test χ2 was employed as methods of error analysis for determining the best-fitting equation. The type 3 pseudo-second-order kinetic model accurately represented the kinetic uptake of Ni(II) by Ca-alginate. Further, the nonlinear method of pseudo-second-order was suitable in estimating biosorption parameters. In addition, the χ2 test was found to be a better method for determination of the best-fitting model. EDX analysis of Ca-alginate biosorbent before and after Ni(II) sorption revealed that the ion-exchange mechanism was the principal sorption process.

In this research, the kinetics and equilibrium of nickel(II) biosorption were studied in aqueous solutions using batch technique. The biosorption was carried on Ca-alginate beads, on nonliving mycelium of Aspergillus awamori immobilized on Ca-alginate, and on free fungal biomass. The biosorbents were characterized by FTIR and SEM analyses. The experimental data were analyzed in terms of pseudo-first-order, pseudo-second-order, and intraparticle diffusion kinetic models. It was observed that the biosorption process of Ni(II) ions followed well pseudo-second-order model on all biosorbents. The experimental results showed that biosorption equilibrium on blank Ca-alginate, free biomass, and immobilized fungal biomass fit better to the Langmuir model when compared with the Freundlich model in concentration range studied (25–75 mg L−1). The results showed that the maximum monolayer biosorption capacity of the immobilized fungal biosorbent was 8.34 mg g−1 when compared with the blank Ca-alginate and free biomass with 4.63 and 7.13 mg g−1, respectively. © 2015 American Institute of Chemical Engineers Environ Prog, 34: 1356–1364, 2015

International audience; The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E-/- mice. Methods: Apolipoprotein E-/- mice were fed the Paigen diet (1.25% cholesterol, 0.5% cholic acid, and 15% fat) without or with ezetimibe (7 mg/kg/d) for 6 wk. In a first set of mice (n = 15), we intravenously injected 3H-cholesteryl oleate-labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set (n = 20), we used the imaging agent 99mTc-cAbVCAM1-5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set (n = 21), we compared VCAM-1 expression with 99mTc-cAbVCAM1-5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL-cholesteryl ester plasma disappearance rate (P < 0.001 vs. control) after 3H-cholesteryl oleate-labeled LDL injection. At 96 h after injection, the hepatic fraction of 3H-tracer was 61% lower in mice treated with ezetimibe (P < 0.001). Meanwhile, LDL-derived 3H-cholesterol excretion in the feces was 107% higher (P < 0.001). The antiatherogenic effect of ezetimibe monitored by 99mTc-cAbVCAM1-5 SPECT showed a 49% reduction in aortic tracer uptake (percentage injected dose per cubic centimeter, 0.95 ± 0.04 vs. 1.87 ± 0.11; P < 0.01). In addition to hypercholesterolemia, the proinflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues, including the aorta, and this expression correlated strongly with 99mTc-cAbVCAM1-5 uptake (r = 0.75; P < 0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes antiatherosclerotic effects through increased LDL cholesterol catabolism and LDL-derived cholesterol fecal excretion and reduces inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding ezetimibe to a statin therapy.

Background. Eosinophilic esophagitis is an inflammatory condition where there is a dense infiltration of eosinophils typically exceeding fifteen cells per high power field. Familial Mediterranean fever is an autosomal recessive disorder characterized by brief, acute, and self-limited episodes of fever and polyserositis that recur at irregular intervals. Case Presentation. A three-year-and-nine-month-old Iranian girl was admitted to our center. The patient’s parents complained of a history of abdominal pain, poor appetite, and poor weight gain from 1.5 years ago and episodes of food impaction after starting solid foods. Eosinophilic esophagitis was diagnosed based on histology. Because of continuing abdominal pain after treatment of eosinophilic esophagitis, the episodic nature of disease, and the presence of fever with pain, screening for familial Mediterranean fever mutation was performed and the patient was found to be heterozygote for Mediterranean fever. Conclusion. We have reported a case of eosinophilic esophagitis coexisting with familial Mediterranean fever which has not been described previously.

Mono-and poly- iodinated peptides form frequently during radioiodination procedures. However, the formation of a single species in its mono-iodinated form is essential for quantitative studies such as determination of tissue concentration or image quantification. Therefore, the aim of the present study was to define the optimal experimental conditions in order to exclusively obtain the mono-iodinated form of L-maurocalcine (L-MCa). L-MCa is an animal venom toxin which was shown to act as a cell-penetrating peptide. In order to apply the current direct radioiodination technique using oxidative agents including chloramine T, Iodo-Gen® or lactoperoxidase, an analogue of this peptide containing a tyrosine residue (Tyr-L-MCa) was synthesized and was shown to fold/oxidize properly. The enzymatic approach using lactoperoxidase/H2O2 was found to be the best method for radioiodination of Tyr-L-MCa. MALDI-TOF mass spectrometry analyses were then used for identification of the chromatographic eluting components of the reaction mixtures. We observed that the production of different radioiodinated species depended upon the reaction conditions. Our results successfully described the experimental conditions of peptide radioiodination allowing the exclusive production of the mono-iodinated form with high radiochemical purity and without the need for a purification step. Mono-radioiodination of L-Tyr-MCa will be crucial for future quantitative studies, investigating the mechanism of cell penetration and in vivo biodistribution.

Vascular cell adhesion molecule 1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. We previously showed that the (99m)Tc-labeled major histocompatibility complex 1-derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits. However, B2702p target-to-background ratio was suboptimal for the in vivo imaging of VCAM-1 expression in atherosclerotic lesions. To improve the target-to-background ratio, 20 derivatives of B2702p (B2702p1-B2702p20) were synthesized using the alanine scan methodology. We hypothesized that (99m)Tc-radiolabeled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis.A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in apolipoprotein E double-knockout (ApoE(-/-)) mice was used (n = 82). (99m)Tc-B2702p and (99m)Tc-B2702p1-(99m)Tc-B2702p20 were injected intravenously in anesthetized animals 3 wk after the ligation. Whole-body planar imaging was performed for 3 h. SPECT imaging of 6 additional ligated ApoE(-/-) mice was also performed with (99m)Tc-B2702p1. The animals were then euthanized, and the biodistribution of (99m)Tc-labeled peptides was evaluated by γ-well counting of excised organs. Expression of VCAM-1 in the ligated and contralateral carotid arteries was evaluated by immunohistology.Robust VCAM-1 immunostaining was observed in the left carotid atherosclerotic lesions as a consequence of artery ligation, whereas no VCAM-1 expression was detected in the contralateral carotid artery. Among all evaluated peptides, (99m)Tc-B2702p1 exhibited the most favorable properties. By γ-well counting, there was a significant 2.0-fold increase in the (99m)Tc-B2702p1 left-to-right carotid artery activity ratio (2.6 ± 0.6) and a 3.4-fold increase in the left carotid-to-blood activity ratio (1.4 ± 0.4) in comparison to (99m)Tc-B2702p (1.3 ± 0.2 and 0.4 ± 0.1, respectively, P0.05 for both comparisons). Similarly, planar image quantification indicated a higher left-to-right carotid activity ratio in (99m)Tc-B2702p1- than in (99m)Tc-B2702p-injected mice (1.2 ± 0.1 vs. 1.0 ± 0.0, respectively, P0.05). Finally, a significantly higher (99m)Tc-B2702p1 activity in the left than in the right carotid artery was observed by SPECT imaging (2.2 ± 0.4 vs. 1.4 ± 0.3 cpm/mm(2)/injected dose, respectively, P0.05).(99m)Tc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.

Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERα and ERβ) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development.Immunoreactive (ir) ezrin, ir-ERα, and ir-ERβ were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response.Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 ( P = .004) and 2× normal in metastatic CXCA. Estrogen receptor α and ERβ H scores fell, reaching significance by CIN3 (ERα, P = .0001; ERβ, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes.During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.

The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E

Gas-liquid membrane contactors offer several practical advantages including high surface area per unit volume; independent control of gas and liquid velocities without any flooding, loading, weeping, or foaming, pre-determined gas–liquid interfacial area, membrane modules, capability of linear scale-up; low corrosion problems, and low operation and capital costs. Two common types of membrane contactors are extensively utilized for gas separation. However, most studies have focused on the hollow-fiber membrane contactors. The main advantage of flat-sheet membrane contactors is that not only any type of membrane can be formed into flat-sheet membrane module but also fabrication of flat-sheet membranes is also easier compared to other types of membranes. A mass transfer model was developed in this study to investigate the performance of flatsheet membrane contactors for gas absorption. The model was based on the behavior of gas and liquid phases in the membrane contactor by taking the distribution of gas concentration as well as the gas and liquid velocity profiles along the flowing direction into account. Both chemical and physical absorptions were considered. The model also uses computational fluid dynamics of mass and momentum transfer in both gas and liquid phases in the membrane contactor. An appropriate numerical method based on the finite element method was applied to solve the model equations. The model predictions were validated against the experimental data obtained from literature for the absorption of CO 2 . The results were in good agreement with the experimental data with different values of flow rates. The model predictions indicated that the removal of CO 2 was increased with increasing the liquid velocity in the membrane contactor. On the other hand, increasing temperature and gas velocity in the flat-sheet membrane contactor showed an opposite effect on the removal of CO 2 . It is indicated that the proposed model well predicts the mass transfer within the flat-sheet membrane contactors.

Natural variables, including environmental conditions and post-mortem interval (PMI), affect the course of tissue decay in forensic and archaeological contexts. Compared with soft tissue, skeletal materials provide longer protection against DNA degradation. However environmental factors, including temperature and humidity, may affect the longevity of DNA survival in bone structure. In this study we describe the development of a semi-quantitative multiplex PCR based method to assess the level of DNA degradation with applications in analysis of forensic specimens. The assay was then applied to assess DNA survival in rib bone samples taken from 12 corpses in the mortuary. Samples were de-fleshed and stored in two different environmental conditions, including ambient conditions and underground burial from 103 to 445 days. Bone DNA was extracted and then assessed by the optimized semi-quantitative PCR and capillary electrophoresis of three products from the human mitochondrial DNA. The results show DNA survive...

Background: Knowledge of intravascular volume (IV) status of a hypotensive patient is of utmost importance. Clinical evaluation and central venous pressure (CVP) measurement are routinely used as a guide for evaluation of IV in these patients. However, clinical assessment may be inaccurate, and CVP measurement is invasive. Moreover, CVP changes slowly with saline therapy, which is unfavorable for fluid resuscitation. Aim: Our aim is to find the correlation and sensitivity of inferior vena cava (IVC) diameter measured by ultrasound to provide a noninvasive method for evaluation of IV among patients with hypotension and hypovolemia in the emergency department (ED). Methods: We measured the IVC diameter of hypotensive patients before and after saline therapy. As all of the patients had central venous line (CV-line) in place, CVP was also measured before and after. Using MedCalc and SPSS software the correlation between these two was determined as expressed with “r.” Then, receiver operating characteristic (ROC) curve was sketched. Results: Ninety-nine patients, 49 (49.5%) males, were evaluated. Mean systolic blood pressure was 90 mmHg with a mean hazard ratio about 104. IVC diameter was 7.44 ± 5.13 mm before and 9.84 ± 5.29 after (P = 0.002) saline therapy. There was a high correlation between IVC diameter and CVP (r = 0.941, P < 0.0001 before saline therapy and r = 0.95, P < 0.0001 after saline therapy). ROC curve for IVC diameter shows a very high sensitivity for all criteria values. Conclusion: IVC diameter measurement using ultrasonography has excellent correlation with CVP. This method is very sensitive to rapid IV changes thus useful to guide saline therapy in hypotensive patients referred to ED. However, its use in certain subsets of patients' needs further studies.

A comprehensive model has been developed for investigating the absorption of carbon dioxide in hot potassium carbonate solution with boric acid catalyst. The model consists of the kinetics of key reactions and considers the interactions between mass-transfer and chemical kinetics. The mass-transfer coefficient was calculated using the surface renewal theory and the chemical reaction in the liquid phase is based on the bicarbonate ion formation from CO2 as the rate-determining step. The mathematical models comprising coupled sets of non-linear differential and algebraic equations were solved using our software package for the absorber. The model was validated using plant data and was used to compute the flow, temperature and concentration profiles in the absorber for sensitivity analysis. The variation in exit CO2 concentration with respect to the operating conditions was also examined.

Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make it a potential peptide of choice for clinical and biotechnological applications. The aim of the present study was to gain new information about the properties of MCa in vivo in order to delineate the future potential applications of this vector. For this purpose, two analogues of this peptide with (Tyr-MCa) and without (Lin-Tyr-MCa) disulfide bridges were synthesized, radiolabeled with 125I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that 125I-Tyr-MCa was stable in vitro and that the disulfide bridges conferred a competitive advantage for the stability of peptide. Following in vivo injection in mice, 125I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal.

Background: Intestinal cholesterol absorption inhibitor ezetimibe (EZE) added to a statin therapy has demonstrated benefits in the IMPROVE-IT trial by further reducing LDL-cholesterol levels than statin therapy alone. We investigated the mechanisms by which EZE could contribute to cardiovascular events reduction in apolipoprotein E knock-out (apoE ko) mice. Methods: ApoE ko mice were fed a Paigen diet without (control) or with EZE (7mg/kg/day) for 6 weeks. To evaluate the effects of EZE on LDL-cholesterol metabolism and excretion, a first set of mice was injected intravenously with 3 H-cholesteryl oleate labeled human LDL. A second set of mice was used for in vivo SPECT/CT imaging of 99m Tc-cAbVCAM1-5, a single domain antibody directed against the Vascular Cell Adhesion Molecule-1 (VCAM-1), which was used as a marker of inflamed atherosclerotic plaques. The same mice were sacrificed for autoradiography and histology of aortic atherosclerotic plaques. Results: Compared with control, EZE treatment for 6 weeks induced a significant 41% and 65% reduction in plasma total cholesterol levels and atherosclerotic plaque area, respectively. After injection of 3 H-cholesteryl oleate labeled human LDL, mice treated with EZE showed a 173% higher LDL-cholesteryl ester catabolism (p3 H-tracer hepatic recovery was reduced by 61% with EZE (p3 H-tracer excretion in the feces was increased by 107% in the fecal cholesterol fraction (p After intravenous injection of 99m Tc-cAbVCAM1-5, mice treated with EZE also showed a significant 52% reduction in aortic uptake, which was confirmed by significant reduction in tracer uptake in ex vivo biodistribution and autoradiography analysis. Conclusion: EZE promotes anti-atherosclerotic effects through increased LDL-cholesterol catabolism and LDL-derived cholesterol fecal excretion, and reduced inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding EZE to a statin therapy.

Introduction RNA interference is efficient in in vitro studies, and appears as a therapeutic tool of major clinical interest. Nevertheless, the clinical utilisation of siRNAs is restrained by the poor availability of biodistribution data on this new class of pharmaceutics. This study aimed at defining the biodistribution and pharmacokinetics properties of an siRNA directed to the Casein Kinase-2 beta (CK2β) subunit, a potential target in cancer therapy. Methods Four CK2β siRNAs were chemically modified on each extremity of sense or anti-sense strand and radioiodinated. The biodistribution of each entity was analysed in glioblastoma-bearing mice using nuclear imaging and compared to a control GFP siRNA. Results The labelling process was associated with preservation of interference activity, except when applied to the 5 ' antisense terminus. Radioactivity was predominantly observed in organs of the excretory system after intravenous administration: liver, kidneys and bladder. Tumor/Contralateral muscle ratio showed significant differences depending on the labelling site. Activity associated with CK2β 5 ' s was quite constant over 2hours, while CK2β 3 ' as activity decreased by 40% in tumor. Finally, synchrotron X-ray analysis showed that CK2β 3 ' s is more abundant in tumor than in liver, brain or muscle, and uniformly distributed between intra- and extracellular compartments. Conclusions In this study, we highlighted the large influence of siRNAs radiolabelling position on their biodistribution and pharmacokinetic profiles, and proposed a systematic approach for the imaging of all siRNAs of clinical interest.

International audience; PurposeThe αvβ3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvβ3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with β− emitters in a nude mouse model of αvβ3 integrin-expressing tumours.MethodsBiodistribution and SPECT/CT imaging studies were performed after injection of 90Y-RAFT-RGD or 177Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with 90Y-RAFT-RGD or 177Lu-RAFT-RGD and 90Y-RAFT-RAD or 177Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvβ3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvβ3. Tumour volume doubling time was used to evaluate the efficacy of each treatment.ResultsInjection of 37 MBq of 90Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of 177Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of 90Y-RAFT-RAD or 37 MBq of 177Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of 90Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours.Conclusion90Y-RAFT-RGD and 177Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy.

"Design of an amplification technique and assessment of a pentanucleotide tandem repeat, with locus of D6Sp57, for human identity testing in forensic sciences were investigated in this study. This short tandem repeat (STR) has a repeating sequence of CACAG. The sequence repetition and the size of STR product are specific to each person. The selective amplification of this locus in different individual genomes by polymerizes chain reaction (PCR) technique needs the optimal processing condition of thermocycler and the master mix. This optimization can be done by the correct choice of the primers and the optimization of PCR protocol. The STR of five blood samples from different individuals was amplified by PCR under the optimal condition. The products of the reaction were electrophoretically separated on a polyacrylamide gel. The results have shown the specificity of the marker to different individuals and approved the applicability of this pentanucletide marker for forensic purposes"