Publications by authors named "Mitra Ahmadi"

33 Publications

Preclinical and clinical evaluation of a new method to assess cardiac insulin resistance using nuclear imaging.

J Nucl Cardiol 2021 Jan 27. Epub 2021 Jan 27.

Univ. Grenoble Alpes, Inserm, CHU Grenoble Alpes, LRB U1039, 38000, Grenoble, France.

Background: Myocardial insulin resistance (IR) could be a predictive factor of cardiovascular events. This study aimed to introduce a new method using I-6-deoxy-6-iodo-D-glucose (6DIG), a pure tracer of glucose transport, for the assessment of IR using cardiac dynamic nuclear imaging.

Methods: 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.

Results: 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<.05) after 7 days of an oral treatment, and 6DIG IR indexes correlated with the gold standard IR index obtained through the hyperinsulinemic-euglycemic clamp (r=.68, P<.02). In human, a factorial analysis was applied on images to obtain vascular and myocardial kinetics before compartmental modeling. 1.5-fold to 2.2-fold decreases in mean cardiac IR indexes from healthy to diabetic volunteers were observed without reaching statistical significance.

Conclusions: These preclinical results demonstrate the reproducibility and sensibility of this novel imaging methodology. Although this first in-human study showed that this new method could be rapidly performed, larger studies need to be planned in order to confirm its performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12350-020-02520-7DOI Listing
January 2021

INCIDENCE OF MALNUTRITION, ESOPHAGEAL STENOSIS AND RESPIRATORY COMPLICATIONS AMONG CHILDREN WITH REPAIRED ESOPHAGEAL ATRESIA.

Arq Bras Cir Dig 2020 18;33(3):e1537. Epub 2020 Dec 18.

Nursing Care Research Center in Chronic Diseases.

Background: Esophageal atresia is congenital anomaly with high mortality. Surgical complications and changes in nutritional status are common problems after surgical correction. Aim: To evaluate nutritional status, esophageal stenosis, and respiratory complications among children who had repaired esophageal atresia.

Methods: Children aged >2 months old with repaired esophageal atresia were included in the current study. Gender, age, weight, and height were recorded for each case. Height for age and weight for age were calculated for each case.

Results: According to weight for length percentile, 41.02% of the cases were underweight. Esophageal stenosis was seen in 54.76% of the obtained esophagograms.

Conclusion: Underweight was present in 41.02 of the patients according to weight-for-height percentile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/0102-672020200003e1537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747482PMC
December 2020

Incidence of malnutrition, esophageal stenosis and respiratory complications among children with repaired esophageal atresia.

Arq Bras Cir Dig 2020 13;33(1):e1486. Epub 2020 Nov 13.

Nursing Care Research Center in Chronic Diseases.

Background: Esophageal atresia is congenital anomaly with high mortality. Surgical complications and changes in nutritional status are common problems after surgical correction.

Aim: o evaluate nutritional status, esophageal stenosis, and respiratory complications among children who had repaired esophageal atresia.

Methods: Children aged >2 months old with repaired esophageal atresia were included in the current study. Gender, age, weight, and height were recorded for each case. Height for age and weight for age were calculated for each case.

Results: According to weight for length percentile, 41.02% of the cases were underweight. Esophageal stenosis was seen in 54.76% of the obtained esophagograms.

Conclusion: Underweight was present in 41.02 of the patients according to weight-for-height percentile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/0102-672020190001e1486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668295PMC
December 2020

Effect of polyethylene glycol versus lactulose on abdominal pain in children occult constipation: a randomized controlled study.

Rev Gastroenterol Peru 2019 Oct-Dec;39(4):323-328

Dept. of Pediatric Gastroenterology, Abuzar Children's Hospital, Ahvaz Jundishapur University of Medical Sciences. Ahvaz, Iran; Alimentary Tract Research Center, Ahvaz Jundishapur University of Medical Sciences. Ahvaz, Iran.

Introduction And Aim: 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.

Materials And Methods: 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.

Results: 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.

Conclusion: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2020

IgG4 subclass and gamma-glutamyl transferase in children with ulcerative colitis with primary sclerosing cholangitis and without sclerosing cholangitis.

Clin Exp Hepatol 2019 Nov 17;5(4):285-288. Epub 2019 Oct 17.

Alimentary Tract Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

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, < 0.001), alkaline phosphatase (ALP; 359.0 U/l vs. 602.0 U/l, < 0.001), and IgG4 (56.0 vs. 73.0, = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5114/ceh.2019.89119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935853PMC
November 2019

In Vivo Assessment of VCAM-1 Expression by SPECT/CT Imaging in Mice Models of Human Triple Negative Breast Cancer.

Cancers (Basel) 2019 Jul 23;11(7). Epub 2019 Jul 23.

Laboratory of Bioclinical Radiopharmaceutics, Universite Grenoble Alpes, Inserm, CHU Grenoble Alpes, LRB, 38000 Grenoble, France.

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 Tc-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, Tc-cAbVCAM1-5 uptake was 2-fold higher in MDA-MB-231 than in HCC70 ( < 0.01), and 4-fold higher than that of the irrelevant control ( < 0.01). Moreover, Tc-cAbVCAM1-5 uptake in MDA-MB-231 lung metastases was also higher than that of Tc-Ctl ( < 0.05). Tc-cAbVCAM1-5 is therefore a suitable tool to evaluate the role of VCAM-1 as a marker of tumor aggressiveness of TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11071039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678795PMC
July 2019

Safety, Biodistribution, and Dosimetry of 123I-6-Deoxy-6-Iodo-D-Glucose, a Tracer of Glucose Transport, in Healthy and Diabetic Volunteers.

Clin Nucl Med 2019 May;44(5):386-393

Department of Nuclear Medicine, CHU Grenoble Alpes, Grenoble, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RLU.0000000000002510DOI Listing
May 2019

A proliferation-inducing ligand-mediated anti-inflammatory response of astrocytes in multiple sclerosis.

Ann Neurol 2019 03 4;85(3):406-420. Epub 2019 Feb 4.

Institute for Advanced Biosciences, Grenoble Alpes University/National Institute of Health and Medical Research U1209/National Center for Scientific Research UMR5309, La Tronche, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25415DOI Listing
March 2019

Inferior vena cava diameter as a guide in hypotensive patients for appropriate saline therapy: An observational study.

Int J Crit Illn Inj Sci 2018 Jul-Sep;8(3):160-164

Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.

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 "." 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 ( = 0.002) saline therapy. There was a high correlation between IVC diameter and CVP ( = 0.941, < 0.0001 before saline therapy and = 0.95, < 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/IJCIIS.IJCIIS_27_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116307PMC
September 2018

Post-Traumatic Pulmonary Pseudocyst following Blunt Chest Trauma; a Case Report.

Emerg (Tehran) 2018 1;6(1):e29. Epub 2018 May 1.

Department of Emergency Medicine, Hasheminejad Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Traumatic pulmonary pseudocyst is a rare complication of chest trauma that has been poorly documented and usually resolves without specific treatment. Here, we present a case of pulmonary pseudocyst in a child with chest trauma without obvious symptoms. It is important to consider this diagnosis in patients with chest trauma to avoid unnecessary invasive procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036524PMC
May 2018

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer.

J Nucl Med 2018 07 23;59(7):1056-1062. Epub 2018 Mar 23.

Université Grenoble Alpes, INSERM, CHU Grenoble Alpes, LRB, Grenoble, France; and.

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 Tc-A1 and Tc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. A1 and C6 were radiolabeled with Tc 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). Both Tc-A1 and Tc-C6 bound mesothelin with high affinity in vitro, with Tc-A1 affinity being 2.4-fold higher than that of Tc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, < 0.05). Tc-A1 and Tc-C6 remained stable in vivo in murine blood (>80% at 2 h) and ex vivo in human blood (>90% at 6 h). In vivo Tc-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 Tc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, < 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of Tc-A1 uptake in HCC70 tumors. Mesothelin-positive tumors were successfully identified by SPECT using Tc-A1 and Tc-C6. Considering its superior characteristics, Tc-A1 was selected as the most suitable tool for further clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.117.203489DOI Listing
July 2018

Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection.

J Clin Invest 2018 01 20;128(1):219-232. Epub 2017 Nov 20.

French National Institute of Health and Medical Research (INSERM) Unit 1111, Lyon, France.

Humoral rejection is the most common cause of solid organ transplant failure. Here, we evaluated a cohort of 49 patients who were successfully grafted with allogenic islets and determined that the appearance of donor-specific anti-HLA antibodies (DSAs) did not accelerate the rate of islet graft attrition, suggesting resistance to humoral rejection. Murine DSAs bound to allogeneic targets expressed by islet cells and induced their destruction in vitro; however, passive transfer of the same DSAs did not affect islet graft survival in murine models. Live imaging revealed that DSAs were sequestrated in the circulation of the recipients and failed to reach the endocrine cells of grafted islets. We used murine heart transplantation models to confirm that endothelial cells were the only accessible targets for DSAs, which induced the development of typical microvascular lesions in allogeneic transplants. In contrast, the vasculature of DSA-exposed allogeneic islet grafts was devoid of lesions because sprouting of recipient capillaries reestablished blood flow in grafted islets. Thus, we conclude that endothelial chimerism combined with vascular sequestration of DSAs protects islet grafts from humoral rejection. The reduced immunoglobulin concentrations in the interstitial tissue, confirmed in patients, may have important implications for biotherapies such as vaccines and monoclonal antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI93542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749508PMC
January 2018

Very early onset inflammatory bowel disease: Investigation of the IL-10 signaling pathway in Iranian children.

Eur J Med Genet 2017 Dec 30;60(12):643-649. Epub 2017 Aug 30.

Sanquin Blood Supply Organization, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2017.08.016DOI Listing
December 2017

Evaluation of Antiatherogenic Properties of Ezetimibe Using H-Labeled Low-Density-Lipoprotein Cholesterol and Tc-cAbVCAM1-5 SPECT in ApoE Mice Fed the Paigen Diet.

J Nucl Med 2017 07 9;58(7):1088-1093. Epub 2017 Mar 9.

INSERM U1039 Radiopharmaceutiques Biocliniques, Grenoble, France

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. 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 ( = 15), we intravenously injected H-cholesteryl oleate-labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set ( = 20), we used the imaging agent Tc-cAbVCAM1-5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set ( = 21), we compared VCAM-1 expression with Tc-cAbVCAM1-5 uptake in various tissues. Mice treated with ezetimibe showed a 173% higher LDL-cholesteryl ester plasma disappearance rate ( < 0.001 vs. control) after H-cholesteryl oleate-labeled LDL injection. At 96 h after injection, the hepatic fraction of H-tracer was 61% lower in mice treated with ezetimibe ( < 0.001). Meanwhile, LDL-derived H-cholesterol excretion in the feces was 107% higher ( < 0.001). The antiatherogenic effect of ezetimibe monitored by Tc-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; < 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 Tc-cAbVCAM1-5 uptake ( = 0.75; < 0.05). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.116.177279DOI Listing
July 2017

A Case of Eosinophilic Esophagitis Accompanying Familial Mediterranean Fever.

Case Rep Gastrointest Med 2017 31;2017:6863921. Epub 2017 Jan 31.

Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

. 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. . 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. . We have reported a case of eosinophilic esophagitis coexisting with familial Mediterranean fever which has not been described previously.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/6863921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306980PMC
January 2017

Multiple-locus variable-number tandem repeat analysis (MLVA) for genotyping of Salmonella enterica subspecies enterica serotype Infantis isolated from human sources.

Microb Pathog 2016 Nov 18;100:299-304. Epub 2016 Oct 18.

Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.micpath.2016.10.012DOI Listing
November 2016

Expression of Ezrin and Estrogen Receptors During Cervical Carcinogenesis.

Reprod Sci 2017 05 29;24(5):706-712. Epub 2016 Sep 29.

1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.

Rationale: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1933719116667222DOI Listing
May 2017

Early Onset Hepatocellular Disease in an Infant with Zellweger Syndrome.

Acta Med Iran 2015 Oct;53(10):656-8

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. َAND Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND 4Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Zellweger syndrome (ZS) is a peroxisomal disorder with a multiple congenital anomalies, characterized by stereotypical facies, profound hypotonia, organ involvement including cerebral, retinal, hepatic, and renal. Herein, a 3-month-old female with ZS is presented who was referred because of increased liver enzymes (subclinical hepatitis), which was detected in work-up of her neck cyst, severe hypotonia, and abnormal facies. An increased concentration of very long chain fatty acid in lipid profile was detected. ZS should be considered in the list of differential diagnosis in infants with stereotypical phenotype, neurodevelopmental delay, and severe hypotonia in association with liver and other organs involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2015

Biodistribution, Stability, and Blood Distribution of the Cell Penetrating Peptide Maurocalcine in Mice.

Int J Mol Sci 2015 Nov 19;16(11):27730-40. Epub 2015 Nov 19.

Grenoble Alpes University, 38041 Saint-Martin-d'Hères, France.

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 (125)I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that (125)I-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, (125)I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms161126054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661912PMC
November 2015

In vivo siRNA distribution and pharmacokinetics assessed by nuclear imaging are modulated according to radiolabelling site.

Nucl Med Biol 2015 Dec 24;42(12):958-66. Epub 2015 Apr 24.

CHU de Grenoble, CS 10217, F38043 Grenoble, France; Grenoble University, F38041, Saint-Martin-d'Hères, France; INSERM U836, Team 7 - Nanomedicine and brain, Rue Fortuné Ferrini, F38706 La Tronche.

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 CK2β5's was quite constant over 2 hours, while CK2β3'as activity decreased by 40% in tumor. Finally, synchrotron X-ray analysis showed that CK2β3'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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nucmedbio.2015.04.007DOI Listing
December 2015

99mTc-cAbVCAM1-5 imaging is a sensitive and reproducible tool for the detection of inflamed atherosclerotic lesions in mice.

J Nucl Med 2014 Oct 25;55(10):1678-84. Epub 2014 Aug 25.

Unité 1039, INSERM, Grenoble, France Radiopharmaceutiques Biocliniques, Université Joseph Fourier Grenoble 1, Grenoble, France.

Unlabelled: (99m)Tc-cAbVCAM1-5, a single-domain antibody fragment directed against mouse or human vascular cell adhesion molecule 1 (VCAM-1), recently has been proposed as a new imaging agent for the detection of inflamed atherosclerotic lesions. Indeed, in a mouse model of atherosclerosis, (99m)Tc-cAbVCAM1-5 specifically bound to VCAM-1-positive lesions, thereby allowing their identification on SPECT images. The purpose of the present study was to investigate (99m)Tc-cAbVCAM1-5 imaging sensitivity using a reference statin therapy.

Methods: Thirty apolipoprotein E-deficient mice were fed a western-type diet. First, the relationship between the level of VCAM-1 expression and (99m)Tc-cAbVCAM1-5 uptake was evaluated in 18 mice using immunohistochemistry and autoradiography. Second, longitudinal SPECT/CT imaging was performed on control (n = 9) or atorvastatin-treated mice (0.01% w/w, n = 9).

Results: (99m)Tc-cAbVCAM1-5 uptake in atherosclerotic lesions correlated with the level of VCAM-1 expression (P < 0.05). Atorvastatin exerted significant antiatherogenic effects, and (99m)Tc-cAbVCAM1-5 lesion uptake was significantly reduced in 35-wk-old atorvastatin-treated mice, as indicated by ex vivo γ-well counting and autoradiography (P < 0.05). SPECT imaging quantification based on contrast-enhanced CT was reproducible (interexperimenter intraclass correlation coefficient, 0.97; intraexperimenter intraclass correlation coefficient, 0.90), and yielded results that were highly correlated with tracer biodistribution (r = 0.83; P < 0.0001). Therefore, reduced (99m)Tc-cAbVCAM1-5 uptake in atorvastatin-treated mice was successfully monitored noninvasively by SPECT/CT imaging (0.87 ± 0.06 vs. 1.11 ± 0.09 percentage injected dose per cubic centimeter in control group, P < 0.05).

Conclusion: (99m)Tc-cAbVCAM1-5 imaging allowed the specific, sensitive, and reproducible quantification of VCAM-1 expression in mouse atherosclerotic lesions. (99m)Tc-cAbVCAM1-5 therefore exhibits suitable characteristics for the evaluation of novel antiatherogenic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.114.143792DOI Listing
October 2014

Quantitative evaluation of the cell penetrating properties of an iodinated Tyr-L-maurocalcine analog.

Biochim Biophys Acta 2014 Oct 22;1843(10):2356-64. Epub 2014 Mar 22.

INSERM, U836, Grenoble Institute of Neuroscience, LabEx Ion Channels, Science and Therapeutics, Grenoble, France; Université Joseph Fourier, Grenoble, France; Smartox Biotechnologies, Grenoble, France. Electronic address:

L-Maurocalcine (L-MCa) is the first reported animal cell-penetrating toxin. Characterizing its cell penetration properties is crucial considering its potential as a vector for the intracellular delivery of drugs. Radiolabeling is a sensitive and quantitative method to follow the cell accumulation of a molecule of interest. An L-MCa analog containing an additional N-terminal tyrosine residue (Tyr-L-MCa) was synthesized, shown to fold and oxidize properly, and successfully radioiodinated to (125)I-Tyr-L-MCa. Using various microscopy techniques, the average volume of the rat line F98 glioma cells was evaluated at 8.9 to 18.9×10(-7)μl. (125)I-Tyr-L-MCa accumulates within cells with a dose-dependency similar to the one previously published using 5,6-carboxyfluorescein-L-MCa. According to subcellular fractionation of F98 cells, plasma membranes keep less than 3% of the peptide, regardless of the extracellular concentration, while the nucleus accumulates over 75% and the cytosol around 20% of the radioactive material. Taking into account both nuclear and cytosolic fractions, cells accumulate intracellular concentrations of the peptide that are equal to the extracellular concentrations. Estimation of (125)I-Tyr-L-MCa cell entry kinetics indicate a first rapid phase with a 5min time constant for the plasma membrane followed by slower processes for the cytoplasm and the nucleus. Once inside cells, the labeled material no longer escapes from the intracellular environment since 90% of the radioactivity remains 24h after washout. Dead cells were found to have a lower uptake than live ones. The quantitative information gained herein will be useful for better framing the use of L-MCa in biotechnological applications. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamcr.2014.03.017DOI Listing
October 2014

Urinary adrenomedullin level in children with acute pyelonephritis before and after treatment.

Iran J Kidney Dis 2013 Jul;7(4):277-81

Division of Pediatric Nephrology, Pediatric Nephrology Research Center, Pediatric Infectious Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: Adrenomedullin (AM) is a 52-amino acid peptide that causes vasodilatation by increased synthesis of nitric oxide. Its production by different cells such as cardiac myocytes, smooth muscle, endothelial, and oncogenic cells is stimulated by inflammatory processes. It has been shown that in the presence of inflammation in the urinary system, concentration of AM increases. In this study, we measured urinary AM in children with acute pyelonephritis before and after treatment and compared its level with that in healthy children.

Materials And Methods: In a case-control study, 31 children with clinical and paraclinical documentation of pyelonephritis (case group) and 30 healthy children without pyelonephritis or other infections (control group) were studied. Urinary AM were measured on spot urine samples by high-performance liquid chromatography, and creatinine was measured by spectrophotometry to report the AM-creatinine ratio.

Results: Urinary AM-creatinine ratios were 61.3 +/- 119.4 pg/mg and 4.26 +/- 11.4 pg/mg, respectively, in the case and control groups (P = .01). After treatment of pyelonephritis in the patients of the case group, this ratio decreased to 13.1 +/- 21.9 (P = .048). The coefficient correlation between urinary AM and leukocytes count was 0.252 (P = .17). Urinary AM levels were 1896 +/- 1748 pg/dL and 391 +/- 477 pg/dL in the patients with 4+ versus negative C-reactive protein levels, respectively (P = .008).

Conclusions: Urinary AM increases in the course of pyelonephritis and decreases significantly after treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2013

Urinary endothellin-1 level in children with pyelonephritis and hydronephrosis.

Saudi J Kidney Dis Transpl 2013 Jul;24(4):731-6

Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran.

Hydronephrosis is a common finding in patients with urinary tract infection (UTI). Endothellin-1 (ET-1) is a potent vasoactive peptide that has vasoconstrictive effects. It has been shown that urinary ET-1 increases in urinary obstructions. In this study, we measured the urinary ET-1 level in patients with UTI and hydronephrosis of various causes. In this case-control study, we evaluated the urinary ET-1 level in 45 patients who had UTI and hydronephrosis, serving as a case group, and 45 patients who had UTI without hydronephrosis, serving as a control group. Urinary ET-1 was quantified using enzyme-linked immunosorbent assay and urinary creatinine (Cr) by Jaffe method. To rule out the effect of urinary flow rate, the urinary ET-1 to Cr correlation was considered for analysis of the results. The mean age of the patients in the case and control groups was 36.5 ± 27.2 and 26.2 ± 15.5 months, respectively (P >0.01). The mean urinary ET-1 was 89.6 ± 41.7 pg/dL in the case group and 29.3 ± 26 pg/dL in the control group, P <0.001. The mean urinary ET-1 was 121 ± 55.4 pg/dL in patients who had grade 4 hydronephrosis. We conclude that urinary ET-1 was significantly higher in the obstructed than in non-obstructed cases. Urinary ET-1 could be a useful marker that can be utilized in young children for diagnosis of hydronephrosis, especially obstructive cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/1319-2442.113865DOI Listing
July 2013

In vivo molecular imaging of atherosclerotic lesions in ApoE-/- mice using VCAM-1-specific, 99mTc-labeled peptidic sequences.

J Nucl Med 2013 Aug 29;54(8):1442-9. Epub 2013 May 29.

INSERM, U1039, Radiopharmaceutiques Biocliniques, Grenoble, France.

Unlabelled: 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.

Methods: 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.

Results: 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, P < 0.05 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, P < 0.05). 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, P < 0.05).

Conclusion: (99m)Tc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.112.115675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886675PMC
August 2013

A safe bacterial microsyringe for in vivo antigen delivery and immunotherapy.

Mol Ther 2013 May 26;21(5):1076-86. Epub 2013 Mar 26.

TIMC-TheREx Laboratory (UMR 5525 CNRS-UJF), Faculty of Medecine, Université Joseph Fourier Grenoble I, La Tronche, France.

The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the "killed but metabolically active" (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/mt.2013.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666637PMC
May 2013

Nanobodies targeting mouse/human VCAM1 for the nuclear imaging of atherosclerotic lesions.

Circ Res 2012 Mar;110(7):927-37

Laboratoire des Radiopharmaceutiques Bioclinique, INSERM 1039, Grenoble, France.

Rationale: A noninvasive tool allowing the detection of vulnerable atherosclerotic plaques is highly needed. By combining nanomolar affinities and fast blood clearance, nanobodies represent potential radiotracers for cardiovascular molecular imaging. Vascular cell adhesion molecule-1 (VCAM1) constitutes a relevant target for molecular imaging of atherosclerotic lesions.

Objective: We aimed to generate, radiolabel, and evaluate anti-VCAM1 nanobodies for noninvasive detection of atherosclerotic lesions.

Methods And Results: Ten anti-VCAM1 nanobodies were generated, radiolabeled with technetium-99m, and screened in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in apolipoprotein E-deficient (ApoE(-/-)) mice. A nontargeting control nanobody was used in all experiments to demonstrate specificity. All nanobodies displayed nanomolar affinities for murine VCAM1. Flow cytometry analyses using human human umbilical vein endothelial cells indicated murine and human VCAM1 cross-reactivity for 6 of 10 nanobodies. The lead compound cAbVCAM1-5 was cross-reactive for human VCAM1 and exhibited high lesion-to-control (4.95±0.85), lesion-to-heart (8.30±1.11), and lesion-to-blood ratios (4.32±0.48) (P<0.05 versus control C57Bl/6J mice). Aortic arch atherosclerotic lesions of ApoE(-/-) mice were successfully identified by single-photon emission computed tomography imaging. (99m)Tc-cAbVCAM1-5 binding specificity was demonstrated by in vivo competition experiments. Autoradiography and immunohistochemistry further confirmed cAbVCAM1-5 uptake in VCAM1-positive lesions.

Conclusions: The (99m)Tc-labeled, anti-VCAM1 nanobody cAbVCAM1-5 allowed noninvasive detection of VCAM1 expression and displayed mouse and human cross-reactivity. Therefore, this study demonstrates the potential of nanobodies as a new class of radiotracers for cardiovascular applications. The nanobody technology might evolve into an important research tool for targeted imaging of atherosclerotic lesions and has the potential for fast clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.112.265140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918224PMC
March 2012

Reduction of renal uptake of 111In-DOTA-labeled and A700-labeled RAFT-RGD during integrin αvβ3 targeting using single photon emission computed tomography and optical imaging.

Cancer Sci 2012 Jun 23;103(6):1105-10. Epub 2012 Apr 23.

INSERM U877, Radiopharmaceutiques Biocliniques, Grenoble, France.

Integrin α(v)β(3) expression is upregulated during tumor growth and invasion in newly formed endothelial cells in tumor neovasculature and in some tumor cells. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin α(v)β(3) in vitro and in vivo. When labeled with indium-111, the RAFT-RGD is partially reabsorbed and trapped in the kidneys, limiting its use for further internal targeted radiotherapy and imaging investigations. We studied the effect of Gelofusine on RAFT-RGD renal retention in tumor-bearing mice. Mice were imaged using single photon emission computed tomography and optical imaging 1 and 24 h following tracer injection. Distribution of RAFT-RGD was further investigated by tissue removal and direct counting of the tracer. Kidney sections were analyzed by confocal microscopy. Gelofusine significantly induced a >50% reduction of the renal reabsorption of (111)In-DOTA-RAFT-RGD and A700-RAFT-RGD, without affecting tumor uptake. Injection of Gelofusine significantly reduced the renal retention of labeled RAFT-RGD, while increasing the tumor over healthy tissue ratio. These results will lead to the development of future therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1349-7006.2012.02286.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685062PMC
June 2012

Distal renal tubular acidosis and its relationship with hearing loss in children: preliminary report.

Iran J Kidney Dis 2010 Jul;4(3):202-6

Pediatric Infectious Research Center and Department of Nephrology, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: In autosomal recessive distal renal tubular acidosis (DRTA), a substantial fraction of the patients have progressive bilateral sensorineural hearing loss. This coexistence is due to the mutations of a gene expressed both in the kidney and in the cochlea. The aim of this study was to assess the correlation between hearing loss and DRTA.

Materials And Methods: In this study, 51 children diagnosed with renal tubular acidosis were evaluated. Diagnosis of DRTA was based on clinical manifestations and detection of normal anion gap metabolic acidosis, urine pH higher than 5.5, and positive urinary anion gap. Audiometry was performed in children with DRTA and sequencing of the ATP6V1B1 gene was done for those with sensorineural hearing loss.

Results: Twenty-seven patients (52.9%) had DRTA, of whom 51.9% were younger than 1 year old, 55.6% were boys, and 44.4% were girls. Eleven patients (40.7%) had bilateral sensorineural hearing loss, consisting of 5 of 15 boys (33.3%) and 6 of 12 girls (50.0%). There was no correlation between hearing loss and gender. Three patients with hearing loss had mutation in the ATP6V1B1 gene (11.1% of patients with DRTA and 27.3% of patients with DRTA and hearing loss).

Conclusions: This study indicated that a significant percentage of the children with DRTA had sensorineural hearing loss and mutation in ATP6V1B1 gene. It is recommended to investigate hearing impairment in all children with DRTA.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2010

mtDNA Deletion in an Iranian Infant with Pearson Marrow Syndrome.

Iran J Pediatr 2010 Mar;20(1):107-12

Department of Pediatric Hematology- Oncology, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran.

Background: Pearson syndrome (PS) is a rare multisystem mitochondrial disorder of hematopoietic system, characterized by refractory sideroblastic anemia, pancytopenia, exocrine pancreatic insufficiency, and variable neurologic, hepatic, renal, and endocrine failure.

Case Presentation: We describe a six-month-old female infant with Pearson marrow syndrome who presented with neurological manifestations. She had several episodes of seizures. Hematopoietic abnormalities were macrocytic anemia and neutropenia. Bone marrow aspiration revealed a cellular marrow with marked vacuolization of erythroid and myeloid precursors. Analysis of mtDNA in peripheral blood showed 8.5 kb deletion that was compatible with the diagnosis of PS.

Conclusion: PS should be considered in infants with neurologic diseases, in patients with cytopenias, and also in patients with acidosis or refractory anemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445998PMC
March 2010