Validation of HPLC and TLC analytical methods to determine radiochemical purity of 99mTc-cAbVCAM1-5, a new experimental radiotracer.

Cardiovascular diseases, including fatal myocardial infarctions from atheromatous plaques, are the primary global mortality cause. Detecting stenotic atheromatous plaques is possible through coronary angiography, but vulnerable plaques with eccentric remodeling are undetectable with current diagnostic methods. Addressing this challenge, our group developed a radiopharmaceutical drug targeting vascular cell adhesion molecule 1 (VCAM-1), radiolabeled with technetium-99m. Given the absence of a monograph in the European Pharmacopoeia, and in order to draft the investigational medicinal product documentation, analytical methods had to be validated by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) to determine the radiochemical purity (RCP) of 99mTc-cAbVCAM1-5. This study therefore presents the results of the validation of analytical methods obtained in this context. The method validation followed the European Association of Nuclear Medicine (EANM) recommendations adapted from ICH Q2(R1), ensuring conformity with specificity, accuracy, repeatability and intermediate precision, linearity, robustness, quantification limit (LoQ), and range criteria. Regarding the results of specificity, both HPLC and TLC methods demonstrated excellent separation of 99mTc-cAbVCAM1-5 from impurities 99mTcO4-. Accuracy results indicated recovery percentages within the range of 99.52-101.40% for the HPLC and 99.51-101.97% for TLC, ensuring reliable measurements for each concentration of 99mTcO4-. Precision of the methods was validated by assessing repeatability and intermediate precision. Linearity was determined over the usual concentrations range and the correlation coefficient was greater than 0.99 for both methods. The limit of quantification was measured by diluting the 99mTcO4- to obtain a signal-to-noise ratio of around 10:1. Under these conditions, we obtained an LOQ of 2.10 MBq/mL for HPLC and 2Mbq/mL for TLC. In conclusion, the analytical methods developed in this study comply with EANM recommendations. This therefore allows us to correctly assess the radiochemical purity of 99mTc-cAbVCAM1-5, a new radiotracer targeting inflammation in vulnerable plaques.

IgE to wheat, prick test, and Patch test among children with celiac disease.

INTRODUCTION AND AIM: Celiac disease is one of the most common autoimmune disorders. This study aimed to evaluate the relationship between celiac disease and wheat sensitization. SUBJECTS AND METHODS: In the current study, children aged < 18 years with confirmed celiac disease were included. Data were analyzed using SPSS. RESULTS: Gastrointestinal problems were the most common indication for evaluation in terms of celiac disease. Prick and patch tests were positive in 43.4% and 34% respectively. CONCLUSION: Prick test and patch test for wheat sensitization were positive in about 30-45% of the children for celiac disease.

Inflammatory bowel disease evolution in the past two decades: a chronological multinational study.

Background: The multifactorial nature of inflammatory bowel disease (IBD), which manifests differently in individuals creates a need for a better understanding of the behaviour and pattern of the disease due to environmental factors. The current study aimed to study the changes in IBD behaviour, presentation, and characteristics in patients over the past two decades with a goal of improving patients' diagnosis, management and outcomes. Methods: During a 6-month period (1/02/2022-30/07/2022), the information of patients with IBD who attended IBD outpatient clinics of 11 referral centre's in six countries was collected, and based on the first time of diagnosis with IBD, they were allocated as group A (those who were diagnosed more than 15 years ago), group B (those who were diagnosed with IBD between 5 and 15 years ago) and group C (IBD cases who diagnosed in recent 5 years). Then the most prevalent subtypes and characters of the disease are evaluated and compared to make clear if the presenting pattern and behaviour of the disease has changed in the last 2 decades. Findings: Overall 1430 patients with IBD including 1207 patients with ulcerative colitis (UC) (84.5%) and 205 patients with Crohn's disease (CD; 14.3%) included. Mean age of participants at the first time of diagnosis with IBD was 30 years. The extra-intestinal involvement of IBD in groups A and B was more prevalent in comparison with group C. Most of those in groups A & B had academic education but in group C, the most prevalent educational status was high school or diploma (P = 0.012). In contrast to groups A and B, the relative prevalence of medium socioeconomic level in group C had decreased (65%). Relative prevalence of UC subtypes was similar among groups A and B (extensive colitis as most prevalent) but in group C, the most prevalent subtype is left side colitis (38.17%). The most prevalent subtype of CD in groups A and B was ileocolic involvement while in group C, upper GI involvement is significantly increased. The rate of food sensitivity among groups A and B was more than group C (P = 0.00001). The relative prevalence of patients with no flare has increased with a steady slope (P < 0.00001). Relative prevalence of presenting symptoms among patients with UC in group C differs and nowadays the rate abdominal pain (70.7%) and bloating (43.9%) have increased and frequency of diarrhoea (67.4%) has decreased. Interpretation: In the recent 5 years, the pattern of UC presentation has changed. The rate of upper GI involvement in CD and relative prevalence of patients with no disease flare increased and the rate of extra intestinal involvement decreased. Funding: None.

TrisOxine abiotic siderophores for technetium complexation: radiolabeling and biodistribution studies.

BACKGROUND: Despite the development of positron emission tomography (PET), single photon emission computed tomography (SPECT) still accounts for around 80% of all examinations performed in nuclear medicine departments. The search for new radiotracers or chelating agents for Technetium-99m is therefore still ongoing. O-TRENSOX and O-TRENOX two synthetic siderophores would be good candidates for this purpose as they are hexadentate ligands based on the very versatile and efficient 8-hydroxyquinoline chelating subunit. First, the radiolabeling of O-TRENOX and O-TRENSOX with 99mTc was investigated. Different parameters such as the quantity of chelating agent, type of reducing agent, pH and temperature of the reaction mixture were adjusted in order to find the best radiolabeling conditions. Then an assessment of the partition coefficient by measuring the distribution of each radiosynthesized complex between octanol and phosphate-buffered saline was realized. The complex's charge was evaluated on three different celluloses (neutral, negatively charged P81 and positively charged DE81), and finally in vivo studies with biodistribution and SPECT imaging of [99mTc]Tc-O-TRENOX and [99mTc]Tc-O-TRENSOX were performed. RESULTS: The radiolabeling studies showed a rapid and efficient complexation of 99mTc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [99mTc]Tc-O-TRENOX complex with a radiochemical purity of more than 98% and the [99mTc]Tc-O-TRENSOX complex with one above 97% at room temperature within 5 min. [99mTc]Tc-O-TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [99mTc]Tc-O-TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice. CONCLUSIONS: These encouraging results allow us to consider the O-TRENOX/99mTc and O-TRENSOX/99mTc complexes as serious candidates for SPECT imaging chelators. This study should be continued by conjugating these tris-oxine ligands to peptides or antibodies and comparing them with the other bifunctional agents used with Tc.

Molecular imaging of liver inflammation using an anti-VCAM-1 nanobody.

To date, a biopsy is mandatory to evaluate parenchymal inflammation in the liver. Here, we evaluated whether molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) could be used as an alternative non-invasive tool to detect liver inflammation in the setting of chronic liver disease. To do so, we radiolabeled anti-VCAM-1 nanobody (99mTc-cAbVCAM1-5) and used single-photon emission computed tomography (SPECT) to quantify liver uptake in preclinical models of non-alcoholic fatty liver disease (NAFLD) with various degree of liver inflammation: wild-type mice fed a normal or high-fat diet (HFD), FOZ fed a HFD and C57BL6/J fed a choline-deficient or -supplemented HFD. 99mTc-cAbVCAM1-5 uptake strongly correlates with liver histological inflammatory score and with molecular inflammatory markers. The diagnostic power to detect any degree of liver inflammation is excellent (AUROC 0.85-0.99). These data build the rationale to investigate 99mTc-cAbVCAM1-5 imaging to detect liver inflammation in patients with NAFLD, a largely unmet medical need.

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

BACKGROUND: 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. 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.

Virulence factors, antibiotic resistance patterns, and molecular types of clinical isolates of Klebsiella Pneumoniae.

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.

EFFICACY OF ENDOSCOPIC BALLOON DILATION IN IRANIAN PEDIATRIC PATIENTS WITH ESOPHAGEAL STRICTURE.

BACKGROUND: Esophageal stenosis (ES) in children is a fixed intrinsic narrowing of the esophagus due to numerous aetiologies. OBJECTIVE: This study aimed to determine the clinical and nutritional impacts of endoscopic balloon dilation (EBD) in Iranian children with an esophageal stricture. METHODS: This retrospective study, pediatric patients (aged <18 years) who underwent EBD for esophageal stricture from April 2015 until March 2020 in Abuzar Children's Hospital (Ahvaz, Iran) were enrolled in the study. Outcome parameters were the frequency of dilations, nutritional status, complications, and clinical success rates. EBD was used in children with radiologic evidence of esophageal stenosis. The nutritional status was evaluated by weight-for-age (z-score). Clinical success was considered as no necessity of EBD for a minimum of one year and/or increasing interval among dilation and the frequency of EBD was less than four times per year. RESULTS: A total of 53 cases (mean age, 4.72±3.38 years) were enrolled. There were 25 (47.2%) females and 28 (52.8%) males. During follow-up, a total of 331 EBD sessions were performed, with an average of 6.24 sessions per patient. There was one case of perforation and one case of mediastinitis, while there was no other complication or mortality. The clinical success rate of EBD therapy was 62.3% (33/53). The mean standard deviation z-score weight-for-age of patients before and after endoscopic dilation was 2.78 (2.41) and 1.18 (1.87), respectively. The t-test showed a significant difference between the weights-for-age (z-score) before and after endoscopic dilation. The majority of the patients had raised weight-for-age (z-score) after EBD treatment. CONCLUSION: EBD attained a good clinical success rate and nutritional improvement in children with an esophageal stricture.

Eficácia da dilatação do balão endoscópico em pacientes pediátricos iranianos com estenose esofágica / Efficacy of endoscopic balloon dilation in iranian pediatric patients with esophageal stricture

ABSTRACT BACKGROUND: Esophageal stenosis (ES) in children is a fixed intrinsic narrowing of the esophagus due to numerous aetiologies. OBJECTIVE: This study aimed to determine the clinical and nutritional impacts of endoscopic balloon dilation (EBD) in Iranian children with an esophageal stricture. METHODS: This retrospective study, pediatric patients (aged <18 years) who underwent EBD for esophageal stricture from April 2015 until March 2020 in Abuzar Children's Hospital (Ahvaz, Iran) were enrolled in the study. Outcome parameters were the frequency of dilations, nutritional status, complications, and clinical success rates. EBD was used in children with radiologic evidence of esophageal stenosis. The nutritional status was evaluated by weight-for-age (z-score). Clinical success was considered as no necessity of EBD for a minimum of one year and/or increasing interval among dilation and the frequency of EBD was less than four times per year. RESULTS: A total of 53 cases (mean age, 4.72±3.38 years) were enrolled. There were 25 (47.2%) females and 28 (52.8%) males. During follow-up, a total of 331 EBD sessions were performed, with an average of 6.24 sessions per patient. There was one case of perforation and one case of mediastinitis, while there was no other complication or mortality. The clinical success rate of EBD therapy was 62.3% (33/53). The mean standard deviation z-score weight-for-age of patients before and after endoscopic dilation was 2.78 (2.41) and 1.18 (1.87), respectively. The t-test showed a significant difference between the weights-for-age (z-score) before and after endoscopic dilation. The majority of the patients had raised weight-for-age (z-score) after EBD treatment. CONCLUSION: EBD attained a good clinical success rate and nutritional improvement in children with an esophageal stricture.

RESUMO CONTEXTO: Estenose esofágica (EE) em crianças é um estreitamento intrínseco fixo do esôfago devido a inúmeras etiologias. OBJETIVO: Este estudo teve como objetivo determinar os impactos clínicos e nutricionais da dilatação do balão endoscópico (DBE) em crianças iranianas com restrição esofágica. MÉTODOS: Foram inscritos neste estudo retrospectivo, pacientes pediátricos (com idade <18 anos) submetidos a DBE para restrição esofágica de abril de 2015 a março de 2020 no Hospital Infantil de Abuzar (Ahvaz, Irã). Os parâmetros de desfecho foram a frequência de dilatações, o estado nutricional, complicações e taxas de sucesso clínico. A DBE foi usada em crianças com evidência radiológica de estenose esofágica. O estado nutricional foi avaliado pelo peso-por-idade (escore z). O sucesso clínico foi considerado como não necessidade de DBE por um período mínimo de um ano e/ou aumento de intervalo entre dilatações e frequência inferior a quatro vezes por ano. RESULTADOS: Foram incluídos 53 casos (média de idade, 4,72±3,38 anos). Eram 25 mulheres (47,2%) e 28 homens (52,8%). Durante o acompanhamento, foram realizadas 331 sessões de DBE, com média de 6,24 sessões por paciente. Houve um caso de perfuração e um caso de mediastinite, enquanto não houve outra complicação ou mortalidade. A taxa de sucesso clínico da terapia de DBE foi de 62,3% (33/53). A média (escore z) peso-para-idade dos pacientes antes e depois da dilatação endoscópica foi de 2,78 (2,41) e 1,18 (1,87), respectivamente. O teste t mostrou uma diferença significativa entre os pesos por idade (escore z) antes e depois da dilatação endoscópica. A maioria dos pacientes havia aumentado o peso por idade (escore z) após o tratamento com DBE. CONCLUSÃO: A DBE atingiu boa taxa de sucesso clínico e melhora nutricional em crianças com restrição esofágica.

In Vivo Biodistribution and Efficacy Evaluation of NeoB, a Radiotracer Targeted to GRPR, in Mice Bearing Gastrointestinal Stromal Tumor.

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 < 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.

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

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.

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

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.

Incidence of malnutrition, esophageal stenosis and respiratory complications among children with repaired esophageal atresia / Incidência de desnutrição, estenose esofágica e complicações respiratórias entre crianças operadas por atresia esofágica

ABSTRACT 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.

RESUMO Racional: Atresia de esôfago é anomalia congênita com mortalidade alta. Complicações cirúrgicas e alterações no estado nutricional são problemas comuns após correção cirúrgica. Objetivo: Avaliar o estado nutricional, a estenose esofágica e as complicações respiratórias em crianças que tiveram a reparação de atresia de esôfago. Métodos: Crianças com idade> 2 meses de idade com atresia esofágica reparada foram incluídas no estudo atual. Sexo, idade, peso e altura foram registrados para cada caso. A altura por idade e o peso por idade foram calculados para cada caso. Resultados: De acordo com o peso para o percentil de comprimento, 41,02% dos casos estavam abaixo do peso. Estenose esofágica foi observada em 54,76% do esofagograma obtido. Conclusão: O baixo peso esteve presente em 41,02 dos pacientes, de acordo com o percentil peso/estatura.

Incidence of malnutrition, esophageal stenosis and respiratory complications among children with repaired esophageal atresia / Incidência de desnutrição, estenose esofágica e complicações respiratórias entre crianças operadas por atresia esofágica

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

RESUMO Racional: Atresia de esôfago é anomalia congênita com mortalidade alta. Complicações cirúrgicas e alterações no estado nutricional são problemas comuns após correção cirúrgica. Objetivo: Avaliar o estado nutricional, a estenose esofágica e as complicações respiratórias em crianças que tiveram a reparação de atresia de esôfago. Métodos: Crianças com idade> 2 meses de idade com atresia esofágica reparada foram incluídas no estudo atual. Sexo, idade, peso e altura foram registrados para cada caso. A altura por idade e o peso por idade foram calculados para cada caso. Resultados: De acordo com o peso para o percentil de comprimento, 41,02% dos casos estavam abaixo do peso. Estenose esofágica foi observada em 54,76% do esofagograma obtido. Conclusão: O baixo peso esteve presente em 41,02 dos pacientes, de acordo com o percentil peso/estatura.

Effect of polyethylene glycol versus lactulose on abdominal pain in children occult constipation: a randomized controlled study: un estudio controlado aleatorio / Efecto del polietilenglicol versus lactulosa sobre el dolor abdominal en el estreñimiento oculto en niños

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.

Introducción y objetivo: El dolor abdominal funcional (FAP) es una de las principales molestias gastrointestinales en la infancia. Los estudios han informado que el estreñimiento oculto (OC) es una de las principales causas de dolor abdominal. Investigaciones recientes han propuesto laxantes como objetivos terapéuticos potentes para el dolor abdominal en pacientes con OC. Sin embargo, ningún estudio ha comparado el efecto del polietilenglicol (PEG) y la lactulosa sobre el estreñimiento oculto. Materiales y métodos: Se estudiaron 51 pacientes de 4 a 18 años con dolor abdominal que tenían OC (definida como impactación fecal en rayos X abdominales). Se registraron datos demográficos y clínicos que incluyen edad, sexo, peso corporal, altura, duración del dolor abdominal, tasa de dolor abdominal y olor fecal. Fueron asignados aleatoriamente para recibir PEG (1 gr/kg) o lactulosa (1 cc/kg) durante al menos dos semanas. Todos los pacientes fueron reevaluados por la escala de medición del dolor después de al menos dos semanas de tratamiento. Resultados: Se indica que la eficacia de PEG para reducir el dolor abdominal en OC fue del 48% mientras que fue del 37% para la lactulosa. Este estudio indicó que esta eficacia no se ve afectada significativamente por el sexo y el olor fecal, sin embargo, esta eficacia está influenciada por la edad, el peso corporal, la duración del dolor abdominal y la tasa de dolor abdominal tanto para PEG como para lactulosa. Conclusión: Se podría concluir que el PEG es un fármaco más eficaz para tratar el dolor abdominal en el estreñimiento oculto que la lactulosa y que su efecto óptimo se puede lograr en pacientes mayores con dolor abdominal más severo.Palabras clave: dolor abdominal, estreñimiento oculto, polietilenglicol, lactulosa.

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

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.

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

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.

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

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.

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

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.