Biodistribution Profile of Magnetic Nanoparticles in Cirrhosis-Associated Hepatocarcinogenesis in Rats by AC Biosusceptometry.

Since magnetic nanoparticles (MNPs) have been used as multifunctional probes to diagnose and treat liver diseases in recent years, this study aimed to assess how the condition of cirrhosis-associated hepatocarcinogenesis alters the biodistribution of hepatic MNPs. Using a real-time image acquisition approach, the distribution profile of MNPs after intravenous administration was monitored using an AC biosusceptometry (ACB) assay. We assessed the biodistribution profile based on the ACB images obtained through selected regions of interest (ROIs) in the heart and liver position according to the anatomical references previously selected. The signals obtained allowed for the quantification of pharmacokinetic parameters, indicating that the uptake of hepatic MNPs is compromised during liver cirrhosis, since scar tissue reduces blood flow through the liver and slows its processing function. Since liver monocytes/macrophages remained constant during the cirrhotic stage, the increased intrahepatic vascular resistance associated with impaired hepatic sinusoidal circulation was considered the potential reason for the change in the distribution of MNPs.

GASTROINTESTINAL MOTILITY IN ELDERLY PATIENTS WITH WELL-CONTROLLED TYPE 2 DIABETES MELLITUS.

BACKGROUND: Gastrointestinal (GI) motility disorders in type 2 diabetes mellitus (T2DM) are common. However, the endpoints in well-controlled T2DM in elderly patients are barely understood. OBJECTIVE: To evaluate GI transit and gastric myoelectric activity in elderly patients with T2DM who were undergoing treatment with metformin and to compare them with non-diabetic healthy controls. METHODS: A total of thirty participants were enrolled in this study: young non-diabetic (n=10), elderly non-diabetic controls (n=10), and patients with T2DM managed with metformin (n=10). After fasting overnight, the participants ingested a standard meal and magnetic markers for non-invasive monitoring of GI transit and gastric contractility using the alternating current biosusceptometry and electrogastrography techniques. RESULTS: Mean gastric emptying time, mean colon arrival time, and mean intestinal transit time were determined. There were no significant differences between the groups and in the parameters evaluated (P>0.05). The frequency and amplitude of gastric myoelectric activity were not different between groups; however, abnormal rhythmic index and the half-bandwidth were slightly higher for both elderly diabetic and non-diabetic groups compared with the young adults (P<0.01 and P<0.05, respectively). CONCLUSION: Our study showed unaltered gastric emptying and intestinal transit in T2DM patients with good glycemic control, and suggest changes in the gastric electrical activity can be a part of aging.

Motilidade gastrintestinal em pacientes idosos com diabetes mellitus tipo 2 bem controlado / Gastrointestinal motility in elderly patients with well-controlled type 2 diabetes mellitus

ABSTRACT Background: Gastrointestinal (GI) motility disorders in type 2 diabetes mellitus (T2DM) are common. However, the endpoints in well-controlled T2DM in elderly patients are barely understood. Objective: To evaluate GI transit and gastric myoelectric activity in elderly patients with T2DM who were undergoing treatment with metformin and to compare them with non-diabetic healthy controls. Methods: A total of thirty participants were enrolled in this study: young non-diabetic (n=10), elderly non-diabetic controls (n=10), and patients with T2DM managed with metformin (n=10). After fasting overnight, the participants ingested a standard meal and magnetic markers for non-invasive monitoring of GI transit and gastric contractility using the alternating current biosusceptometry and electrogastrography techniques. Results: Mean gastric emptying time, mean colon arrival time, and mean intestinal transit time were determined. There were no significant differences between the groups and in the parameters evaluated (P>0.05). The frequency and amplitude of gastric myoelectric activity were not different between groups; however, abnormal rhythmic index and the half-bandwidth were slightly higher for both elderly diabetic and non-diabetic groups compared with the young adults (P<0.01 and P<0.05, respectively). Conclusion: Our study showed unaltered gastric emptying and intestinal transit in T2DM patients with good glycemic control, and suggest changes in the gastric electrical activity can be a part of aging.

RESUMO Contexto: As desordens da motilidade gastrintestinal (GI) no diabetes mellitus tipo 2 (DM2) são comuns. No entanto, os desfechos em pacientes idosos com DM2 bem controlado são pouco compreendidos. Objetivo: Avaliar o trânsito GI e a atividade mioelétrica gástrica em idosos com DM2 em tratamento com metformina e compará-los com controles saudáveis não diabéticos. Métodos: Trinta participantes foram incluídos neste estudo: adultos jovens não diabéticos (n=10), idosos não diabéticos (n=10) e pacientes com DM2 tratados com metformina (n=10). Após jejum noturno, os participantes ingeriram uma refeição padrão e marcadores magnéticos para monitoramento não invasivo do trânsito GI e da contratilidade gástrica usando as técnicas de biosusceptometria de corrente alternada e eletrogastrografia. Resultados: Foram determinados o tempo médio de esvaziamento gástrico, o tempo médio de chegada ao cólon e o tempo médio de trânsito intestinal. Não houve diferenças significativas entre os grupos e nos parâmetros avaliados (P>0,05). A frequência e amplitude da atividade mioelétrica gástrica não foram diferentes entre os grupos; entretanto, o índice rítmico anormal e a meia largura de banda foram ligeiramente maiores para os grupos idosos diabéticos e não diabéticos em comparação com os adultos jovens (P<0,01 e P<0,05, respectivamente). Conclusão: Nosso estudo mostrou esvaziamento gástrico e trânsito intestinal inalterados em pacientes com DM2 com bom controle glicêmico, sugerindo que as alterações na atividade elétrica gástrica podem fazer parte do envelhecimento.

Long-Term Clearance and Biodistribution of Magnetic Nanoparticles Assessed by AC Biosusceptometry.

Once administered in an organism, the physiological parameters of magnetic nanoparticles (MNPs) must be addressed, as well as their possible interactions and retention and elimination profiles. Alternating current biosusceptometry (ACB) is a biomagnetic detection system used to detect and quantify MNPs. The aims of this study were to evaluate the biodistribution and clearance of MNPs profiles through long-time in vivo analysis and determine the elimination time carried out by the association between the ACB system and MnFe2O4 nanoparticles. The liver, lung, spleen, kidneys, and heart and a blood sample were collected for biodistribution analysis and, for elimination analysis, and over 60 days. During the period analyzed, the animal's feces were also collectedd. It was possible to notice a higher uptake by the liver and the spleen due to their characteristics of retention and uptake. In 60 days, we observed an absence of MNPs in the spleen and a significant decay in the liver. We also determined the MNPs' half-life through the liver and the spleen elimination. The data indicated a concentration decay profile over the 60 days, which suggests that, in addition to elimination via feces, there is an endogenous mechanism of metabolization or possible agglomeration of MNPs, resulting in loss of ACB signal intensity.

The Influence of Omeprazole on the Dissolution Processes of pH-Dependent Magnetic Tablets Assessed by Pharmacomagnetography.

Pharmacomagnetography involves the simultaneous assessment of solid dosage forms (SDFs) in the human gastrointestinal (GI) tract and the drug plasmatic concentration, using a biomagnetic technique and pharmacokinetics analysis. This multi-instrumental approach helps the evaluation, as GI variables can interfere with the drug delivery processes. This study aimed to employ pharmacomagnetography to evaluate the influence of omeprazole on the drug release and absorption of metronidazole administered orally in magnetic-coated tablets. Magnetic-coated tablets, coated with Eudragit® E-100 (E100) and containing 100 mg of metronidazole, were produced. For the in vivo experiments, 12 volunteers participated in the two phases of the study (placebo and omeprazole) on different days to assess the bioavailability of metronidazole. The results indicated a shift as the pH of the solution increased and a delay in the dissolution of metronidazole, showing that the pH increase interferes with the release processes of tablets coated with E100. Our study reinforced the advantages of pharmacomagnetography as a tool to perform a multi-instrumental correlation analysis of the disintegration process and the bioavailability of drugs.

Gastrointestinal Side Effects of Triple Immunosuppressive Therapy Evaluated by AC Biosusceptometry and Electrogastrography in Rats.

BACKGROUND: Triple immunosuppressive therapy is associated with several gastrointestinal disorders. The aim of this study was to investigate the effects induced by the triple immunosuppressive therapy on the gastrointestinal tract of rats. METHODS: Male Wistar rats were randomly assigned into three experimental groups: Control: filtered water; TAC + MPS + PRED: treated with Tacrolimus plus Mycophenolate Sodium plus Prednisone; and CSA + AZA + PRED: treated with Cyclosporine plus Azathioprine plus Prednisone. The treatment was done for 14 days by gavage. Gastric emptying and contractility were evaluated by the Alternating Current Biosusceptometry (ACB) and Electrogastrography (EGG). Histological, biochemical and hematological analyses were also performed. RESULTS: Gastric emptying time was slower in the CSA + AZA + PRED group in comparison with control (p<0.01) and TAC + MPS + PRED groups (p<0.001). Animals treated with TAC + MPS + PRED showed accelerated gastric emptying (p<0.05) compared to control. The amplitude of gastric contractions in both immunosuppressed groups was higher than observed in the control. The frequency of gastric contractions for the CSA + AZA + PRED group was also increased (p<0.01). Results obtained by EGG were similar to those recorded with the ACB. The thickness of the circular layer from stomach muscle decreased in both immunosuppressed groups, while the longitudinal layer was reduced only in the CSA + AZA + PRED group. CONCLUSION: Triple immunosuppressive therapy alters gastric motility, compromises the muscular layers and the association between CSA, AZA, and PRED provokes the major alterations in the structure and gastric function. Specific gastrointestinal side effects resulting from different immunosuppressive therapies still need to be elucidated in order to provide more effective and personalized therapy for patients.

Changes in colonic contractility in response to inflammatory bowel disease: Long-term assessment in a model of TNBS-induced inflammation in rats.

AIMS: Inflammatory bowel disease is a chronic relapsing inflammation that affects the gastrointestinal tract, causing changes in colonic motility. The evolution of these changes is not completely understood and possibly related to symptoms that appear in different degrees of the intestinal inflammation. Therefore, our aim is evaluate during 14 days of assessment aspects of colonic contractility using 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of inflammation in rats and associate the inflammatory process with colonic motility. METHODS: Contractility and inflammatory parameters were assessed in the same animal in six different moments: before intestinal inflammation induction, 2, 5, 8, 11, and 14 days after induction. The mechanical activity was determined by alternating current biosusceptometry (ACB) and subdivided into rhythmic propagating ripples (RPR) and rhythmic propulsive motor complexes (RPMC). We assessed inflammation by determining myeloperoxidase activity in feces. RESULTS: Transient and permanent changes were observed in colonic motility as a function of the inflammatory process evaluated through myeloperoxidase activity. We identified two contraction profiles: RPR and RPMC. The microscopic analysis demonstrated a depth of damage caused by an injury that was associated with changes in motility. CONCLUSIONS: We implemented a robust and adequate (specific) signal processing to quantify two measured colonic frequency patterns. Thus, we performed a detailed temporal analysis of the consequences of TNBS-induced inflammation on colonic motility in rats. Our approach enables further long-term assessments in the same animal with different mechanisms and duration of injury, remission, treatments and their motor consequences.

Albumin Coating Prevents Cardiac Effect of the Magnetic Nanoparticles.

We have showed that surface layer can determine cardiac effects of the magnetic nanoparticles (MNPs). Considering the high binding capacity of albumin and low side-effects, the aim of this study was to evaluate the influence of albumin coating on the cardiovascular effects of two manganese ferrite-based MNPs: citrate-coated and bare MNPs. Isolated rat hearts were perfused with citrate-coated magnetic nanoparticles (CiMNPs), citrate albumin-coated magnetic nanoparticles (CiAlbMNPs), bare magnetic nanoparticles (BaMNPs), and albumin-coated magnetic nanoparticles (AlbMNPs). CiMNPs induce a transient decrease in the left ventricular end-systolic pressure, +dP/dt and -dP/dt. These effects were not worsened by albumin coating. BaMNPs significantly increased the left ventricular end-diastolic pressure and perfusion pressure and decreased the +dP/dt and -dP/dt. These effects were completely absent in hearts perfused with AlbMNPs. None of the MNPs changed heart rate or arterial blood pressure in conscious rats. Magnetic signals in isolated hearts perfused with BaMNPs were significantly higher than AlbMNPs perfused hearts. However, the magnetic signal in heart tissue was similar when the MNPs were infused in conscious rats. These data indicate that albumin-coated can reduce cardiovascular effects of MNPs. These findings suggest a protective effect of albumin surface in MNPs, favoring its future therapeutic applications.

Multichannel AC Biosusceptometry System to Map Biodistribution and Assess the Pharmacokinetic Profile of Magnetic Nanoparticles by Imaging.

In this paper, the application of a technique to evaluate in vivo biodistribution of magnetic nanoparticles (MNP) is addressed: the Multichannel AC Biosusceptometry System (MC-ACB). It allows real-time assessment of magnetic nanoparticles in both bloodstream clearance and liver accumulation, where a complex network of inter-related cells is responsible for MNP uptake. Based on the acquired MC-ACB images, we propose a mathematical model which helps to understand the distribution and accumulation pharmacokinetics of MNP. The MC-ACB showed a high time resolution to detect and monitor MNP, providing sequential images over the particle biodistribution. Utilizing the MC-ACB instrument, we assessed regions corresponding to the heart and liver, and we determined the MNP transfer rates between the bloodstream and the liver. The pharmacokinetic model resulted in having a strong correlation with the experimental data, suggesting that the MC-ACB is a valuable and accessible imaging device to assess in vivo and real-time pharmacokinetic features of MNP.

Real-time in vivo monitoring of magnetic nanoparticles in the bloodstream by AC biosusceptometry.

BACKGROUND: We introduce and demonstrate that the AC biosusceptometry (ACB) technique enables real-time monitoring of magnetic nanoparticles (MNPs) in the bloodstream. We present an ACB system as a simple, portable, versatile, non-invasive, and accessible tool to study pharmacokinetic parameters of MNPs, such as circulation time, in real time. We synthesized and monitored manganese doped iron oxide nanoparticles in the bloodstream of Wistar rats using two different injection protocols. Aiming towards a translational approach, we also simultaneously evaluated cardiovascular parameters, including mean arterial pressure, heart rate, and episodes of arrhythmia in order to secure the well-being of all animals. RESULTS: We found that serial injections increased the circulation time compared with single injections. Immediately after each injection, we observed a transitory drop in arterial pressure, a small drop in heart rate, and no episodes of arrhythmia. Although some cardiovascular effects were observed, they were transitory and easily recovered in both protocols. CONCLUSIONS: These results indicate that the ACB system may be a valuable tool for in vivo, real-time MNP monitoring that allows associations with other techniques, such as pulsatile arterial pressure and electrocardiogram recordings, helping ensuring the protocol safety, which is a fundamental step towards clinical applications.

Real-time liver uptake and biodistribution of magnetic nanoparticles determined by AC biosusceptometry.

We describe the development of a joint in vivo/ex vivo protocol to monitor magnetic nanoparticles in animal models. Alternating current biosusceptometry (ACB) enables the assessment of magnetic nanoparticle accumulation, followed by quantitative analysis of concentrations in organs of interest. We present a study of real-time liver accumulation, followed by the assessment of sequential biodistribution using the same technique. For quantification, we validated our results by comparing all of the data with electron spin resonance (ESR). The ACB had viable temporal resolution and accuracy to differentiate temporal parameters of liver accumulation, caused by vasculature extravasation and macrophages action. The biodistribution experiment showed different uptake profiles for different doses and injection protocols. Comparisons with the ESR system indicated a correlation index of 0.993. We present the ACB system as an accessible and versatile tool to monitor magnetic nanoparticles, allowing in vivo and real-time evaluations of distribution and quantitative assessments of particle concentrations.

Quantification of Pulmonary Inflammatory Processes Using Chest Radiography: Tuberculosis as the Motivating Application.

The purpose of this work was to develop a quantitative method for evaluating the pulmonary inflammatory process (PIP) through the computational analysis of chest radiography exams in posteroanterior (PA) and lateral views. The quantification procedure was applied to patients with tuberculosis (TB) as the motivating application.A study of high-resolution computed tomography (HRCT) examinations of patients with TB was developed to establish a relation between the inflammatory process and the signal difference-to-noise ratio (SDNR) measured in the PA projection. A phantom essay was used to validate this relation, which was implemented using an algorithm that is able to estimate the volume of the inflammatory region based solely on SDNR values in the chest radiographs of patients.The PIP volumes that were quantified for 30 patients with TB were used for comparisons with direct HRCT analysis for the same patient. The Bland-Altman statistical analyses showed no significant differences between the 2 quantification methods. The linear regression line had a correlation coefficient of R = 0.97 and P < 0.001, showing a strong association between the volume that was determined by our evaluation method and the results obtained by direct HRCT scan analysis.Since the diagnosis and follow-up of patients with TB is commonly performed using X-rays exams, the method developed herein can be considered an adequate tool for quantifying the PIP with a lower patient radiation dose and lower institutional cost. Although we used patients with TB for the application of the method, this method may be used for other pulmonary diseases characterized by a PIP.

Enhancing the versatility of alternate current biosusceptometry (ACB) through the synthesis of a dextrose-modified tracer and a magnetic muco-adhesive cellulose gel.

Alternate Current Biosusceptometry (ACB) is a promising bio-magnetic method, radiation free and easily performed used for gastric emptying exams. Due to development on its sensitivity level, interesting nature, noninvasiveness and low cost it has attracted a lot of attention. In this work, magnetic nanoparticles of Mn-Zn ferrite as well as dextrose-modified nanoparticles were synthesized to be used as possible tracers in ACB gastric emptying exams. In addition, a magnetic muco-adhesive gel was obtained by modifying the ferrite nanoparticles with cellulose. Based on in-vivo tests in rats, we show that the pure ferrite nanoparticles, whose isoelectric point was found to be at pH=3.2, present a great sensitivity to pH variations along the gastrointestinal tract, while the reduction of the isoelectric point by the dextrose modification leads to suitable nanoparticles for rapid gastric emptying examinations. On the other hand, the in-vivo tests show that the muco-adhesive cellulose gel presents substantial stomach adhesion and is a potential drug delivery system easily traceable by the ACB system.

Objective CT-based quantification of lung sequelae in treated patients with paracoccidioidomycosis.

This study presents methodology for objectively quantifying the pulmonary region affected by emphysemic and fibrotic sequelae in treated patients with paracoccidioidomycosis. This methodology may also be applied to any other disease that results in these sequelae in the lungs.Pulmonary high-resolution computed tomography examinations of 30 treated paracoccidioidomycosis patients were used in the study. The distribution of voxel attenuation coefficients was analyzed to determine the percentage of lung volume that consisted of emphysemic, fibrotic, and normal tissue. Algorithm outputs were compared with subjective evaluations by radiologists using a scale that is currently used for clinical diagnosis.Affected regions in the patient images were determined by computational analysis and compared with estimates by radiologists, revealing mean (± standard deviation) differences in the scores for fibrotic and emphysemic regions of 0.1% ±â€Š1.2% and -0.2% ±â€Š1.0%, respectively.The computational results showed a strong correlation with the radiologist estimates, but the computation results were more reproducible, objective, and reliable.

Analysis of biological tissues in infant chest for the development of an equivalent radiographic phantom.

PURPOSE: The main purpose of the present study was to determine the amounts of different tissues in the chest of the newborn patient (age ≤1 year), with the aim of developing a homogeneous phantom chest equivalent. This type of phantom is indispensable in the development of optimization procedures for radiographic techniques, including dosimetric control, which is a crucial aspect of pediatric radiology. The authors present a systematic set of procedures, including a computational algorithm, to estimate the amounts of tissues and thicknesses of the corresponding simulator material plates used to construct the phantom. METHODS: The Gaussian fit of computed tomographic (CT) analysis was applied to classify and quantify different biological tissues. The methodology is summarized with a computational algorithm, which was used to quantify tissues through automated CT analysis. The thicknesses of the equivalent homogeneous simulator material plates were determined to construct the phantom. RESULTS: A total of 180 retrospective CT examinations with anterior-posterior diameter values ranging 8.5-13.0 cm were examined. The amounts of different tissues were evaluated. The results provided elements to construct a phantom to simulate the infant chest in the posterior-anterior or anterior-posterior (PA/AP) view. CONCLUSIONS: To our knowledge, this report represents the first demonstration of an infant chest phantom dedicated to the radiology of children younger than one year. This phantom is a key element in the development of clinical charts for optimizing radiographic technique in pediatric patients. Optimization procedures for nonstandard patients were reported previously [Pina et al., Phys. Med. Biol. 49, N215-N226 (2004) and Pina et al., Appl. Radiat. Isot. 67, 61-69 (2009)]. The constructed phantom represents a starting point to obtain radiologic protocols for the infant patient.

Estudo da atividade de contraçäo gástrica por susceptometria AC / Study of gastric contraction activity by AC susceptometry

A medida da atividade de contração gástrica é um importante parâmetro para análise clínica de diversas anomalias do trato gastrointestinal e pode fornecer importantes informações sobre a fisiologia deste órgão. Esta atividade foi medida com ótima performance através da técnica de susceptometria AC

Abstract -The gastric contraction activity measurements is an important parameter for clinical analysis of many gastrointestinal tract adnormalities and is able to give important informations about this organ phisiology. This activity was measured with a high performance though AC susceptometer technique