The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

Incidence of Infectious Adverse Events in Patients With Rheumatoid Arthritis and Spondyloarthritis on Biologic Drugs-Data From the Brazilian Registry for Biologics Monitoring.

BACKGROUND: The safety profile of biologic drugs might present substantial regional differences. Since 2009, the Brazilian Society of Rheumatology has maintained BIOBADABRASIL (Brazilian Registry for Biologic Drugs), a registry for monitoring of biologic therapies in rheumatic diseases. OBJECTIVES: The aim of this study was to verify the incidence rate (IR) of serious infections in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients on biologic drugs. METHODS: BIOBADABRASIL prospectively included patients with rheumatic diseases who started the first biologic drug or a synthetic disease-modifying antirheumatic drug as a parallel control group. This study focuses on serious infectious adverse events (SIAEs) in RA and SpA patients on biologic drugs compared with controls, from January 2009 to June 2015. Time of exposure was set from initiation of the drug to the date of last administration or censorship. Serious infectious adverse events IR was calculated per 1000 patient/years with 95% confidence interval (CI). RESULTS: A total of 1698 patients (RA, 1121; SpA, 577) were included, 7119 patient/years. Serious infectious adverse events were more common among patients on tumor necrosis factor inhibitors (TNFi's) than controls (adjusted IR ratio, 2.96 [95% CI, 2.01-4.36]; p < 0.001). Subsequent TNFi was associated with a higher SIAEs incidence when compared with first TNFI (adjusted IR ratio, 1.55 [95% CI, 1.15-2.08]; p = 0.004). Serious infectious adverse events were associated with age and corticosteroids intake. Serious infectious adverse events were more frequent in the respiratory tract in all subgroups. CONCLUSIONS: In BIOBADABRASIL, biologic drugs, especially the subsequent TNFi, were associated with a higher risk of serious infections compared with synthetic DMARDs. Corticosteroid intake and age represented risk factors for SIAEs. Constant monitoring is required to follow the safety profile of drugs in the clinical setting of rheumatic conditions in Brazil.

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.

Insights into cardiovascular effects of proline-rich oligopeptide (Bj-PRO-10c) revealed by structure-activity analyses: dissociation of antihypertensive and bradycardic effects.

We have previously reported that the proline-rich decapeptide from Bothrops jararaca (Bj-PRO-10c) causes potent and sustained antihypertensive and bradycardic effects in SHR. These activities are independent of ACE inhibition. In the present study, we used the Ala-scan approach to evaluate the importance of each amino acid within the sequence of Bj-PRO-10c (Pyr(1)-Asn(2)-Trp(3)-Pro(4)-His(5)-Pro(6)-Gln(7)-Ile(8)-Pro(9)-Pro(10)). The antihypertensive and bradycardic effects of the analogues Bj-PRO-10c Ala(3), Bj-PRO-10c Ala(7), Bj-PRO-10c Ala(8) were similar to those of Bj-PRO-10c, whereas the analogues Bj-PRO-10c Ala(2), Bj-PRO-10c Ala(4), Bj-PRO-10c Ala(5), Bj-PRO-10c Ala(9), and Bj-PRO-10c Ala(10) kept the antihypertensive activity and lost bradycardic activity considerably. In contrast, Bj-PRO-10c Ala(1) and Bj-PRO-10c Ala(6) were unable to provoke any cardiovascular activity. In summary, we demonstrated that (1) the Pyr(1) and Pro(6) residues are essential for both, the antihypertensive and bradycardic effects of Bj-PRO-10c; (2) Ala-scan approach allowed dissociating blood pressure reduction and bradycardic effects. Conformational properties of the peptides were examined by means of circular dichroism (CD) spectroscopy. The different Ala-scan analogues caused either an increase or decrease in the type II polyproline helix content compared to Bj-PRO-10c. The complete loss of activity of the Pro(6) â†’ Ala(6) mutant is probably due to the fact that in the parent peptide the His(5)-Pro(6) bond can exist in the cis configuration, which could correspond to the conformation of this bond in the bound state. Current data support the Bj-PRO-10c as a promising leader prototype to develop new agents to treat cardiovascular diseases and its co-morbidities.

Dinuclear pyridine-4-thiolate-bridged rhodium and iridium complexes as ditopic building blocks in molecular architecture.

A series of dinuclear pyridine-4-thiolate (4-Spy)-bridged rhodium and iridium compounds [M(µ-4-Spy)(diolef)]2 [diolef = 1,5-cyclooctadiene (cod), M = Rh (1), Ir (2); diolef = 2,5-norbornadiene (nbd), M = Rh (3)] were prepared by the reaction of Li(4-Spy) with the appropriate compound [M(µ-Cl)(diolef)]2 (M = Rh, Ir). The dinuclear compound [Rh(µ-4-Spy)(CO)(PPh3)]2 (4) was obtained by the reaction of [Rh(acac)(CO)(PPh3)] (acac = acetylacetonate) with 4-pySH. Compounds 1-4 were assessed as metalloligands in self-assembly reactions with the cis-blocked acceptors [M(cod)(NCCH3)2](BF4) [M = Rh (a), Ir (b)] and [M(H2O)2(dppp)](OTf)2 [M = Pd (c), Pt (d); dppp = 1,3-bis(diphenylphosphino)propane]. The homometallic hexanuclear metallomacrocycles [{M2(µ-4-Spy)2(cod)2}2{M(cod)}2](BF4)2 (M = Rh [(1a)2], Ir [(2b)2]) and the heterometallic hexanuclear metallomacrocycles [{Rh2(µ-4-Spy)2(cod)2}2{Ir(cod)}2](BF4)2 [(1b)2], [{Rh2(µ-4-Spy)2(cod)2}2{M'(dppp)}2](OTf)4 (M' = Pd [(1c)2], Pt [(1d)2]), and [{Ir2(µ-4-Spy)2(cod)2}2{M'(dppp)}2](OTf)4 (M' = Pd [(2c)2], Pt [(2d)2]) were obtained. NMR spectroscopy in combination with electrospray ionization mass spectrometry was used to elucidate the nature of the metalloligands and their respective supramolecular assemblies. Most of the synthesized species were found to be nonrigid in solution, and their fluxional behavior was studied by variable-temperature (1)H NMR spectroscopy. An X-ray diffraction study of the assemblies (1a)2 and (1d)2 revealed the formation of rectangular (9.6 Å × 6.6 Å) hexanuclear metallomacrocycles with alternating dinuclear (Rh2) and mononuclear (Rh or Pt) corners. The hexanuclear core is supported by four pyridine-4-thiolate linkers, which are bonded through the thiolate moieties to the dinuclear rhodium units, exhibiting a bent-anti arrangement, and through the peripheral pyridinic nitrogen atoms to the mononuclear corners.

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.

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.

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.

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.

Hydride mobility in trinuclear sulfido clusters with the core [Rh3(µ-H)(µ3-S)2]: molecular models for hydrogen migration on metal sulfide hydrotreating catalysts.

The treatment of [{Rh(µ-SH){P(OPh)(3)}(2)}(2)] with [{M(µ-Cl)(diolef)}(2)] (diolef=diolefin) in the presence of NEt(3) affords the hydrido-sulfido clusters [Rh(3)(µ-H)(µ(3)-S)(2)(diolef){P(OPh)(3)}(4)] (diolef=1,5-cyclooctadiene (cod) for 1, 2,5-norbornadiene (nbd) for 2, and tetrafluorobenzo[5,6]bicyclo[2.2.2]octa-2,5,7-triene (tfb) for 3) and [Rh(2)Ir(µ-H)(µ(3)-S)(2)(cod){P(OPh)(3)}(4)] (4). Cluster 1 can be also obtained by treating [{Rh(µ-SH){P(OPh)(3)}(2)}(2)] with [{Rh(µ-OMe)(cod)}(2)], although the main product of the reaction with [{Ir(µ-OMe)(cod)}(2)] was [RhIr(2)(µ-H)(µ(3)-S)(2)(cod)(2){P(OPh)(3)}(2)] (5). The molecular structures of clusters 1 and 4 have been determined by X-ray diffraction methods. The deprotonation of a hydrosulfido ligand in [{Rh(µ-SH)(CO)(PPh(3))}(2)] by [M(acac)(diolef)] (acac=acetylacetonate) results in the formation of hydrido-sulfido clusters [Rh(3)(µ-H)(µ(3)-S)(2)(CO)(2) (diolef)(PPh(3))(2)] (diolef=cod for 6, nbd for 7) and [Rh(2)Ir(µ-H)(µ(3)-S)(2)(CO)(2)(cod)(PPh(3))(2)] (8). Clusters 1-3 and 5 exist in solution as two interconverting isomers with the bridging hydride ligand at different edges. Cluster 8 exists as three isomers that arise from the disposition of the PPh(3) ligands in the cluster (cis and trans) and the location of the hydride ligand. The dynamic behaviour of clusters with bulky triphenylphosphite ligands, which involves hydrogen migration from rhodium to sulfur with a switch from hydride to proton character, is significant to understand hydrogen diffusion on the surface of metal sulfide hydrotreating catalysts.

Corona protein impacts on alternating current biosusceptometry signal and circulation times of differently coated MnFe2O4 nanoparticles.

Background: We evaluated the impacts of corona protein (CP) formation on the alternating current biosusceptometry (ACB) signal intensity and in vivo circulation times of three differently coated magnetic nanoparticles (MNP): bare, citrate-coated and bovine serum albumin-coated MNPs. Methods: We employed the ACB system, gel electrophoresis and mass spectrometry analysis. Results: Higher CP formation led to a greater reduction in the in vitro ACB signal intensity and circulation time. We found fewer proteins forming the CP for the bovine serum albumin-coated MNPs, which presented the highest circulation time in vivo among the MNPs studied. Conclusion: These data showed better biocompatibility, stability and magnetic signal uniformity in biological media for bovine serum albumin-coated MNPs than for citrate-coated MNPs and bare MNPs.

Gluten-Free Labeling Is Misused Frequently in Foods Marketed in Northwestern Mexico.

Background: Patients with celiac disease (CD) require a gluten-free (GF) diet, including industrialized products containing ≤ 20 mg gluten/kg. The market status of GF food products is almost unknown in Mexico. Therefore, we studied the GF-labeled products on the northwestern Mexican market and analyzed their gluten content. Methods: We searched for GF type of foods in three different supermarkets of each chain in Mexicali Baja California and Hermosillo Sonora and corroborated the price, origin, and GF certification of each item using internet sites. We quantified the gluten in the foods using the sandwich R5-enzyme-linked immunosorbent assay (ELISA) and detected their immune-reactivity for IgA from patients with CD. Results: The study included >263 different GF-labeled foodstuffs, and 55% of them were made in Mexico. The Mexican items were principally flours, sausages, bread and bakery, milk-type products, and tortillas, while pasta, snacks, and breakfast cereals were mainly imported. The cost ratio of GF products to the conventional mean was 3.5, ranging principally from 1 to 13. The most common GF-labeled foods were flours and pasta (34), cookies and snacks (32), breakfast cereals, sausages, and milk-type products (18-20). Although 36% of the products were certified, 17.4% of the analyzed samples contained >20 mg gluten/kg, mainly the non-certified ones and those made in Mexico. IgA from patients with CD reacted in vitro against gluten proteins from the contaminated GF-labeled products. Conclusion: The accessibility of GF products in the northwestern Mexican market is wide; however, such products are expensive, and some could be risky for patients with CD because they contain gluten, which is recognized by the immune systems of these patients.

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.

Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil).

OBJECTIVE: To evaluate the safety of the methotrexate (MTX)-leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease-modifying antirheumatic drugs (DMARDs) or Janus kinase inhibitors (JAKi). METHODS: Patients with RA starting a treatment course with a csDMARD (without previous use of bDMARD or JAKi) or their first bDMARD/JAKi were followed up in a registry-based, multicentric cohort study in Brazil (BiobadaBrasil). The primary outcome was the incidence of serious adverse events (SAEs); secondary outcomes included serious infections. Multivariate Cox proportional hazards models and propensity score matching analysis (PSMA) were used for statistical comparisons. RESULTS: In total, 1671 patients (5349 patient-years [PY]) were enrolled; 452 patients (1537 PY) received MTX + LEF. The overall incidence of SAEs was 5.6 per 100 PY. The hazard of SAEs for MTX + LEF was not higher than for MTX or LEF (adjusted HR [aHR] 1.00, 95% CI 0.76-1.31, P = 0.98). MTX + LEF presented a lower hazard of SAEs (aHR 0.56, 95% CI 0.36-0.88, P = 0.01) and infectious SAEs (aHR 0.48, 95% CI 0.25-0.94, P = 0.03) than bDMARDs/JAKi with MTX or LEF. MTX + LEF presented lower hazard of SAEs than MTX + sulfasalazine (SSZ; aHR 0.33, 95% CI 0.16-0.65, P = 0.002). Analysis using PSMA confirmed the results obtained with traditional multivariate Cox analysis. CONCLUSION: In our study, MTX + LEF presented a relatively good overall safety profile in comparison to MTX + SSZ and schemes involving advanced therapies in RA.

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.

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.