Background
One-anastomosis gastric bypass/mini-gastric bypass (OAGB/MGB) remains controversial because it may cause chronic biliary reflux (BR). The risk of developing esogastric cancer due to BR ...after OAGB/MGB is based on the results of experimental rat studies using esojejunostomy (EJ). The aim of this study was to analyze the potential long-term consequences of BR on the esogastric mucosae in OAGB/MGB-operated rats and to compare these results to those from the use of EJ.
Methods
Wistar rats received OAGB/MGB (
n
= 16), EJ (
n
= 16), and sham (
n
= 8) operations. Mortality and weight changes were evaluated throughout the experiment. BR was measured using magnetic resonance imaging (MRI). Rats received follow-ups for 30 weeks. A double-blinded histological analysis was performed in the esogastric segments.
Results
BR was diagnosed in OAGB/MGB and EJ rats using the MRI technique; no BR occurred in the sham group. After a 30-week follow-up, no incidences of dysplasia or cancer were observed in the three groups. Additionally, esophageal intestinal metaplasia and mucosal ulcerations were observed in 41.7% and 50% of EJ rats, respectively, and no incidences of these conditions were observed in OAGB/MGB and sham rats. The incidence of esophagitis was significantly higher and more severe in the EJ group compared to those in the OAGB/MGB and sham groups (EJ = 100%, OAGB/MGB = 16.7%, sham = 8.3%;
p
< 0.001).
Conclusions
After a 30-week follow-up period, OAGB/MGB rats did not develop any precancerous or cancerous lesions when more than 40% of EJ rats had intestinal metaplasia.
The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic ...hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermoresponsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery, having in mind the clinical translation of the nanoplatform. We have chosen iron oxide based nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles such as our iron oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simple irradiation of a copper-mediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded-TR-cubes) without compromising their thermoresponsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The biodistribution of intravenously injected TR-cubes showed signs of renal clearance within 1 week and complete clearance after 5 months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH: i.e., being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).
Collecting information on multiple pathophysiological parameters is essential for understanding complex pathologies, especially given the large interindividual variability. We report here ...multifunctional nanoparticles which are luminescent probes, oxidant sensors, and contrast agents in magnetic resonance imaging (MRI). Eu3+ ions in an yttrium vanadate matrix have been demonstrated to emit strong, nonblinking, and stable luminescence. Time- and space-resolved optical oxidant detection is feasible after reversible photoreduction of Eu3+ to Eu2+ and reoxidation by oxidants, such as H2O2, leading to a modulation of the luminescence emission. The incorporation of paramagnetic Gd3+ confers in addition proton relaxation enhancing properties to the system. We synthesized and characterized nanoparticles of either 5 or 30 nm diameter with compositions of GdVO4 and Gd0.6Eu0.4VO4. These particles retain the luminescence and oxidant detection properties of YVO4:Eu. Moreover, the proton relaxivity of GdVO4 and Gd0.6Eu0.4VO4 nanoparticles of 5 nm diameter is higher than that of the commercial Gd3+ chelate compound Dotarem at 20 MHz. Nuclear magnetic resonance dispersion spectroscopy showed a relaxivity increase above 10 MHz. Complexometric titration indicated that rare-earth leaching is negligible. The 5 nm nanoparticles injected in mice were observed with MRI to concentrate in the liver and the bladder after 30 min. Thus, these multifunctional rare-earth vanadate nanoparticles pave the way for simultaneous optical and magnetic resonance detection, in particular, for in vivo localization evolution and reactive oxygen species detection in a broad range of physiological and pathophysiological conditions.
Takotsubo cardiomyopathy is a stress-induced cardiovascular disease with symptoms comparable to those of an acute coronary syndrome but without coronary obstruction. Takotsubo was initially ...considered spontaneously reversible, but epidemiological studies revealed significant long-term morbidity and mortality, the reason for which is unknown. Here, we show in a female rodent model that a single pharmacological challenge creates a stress-induced cardiomyopathy similar to Takotsubo. The acute response involves changes in blood and tissue biomarkers and in cardiac in vivo imaging acquired with ultrasound, magnetic resonance and positron emission tomography. Longitudinal follow up using in vivo imaging, histochemistry, protein and proteomics analyses evidences a continued metabolic reprogramming of the heart towards metabolic malfunction, eventually leading to irreversible damage in cardiac function and structure. The results combat the supposed reversibility of Takotsubo, point to dysregulation of glucose metabolic pathways as a main cause of long-term cardiac disease and support early therapeutic management of Takotsubo.
Preeclampsia is a major hypertensive disease caused by pregnancy, inducing proteinuria and increased blood pressure starting from the second half of pregnancy (early preeclampsia) or near the end of ...pregnancy (late preeclampsia). Pre-symptomatic diagnosis would allow for therapeutic interventions, such as with low-dose aspirin. Among non-invasive methods to explore organ physiology, Doppler ultrasonography (US) and functional blood oxygenation level-dependent (BOLD) MRI (which do not need radioactive contrast agents such as gadolinium) can be used in pregnant women.
In this study, we used US and BOLD MRI to finely characterize the phenotype of preeclampsia induced by the foeto-placental overexpression of the transcription factor storkhead box 1A (STOX1A) in female mice.
We could observe late fetal growth restriction consistent with the placental dysfunction revealed by US and the known association between preeclampsia and intra-uterine growth restriction. On US, uterine and umbilical artery as well as heart and kidney parameters were modified in preeclamptic mice. On BOLD MRI, mean T2* values revealed considerable differences between control and preeclamptic placentas, which suggests altered dynamics of oxygen release and ratio of oxyhemoglobin to deoxyhemoglobin in the model.
These preliminary pre-clinical results suggest that BOLD MRI could be evaluated as a prognostic/diagnostic tool for preeclampsia.
Anterior cruciate ligament (ACL) repair techniques are new emerging strategies prevailing, in selected cases, over standard reconstruction of the ACL with excision of its remnants. Mid-substance ACL ...tears represent a challenge for ACL repair techniques, and remnants-preserving ACL reconstruction (rp-ACLR) using an autograft remains the recommended treatment in this situation. However, morbidity associated with the autograft harvesting prompts the need for alternative surgical strategies based on the use of synthetic scaffolds. Relevant small animal models of mid-substance tears with ACL remnants preservation and reconstruction are necessary to establish the preliminary proof of concept of these new strategies.
A rat model of rp-ACLR using a tendinous autograft after complete mid-substance ACL transection was established. Twelve weeks following surgery, clinical outcomes and knee joints were assessed through visual gait analysis, Lachman tests, thigh perimeter measurements, magnetic resonance imaging, micro-computed tomography, and histology, to evaluate the morbidity of the procedure, accuracy of bone tunnel positioning, ACL remnants fate, osteoarthritis, and autograft bony integration. Results were compared with those obtained with isolated ACL transection without reconstruction and to right non-operated knees.
Most operated animals were weight-bearing the day following surgery, and no adverse inflammatory reaction has been observed for the whole duration of the study. Autograft fixation with cortical screws provided effective graft anchorage until sacrifice. Healing of the transected ACL was not observed in the animals in which no graft reconstruction was performed. rp-ACLR was associated with a reduced degeneration of the ACL remnants (p = 0.004) and cartilages (p = 0.0437). Joint effusion and synovitis were significantly lower in the reconstructed group compared to the transected ACL group (p = 0.004). Most of the bone tunnel apertures were anatomically positioned in the coronal and/or sagittal plane. The most deviated bone tunnel apertures were the tibial ones, located in median less than 1 mm posteriorly to anatomical ACL footprint center.
This study presents a cost-effective, new relevant and objective rat model associated with low morbidity for the preliminary study of bio-implantable materials designed for remnants-preserving ACL surgery after mid-substance ACL tear.
To determine the maternofetal pharmacokinetics of gadoterate meglumine in mice during the first 48 hours following maternal intravenous injection of a high dose of 0.5 mmol of gadolinium per ...kilogram.
All the studies complied with French law and the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Balb/C mice (n = 23) at 16 days of gestation were examined for 48 hours after maternal intravenous administration of 0.5 mmol gadolinium per kilogram of gadoterate meglumine. Gadolinium concentration in the placentas, fetuses, and amniotic fluid was determined by using mass spectrometry, and the total placental and fetal gadolinium content was calculated. Gadoterate meglumine half-life in the different compartments was estimated with one- and two-compartment models. Kruskal-Wallis and Wilcoxon signed-rank tests were used to compare the pharmacokinetic profiles.
Gadoterate meglumine passed the placental barrier, entering the fetuses and amniotic fluid before being redistributed back to the mother. The placental gadolinium concentration showed two-compartmental decay, with a first half-life of distribution of 47 minutes and a second half-life of elimination of 107 hours. The half-lives in the fetuses and amniotic fluid were, respectively, 4 and 5 hours and followed a monocompartmental model after the initial peak. The maximal gadolinium fetal concentration (31.8 nmol/g) was observed 30 minutes after injection, which corresponded to a total fetal content of 0.077% of the injected dose.
In mice, gadoterate meglumine, an extracellular nonspecific gadolinium chelate contrast medium, passed the placenta before being redistributed back to the mother, resulting in undetectable fetal concentrations after 48 hours.
Current treatments of chemotherapy-induced cardiomyopathy (CCM) are of limited efficacy. We assessed whether repeated intravenous injections of human extracellular vesicles from cardiac progenitor ...cells (EV-CPC) could represent a new therapeutic option and whether EV manufacturing according to a Good Manufacturing Practices (GMP)-compatible process did not impair their bioactivity.
Immuno-competent mice received intra-peritoneal injections (IP) of doxorubicin (DOX) (4 mg/kg each; cumulative dose: 12 mg/kg) and were then intravenously (IV) injected three times with EV-CPC (total dose: 30 billion). Cardiac function was assessed 9-11 weeks later by cardiac magnetic resonance imaging (CMR) using strain as the primary end point. Then, immuno-competent rats received 5 IP injections of DOX (3 mg/kg each; cumulative dose 15 mg/kg) followed by 3 equal IV injections of GMP-EV (total dose: 100 billion). Cardiac function was assessed by two dimensional-echocardiography.
In the chronic mouse model of CCM, DOX + placebo-injected hearts incurred a significant decline in basal (global, epi- and endocardial) circumferential strain compared with sham DOX-untreated mice (
= 0.043,
= 0.042,
= 0.048 respectively) while EV-CPC preserved these indices. Global longitudinal strain followed a similar pattern. In the rat model, IV injections of GMP-EV also preserved left ventricular end-systolic and end-diastolic volumes compared with untreated controls.
Intravenously-injected extracellular vesicles derived from CPC have cardio-protective effects which may make them an attractive user-friendly option for the treatment of CCM.
Abstract Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK , an endothelial transmembrane receptor signaling through PIK3CA. ...Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA -related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations’ occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA ( n = 16) or TEK ( n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK -related capillary venous malformations.
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