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BACKGROUND: Diffusion-weighted imaging (DWI) has come up as a newer diagnostic modality for the diagnosis of early functional changes in various organs including the pancreas. DWI has shown the ability of early and accurate diagnosis of inflammatory pathologies, before the appearance of morphological changes on imaging. OBJECTIVES: The objectives of this study were to study the diagnostic accuracy of DWI in the diagnosis of early acute interstitial pancreatitis. MATERIALS AND METHODS: The present retrospective observational study was conducted at the department of radiodiagnosis of a tertiary teaching hospital for 1 year. Fifty patients who underwent magnetic resonance imaging of the pancreas with clinical or laboratory diagnosis of early pancreatitis were included in the study. The diagnostic accuracy of DWI was analyzed on the basis of quantitative (apparent diffusion coefficient [ADC] values) evaluation in the diagnosis of early acute pancreatitis. Threshold values for ADC were derived for differentiation of inflamed versus normal pancreas. Sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) were obtained by drawing the receiver operating characteristic (ROC) curve. RESULTS: The mean ADC values in the patient group (0.882 × 10-3 mm2/s ± 0.102) were significantly lower than the control group (1.178 × 10-3 mm2/s ± 0.232) with P < 0.001. The ROC curve deciphered a cutoff value of 0.937 × 10-3 mm2/s with a sensitivity of 84%, specificity of 86%, PPV of 85.71%, and NPV of 84.31% for diagnosis of acute pancreatitis using quantitative ADC values. CONCLUSION: DWI can thus be a succinct modality for early diagnosis of pancreatitis with excellent diagnostic accuracy and superlative advantage of lack of contrast and radiation in comparison to computed tomography scan.
Résumé Contexte:L'imagerie pondérée en diffusion (DWI) est apparue comme une nouvelle modalité de diagnostic pour le diagnostic des changements fonctionnels précoces.dans divers organes, dont le pancréas. DWI a montré la capacité de diagnostic précoce et précis des pathologies inflammatoires , avant apparition de modifications morphologiques à l'imagerieObjectifs:Les objectifs de cette étude étaient d'étudier la précision diagnostique du CFA chez le diagnostic de pancréatite interstitielle aiguë précoceMatériels et méthodes:La présente étude observationnelle rétrospective a été menée à le service de radiodiagnostic d'un CHU pendant 1 an. Cinquante patients ayant bénéficié d'une imagerie par résonance magnétique du les pancréas présentant un diagnostic clinique ou de laboratoire de pancréatite précoce ont été inclus dans l'étude. La précision diagnostique du DWI a été analysée sur la base d'une évaluation quantitative (valeurs du coefficient de diffusion apparent [ADC]) dans le diagnostic de la pancréatite aiguë précoce. Seuil les valeurs de l'ADC ont été dérivées pour différencier le pancréas enflammé du pancréas normal. Sensibilité, spécificité, valeur prédictive positive (VPP),et des valeurs prédictives négatives (NPV) ont été obtenues en traçant la courbe des caractéristiques de fonctionnement du récepteur (ROC)Résultats:L'ADC moyenles valeurs du groupe de patients (0.882 × 10−3 mm2/s ± 0.102) étaient significativement inférieures à celles du groupe témoin (1.178 × 10−3 mm2/s ± 0.232) avec P < 0.001. La courbe ROC a décrypté une valeur seuil de 0.937 × 10−3 mm2/s avec une sensibilité de 84 %, une spécificité de 86 %, une VPP de 85.71 %, et VPN de 84.31 % pour le diagnostic de pancréatite aiguë à l'aide des valeurs quantitatives de l'ADCConclusion:La DWI peut donc être une modalité succincte pour le diagnostic précoce de la pancréatite avec une excellente précision diagnostique et l'avantage exceptionnel de l'absence de contraste et de rayonnement par rapport à la tomodensitométrie.
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The mortality caused by tuberculosis (TB) infections is a global concern, and there is a need to improve understanding of the disease. Current in vitro infection models to study the disease have limitations such as short investigation durations and divergent transcriptional signatures. This study aims to overcome these limitations by developing a 3D collagen culture system that mimics the biomechanical and extracellular matrix (ECM) of lung microenvironment (collagen fibers, stiffness comparable to in vivo conditions) as the infection primarily manifests in the lungs. The system incorporates Mycobacterium tuberculosis (Mtb) infected human THP-1 or primary monocytes/macrophages. Dual RNA sequencing reveals higher mammalian gene expression similarity with patient samples than 2D macrophage infections. Similarly, bacterial gene expression more accurately recapitulates in vivo gene expression patterns compared to bacteria in 2D infection models. Key phenotypes observed in humans, such as foamy macrophages and mycobacterial cords, are reproduced in the model. This biomaterial system overcomes challenges associated with traditional platforms by modulating immune cells and closely mimicking in vivo infection conditions, including showing efficacy with clinically relevant concentrations of anti-TB drug pyrazinamide, not seen in any other in vitro infection model, making it reliable and readily adoptable for tuberculosis studies and drug screening.
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Hydrogen sulfide (H2S) and associated sulfur species known as persulfide or sulfane sulfur are considered among the first responders to oxidative stress. However, tools that reliably generate these species without any potentially toxic byproducts are limited, and even fewer report the generation of a persulfide. Here, using a latent fluorophore embedded with N-acetylcysteine persulfide, we report a new tool that is cleaved by esterase to produce a persulfide as well as a fluorescence reporter without any electrophilic byproducts. The rate of formation of the fluorescence reporter is nearly identical to the rate of formation of the persulfide suggesting that the use of this probe eliminates the need for secondary assays that report persulfide formation. Symptomatic with persulfide generation, the newly developed donor was able to protect chondrocyte cells from oxidative stress.
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Esterases , Sulfeto de Hidrogênio , Fluorescência , Sulfetos , EnxofreRESUMO
The COVID-19 pandemic highlights an urgent need for effective antivirals. Targeting host processes co-opted by viruses is an attractive antiviral strategy with a high resistance barrier. Picolinic acid (PA) is a tryptophan metabolite endogenously produced in mammals. Here, we report the broad-spectrum antiviral activity of PA against enveloped viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), flaviviruses, herpes simplex virus, and parainfluenza virus. Mechanistic studies reveal that PA inhibits enveloped virus entry by compromising viral membrane integrity, inhibiting virus-cellular membrane fusion, and interfering with cellular endocytosis. More importantly, in pre-clinical animal models, PA exhibits promising antiviral efficacy against SARS-CoV-2 and IAV. Overall, our data establish PA as a broad-spectrum antiviral with promising pre-clinical efficacy against pandemic viruses SARS-CoV-2 and IAV.
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COVID-19 , Vírus da Influenza A , Animais , Humanos , SARS-CoV-2/metabolismo , Internalização do Vírus , Pandemias , Replicação Viral , Antivirais/farmacologia , Antivirais/uso terapêutico , Mamíferos/metabolismoRESUMO
Objectives: Psoas muscle parameters have been proposed as a simple and quick method for sarcopenia assessment. The aim of this study was to assess sarcopenia in cirrhotics by psoas muscle on computed tomography and its impact on mortality. Methods: One hundred and fifty patients (75 cirrhotics, 75 subjects) were assessed for psoas muscle on CT scan. Psoas muscle index (PMI) was calculated as 'total psoas muscle area/(height of subject)2'. Cut off values for sarcopenia diagnosis were derived from local subjects (n = 75) who did not have cirrhosis/other causes of sarcopenia. Results: Sarcopenia assessed by PMI was seen in 36% (n = 27) of the cirrhotics. Sarcopenia was significantly higher in patients having Child-Pugh C. Ascites, hepatic encephalopathy (HE) and gastro-intestinal bleed were seen in 48%, 18.7% and 24%, respectively. Sarcopenia was significantly associated with ascites and HE (P < 0.05). Out of the 75 cases, 53 cases completed the follow-up period of 1 year. Among the 20 cases who had sarcopenia, 35% (n = 7) succumbed to liver-related illness during 1 year follow-up, and out of the 33 cases without sarcopenia, only 6% (n = 2) died. The association of sarcopenia and 1 year mortality was statistically significant (P = 0.01). Conclusions: The PMI, a simple method for sarcopenia assessment detected sarcopenia in 36% of cirrhotics. Patients with sarcopenia had a significantly higher 1 year mortality rate and appropriate prognostication of such patients is needed.
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Osteoarthritis (OA) is the most common joint disorder and currently affects >500 million patients worldwide, with ~60% of them also suffering from obesity. There is no drug approved for human use that changes the course of OA progression. OA is one of the most common comorbidities of obesity, and obesity-related OA (ObOA) is a serious health concern because it shows heightened severity of tissue damage and also predominantly affects the working population. Unresolved inflammation is a major driver of ObOA, thus, resolving disease-associated inflammation is a viable strategy to treat ObOA. Resolvins are highly potent molecules that play a role in the resolution of inflammation and promote tissue healing. However, small molecules (like Resolvin D1; RvD1) have to be administered frequently or prior to injury because they lose their in vivo activity rapidly either by lymphatic clearance, or oxidation-mediated deactivation. In this study, we have encapsulated RvD1 in liposomes and established its efficacy in the mouse model of ObOA at much lower dosages than freely administered RvD1. Liposomal RvD1 (lipo-RvD1) acted as a source of the RvD1 molecules for ~11 days in vitro in synovial fluid derived from patients. When administered prophylactically or therapeutically, lipo-RvD1 suppressed cartilage damage in male C57BL/6 mice compared to untreated and free RvD1 treatments. This efficacy was achieved by increasing the proportion of the proresolution M2 macrophages over proinflammatory M1 macrophages in the synovial membrane. These results show the potential of lipo-RvD1 as an anti-OA agent.
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Lipossomos , Osteoartrite , Camundongos , Animais , Humanos , Masculino , Camundongos Obesos , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Camundongos Endogâmicos C57BL , Osteoartrite/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológicoRESUMO
Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Rapamycin-loaded in poly(lactic-co-glycolic acid) microparticles (RMPs) induced autophagy, prevented senescence, and sustained sulphated glycosaminoglycans production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, the study demonstrates the feasibility of using RMPs as a potential clinically translatable therapy to prevent the progression of post-traumatic OA.
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Tuberculosis (TB) is one of the most widely prevalent infectious diseases that cause significant mortality. Bacillus Calmette-Guérin (BCG), the current TB vaccine used in clinics, shows variable efficacy and has safety concerns for immunocompromised patients. There is a need to develop new and more effective TB vaccines. Outer membrane vesicles (OMVs) are vesicles released by Mycobacteria that contain several lipids and membrane proteins and act as a good source of antigens to prime immune response. However, the use of OMVs as vaccines has been hampered by their heterogeneous size and low stability. Here we report that mycobacterial OMVs can be stabilized by coating over uniform-sized 50 nm gold nanoparticles. The OMV-coated gold nanoparticles (OMV-AuNP) show enhanced uptake and activation of macrophages and dendritic cells. Proteinase K and TLR inhibitor studies demonstrated that the enhanced activation was attributed to proteins present on OMVs and was mediated primarily by TLR2 and TLR4. Mass spectrometry analysis revealed several potential membrane proteins that were common in both free OMVs and OMV-AuNP. Such strategies may open up new avenues and the utilization of novel antigens for developing TB vaccines.
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Membrana Externa Bacteriana , Proteínas de Membrana , Nanopartículas Metálicas , Mycobacterium tuberculosis , Vacinas , Membrana Externa Bacteriana/imunologia , Vesículas Revestidas/imunologia , Ouro , Humanos , Imunidade , ImunomodulaçãoRESUMO
Current treatments for osteoarthritis (OA) offer symptomatic relief but do not prevent or halt the disease progression. Chronic low-grade inflammation is considered a significant driver of OA. Specialized proresolution mediators are powerful agents of resolution but have a short in vivo half-life. In this study, we have engineered a Resolvin D1 (RvD1)-loaded nanoliposomal formulation (Lipo-RvD1) that targets and resolves the OA-associated inflammation. This formulation creates a depot of the RvD1 molecules that allows the controlled release of the molecule for up to 11 days in vitro. In surgically induced mice model of OA, only controlled-release formulation of Lipo-RvD1 was able to treat the progressing cartilage damage when administered a month after the surgery, while the free drug was unable to prevent cartilage damage. We found that Lipo-RvD1 functions by damping the proinflammatory activity of synovial macrophages and recruiting a higher number of M2 macrophages at the site of inflammation. Our Lipo-RvD1 formulation was able to target and suppress the formation of the osteophytes and showed analgesic effect, thus emphasizing its ability to treat clinical symptoms of OA. Such controlled-release formulation of RvD1 could represent a patient-compliant treatment for OA.
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Inhalable microparticle-based drug delivery platforms are being investigated extensively for Tuberculosis (TB) treatment as they offer efficient deposition in lungs and improved pharmacokinetics of the encapsulated cargo. However, the effect of physical parameters of microcarriers on interaction with Mycobacterium tuberculosis (Mtb) infected mammalian cells is underexplored. In this study, we report that Mtb-infected macrophages are highly phagocytic and microparticle surface charge plays a major role in particle internalization by infected cells. Microparticles of different sizes (0.5-2 µm) were internalized in large numbers by Mtb-infected THP-1 macrophages and murine primary Bone Marrow Derived Macrophages in vitro. Drastic improvement in particle uptake was observed with cationic particles in vitro and in mice lungs. Rapid uptake of rifampicin-loaded cationic microparticles allowed high intracellular accumulation of the drug and led to enhanced anti-bacterial function when compared to non-modified rifampicin-loaded microparticles. Cytocompatibility assay and histological analysis in vivo confirmed that the formulations were safe and did not elicit any adverse reaction. Additionally, pulmonary delivery of cationic particles in mice resulted in two-fold higher uptake in resident alveolar macrophages compared to non-modified particles. This study provides a framework for future design of drug carriers to improve delivery of anti-TB drugs inside Mtb-infected cells.
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Mycobacterium tuberculosis , Tuberculose , Animais , Antituberculosos/farmacologia , Macrófagos , Mamíferos , Camundongos , Rifampina/farmacologia , Tuberculose/tratamento farmacológicoRESUMO
Respiratory viral pathogens like influenza and coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused outbreaks leading to millions of deaths. Vaccinations are, to date, the best and most economical way to control such outbreaks and have been highly successful for several pathogens. Currently used vaccines for respiratory viral pathogens are primarily live attenuated or inactivated and can risk reversion to virulence or confer inadequate immunity. The recent trend of using potent biomolecules like DNA, RNA, and protein antigenic components to synthesize vaccines for diseases has shown promising results. Still, it remains challenging to translate due to their high susceptibility to degradation during storage and after delivery. Advances in bioengineering technology for vaccine design have made it possible to control the physicochemical properties of the vaccines for rapid synthesis, heightened antigen presentation, safer formulations, and more robust immunogenicity. Bioengineering techniques and materials have been used to synthesize several potent vaccines, approved or in trials, against coronavirus disease 2019 (COVID-19) and are being explored for influenza, SARS, and Middle East respiratory syndrome (MERS) vaccines as well. Here, we review bioengineering strategies such as the use of polymeric particles, liposomes, and virus-like particles in vaccine development against influenza and coronaviruses and the feasibility of adopting these technologies for clinical use.
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COVID-19 , Desenvolvimento de Vacinas , Bioengenharia , Humanos , SARS-CoV-2 , VacinaçãoRESUMO
BACKGROUND AND STUDY AIMS: Endoscopic sphincterotomy combined with endoscopic papillary balloon dilatation, mechanical lithotripsy or both, are effective modalities for the ex- traction of difficult common bile duct (CBD) stones. However, approximately 5-15% of cases are still difficult to treat. In the present study, we have evaluated the safety and efficacy of single- operator cholangioscopy guided laser lithotripsy (LL) for difficult to treat CBD stones. PATIENTS AND METHODS: Consecutive patients undergoing LL for the extraction of difficult CBD stones were enrolled in the study. The primary outcomes were related to the efficacy of the procedure in terms of ductal clearance and safety in terms of complications. RESULTS: During the 36 months, 764 patients presented for biliary stone extraction. Most of the patients, 683 (89.4%), had a successful stone extraction with standard techniques. Thirteen patients (1.7%) were not suitable for endoscopic therapy or did not consent for endoscopic therapy, and were referred directly for surgical treatment. Sixty-seven patients (8.8%) were included in the study. Cholangioscope was able to reach the stone in all the cases but one. Complete ductal clearance was achieved in 61 (91%) patients. Complications were encountered in 8 (11.9%) patients. All patients were asymptomatic at one-month of follow-up. CONCLUSION: LL is a highly effective and safe procedure with minimal and transient complications.
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Cálculos Biliares , Litotripsia a Laser , Colangiopancreatografia Retrógrada Endoscópica , Cálculos Biliares/cirurgia , Humanos , Índia , Estudos Prospectivos , Esfinterotomia Endoscópica , Centros de Atenção Terciária , Resultado do TratamentoRESUMO
Intracellular pathogens reside in specialised compartments within the host cells restricting the access of antibiotics. Insufficient intracellular delivery of antibiotics along with several other resistance mechanisms weaken the efficacy of current therapies. An alternative to antibiotic therapy could be bacteriophage (phage) therapy. Although phage therapy has been in practice for a century against various bacterial infections, the efficacy of phages against intracellular bacteria is still being explored. In this review, we will discuss the advancement and challenges in phage therapy, particularly against intracellular bacterial pathogens. Finally, we will highlight the uptake mechanisms and approaches to overcome the challenges to phage therapy against intracellular bacteria.
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Bactérias/virologia , Infecções Bacterianas/terapia , Bacteriófagos/fisiologia , Terapia por Fagos , Animais , Bactérias/genética , Infecções Bacterianas/microbiologia , Fenômenos Fisiológicos Bacterianos , Bacteriófagos/genética , HumanosRESUMO
Antibiotic resistance continues to be a major global health risk with an increase in multi-drug resistant infections seen across nearly all bacterial diseases. Mycobacterial infections such as Tuberculosis (TB) and Non-Tuberculosis infections have seen a significant increase in the incidence of multi-drug resistant and extensively drug-resistant infections. With this increase in drug-resistant Mycobacteria, mycobacteriophage therapy offers a promising alternative. However, a comprehensive study on the infection dynamics of mycobacteriophage against their host bacteria and the evolution of bacteriophage (phage) resistance in the bacteria remains elusive. We aim to study the infection dynamics of a phage cocktail against Mycobacteria under various pathophysiological conditions such as low pH, low growth rate and hypoxia. We show that mycobacteriophages are effective against M. smegmatis under various conditions and the phage cocktail prevents emergence of resistance for long durations. Although the phages are able to amplify after infection, the initial multiplicity of infection plays an important role in reducing the bacterial growth and prolonging efficacy. Mycobacteriophages are effective against antibiotic-resistant strains of Mycobacterium and show synergy with antibiotics such as rifampicin and isoniazid. Finally, we also show that mycobacteriophages are efficient against M. tuberculosis both under lag and log phase for several weeks. These findings have important implications for developing phage therapy for Mycobacterium.
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BACKGROUND: Device-assisted enteroscopy including single-balloon enteroscopy (SBE) allows direct visualization of the small bowel and has good safety and efficacy in experienced hands. Our study is aimed to share our single-centre experience of SBE in diagnosing and treating small-bowel disorders. METHODS: We reviewed the prospectively collected data (from December 2016 to December 2019) of 180 consecutive anterograde and/or retrograde procedures. Analysis of baseline characteristics, endoscopic findings, and diagnostic and therapeutic rates was done. RESULTS: SBE was done in 158 patients with a median age of 55 years (range, 13-94 years) for suspected small-bowel lesions. Dual enteroscopy (anterograde plus retrograde) was done in 22 patients (13.92%). The indication for the procedure was obscure gastrointestinal bleeding in 129 (71.66%), chronic unexplained abdominal pain in 20 (11.11%), suspected small-bowel abnormality in the form of narrowing and/or mass on imaging in 10 (5.5%), chronic diarrhea in 9 (5%), unexplained iron deficiency anemia in 9 (5%), and retained capsule in 2 (1.11%). The most common finding was ulcer, which was noted in 45 (25%) patients followed by stricture in 8 (4.44%) and both ulcers and strictures in 6 (3.33%) patients. SBE was normal in 61 (33.88%) patients. SBE gave a diagnosis in 66.11% while in 28.43% cases, therapeutic intervention was done. Minor complications like bleeding were noted in 3 patients and mild acute pancreatitis in 2 patients. Jejunal perforation requiring surgical intervention was noted in 1 patient. CONCLUSION: SBE is a safe and effective procedure in diagnosing and treating small-bowel diseases.
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Enteropatias/diagnóstico , Enteropatias/cirurgia , Intestino Delgado/patologia , Intestino Delgado/cirurgia , Enteroscopia de Balão Único/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Enteropatias/patologia , Masculino , Pessoa de Meia-Idade , Segurança , Enteroscopia de Balão Único/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Osteoarthritis (OA) is a joint disease characterized by progressive damage of articular cartilage and the adjoining subchondral bone. Chondrocytes, the primary cells of the cartilage, have limited regenerative capacity and when they undergo stress due to trauma or with aging, they senesce or become apoptotic. Rapamycin, a potent immunomodulator, has shown promise in OA treatment. It activates autophagy and is known to prevent senescence. However, its clinical translation for OA is hampered due to systemic toxicity as high and frequent doses are required. Here, we have fabricated rapamycin encapsulated poly(lactic-co-glycolic acid) (PLGA) based carriers that induced autophagy and prevented cellular senescence in human chondrocytes. The microparticle (MP) delivery system showed sustained release of the drug for several weeks. Rapamycin microparticles protected in vitro cartilage mimics (micromass cultures) from degradation, allowing sustained production of sGAG, and demonstrated a prolonged senescence preventive effect under oxidative and genomic stress conditions. These microparticles also exhibited a residence time of â¼30 days after intra-articular injections in murine knee joints. Such particulate systems are promising candidates for intra-articular delivery of rapamycin for the treatment of osteoarthritis.
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Cartilagem Articular , Osteoartrite , Preparações Farmacêuticas , Animais , Condrócitos , Camundongos , Osteoartrite/tratamento farmacológico , Sirolimo/farmacologiaRESUMO
OBJECTIVE: This study was aimed to determine the relationship between static and dynamic intra-abdominal pressure (IAP) with the mortality and outcome of acute pancreatitis. METHODS: From July 2017 to December 2018, 150 patients admitted at the Institute of Gastrosciences and Liver and diagnosed as acute pancreatitis were included in the study. Intra-abdominal pressure was measured for the first few days, and mean value of day 1 (static IAP) and highest value on day 2 and day 3 (dynamic IAP) were calculated and categorized into intra-abdominal hypertension and abdominal compartment syndrome. RESULTS: A statistical relationship was observed between static and dynamic IAP with the severity and mortality of acute pancreatitis. Both static and dynamic IAPs tended to be higher in nonsurvivors (83.33% and 88.88%, respectively) compared with survivors (51.51% and 63.63%, respectively). Higher IAP had more severe disease. However, IAP did not correlate with the evidence of sepsis or serum procalcitonin levels. CONCLUSION: Determination of static IAP is an easy, useful, and inexpensive method to determine and predict the mortality of acute pancreatitis. Prevention and/or early detection of intra-abdominal hypertension helps in reducing the mortality in acute pancreatitis.
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Hipertensão Intra-Abdominal/fisiopatologia , Pancreatite/diagnóstico , Pancreatite/fisiopatologia , Índice de Gravidade de Doença , APACHE , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/fisiopatologia , Pancreatite/mortalidade , Pressão , Estudos Prospectivos , Sensibilidade e Especificidade , Taxa de Sobrevida , Adulto JovemRESUMO
High-valent chiral oxidovanadium(V) complexes derived from 3,5-substituted-N-salicylidene-l-tert-leucine were used as catalysts in asymmetric reduction of N-benzyl-ß-ketoamides. Among six different solvents, three different alcohol additives, and two different boranes examined, the use of pinacolborane in tetrahydrofuran (THF) with a t-BuOH additive led to the best results at -20 °C. The corresponding ß-hydroxyamides can be furnished with yields up to 92% and an enantiomeric excess (ee) up to 99%. We have successfully extended this catalytic protocol for the synthesis of an (S)-duloxetine precursor.
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Resolution of intestinal inflammation and wound repair are active processes that mediate epithelial healing at mucosal surfaces. Lipid molecules referred to as specialized proresolving mediators (SPMs) play an important role in the restorative response. Resolvin E1 (RvE1), a SPM derived from omega-3 fatty acids, has been reported to dampen intestinal inflammation by promoting anti-inflammatory responses including increased neutrophil spherocytosis and macrophage production of IL-10. Despite these observations, a role for RvE1 in regulating intestinal epithelial cell migration and proliferation during mucosal wound repair has not been explored. Using an endoscopic biopsy-based wound healing model, we report that RvE1 is locally produced in response to intestinal mucosal injury. Exposure of intestinal epithelial cells to RvE1 promoted wound repair by increasing cellular proliferation and migration through activation of signaling pathways including CREB, mTOR, and Src-FAK. Additionally, RvE1-triggered activation of the small GTPase Rac1 led to increased intracellular reactive oxygen species (ROS) production, cell-matrix adhesion, and cellular protrusions at the leading edge of migrating cells. Furthermore, in situ administration of RvE1-encapsulated synthetic targeted polymeric nanoparticles into intestinal wounds promoted mucosal repair. Together, these findings demonstrate that RvE1 functions as a prorepair lipid mediator by increasing intestinal epithelial cell migration and proliferation, and highlight potential therapeutic applications for this SPM to promote mucosal healing in the intestine.
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Ácido Eicosapentaenoico/análogos & derivados , Mucosa Intestinal/metabolismo , Cicatrização/fisiologia , Animais , Adesão Celular , Linhagem Celular , Colo , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacologia , Humanos , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Neuropeptídeos , Organoides , Espécies Reativas de Oxigênio , Proteínas rac1 de Ligação ao GTPRESUMO
Background and study aims Although endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) is an established modality for pathological sampling of pancreatic and biliary lesions, limited data are available on the diagnostic value of EUS-FNA for evaluation of gallbladder mass lesions, a common cause of obstructive jaundice. We aimed to evaluate the usefulness of EUS-FNA for diagnosis of gallbladder mass lesions presenting with biliary obstruction. Patients and methods This study was a retrospective analysis of data from patients who had undergone EUS-FNA for gallbladder mass lesions. FNA was performed on either a gallbladder mass, metastatic node or liver lesions. Outcome measures were diagnostic yield of EUS FNA and adverse events. Results From April 2011 to August 2018, 101 patients with gallbladder mass lesions with biliary obstruction underwent EUS-FNA. The final diagnosis was malignancy in 98, benign disease in one, and two patients were lost to follow-up.âEUS-FNA confirmed the diagnosis in 89 of 98 patients with malignancy (sensitivity 90.81â%); was false negative in nine of 98 cases with malignancy; and was truly negative in the solitary patient with benign disease (specificity 100â%). Positive predictive value, negative predictive value (NPV), and accuracy were 100â%, 10â%, and 90.90â%, respectively. Two patients had self-limiting pain. Conclusion EUS-FNA is a sensitive tool for evaluation of gallbladder mass lesions presenting with obstructive jaundice. However, because of low NPV, lesions in which FNA is negative should be further evaluated.