Objective
The NLRP3 inflammasome is closely linked to the pathophysiology of a wide range of inflammatory diseases. This study was undertaken to identify small molecules that directly bind to NLRP3 ...in order to develop pharmacologic interventions for NLRP3‐related diseases.
Methods
A structure‐based virtual screening analysis was performed with ~62,800 compounds to select efficient NLRP3 inhibitors. The production of caspase 1‐p10 and interleukin‐1β (IL‐1β) was measured by immunoblotting and enzyme‐linked immunosorbent assay to examine NLRP3 inflammasome activation. Two gouty arthritis models and an air pouch inflammation model induced by monosodium urate monohydrate (MSU) crystal injection were used for in vivo experiments. Primary synovial fluid cells from gout patients were used to determine the relevance of NLRP3 inflammasome inhibition in human gout.
Results
Beta‐carotene (provitamin A) suppressed the NLRP3 inflammasome activation induced by various activators, including MSU crystals, in mouse bone marrow–derived primary macrophages (P < 0.05). Surface plasmon resonance analysis demonstrated the direct binding of β‐carotene to the pyrin domain (PYD) of NLRP3 (KD = 3.41 × 10−6). Molecular modeling and mutation assays revealed the interaction mode between β‐carotene and the NLRP3 PYD. Inflammatory symptoms induced by MSU crystals were attenuated by oral administration of β‐carotene in gouty arthritis mouse models (P < 0.05), correlating with its suppressive effects on the NLRP3 inflammasome in inflamed tissues. Furthermore, β‐carotene reduced IL‐1β secretion from human synovial fluid cells isolated from gout patients (P < 0.05), showing its inhibitory efficacy in human gout.
Conclusion
Our results present β‐carotene as a selective and direct inhibitor of NLRP3, and the binding of β‐carotene to NLRP3 PYD as a novel pharmacologic strategy to combat NLRP3 inflammasome–driven diseases, including gouty arthritis.
Staphylococcus aureus belongs to the group of major contagious mastitis pathogens, whereas the coagulase-negative staphylococci (CNS) are also capable of causing opportunistic bovine mastitis. Many ...of these strains are resistant to penicillin or ampicillin because of the long-term use of β-lactam antibiotics in agricultural and healthcare settings. Based on the simple and highly specific coagulase genotyping by PCR-RFLP used for discriminating among Staph. aureus strains, the relationship between phenotypic antibiogram and the polymorphism of coagulase gene was determined in this study. The staphylococci strains (835 Staph. aureus and 763 CNS) were isolated from 3,047 bovine mastitic milk samples from 153 dairy farms in 8 provinces from 1997 to 2004 in the Republic of Korea. Twenty-one (2.5%) Staph. aureus and 19 (2.4%) CNS strains were resistant to methicillin oxacillin minimum inhibitory concentration (MIC) ≥4μg/mL. The mecA gene was also found in 13 methicillin-resistant Staph. aureus (MRSA) and 12 methicillin-resistant CNS (MRCNS) isolates with a significantly higher detection rate of the mecA gene in MRSA with high MIC (≥16μg/mL) compared with those with MIC≤8μg/mL. Methicillin-resistant Staph. aureus and MRCNS were also more resistant to other antibiotics (ampicillin, cephalothin, kanamycin, and gentamicin) than methicillin-susceptible staphylococci. Among 10 different coa PCR-RFLP patterns (A to J) in 706 Staph. aureus strains, the main types were A (26.9%), B (17.0%), G (10.5%), and H (15.4%), with the frequent observation of the A and H types (6 and 10 isolates) in MRSA. This study indicates that major epidemic Staph. aureus clones may be spread between different dairy farms, and the profile of coa genotype can be applied for epidemiological investigations and control of bovine mastitis, particularly one caused by MRSA with specific prevalent coa types.
Presented in the paper is a virtual commissioning methodology for the design and verification of an OHT (Overhead Hoist Transporter), which is a vehicle that travels on the overhead track in a FAB ...(Factory for making semiconductor chips), and directly accesses the load port of the stocker or process equipment by the belt driven hoisting mechanism. Since the material flows of a FAB is extremely complicated, it is important to design the OHT control software by considering various situations. The proposed virtual commissioning methodology supports the full verification of the OHT control software by performing the simulation involving a 'virtual OHT model' and a 'real OHT controller'. We separate the virtual OHT model into two parts, a physical model (mechanical part) and a logical model (electrical part) to achieve the concurrency of mechanical and electrical designs of an OHT. Virtual commissioning identifies and addresses design flaws and operational faults so that significant savings can be achieved. The prototype of the proposed virtual commissioning methodology has been implemented and tested with several examples.
Post-polypectomy coagulation syndrome (PPCS) is a well known complication of colonoscopic polypectomy. However, no previous studies have reported on the clinical outcomes or risk factors of PPCS. The ...aim of the current study was to analyze the clinical outcomes and risk factors of PPCS developing after a colonoscopic polypectomy.
Data for all patients who underwent colonoscopic polypectomies and required hospitalization in nine university hospitals were analyzed retrospectively. The incidence, clinicopathological characteristics, and clinical outcomes of PPCS cases were examined. Additionally, patients who developed PPCS were compared with controls who were matched by age and sex, in order to assess for possible risk factors.
The rate of PPCS that required hospitalization after colonoscopic polypectomy was 0.7/1000. All patients with PPCS were treated medically without the need for surgical interventions. The median durations of therapeutic fasting, hospitalization, and antibiotic use were 3 days, 5.5 days, and 7 days, respectively. The rates of major PPCS and mortality were 2.9 % and 0 %, respectively. On multivariate analysis, hypertension (OR = 3.023, 95 %CI 1.034 - 8.832), large lesion size (OR = 2.855, 95 %CI 1.027 - 7.937), and non-polypoid configuration (OR = 3.332, 95 %CI 1.029 - 10.791) were found to be independent risk factors related to the development of PPCS.
In this study, the rates of major PPCS and mortality were only 2.9 % and 0 %, respectively. Hypertension, large lesion size, and non-polypoid configuration of the lesion were independently associated with PPCS. Therefore, patients may be reassured by the excellent prognosis of PPCS, while endoscopists should be especially careful when performing colonoscopic polypectomies in patients with hypertension or large and non-polypoid lesions.
Objective
The objective of this paper is to identify the prevalence, risk factors, and impact on mortality of neuropsychiatric systemic lupus erythematosus (NPSLE).
Methods
Patients from the Hanyang ...BAE lupus cohort were registered and followed from 1998 to 2015. NPSLE was defined using American College of Rheumatology (ACR) case definitions and Ainiala criteria. Demographics, autoantibodies, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and Systemic Lupus International Collaborating Clinic (SLICC)/ACR Damage Index were collected at baseline and then annually. Mortality data were derived by linking data from the Korean National Statistics Office. Multivariable logistic regression and Cox regression analysis were conducted in the inception cohort to assess the risk factors and mortality impact of NPSLE.
Results
Of 1121 registered patients, 429 (38.3%) had NPSLE manifestations according to ACR criteria and 216 (19.3%) by Ainiala criteria. In multivariable logistic regression analysis, higher SLEDAI (OR 1.08, CI 1.01–1.16, p = 0.02) and antiphospholipid antibody positivity (OR 1.72, CI 1.03–2.87, p = 0.04) at SLE diagnosis increased NPSLE risk, while elevated anti-dsDNA antibodies (OR 0.43, CI 0.24–0.78, p < 0.01) and greater education duration (OR 0.92, CI 0.85–1.00, p = 0.04) showed reduced risk of NPSLE. Cox proportional hazard models demonstrated that presence of NPSLE had a three-fold increased risk of mortality (HR 3.09, CI 1.03–9.21, p = 0.04), especially in patients with focal CNS NPSLE (HR = 7.83, CI 2.12–28.96, p < 0.01).
Conclusion
Higher SLEDAI, antiphospholipid antibody positivity, absence of anti-dsDNA antibody at SLE diagnosis, and fewer years of education are risk factors for development of NPSLE. Presence of NPSLE, especially focal CNS NPSLE, increased the risk of mortality in SLE patients.
An effective post-exposure prophylaxis (PEP) strategy may limit the spread of infection. However, there is no consensus regarding PEP for Middle East respiratory syndrome coronavirus (MERS-CoV) ...infection. This study assessed the efficacy of ribavirin and lopinavir/ritonavir as PEP for healthcare workers (HCWs) exposed to patients with severe MERS-CoV pre-isolation pneumonia. The safety of the PEP regimen was assessed. HCWs with high-risk exposure to MERS-CoV pre-isolation pneumonia were retrospectively enrolled. HCWs who received PEP therapy were classified into the PEP group. PEP therapy was associated with a 40% decrease in the risk of infection. There were no severe adverse events during PEP therapy.
Chronic inflammation is known to promote the development of many chronic diseases. Pattern recognition receptors (PRRs), Toll‐like receptors (TLRs), and nucleotide‐binding oligomerization domain ...proteins (NODs) mediate both infection‐induced inflammation and sterile inflammation by recognizing pathogen‐ associated molecular patterns and endogenous molecules, respectively. PRR‐mediated inflammation is an important determinant in altering the risk of many chronic diseases. Saturated fatty acids (SFAs) can activate PRRs, leading to enhanced expression of pro‐inflammatory target gene products. However, n‐3 polyunsaturated fatty acids (PUFAs) inhibit agonist‐induced activation of PRRs. These results suggest that SFAs and n‐3 PUFAs can reciprocally modulate PRR‐mediated inflammation, and that PRRs and their downstream signaling components are molecular targets for dietary strategies to reduce chronic inflammation and subsequent risk of chronic diseases. This advancement in knowledge provides a new paradigm for understanding the mechanism by which different dietary fatty acids modify risk of chronic diseases including insulin resistance, atherosclerosis, and cancer.
This phase 2 trial evaluated PET-adapted nivolumab alone or in combination with ifosfamide, carboplatin, and etoposide (NICE) as first salvage therapy and bridge to autologous hematopoietic cell ...transplantation (AHCT) in relapsed/refractory (RR) classical Hodgkin lymphoma (cHL). Patients with RR cHL received 240 mg nivolumab every 2 weeks for up to 6 cycles (C). Patients in complete response (CR) after C6 proceeded to AHCT, whereas patients with progressive disease at any point or not in CR after C6 received NICE for 2 cycles. The primary endpoint was CR rate per the 2014 Lugano classification at completion of protocol therapy. Forty-three patients were evaluable for toxicity; 42 were evaluable for response. Thirty-four patients received nivolumab alone, and 9 patients received nivolumab+NICE. No unexpected toxicities were observed after nivolumab or NICE. After nivolumab, the overall response rate (ORR) was 81%, and the CR rate was 71%. Among 9 patients who received NICE, all responded, with 8 (89%) achieving CR. At the end of protocol therapy, the ORR and CR rates were 93% and 91%. Thirty-three patients were bridged directly to AHCT, including 26 after Nivo alone. The 2-year progression-free survival (PFS) and overall survival in all treated patients (n = 43) were 72% and 95%, respectively. Among 33 patients who bridged directly to AHCT, the 2-year PFS was 94% (95% CI: 78-98). PET-adapted sequential salvage therapy with nivolumab/nivolumab+NICE was well tolerated and effective, resulting in a high CR rate and bridging most patients to AHCT without chemotherapy. This trial was registered at www.clinicaltrials.gov #NCT03016871.
The volatile anesthetic isoflurane protects against renal ischemia and reperfusion injury by releasing renal tubular TGF-β1. As adenosine is a powerful cytoprotective molecule, we tested whether ...TGF-β1 generated by isoflurane induces renal tubular ecto-5′-nucleotidase (CD73) and adenosine to protect against renal ischemia and reperfusion injury. Isoflurane induced new CD73 synthesis and increased adenosine generation in cultured kidney proximal tubule cells and in mouse kidney. Moreover, a TGF-β1-neutralizing antibody prevented isoflurane-mediated induction of CD73 activity. Mice anesthetized with isoflurane after renal ischemia and reperfusion had significantly reduced plasma creatinine and decreased renal tubular necrosis, neutrophil infiltration, and apoptosis compared with pentobarbital-anesthetized mice. Isoflurane failed to protect against renal ischemia and reperfusion injury in CD73-deficient mice, in mice pretreated with a selective CD73 inhibitor, or in mice treated with an adenosine receptor antagonist. The TGF-β1-neutralizing antibody or the CD73 inhibitor attenuated isoflurane-mediated protection against HK-2 cell apoptosis. Thus, isoflurane causes TGF-β1-dependent induction of renal tubular CD73 and adenosine generation to protect against renal ischemia and reperfusion injury. Modulation of this pathway may have important therapeutic implications to reduce morbidity and mortality arising from ischemic acute kidney injury.
This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic ...myeloid leukemia (CML).
In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy.
The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR.
The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.
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