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ID PMID Title PublicationDate abstract
25466887 Epoxyeicosanoids suppress osteoclastogenesis and prevent ovariectomy-induced bone loss. 2015 Mar Epoxyeicosatrienoic acids (EETs) are products of arachidonic acid metabolism catalyzed by cytochrome P450 epoxygenases. These small molecules are autocrine and paracrine lipid mediators with important roles in inflammation, cardiovascular function, and angiogenesis. Recent evidence has highlighted EETs as potent promoters of organ regeneration and malignant metastasis. We speculated that EETs might impact osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, we observed that EETs significantly attenuated bone loss and inhibited osteoclast formation and activity, which were associated with a decreased receptor activator of NF-κB ligand (RANKL):osteoprotegerin ratio and serum levels of TNF-α and IL-1β. At the molecular level, EETs abrogated RANKL-induced activation of NF-κB, activator protein-1 (AP-1), and MAPKs, including ERK and JNK, but not p38, during osteoclast formation. EETs also prevented the production of reactive oxygen species (ROS) following RANKL stimulation. As a result, EETs suppressed osteoclast-specific gene expression, including tartrate resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)-9, and receptor activator of NF-κB (RANK). In conclusion, our findings demonstrate that EETs inhibit osteoclastogenesis through modulation of multiple pathways both upstream and downstream of RANKL signaling. The administration or stabilized endogenous levels of EETs could represent a novel therapeutic strategy for osteoclast-related disorders, such as rheumatoid arthritis and postmenopausal osteoporosis.
25446603 Differential cytotoxic properties of Helleborus niger L. on tumour and immunocompetent cel 2015 Jan 15 ETHNOPHARMACOLOGICAL RELEVANCE: In Romanian folk medicine, Helleborus niger L. is used for the treatment of rheumatoid arthritis or viral infections and in complementary therapy, especially in anthroposophic medicine (AM), where the plant is administered as an adjuvant to treat malignant diseases. In the present study, we investigated the differential cytotoxic effects of H. niger on human tumour and healthy cells of the human immune system in vitro. MATERIAL AND METHODS: Protoanemonin and saponins, as significant constituents of H. niger extracts, were quantified in five individual batches using validated HPLC methods. Further, the impact of H. niger on proliferation capacity (MTT assay) as well as on apoptosis and necrosis induction in a panel of tumour cell lines and human lymphocytes (combined annexin V and propidium iodide staining) was monitored. In addition, NK cell function (degranulation-CD107a assay and IFN-gamma secretion) was also investigated since these immunocompetent cells are important for the control of malignancies within the human body. RESULTS: Extracts of H. niger induced proliferation inhibition not only of lymphoblastic leukaemia cells (MOLT4; IC50: 171 µg/mL) but also of myosarcoma (SK-UT-1b; IC50: 304 µg/mL) and melanoma cells (HT-144; IC50: 569 µg/mL) due to the induction of apoptosis. Purified T cells or NK cells were significantly affected through the presence of high H. niger concentrations while bulk lymphocytes were not affected. NK cells' anti-tumour functions expressed by degranulation capacity as well as IFN-y production were unaffected by the presence of the H. niger extract. Since protoanemonin and saponins have been reported in the literature to exert cytotoxic effects, their content was also determined. CONCLUSIONS: H. niger extracts exhibit differential cytotoxicity towards tumour cell lines and healthy human T- and NK-cells.
25037725 Long-term mortality rates (>8-year) improve as compared to the general and obese populatio 2015 Mar INTRODUCTION: Sparse data are available on long-term patient mortality following bariatric surgery as compared to the general population. The purpose of this study was to assess long-term mortality rates and identify risk factors for all-cause mortality following bariatric surgery. METHODS: New York State (NYS) Planning and Research Cooperative System (SPARCS) longitudinal administrative data were used to identify 7,862 adult patients who underwent a primary laparoscopic bariatric surgery from 1999 to 2005. The Social Security Death Index database identified >30-day mortalities. Risk factors for mortality were screened using a univariate Cox proportional hazard (PH) model and analyzed using a multiple PH model. Based on age, gender, and race/ethnicity, actuarial projections for NYS mortality rates obtained from Centers of Disease Control were compared to the actual post-bariatric surgery mortality rates observed. RESULTS: The mean bariatric mortality rate was 2.5 % with 8-14 years of follow-up. Mean time to death ranged from 4 to 6 year and did not differ by operation (p = 0.073). From 1999 to 2010, the actuarial mortality rate predicted for the general NYS population was 2.1 % versus the observed 1.5 % for the bariatric surgery population (p = 0.005). Extrapolating to 2013, demonstrated the actuarial mortality predictions at 3.1 % versus the bariatric surgery patients' observed morality rate of 2.5 % (p = 0.01). Risk factors associated with an earlier time to death included: age, male gender, Medicare/Medicaid insurance, congestive heart failure, rheumatoid arthritis, pulmonary circulation disorders, and diabetes. No procedure-specific or perioperative complication impact for time-to-death was found. CONCLUSION: Long-term mortality rate of patients undergoing bariatric surgery significantly improves as compared to the general population regardless of bariatric operation performed. Additionally, perioperative complications do not increase long-term mortality risk. This study did identify specific patient risk factors for long-term mortality. Special attention and consideration should be given to these "at risk" patient sub-populations.
24997524 Factors affecting postoperative activities of daily living in patients with osteoporotic v 2015 Jul Surgical treatment of osteoporotic vertebral collapse (OVC) with neurological deficits presents significant clinical challenges because some patients have fragile bones and often have medical comorbidities, which affect the severity of osteoporosis. We hypothesized that clinical results of surgery in these patients depend on the extent of medical comorbidities that induce secondary osteoporosis. The aim of this study is to examine the effects of medical history and comorbidities on surgical outcomes for these patients, along with the factors that predict postoperative function in activities of daily living (ADL). We retrospectively reviewed data for 88 patients with OVC and neurological deficits who underwent surgery. We assessed clinical results regarding neurological deficits and function in ADL. The presence or absence of comorbidities responsible for secondary osteoporosis and treatments or medical events that affect bone metabolism were examined. We performed statistical analysis to examine prognostic factors for postoperative function in ADL. Of 88 patients, the distributions of comorbidities, treatment, and events in medical history were as follows: hypertension, 57 patients (64.8%); chronic kidney disease (CKD) stage 3 or 4, 32 (36.4%); diabetes mellitus, 16 (18.2%); liver dysfunction, 11 (12.5%); cardiovascular disease, 10 (11.4%); rheumatoid arthritis, 9 (10.2%); and glucocorticoid intake, 8 (9.1%). Twenty-five patients (28.4%) represented poor postoperative ADL (chair-bound or bed-bound), and 11 of 25 patients with poor postoperative ADL represented full neurological recovery. Multivariate analysis revealed decreased estimated glomerular filtration rate (odds ratio 0.96; 95% confidence interval 0.93-0.99; p = 0.005) and a high serum alkaline phosphatase (ALP) level (odds ratio 1.01; 95% CI 1.00-1.02; p = 0.01) were strong predictive factors for poor postoperative function in ADL. The majority of patients with poor postoperative function in ADL had advanced CKD with a disorder of bone metabolism as well as bone fragility.
27999674 Development and validation of a novel bioassay to determine glucocorticoid sensitivity. 2016 BACKGROUND: Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group of GC resistant patients is typically exposed to high-dose GCs and their side-effects before more appropriate immunotherapy is instituted. Hence, there is a pressing clinical need for a predictive biomarker of GC responsiveness. The availability of such a tool would also enable patient stratification for the conduct of smart clinical trials in GC resistance. Lymphocyte GC sensitivity has been shown to be closely associated with clinical GC sensitivity in a number of inflammatory diseases. However, the method for determining in vitro GC response is not standardized and requires the use of specialist equipment, including a radioisotope to quantify cellular proliferation, making it challenging to translate into clinical practice. RESULTS: Here we describe the optimization and validation of a novel non-radioactive in vitro bioassay based on measuring cellular proliferation by incorporation of bromodeoxyuridine (BrdU), termed the BrdU incorporation in lymphocyte steroid sensitivity assay (BLISS). In comparison to the current gold standard lymphocyte GC sensitivity assay in 101 healthy control samples, BLISS has an area under receiver operating characteristic of 0.82 and a sensitivity of 83% for correctly identifying GC resistant subjects. CONCLUSIONS: The performance of the novel BLISS bioassay makes it a strong candidate biomarker for clinical application. It now requires validation in a prospective patient cohort.
27965978 Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Ost 2016 Objectives. Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis.
27923216 Efficacy of a Cellular Bone Allograft for Foot and Ankle Arthrodesis and Revision Nonunion 2017 Mar BACKGROUND: Bone graft substitutes are often required in patients at risk for nonunion, and therefore, an allograft that most closely mimics an autograft is highly sought after. This study explored the utility and efficacy of a cellular bone allograft used for foot and ankle arthrodesis and revision nonunion procedures in a patient population at risk for nonunion. METHODS: An institutional review board-approved retrospective review of consecutive patients who underwent arthrodesis and revision nonunion procedures with a cellular bone allograft was performed at a single academic institution. No external sources of funding were provided for this study. Inclusion criteria included patients who were more than 1 year after surgery or less than 1 year after surgery if they had undergone a second operative procedure for nonunion or if they had computed tomography-documented union. Forty operative procedures in 36 patients with a mean follow-up of 13 months (range, 6-25 months) were included for data analysis. All patients had at least one of the following risk factors associated with nonunion: current smoker, diabetes, avascular necrosis (AVN) of the involved bone, active same-site operative infection, history of nonunion, previous same-site surgery, or gap of 5 mm or greater after joint preparation. The primary outcome was radiographic union. RESULTS: The union rate in this high-risk population was 83% (33/40). Univariate analysis demonstrated that the use of a cellular bone allograft helped mitigate the presence of risk factors known to cause nonunion. There was no significant difference in fusion rates among groups with current smoking, AVN of the involved bone, active same-site operative infections, history of nonunion, rheumatoid arthritis on medication, previous same-site operative procedures or infections, or a gap of 5 mm or greater after joint preparation. However, in this population, diabetic and female patients remained at a high risk of recurrent nonunion ( P = .0015), despite the use of a cellular bone allograft. Chi-square analysis of patients with increasing numbers of risk factors directly correlated with an increased risk of nonunion ( P = .025). Four wound complications were reported in this cohort that required irrigation and debridement (10%). CONCLUSION: These data demonstrated a union rate of 83% in patients with risk factors known to cause nonunion. The benefits of the use of a cellular bone allograft allowed for the avoidance of morbidity associated with autograft harvesting while still improving the local biology to facilitate fusion in a difficult patient population to attain a successful fusion mass. LEVEL OF EVIDENCE: Level IV, retrospective case series.
27662115 Pharmacokinetic characterization of anhuienoside C and its deglycosylated metabolites in r 2017 Oct 1. Anhuienoside C (AC), a triterpenoid saponin derived from the traditional Chinese medicine (TCM) "Di Wu", has significant anti-inflammatory and anti-rheumatoid arthritis activities. Here we aimed to characterize the pharmacokinetics of AC and its deglycosylated metabolites in rats. 2. AC was administered to rats by intravenous injection or oral gavage. AC and its four deglycosylated metabolites (M1, M2, M3 and M4) in biological samples were quantified using a UPLC-QTOF/MS system. The pharmacokinetic data were analyzed by compartmental modeling. The metabolism of M1, M2, M3 and M4 was determined using rat liver microsomes (RLM) and rat intestine microsomes (RIM). The intestinal permeabilities of AC and its metabolites were evaluated using Parallel artificial membrane permeability assay (PAMPA) and MDR1-transfected Madin-Darby canine kidney cell (MDCK-MDR1) cell model. 3. AC pharmacokinetics was well described by the one-compartment model. The oral bioavailability of AC was exceedingly low (F = 0.03%). Consistently, AC was poorly distributed (< 0.08 μM) in major organs including the heart, liver, spleen, lung and kidney after oral uptake. Three of four deglycosylated metabolites (M2, M3, and M4) underwent further metabolism in RLM, generating five, two and five oxidized products, respectively. Both PAMPA and MDCK-MDR1 experiments showed that AC and its metabolites were poorly permeable. Furthermore, the net flux ratios derived from MDCK-MDR1 versus wild-type MDCK cells were, respectively 1.3, 1.5, 0.7, 1.2 and 0.6 for AC, M1, M2, M3 and M4, suggesting that these compounds were non-substrates of P-glycoprotein. 4. In conclusion, extensive pre-systemic metabolism and poor permeability were the main causes of low systemic exposures of oral AC and its four metabolites.
27586797 Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases. 2016 Jul Loss of homeostasis, as a result of pathogen invasion or self imbalance, causes tissue damage and inflammation. In addition to its well-established role in promoting clearance of pathogens or cell corpses, inflammation is also key to drive tissue repair and regeneration. Conserved from flies to humans, a transient, well-balanced inflammatory response is critical for restoration of tissue homeostasis after damage. The absence of such a response can result in failure of tissue repair, leading to the development of devastating immunopathologies and degenerative diseases. Studies in the past decade collectively suggest that a malfunction of NLRP3 inflammasome, a key tissue damage sensor, is a dominant driver of various autoinflammatory and autoimmune diseases, including gout, rheumatoid arthritis, and lupus. It is therefore crucial to understand the biology and regulation of NLRP3 inflammasome and determine its affect in the context of various diseases. Of note, various studies suggest that autophagy, a cellular waste removal and rejuvenation process, serves an important role as a macrophage-intrinsic negative regulator of NLRP3 inflammasome. Here, we review recent advances in understanding how autophagy regulates NLRP3 inflammasome activity and discuss the implications of this regulation on the pathogenesis of autoinflammatory and autoimmune diseases.
27399597 Development of a Korean Fracture Risk Score (KFRS) for Predicting Osteoporotic Fracture Ri 2016 BACKGROUND: Asian-specific prediction models for estimating individual risk of osteoporotic fractures are rare. We developed a Korean fracture risk prediction model using clinical risk factors and assessed validity of the final model. METHODS: A total of 718,306 Korean men and women aged 50-90 years were followed for 7 years in a national system-based cohort study. In total, 50% of the subjects were assigned randomly to the development dataset and 50% were assigned to the validation dataset. Clinical risk factors for osteoporotic fracture were assessed at the biennial health check. Data on osteoporotic fractures during the follow-up period were identified by ICD-10 codes and the nationwide database of the National Health Insurance Service (NHIS). RESULTS: During the follow-up period, 19,840 osteoporotic fractures were reported (4,889 in men and 14,951 in women) in the development dataset. The assessment tool called the Korean Fracture Risk Score (KFRS) is comprised of a set of nine variables, including age, body mass index, recent fragility fracture, current smoking, high alcohol intake, lack of regular exercise, recent use of oral glucocorticoid, rheumatoid arthritis, and other causes of secondary osteoporosis. The KFRS predicted osteoporotic fractures over the 7 years. This score was validated using an independent dataset. A close relationship with overall fracture rate was observed when we compared the mean predicted scores after applying the KFRS with the observed risks after 7 years within each 10th of predicted risk. CONCLUSION: We developed a Korean specific prediction model for osteoporotic fractures. The KFRS was able to predict risk of fracture in the primary population without bone mineral density testing and is therefore suitable for use in both clinical setting and self-assessment. The website is available at http://www.nhis.or.kr.
27327630 Novel treatment of 99Tc-MDP improves clinical and radiographic results for patients with o 2019 Jun BACKGROUND: Management of osteochondral lesions of talus (OLT) remains controversial. 99Tc-MDP, a decay product of 99mTc-MDP which is widely used for bone scan, is effective in the clinical treatment of rheumatoid arthritis. The purpose of the study is to investigate the effects of 99Tc-MDP treatment on OLT. METHODS: In the clinical evaluation, 66 patients with a total of 83 lesions of OLT who failed appropriate non-operative treatment and surgery were retrospectively included and treated with intravenous injection of 99Tc-MDP and Chinese herbal fumigation (CHF). The effects of 99Tc-MDP and CHF on OLT were evaluated by the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Score (AOFAS), Visual Analog Scale (VAS), activities of daily living (Barthel Index), and MRI, 99mTc-MDP SPECT/CT and CT. Radiographic changes were also assessed by the transverse long diameter of the cyst on CT. RESULTS: At the last follow-up, AOFAS, VAS and Barthel Index improved significantly from 68.66±9.76, 3.05±0.34 and 85±8.31 to 85.4±8.31, 1.85±0.36 and 94.7±4.99 (P<0.01), respectively after one course treatment in 66 patients with OLT. Thirty one (31/66) patients had a second treatment course. Their AOFAS, VAS and Barthel Index also improved significantly after the mean follow-up of 7±2 (6-15) months. And the average diameter of the cysts decreased from 8.01±3.35 mm to 4.74±2.83 mm (P<0.01) in the 31 patients. CONCLUSIONS: The retrospective study indicates that a combination treatment of 99Tc-MDP and CHF is effective in pain relief and return of function in a short term of follow-up for patients with OLT. Our results suggest that the small cystic lesions with increased uptake of 99mTc-MDP on SPECT/CT can be well treated by 99Tc-MDP and CHF. This novel technique holds the potential to emerge as an effective conservative treatment for OLT without adverse effects. The level of evidence for 99Tc-MDP is medium for the number of patients and retrospective study.
27195110 Human lymph-node CD8(+) T cells display an altered phenotype during systemic autoimmunity. 2016 Apr Although many studies are focused on auto-reactive CD4(+) T cells, the precise role of CD8(+) T cells in autoimmunity is poorly understood. The objective of this study is to provide more insight into the phenotype and function CD8(+) T cells during the development of autoimmune disease by studying CD8(+) T cells in human lymph-node biopsies and peripheral blood obtained during the earliest phases of rheumatoid arthritis (RA). Here, we show that lymphoid pro-inflammatory CD8(+) T cells exhibit a less-responsive phenotype already during the earliest phases of autoimmunity compared with healthy individuals. We found an increase in CD8(+) memory T cells in lymphoid tissue during the earliest phases of autoimmunity, even before clinical onset of RA, accompanied by an increased frequency of non-circulating or recently activated (CD69(+)) CD8(+) T cells in lymphoid tissue and peripheral blood. Importantly, lymphoid pro-inflammatory CD8(+)IL-17A(+) T cells displayed a decreased capacity of cytokine production, which was related to disease activity in early RA patients. In addition, a decreased frequency of regulatory CD8(+)IL-10(+) T cells in peripheral blood was also related to disease activity in early RA patients. Our results suggest that different CD8(+) T-cell subsets are affected already during the earliest phases of systemic autoimmunity.
26716515 Mitotic cell death caused by follistatin-like 1 inhibition is associated with up-regulated 2016 Apr 5 Follistatin-like 1 (FSTL1) was identified as a novel pro-inflammatory protein showing high-level expression in rheumatoid arthritis. The protective effect of FSTL1 via the inhibition of apoptosis was reported in myocardial injury. However, the functional mechanism of FSTL1 in cancer is poorly characterized, and its proliferative effects are ambiguous. Here, we examined the effects of FSTL1 on cellular proliferation and cell cycle checkpoints in lung cancer cells. FSTL1 inhibition induced the cellular portion of G2/M phase in human lung cancer cells via the accumulation of regulators of the transition through the G2/M phase, including the cyclin-dependent kinase 1 (Cdk1)-cyclin B1 complex. An increase in histone H3 phosphorylation (at Ser10), another hallmark of mitosis, indicated that the knockdown of FSTL1 in lung cancer cells stimulated a mitotic arrest. After that, apoptosis was promoted by the activation of caspase-3 and -9. Protein level of Bim, a BH3 domain-only, pro-apoptotic member and its isoforms, BimL, BimS, and BimEL were up-regulated by FSTL1 inhibition. Degradation of Bim was blocked in FSTL1-knockdown cells by decreased phosphorylation of Bim. Increased BimEL as well as decreased phosphorylated Erk1/2 is essential for cell death by FSTL1 inhibition in NCI-H460 cells. Taken together, our results suggest that the knockdown of FSTL1 induces apoptosis through a mitotic arrest and caspase-dependent cell death. FSTL1 plays the important roles in cellular proliferation and apoptosis in lung cancer cells, and thus can be a new target for lung cancer treatment.
26578261 Non-Canonical (RANKL-Independent) Pathways of Osteoclast Differentiation and Their Role in 2016 Aug Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, macrophages); in the canonical pathway of osteoclastogenesis, these cells fuse and differentiate to form specialised bone-resorbing osteoclasts in the presence of receptor activator for nuclear factor kappa B ligand (RANKL). Non-canonical pathways of osteoclastogenesis have been described in which several cytokines and growth factors are able to substitute for RANKL. These humoral factors can generally be divided into those which, like RANKL, are tumour necrosis family (TNF) superfamily members and those which are not; the former include TNFα lymphotoxin exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF); the latter include transforming growth factor beta (TGF-β), interleukin-6 (IL-6), IL-8, IL-11, nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and IGF-II. This review summarises the evidence for these RANKL substitutes in inducing osteoclast differentiation from tissue-derived and circulating mononuclear phagocytes. It also assesses the role these factors are likely to play in promoting the pathological bone resorption seen in many inflammatory and neoplastic lesions of bone and joint including rheumatoid arthritis, aseptic implant loosening and primary and secondary tumours of bone.
25889349 CdSe quantum dot-functionalized TiO2 nanohybrids as a visible light induced photoelectroch 2015 Sep 15 Proprotein convertase subtilisin/kexin type 6 (PCSK6) plays a major role in promoting the progression of rheumatoid arthritis to a higher aggressive status. A novel highly sensitive photoelectrochemical platform was developed for the detection of PCSK6 by using CdSe quantum dots (QDs)-functionalized TiO2 nanoparticles (NPs) nanohybrids (TiO2@CdSe) as the photo-to-electron conversion medium. TiO2@CdSe showed excellent visible-light absorbency, and much higher photoelectrochemical activity than both CdSe QDs and TiO2 NPs. The 5' and 3' primers of PCSK6 ssDNA acted as capture probes to realize the detection of PCSK6 ssDNA by the specific recognition. The capture probes can be fixed by poly-l-lysine (PLL) through positively strong electrostatic attraction and the carboxyl group of TiO2@CdSe nanohybrids. PLL was electropolymerized on ITO electrode by cyclic voltammetry (CV). Simultaneously, the amino group of PLL can interact with the carboxyl group of TiO2@CdSe nanohybrids to enhance the stability of the photoelectrochemical signal. The fabricated aptsensor exhibited excellent performance towards PCSK6 with a wide linear range (0.5 pg/mL to 80.0 ng/mL) and a detection limit of 0.1 fg/mL. This work opens up a new detection platform for PCSK6 with good sensitivity, reproducibility and stability.
25424656 Theoretical study of the mechanism of protein arginine deiminase 4 (PAD4) inhibition by F- 2015 Feb Protein arginine deiminase 4 (PAD4) catalyzes the hydrolysis of a peptidylarginine residue to form a citrulline residue and ammonia during posttranslational modification. This process plays a pivotal role in rheumatoid arthritis (RA) and gene regulation. F-amidine belongs to a series of haloacetamidine compounds that are the most potent PAD4 inhibitors described to date. F-amidine acts as a mechanism-based inhibitor of PAD4, inactivating PAD4 by the covalent modification of the active site Cys645. In this manuscript, the fundamental mechanism of PAD4 inhibition by F-amidine is investigated using a QM/MM approach. Our simulations show that in the PAD4-F-amidine reactant complex, the active site Cys645 exists as a thiolate and His471 is protonated. This is consistent with the reverse protonation mechanism wherein the active site nucleophile, Cys645, in PAD4 exists as a thiolate in the active form of the enzyme. Inhibition of PAD4 by F-amidine is initiated by the nucleophilic addition of Sγ to the Cζ of F-amidine, leading to the formation of a tetrahedral intermediate. His471 serves as a proton donor, helping F to leave the fluoroacetamidine moiety of F-amidine; meanwhile, Sγ forms a three-membered ring with Cζ and Cη of F-amidine. Subsequently, the three-membered sulfonium ring collapses and rearranges to the final thioether product. His471 acts as a proton donor in the transition state and facilitates the inhibition reaction of PAD4.
26467808 Medial unicondylar knee arthroplasty combined to anterior cruciate ligament reconstruction 2017 Mar PURPOSE: The purpose of the present study was to retrospectively evaluate the outcomes of patients who underwent combined medial unicompartmental knee arthroplasty (UKA) and anterior cruciate ligament (ACL) reconstruction. The hypothesis was that this procedure would lead to a high success rate in patients affected by isolated medial unicompartmental osteoarthritis and concomitant ACL deficiency. METHODS: Fourteen patients with primary ACL lesion and concomitant medial compartment symptomatic osteoarthritis treated from 2006 to 2010 were followed up for an average time of 26.7 months (SD 4.2). Assessment included KOOS score, Oxford Knee score, American Knee Society scores, WOMAC index of osteoarthritis, Tegner activity level and objective examination including instrumented laxity test with KT-1000 arthrometer. Radiological assessment was done with standard simple radiographs in order to get information about any presence of loosening of the components. RESULTS: KOOS score, OKS, WOMAC index and the AKSS improved significantly after surgery (p < 0.001). Regarding AKSS, improvement was noted both in the objective score and in the functional one (p < 0.001). There was no clinical evidence of instability in any of the knees as evaluated with clinical laxity testing. No pathologic radiolucent lines were observed around the components. In one patient signs of osteoarthritis in the lateral compartment were observed 28 months after surgery. CONCLUSIONS: UKA combined with ACL reconstruction is a valid therapeutic option for the treatment of combined medial unicompartmental knee osteoarthritis and ACL deficiency in young and active patients and confirms subjective and objective clinical improvement 2 years after surgery. The use of a fixed-bearing prosthesis represents a reliable feature as it allows to overcome problems of improper ligament tensioning during the implantation of the components. LEVEL OF EVIDENCE: IV.
26408195 Patterns of uveitis at the Apex Institute for Eye Care in India: Results from a prospectiv 2016 Jun The purpose of the study was to identify the clinical and etiological profile of uveitis at the apex institute for eye care in India. This is a prospective, prevalence study. 980 consecutive patients with uveitis referred to uvea clinic, Dr. RP Centre for Ophthalmic Sciences (Ophthalmology division, All India Institute of Medical Sciences). Demographic data of each patient were noted and a thorough ocular examination including slit lamp examination and dilated fundus evaluation was carried out. OCT and fluorescein angiography were undertaken whenever indicated. Uveitis was classified based on the anatomic location of inflammation (IUSG classification). Relevant serological and radiological investigations were obtained based on systemic symptomatology, and if the uveitis was recurrent (even in the absence of systemic symptoms). The presence of a systemic disease was confirmed by obtaining an internist consultation. The main outcome measures include pattern of uveitis according to anatomical classification and the etiology. Out of 980 patients with uveitis, 413 (42.14 %) patients had anterior uveitis, 131 (13.36 %) had intermediate uveitis, 165 (16.83 %) had posterior uveitis, 91 (9.2 %) had panuveitis, 47 (4.7 %) had retinal vasculitis, 22 (2.24 %) had scleritis, 17 (1.7 %) had masquerade syndromes, 8 (0.8 %) had keratouveitis, 22 (2.24 %) had sclerokeratouveitis, 19 (1.9 %) had endophthalmitis and 45 (4.5 %) had other causes of inflammation including trauma and intraocular surgery. Out of all uveitic patients definite etiological correlation could be made out in 225 (23 %) patients; thus 77 % were categorised as idiopathic. Only 9 % of all patients were found to have uveitis with an infectious etiology. Amongst infectious causes of uveitis tuberculosis was the leading cause, accounting for sixty percent of all infectious uveitis (approximately 5 % of overall uveitis). Non-infectious uveitis etiology accounted for more than 90 % of all cases with ankylosing spondylitis being the most common followed by sarcoidosis and juvenile rheumatoid arthritis. Amongst known uveitic syndromes serpiginous like choroidopathy was the most common and was followed by acute posterior placoid pigmented epitheliopathy and Fuch's heterochromic iridocyclitis. Infection, including tuberculosis, is an infrequent cause of uveitis in the study population. Multicentric, collaborative efforts are required to improve levels of clinical evidence and evolve consensus in establishing stringent guidelines for labelling uveitis as being of infectious etiology.
26327779 Autoantibody Profiles in Collagen Disease Patients with Interstitial Lung Disease (ILD): A 2015 Interstitial lung disease (ILD) is frequently associated with collagen disease. It is then designated as collagen vascular disease-associated ILD (CVD-ILD), and influences patients' prognosis. The prognosis of acute-onset diffuse ILD (AoDILD) occurring in patients with collagen disease is quite poor. Here, we report our investigation of auto-antibody (Ab) profiles to determine whether they may be useful in diagnosing CVD-ILD or AoDILD in collagen disease. Auto-Ab profiles were analyzed using the Lambda Array Beads Multi-Analyte System, granulocyte immunofluorescence test, Proto-Array Human Protein Microarray, AlphaScreen assay, and glutathione S-transferase capture enzyme-linked immunosorbent assay in 34 patients with rheumatoid arthritis (RA) with or without CVD-ILD and in 15 patients with collagen disease with AoDILD. The average anti-major histocompatibility complex class I-related chain A (MICA) Ab levels were higher in RA patients with CVD-ILD than in those without (P = 0.0013). The ratio of the average anti-MICA Ab level to the average anti-human leukocyte antigen class I Ab level (ie, MICA/Class I) was significantly higher in RA patients with CVD-ILD compared with those without (P = 4.47 × 10(-5)). To the best of our knowledge, this is the first report of auto-Ab profiles in CVD-ILD. The MICA/Class I ratio could be a better marker for diagnosing CVD-ILD than KL-6 (Krebs von den lungen-6).
26317186 [Use of the anatomical cemented femoral stem SAS I: mid-term results]. 2015 PURPOSE OF THE STUDY In view of increasing interest in a relationship between the surface of an implant and its behaviour and longevity in total hip arthroplasty (THA), the aim of this study is to present the clinical and radiographic results, as well as complications, of hip replacement surgery using the cemented femoral stem SAS I. MATERIAL AND METHODS A total of 298 cemented femoral stems SAS I were implanted in 275 patients at our department between 1996 and 2005. The patient average age was 72.1 years, with the range from 64 to 92 years. The pre-operative diagnoses were as follows: primary osteoarthritis in 179 (30.1%); post-dysplastic osteoarthritis in 41 (13.7%); femoral neck fracture in 44 (14.8%); avascular necrosis of the femoral head in 23 (7.7%); rheumatoid arthritis in nine (3%) and other causes in two (0.7%) patients. Of the 275 patients who had the surgery, 186 (204 THAs) underwent clinical and X-ray examination at an average follow-up of 11.5 years (range, 8 to 17 years). The clinical results were used to calculate the Harris hip score and radiographic evaluation was based on antero-posterior views. RESULTS The group of 186 assessed patients (204 THAs) comprised 106 women and 80 men, who were on average 85.4 years old on evaluation (range, 72 to 92 years). Of the remaining patients, 62 patients (64 THAs) died from causes unrelated to the surgery and 27 patients (30 THAs) were lost to follow-up. The functional outcome of surgery assessed by the Harris hip score was excellent in 61 (32.8%), good in 94 (50.5%), satisfactory in 26 (14%) and poor in five (2.7%) patients. The 93.1% SAS I stem longevity was recorded in relation to aseptic loosening; reimplantation for this indication was performed in 14 THAs. No revision surgery for failure due to valgus/varus deviations of the stem was carried out. Of the 204 hips, 188 had femoral stems aligned in neutral, 12 (5.9%) in valgus and four (2%) in varus positions. DISCUSSION The anatomical femoral stem SAS I is an implant made to fit the proximal femur anatomy. Its highly polished surface allows for optimal fitting with the supporting bone and for even distribution of weight bearing. This results in a low rate of THA failure. In accordance with the relevant literature, the acetabular components is considered to be the weakest element in total hip replacement in terms of aseptic loosening and implant failure. At present, the SAS I stem has no Morse Eurocone taper and this is the chief obstacle hindering its more frequent use in endoprosthetics. CONCLUSIONS The results of our study are in agreement with those of other successfully implanted polished cemented femoral components. Key words: anatomical cemented femoral component, surface adjustment of the femoral stem, complications.