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ID PMID Title PublicationDate abstract
27659251 Searching for Novel Janus Kinase-2 Inhibitors Using a Combination of Pharmacophore Modelin 2017 The Janus kinases (JAKs) play a pivotal role in cytokine receptor signaling pathways via activation of downstream signal transducers and activators of transcription (STAT) pathway. Intracellular pathways that include JAKs are critical to immune cell activation and pro-inflammatory cytokine production. Selective inhibitors of JAKs are potentially disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis (RA). Each of the four members of the JAK family plays an individual role in the oncogenesis of the immune system, and therefore, the development of potent and specific inhibitors for each member is needed. Although there is a high sequence homology and structural identity of JAK1 and JAK2, such as a very similar binding mode of inhibitors at the ATPbinding site of enzymes, obvious differences surrounding the JAK1 and JAK2 ATP-binding sites provide a platform for the rational design of JAK2- and JAK1-specific inhibitors. In the present study, a dataset of 33 compounds characterized by a common scaffold of 2-amino-[1,2,4]triazolo[1,5-α]pyridine with well-defined in vitro activity values was computationally explored. Most of the compounds included in the dataset had higher ligand efficiency against JAK2 than JAK1. To improve further the selectivity of these triazolopyridines, Common Pharmacophore Hypotheses (CPHs) were generated and 3D-QSAR studies were carried out on them, in order to comprehend on the molecular features responsible for their selectivity. The proposed computational approach was applied in order to perform an in silico database virtual screening study with the aim to discover novel potent and selective JAK2 inhibitors.
27505147 Tumor Necrosis Factor Alpha Promotes Osteoclast Formation Via PI3K/Akt Pathway-Mediated Bl 2017 Jun Tumor necrosis factor alpha (TNF-α)-induced osteoclastogenesis have profound effects in states of inflammatory osteolysis such as rheumatoid arthritis, periprosthetic implant loosening, and periodontitis. However, the exact mechanisms by which TNF-α promotes RANKL-induced osteoclast formation remains poorly understood. B lymphocyte-induced maturation protein-1 (Blimp1) is a transcriptional repressor that plays crucial roles in the differentiation and/or function of various kinds of cells including osteoclasts. A novel mechanism was identified where TNF-α-mediated Blimp1 expression, which contributed to RANKL-induced osteoclastogenesis. It is shown that TNF-α could promote the level of Blimp1 expression during osteoclast differentiation. Silencing of Blimp1 in osteoclast precursor cells obviously attenuated the stimulatory effect of TNF-α on osteoclastogenesis. Mechanistically, TNF-α-induced Blimp1 expression was markedly rescued by blocking the PI3K/Akt signaling pathway, which suggested that PI3K/Akt signaling was involved in the regulation of TNF-α-stimulated Blimp1 expression. Taken together, the results established a molecular mechanism of TNF-α-induced osteoclasts differentiation, and provided insights into the potential contribution of Blimp1 in the regulation of osteoclastogenesis by TNF-α. J. Cell. Biochem. 118: 1308-1315, 2017. © 2016 Wiley Periodicals, Inc.
28879887 Characteristics of nerve conduction studies in carpal tunnel syndrome. 2017 Sep BACKGROUND: Numerous nerve conduction tests are used for the electrodiagnosis of carpal tunnel syndrome (CTS), with a wide range of sensitivity and specificity reported for each test in clinical studies. AIMS: The purpose of this study was to compare the diagnostic accuracy of various nerve conduction tests and determine the properties of the most accurate test. SETTINGS AND DESIGN: A prospective observational case control study. PATIENTS AND METHODS: Eighty patients with clinically confirmed CTS and 80 asymptomatic healthy controls were included in the study. All patients underwent the routine hematological investigations as per the protocol. All cases and controls were subjected to various nerve conduction study protocols for CTS. Results were analyzed statistically. STATISTICAL ANALYSIS USED: The two-tailed Student's t-test was used for the comparative statistical analysis. The sensitivity of each test was calculated as (the number of hands with an abnormal study result/the number of CTS hands) × 100. Comparison between percentages was performed by the McNemar test. RESULTS: The mean age was 38.19 ± 10.13 years and the female:male ratio was 1.5:1. The mean duration of disease was 0.89 ± 0.61 years. Hypothyroidism was present in 21 (26.25%) patients, whereas 13 (16.25%) and 4 (5%) patients had diabetes mellitus and rheumatoid arthritis, respectively. The median nerve motor latency was 4.73 ± 0.83 ms while the sensory latency was 3.44 ± 0.56 ms. The median nerve orthodomic sensory latency was found to be 2.57 ± 0.31 ms. The conduction velocity across the palm and wrist was 41.37 ± 0.67 ms. The sensitivity was the highest in the inching method (86.25%) and lowest for the conventional median motor and sensory latencies (56.25% and 45%, respectively). CONCLUSIONS: Addition of a single test of median and ulnar sensory latency, the median and radial sensory latency or the inching method, in routine protocol will improve the sensitivity for the diagnosis of CTS in all patients.
28875995 Anti-inflammatory effects of octadecylamine-functionalized nanodiamond on primary human ma 2017 Sep 26 Chronic inflammatory disorders such as rheumatoid arthritis are characterized by excessive pro-inflammatory or "M1" activation of macrophages, the primary cells of the innate immune system. Current treatments include delivery of glucocorticoids (e.g. dexamethasone - Dex), which reduce pro-inflammatory M1 behaviour in macrophages. However, these treatments have many off-target effects on cells other than macrophages, resulting in broad immunosuppression. To limit such side effects, drug-incorporated nano- and microparticles may be used to selectively target macrophages via phagocytosis, because of their roles as highly effective phagocytes in the body. In this study, surface-modified nanodiamond (ND) was explored as a platform for the delivery of dexamethasone to macrophages because of ND's rich surface chemistry, which contributes to ND's high potential as a versatile drug delivery platform. After finding that octadecylamine-functionalized nanodiamond (ND-ODA) enhanced adsorption of Dex compared to carboxylated ND, the effects of Dex, ND-ODA, and Dex-adsorbed ND-ODA on primary human macrophage gene expression were characterized. Surprisingly, even in the absence of Dex, ND-ODA had strong anti-inflammatory effects, as determined by multiplex gene expression via NanoString and by protein secretion analysis via ELISA. ND-ODA also inhibited expression of M2a markers yet increased the expression of M2c markers and phagocytic receptors. Interestingly, the adsorption of Dex to ND-ODA further increased some anti-inflammatory effects, but abrogated the effect on phagocytic receptors, compared to its individual components. Overall, the ability of ND-ODA to promote anti-inflammatory and pro-phagocytic behaviour in macrophages, even in the absence of loaded drugs, suggests its potential for use as an anti-inflammatory therapeutic to directly target macrophages through phagocytosis.
28721016 A review of the literature analyzing benefits and concerns of infliximab biosimilar CT-P13 2017 The introduction of biological agents drastically changed the treatment paradigm of inflammatory arthritides, ameliorating the natural history of the diseases but concomitantly increasing the drug costs due to the manufacturing process. On this concern, biosimilar drugs may represent a valid option for reducing this elevated cost and increasing the availability of these highly effective treatments. Recently, CT-P13, the first biosimilar of infliximab, has been approved with the same indications established for the reference product (RP), and its daily use is progressively increasing. However, the experience with biosimilar drugs in the field of rheumatology is still limited, raising potential doubts and concerns on their correct management in real-life settings. Comparability analysis between CT-P13 and its RP was evaluated in equivalence randomized controlled trials (RCTs) - PLANETRA and PLANETAS - performed on patients with rheumatoid arthritis and axial spondylitis, respectively. CT-P13 and RP showed similar profile in terms of quality, biological activity, safety, immunogenicity, and efficacy. However, the interchangeability between infliximab RP and its biosimilar still represents the most challenging issue because of a lack of a long-lasting experience. To date, reassuring preliminary data on this topic were reported in open-label extensions of PLANETRA and PLANETAS RCTs and in ongoing real-life observational studies. These findings, taken all together, significantly affect the landscape of biosimilar regulatory pathways and strongly support CT-P13 introduction as a great opportunity for expanding the accessibility to these very effective and high-cost therapies.
28515226 A neutralizing anti-G-CSFR antibody blocks G-CSF-induced neutrophilia without inducing neu 2017 Aug Neutrophils are the most abundant WBCs and have an essential role in the clearance of pathogens. Tight regulation of neutrophil numbers and their recruitment to sites of inflammation is critical in maintaining a balanced immune response. In various inflammatory conditions, such as rheumatoid arthritis, vasculitis, cystic fibrosis, and inflammatory bowel disease, increased serum G-CSF correlates with neutrophilia and enhanced neutrophil infiltration into inflamed tissues. We describe a fully human therapeutic anti-G-CSFR antibody (CSL324) that is safe and well tolerated when administered via i.v. infusion to cynomolgus macaques. CSL324 was effective in controlling G-CSF-mediated neutrophilia when administered either before or after G-CSF. A single ascending-dose study showed CSL324 did not alter steady-state neutrophil numbers, even at doses sufficient to completely prevent G-CSF-mediated neutrophilia. Weekly infusions of CSL324 (≤10 mg/kg) for 3 wk completely neutralized G-CSF-mediated pSTAT3 phosphorylation without neutropenia. Moreover, repeat dosing up to 100 mg/kg for 12 wk did not result in neutropenia at any point, including the 12-wk follow-up after the last infusion. In addition, CSL324 had no observable effect on basic neutrophil functions, such as phagocytosis and oxidative burst. These data suggest that targeting G-CSFR may provide a safe and effective means of controlling G-CSF-mediated neutrophilia as observed in various inflammatory diseases.
28481943 Citrullination only infrequently impacts peptide binding to HLA class II MHC. 2017 It has been hypothesized that HLA class II alleles associated with rheumatoid arthritis (RA) preferentially present self-antigens altered by post-translational modification, such as citrullination. To understand the role of citrullination we tested four RA-associated citrullinated epitopes and their corresponding wild-type version for binding to 28 common HLA class II. Binding patterns were variable, and no consistent impact of citrullination was identified. Indeed, in one case citrullination significantly increased binding compared to the WT peptide, in another citrullination was associated with a reduction in promiscuity by 40%. For a more comprehensive analysis, we tested over 200 citrullinated peptides derived from vimentin and collagen II for their capacity to bind the RA-associated shared epitope alleles DRB1*01:01 and DRB1*04:01. The overall effect of citrullination on binding was found to be relatively minor, and only rarely associated with 3-fold increases or decreases in affinity. Previous studies have suggested that citrullination of MHC anchor residues, in particular P4, is associated with generation of novel RA-associated epitopes. However, analysis of the predicted MHC-binding cores of all peptides tested found that in modified peptides with increased binding affinity the citrullinated residue was predicted to occupy an anchor position in only a minority of cases. Finally, we also show that identification of citrullinated peptide binders could be facilitated by using the NetMHCIIpan 3.1 algorithm, representing citrullination as a wildcard. Our studies identify a total of 117 citrullinated peptides that bound RA-associated alleles with an affinity of 1000 nM or better.
28325750 Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target. 2017 Jun 15 With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, there is tremendous interest in finding new ways to augment antitumor responses by targeting other inhibitory molecules. In this review, we describe one such molecule. B7-H4, a member of the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine production through ligation of an unknown receptor expressed by activated T cells. Notably, B7-H4 protein expression is observed in a high proportion of patients' tumors across a wide variety of malignancies. This high expression by tumors in combination with its low or absent protein expression in normal tissues makes B7-H4 an attractive immunotherapeutic target. Preclinical investigation into B7-H4-specific chimeric antigen receptor (CAR) T cells, antibody-mediated blockade of B7-H4, and anti-B7-H4 drug conjugates has shown antitumor efficacy in mouse models. The first clinical trials have been completed to assess the safety and efficacy of a B7-H4 fusion protein in ameliorating rheumatoid arthritis. Clin Cancer Res; 23(12); 2934-41. ©2017 AACR.
28244020 Air Travel, Circadian Rhythms/Hormones, and Autoimmunity. 2017 Aug Biological rhythms are fundamental for homeostasis and have recently been involved in the regulatory processes of various organs and systems. Circadian cycle proteins and hormones have a direct effect on the inflammatory response and have shown pro- or anti-inflammatory effects in animal models of autoimmune diseases. The cells of the immune system have their own circadian rhythm, and the light-dark cycle directly influences the inflammatory response. On the other hand, patients with autoimmune diseases characteristically have sleep disorders and fatigue, and in certain disease, such as rheumatoid arthritis (RA), a frank periodicity in the signs and symptoms is recognized. The joint symptoms predominate in the morning, and apparently, subjects with RA have relative adrenal insufficiency, with a cortisol peak unable to control the late night load of pro-inflammatory cytokines. Transatlantic flights represent a challenge in the adjustment of biological rhythms, since they imply sleep deprivation, time zone changes, and potential difficulties for drug administration. In patients with autoimmune diseases, the use of DMARDs and prednisone at night is probably best suited to lessen morning symptoms. It is also essential to sleep during the trip to improve adaptation to the new time zone and to avoid, as far as possible, works involving flexible or nocturnal shifts. The study of proteins and hormones related to biological rhythms will demonstrate new pathophysiological pathways of autoimmune diseases, which will emphasize the use of general measures for sleep respect and methods for drug administration at key daily times to optimize their anti-inflammatory and immune modulatory effects.
28230336 The endothelial border to health: Mechanistic evidence of the hyperglycemic culprit of inf 2017 Mar The endothelial cell (EC) layer constitutes a barrier that controls movements of fluid, solutes and cells between blood and tissue. Further, the endothelial layer regulates vascular tone and directs local humoral and cellular inflammatory processes. The strategic position makes it an important player for maintenance of health and for development of a number of diseases. Endothelial dysfunction is known to be an important component of type 2 diabetes, but is also assumed to be involved in many other diseases, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and cardiovascular diseases. We here suggest that the EC plays a pivotal role in disease pathophysiology through initiation, potentiation, and maintenance of several inflammatory mechanisms. Our contention is based on the observation that hyperglycemia-intermittent or sustained, local or systemic-is a major culprit for several endothelial dysfunctions. There is also mounting epidemiological evidence that dietary intake of refined sugars is important for the development of a number of diseases beyond obesity and type 2 diabetes. Various diseases involving inflammatory and immunological components are accelerated by hyperglycemic events because the endothelium transduces "high glucose" signaling into significant pathophysiological phenomena leading to reduced endothelial barrier function, compromised vascular tone regulation and inflammation (e.g., cytokine secretion and RAGE activation). In addition, endothelial extracellular proteins form epitopes for potential specific antibody formation upon interactions with reducing sugars. This paper reviews the endothelial metabolism, biology, inflammatory processes, physical barrier functions, and summarizes evidence that although stochastic in nature, endothelial responses to hyperglycemia are major contributors to disease pathophysiology. We present molecular and mechanistic evidence that both biological and physical barriers, protein function, specific immunity, and inflammatory processes are compromised by hyperglycemic events and thus, hyperglycemic events alone should be considered risk factors for numerous human diseases. © 2017 IUBMB Life, 69(3):148-161, 2017.
28219308 Perceived risk factors for nonunion following foot and ankle arthrodesis. 2017 Jan BACKGROUND: A major complication of foot and ankle arthrodesis is nonunion, which occurs in approximately 12% of cases. Various factors influence a patient's risk for nonunion following foot and ankle arthrodesis. We surveyed international foot and ankle surgeons to determine (1) risk factors perceived most important for nonunion, (2) factors considered absolute contraindications for arthrodesis, and (3) differences among expert groups regarding perceived risk factors and their stratification. METHODS: A questionnaire was e-mailed to members of a major foot and ankle journal editorial board and four foot and ankle society executive committees. The relative risk of 18 potential nonunion risk factors was rated from 1 to 10, using smoking 1 pack/day as a benchmark score of 5.00. RESULTS: The response rate was 72% (100/139); 81% declared foot and ankle surgery encompasses >90% of their practice. The highest perceived risk factors ( p < 0.001) were smoking 2 packs/day (mean score 8.69), lack of fusion site stability (8.66), and poor local vascularity (7.66). The least important risk factors ( p < 0.001) were perceived to be age >60 years (mean score 2.54), rheumatoid arthritis (3.05), and osteoporosis (3.56). The most frequently cited absolute contraindications to arthrodesis surgery were local infection (46%), poor local vascularity (41%), and smoking (32%). CONCLUSION: To improve arthrodesis outcomes, resource allocation and patient and surgeon education should focus on smoking, construct stability, and local vascularity. Development of an objective nonunion risk assessment tool to identify patients at risk for nonunion using these results could help maximize the efficiency of available resources.
28204927 Bicortical facet screws as a new option for posterior C2 fixation: anatomical study and cl 2017 Apr PURPOSE: C2 fixation is a demanding procedure, particularly in patients with variants of C1-C2 anatomy. The inferior articular process (IAP) of the axis can be an alternative for screw placement. We report the results of a CT study of C2 IAP anatomy and we present the clinical experience of 28 patients operated with this technique. METHODS: Anatomical study: 50 CT angiographies of the vertebral arteries (VA) were used for this study and, therefore, 100 IAPs were considered. We measured on the axial and sagittal planes the length, height and width of the facet, the distance between the anterior cortex and the VA and the distance between the screw entry point and the VA. We also measured the angle between the sagittal plane and the external tangent line of the VA. CLINICAL REPORT: 28 patients were treated with C2 IAP screws at the Spine Surgery Department of the University Hospital in Lyon, France, from January 2014 to January 2016. RESULTS: Anatomical study: the mean length of C2 IAP was 12 ± 2 mm, the mean distance between the anterior cortical layer and the VA was 5.2 ± 1.4 mm, and the mean angle we found was 0.2° ± 5.3°. CLINICAL REPORT: 16 of the 28 patients presented post-traumatic C1-C2 instability, 8 patients presented degenerative disease, 1 patient was treated for pseudoarthrosis, 1 for tumour, 1 for OPLL and 1 for rheumatoid arthritis. All the screws were correctly positioned and there was no VA injury. CONCLUSION: IAP screws can represent a safe alternative option for C2 fixation.
28029071 Predicting Citrullination Sites in Protein Sequences Using mRMR Method and Random Forest A 2017 BACKGROUND: As one of essential post-translational modifications (PTMs), the citrullination or deimination on an arginine residue would change the molecular weight and electrostatic charge of its side-chain. And it has been found that the citrullination in protein sequences was catalyzed by a type of Ca2+-dependent enzyme family called peptidylarginine deiminase (PAD), which include five isotypes: PAD1, 2, 3, 4/5, and 6. Citrullinated proteins participate in many biological processes, e.g. the citrullination of myelin basic protein (MBP) assists the early development of central nervous system. However, abnormal modifications on citrullinated proteins would also lead to some severe human diseases including multiple sclerosis and rheumatoid arthritis. OBJECTIVE: Therefore, it is necessary and important to identify the citrullination sites in protein sequences. The information about the location of citrulliantion sites in protein sequences will be useful to investigate the molecular functions and disease mechanisms related to citrullinated proteins. MATERIALS AND METHODS: In this study, we investigated the peptide segments that contain the citrullination sites in the centers, which were encoded into numeric digits from four aspects. Thus, we yielded a training set with 116 positive samples and 232 negative samples. Then, a reliable feature selection technique, called maximum-relevance-minimum-redundancy (mRMR), was applied to analyze these features, and four algorithms, including random forest (RF), Dagging, nearest neighbor algorithm (NNA), and support vector machine (SVM), together with the incremental feature selection (IFS) method were adopted to extract important features. RESULTS: Finally an optimal classifier derived from RF algorithm was constructed to predict citrullination sites. 44 most prominent features were comprehensively analyzed and their biological characteristics in citrullination catalysis were also revealed. CONCLUSION: We believed that the biological features obtained in this pioneering work would provide some useful insights into the formation and function of citrullination and the optimal classifier could be a useful tool to identify citrullination sites in protein sequences.
28025216 Hydroxychloroquine for the prevention of recurrent cardiovascular events in myocardial inf 2017 Apr 1 BACKGROUND: Inflammation of the arterial wall plays a central role in the pathogenesis of atherosclerosis. Among patients with rheumatic diseases, anti-rheumatic medication reduces the incidence of cardiovascular (CV) diseases, but only few studies have addressed their cardioprotective effects on patients with no rheumatic diseases. Hydroxychloroquine (HCQ) is an anti-rheumatic drug commonly used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. In addition to its anti-inflammatory properties, HCQ reduces cholesterol levels and the risk of type II diabetes, and has also anti-platelet effects. DESIGN: The OXI trial is an event-driven trial that will randomize 2500 patients hospitalized for myocardial infarction (MI). Participants will receive active HCQ or placebo for at least 12 months, and until 350 CV events are confirmed. The primary trial endpoint is the composite of death, MI, hospitalization for unstable angina, urgent percutaneous coronary intervention, and urgent coronary artery bypass grafting. Secondary trial endpoints are the primary end point plus stroke, the effect of HCQ treatment on lipids, on the incidence of Type 2 diabetes, on the level of haemoglobin A1c, and on inflammatory parameters. A 6 months placebo-controlled safety pilot trial with 200 patients is currently ongoing to assess the safety of HCQ in the setting of MI. SUMMARY: The OXI trial will determine whether treatment with HCQ, as compared with placebo, will reduce recurrent CV events among MI patients. If positive, then the OXI trial would provide an entirely novel multitarget approach for the secondary prevention of atherosclerotic cardiovascular diseases (ACVD).
27862093 Bioanalytical method for the estimation of co-administered esomeprazole, leflunomide and i 2017 May The present study represents a connection between basic science and clinical applied science through providing a bioanalytical method for the analysis of certain co-administered drugs used for the treatment of rheumatoid arthritis. The studied drugs are esomeprazole, leflunomide and ibuprofen. The proposed bioanalytical method is a simple reversed phase high performance liquid chromatographic method using micellar mobile phase. The method is conducted using a Shim-pack VP-ODS (150 mm × 4.6 mm ID) stainless steel column at ambient temperature with ultraviolet detection at 285 nm. The micellar mobile phase consisted of 0.1 m sodium dodecyl sulfate, 10% n-propanol, 0.3% triethylamine in 0.02 m orthophosphoric acid (pH 3.5) and is pumped at a flow rate of 1.0 mL/min. The calibration curve was rectilinear over the concentration range of 0.1-5.0, 0.5-10.0 and 1.0-20.0 μg/mL for esomeprazole, leflunomide and ibuprofen respectively. The proposed method was successfully applied to the analysis of these drugs in dosage forms. The method is extended to the in-vitro, in-vivo determination of these drugs in spiked and real human plasma samples.
30728673 The Differential Influence of Immunological Process of Autoimmune Disease on Lipid Metabol 2019 Jan Metabolic parameters like uric acid, lipids and homocysteine are influenced by immunopathological mechanisms underlying the autoimmune disease processes. The current study examined the differences in these parameters and the correlation between inflammatory and metabolic variables in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. The cross-sectional prospective study included 24 treatment-naïve patients with moderate to severe diseases-15 subjects had RA and 9 had SLE. Atherogenic index of plasma (AIP) was used to assess the cardiovascular risk of the patients. Spearman's correlation was performed to verify the relationship between inflammatory and metabolic parameters. A two-tailed P < 0.05 was considered statistically significant for all the analysis. SLE patients had higher uric acid levels, very low density lipoprotein-cholesterol, total cholesterol/high density lipoprotein-cholesterol ratio (TC/HDL-C) and logarithmic ratio of triglycerides to HDL-cholesterol (log[TG/HDL-C]) than RA. Whereas, reduced total lymphocyte count, lipoprotein(a), and low density lipoprotein cholesterol were noted in the former than latter group. Majority of the SLE patients had increased risk of cardiovascular diseases (> 0.24 AIP score) and RA patients in comparison had lower risk. Correlation among serum uric acid, lipid profile constituents and AIP was noted. The immunological process of SLE has greater impact on the metabolic parameters. Higher uric acid levels are suggestive of dysfunctional lipid profile. Understanding the implications of risk factors and its inflammatory role in autoimmune processes may assist in disease management.
29193331 Host modulation therapy with anti-inflammatory agents. 2018 Feb Host modulation therapy refers to a treatment concept in which drug therapies are used as an adjunct to conventional periodontal treatment to ameliorate destructive aspects of the host inflammatory response. This strategy is not new in the treatment of periodontitis. Previously, nonsteroidal anti-inflammatory drugs have been investigated in this regard, with evidence of reductions in alveolar bone resorption when these drugs are used for prolonged periods of time. However, the risk of significant unwanted effects precludes the use of both nonselective nonsteroidal anti-inflammatory drugs and the selective cyclooxygenase-2 inhibitors as adjunctive treatments for periodontitis. Currently, the only available adjunctive host response modulator that is licensed for the treatment of periodontitis is subantimicrobial dose doxycycline, which functions as an inhibitor of matrix metalloproteinases. Although clinical benefits have been shown in carefully conducted randomized controlled trials, the efficacy of subantimicrobial dose doxycycline in routine clinical practice has yet to be determined. Anti-cytokine therapies have been developed for use in the treatment of rheumatoid arthritis, the pathogenesis of which bears many similarities to that of periodontitis; however, the significant risk of unwanted effects (as well as cost and lack of human trials in the treatment of periodontal diseases) precludes the use of any of the currently available anti-cytokine therapies in the treatment of periodontitis. The identification of pro-resolving lipid mediators as well as small molecule biologicals that influence inflammatory responses offers the best potential, at the present time, for the development of novel host response modulators in periodontal therapy, but much research remains to be done to confirm safety and efficacy.
28945457 Preferences for Medical Marijuana over Prescription Medications Among Persons Living with 2018 Feb OBJECTIVES: Despite expanded legalization and utilization of medical cannabis (MC) internationally, there is a lack of patient-centered data on how MC is used by persons living with chronic conditions in tandem with or instead of prescription medications. This study describes approaches to use of MC vis-à-vis prescription medications in the treatment of selected chronic conditions. DESIGN: Participants completed semistructured telephone interviews with open-ended questions. Content analysis of qualitative data identified themes and subthemes relating to patient approaches to using MC products. PARTICIPANTS: Thirty persons (mean age = 44.6 years) living with a range of chronic conditions (e.g., rheumatoid arthritis, Crohn's disease, spinal cord injury/disease, and cancer) who had qualified for and used MC in Illinois. RESULTS: Participants described a range of approaches to using MC, including (1) as alternatives to using prescription or over-the-counter medications; (2) complementary use with prescription medications; and (3) as a means for tapering off prescription medications. Motives reported for reducing or eliminating prescription medications included concerns regarding toxicity, dependence, and tolerance, and perceptions that MC improves management of certain symptoms and has quicker action and longer lasting effects. CONCLUSIONS: MC appears to serve as both a complementary method for symptom management and treatment of medication side-effects associated with certain chronic conditions, and as an alternative method for treatment of pain, seizures, and inflammation in this population. Additional patient-centered research is needed to identify specific dosing patterns of MC products associated with symptom alleviation and produce longitudinal data assessing chronic disease outcomes with MC use.
28463373 Synthesis and structural investigation of 2-aminomethyl-3-(4-methoxy-phenyl)-propionic aci 2017 May 16 The incorporation of a single β-amino acid moiety in a highly amyloidogenic peptide sequence resulted in the complete inhibition of amyloid fibril formation. The Boc-l-Phe-l-Leu-OMe sequence 1, which has sequence identity with the N-terminal AS(6-7) of the non-immunoglobulin amyloid fibril protein AS, which is responsible for rheumatoid arthritis, self-associates to produce fibrils. The d-Phe analogue peptide 2 shows an elongated ribbon-like morphology. However, the 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing analogue peptide 3 exhibits a polydisperse microsphere morphology. Moreover, fibrils from peptides 1 and 2 exhibit typical green-gold birefringence upon Congo red (CR) staining and show an amyloid-like morphological resemblance. However, the 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid modified peptide 3 does not respond to the Congo red assay. From X-ray crystallography, peptide 1 with the l-Phe residue adopts an extended structure, whereas the d-Phe analogue 2 adopts a kink-like structure. Both peptides 1 and 2 show twisted anti-parallel sheet-like structures at higher order assembly. However, peptide 3 adopts a nine-membered hydrogen bonded δ-turn-like structure in the solid state and self-associates to form a loop-like supramolecular structure through multiple intermolecular hydrogen bonds. The structural analysis presented herein may foster new studies for de novo design and therapeutics.
28336462 The molecular mechanisms of androgen receptor in nephrolithiasis. 2017 Jun 15 OBJECTIVES: This study aimed to investigate the molecular mechanisms of androgen receptor (AR) in nephrolithiasis. METHODS: Human kidney 2(HK-2) cells were transfected with Lentiviruses expressing AR (DEC-AR), shRNA targeting AR (sh-AR) or the empty vector control using the pLEX lentiviral vector system. The expression levels of AR were measured by qRT-PCR at 72h postinfection, and cells under different treatments were collected for microarray analysis. Differentially expressed genes (DEGs) were identified using Student's t-test. The protein-protein interaction (PPI) network was constructed for negatively correlated DEGs using GeneMANIA. Then, functional and pathway enrichment analysis were performed for the genes in the PPI network. RESULTS: The qRT-PCR revealed that expression level of AR in DEC-AR cells was obviously increased and decreased in sh-AR cells at 72h postinfection (p<0.05). Totally, 64 negatively correlated DEGs showed lower expressions and 63 negatively correlated DEGs were up-regulated in the DEC-AR HK2 cells. Negatively correlated DEGs were significantly related to cell differentiation, response to stimulus, multicellular organismal process and multicellular organismal development. Pathway enrichment analysis revealed that DEGs mainly participated in the rheumatoid arthritis (CCL2, CSF1, IL11, LTB and MMP1), gematopoietic cell lineage (CD33, CD44, CSF1 and IL11) and TNF signaling pathway (CCL2, CSF1, MMP9 and VCAM1). Meanwhile, CD44, LAMC2 and THBS2 were significantly enriched in ECM-receptor interaction. CONCLUSION: The negatively correlated DEGs, especially CCL2, CD44, MMP1 and MMP9, might play critical roles in nephrolithiasis.